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Essentials of

Pharmacology
for Dentistry
Essentials of
Pharmacology
for Dentistry
2ND EDITION

KD TRIPATHI MD
Ex-Director-Professor and Head of Pharmacology
Maulana Azad Medical College and associated
LN and GB Pant Hospitals
New Delhi, India

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD


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© 2011 KD Tripathi

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This book has been published in good faith that the contents provided by the author contained herein are original, and
is intended for educational purposes only. While every effort is made to ensure accuracy of information, the publisher
and the author specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use or
application of any of the contents of this work. If not specifically stated, all figures and tables are courtesy of the author.
Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device.

Publisher: Jitendar P Vij


Publishing Director: Tarun Duneja
Managing Editor: M. Tripathi

Essentials of Pharmacology for Dentistry

First Edition: 2005


Second Edition: 2011

ISBN-13: 978-93-5025-385-4

Printed at Replika Press, Kundli


Preface to the Second Edition
With phenomenal growth of information on mechanism of action and clinical application of drugs,
as well as rapid introduction of new drugs, pharmacology, the science of drugs (medicines), has
become increasingly important to all health professionals who prescribe/administer drugs. Practice
of dentistry utilizes drugs both as primary treatment modality as well as facilitator of dental
procedures. Dentists may have to manage a medical emergency arising in their clinic. Moreover,
many dental patients could be receiving other medication that may have orodental implications,
or may interact with drugs prescribed by the dentist. As such, a broad knowledge of pharmacology
with emphasis on certain aspects is needed by the dentist.
This book is divided into three sections. The first describes the general pharmacological principles
with which all professionals involved in drug therapy must be conversant. The second on systemic
pharmacology presents a brief account of drugs acting on various organ systems and used in the
treatment of common disorders affecting the systems. Each chapter is organised systematically. The
opening sentence defines the class of drugs, followed by their classification. The ‘prototype’ approach
is followed by describing the representative drug of the class. In these chapters, matters particularly
relevant to dental therapeutics have been highlighted by italicizing. Wherever applicable, the
implications in dentistry are prominently elaborated, e.g. drugs and diseases affecting postextraction
haemostasis, dental procedures in patients on corticosteroid therapy or in diabetics, oral
complications of cancer chemotherapy, conscious sedation in dentistry, etc. Management of medical
emergencies like anaphylactic shock, seizures, angina, or asthmatic attack during dental treatment
is outlined.
The third section covers antimicrobials and other drugs which the dentists prescribe or administer
themselves. However, the allocation of topics in sections two and three does not indicate water-
tight distinction, which is impossible, but has been done with a view to focus attention on drugs
that have greater relevance in dentistry. To mention a few, the application of analgesics and NSAIDs
in dental pain, dental anaesthesia, role of each class of antimicrobials in orodental infections,
prophylaxis of postextraction infection and endocarditis in patients at special risk are emphasized.
The highlight of this 2nd edition is a new chapter on drugs and aids having specific application
in dental disorders and in dental care. Drugs for dental plaque, caries tooth, dentine sensitivity
alongwith aids like dentifrices, bleaching agents, disclosing agents, etc. are described pointing out
their current role in practice. The last chapter on drug interactions highlights those that may be
encountered in dental practice.
All chapters in the present edition have been thoroughly updated to include latest information
and new drugs. Presentation and illustrations have been improved. Leading trade names and dosage
forms of drugs generally prescribed by dentists are mentioned distinctively. Thus, the book is oriented
vi Essentials of Pharmacology for Dentistry

to provide core and contemporary pharmacological knowledge based on understanding of the


rationale. It is designed to meet the specific needs of dental students and practitioners.
I am indebted to my colleagues in pharmacology and dentistry as well as to readers of the 1st
edition for their comments and suggestions which helped in orienting the 2nd edition. As always,
the motivational influence of Shri J.P. Vij, Chairman and Managing Director, Jaypee Brothers, was
crucial. The meticulous preparation of the manuscript and illustrations by Ms Sunita Katla, Mr Manoj
Pahuja and others in the editorial section is highly appreciated. The participation and cooperation
of my wife is sincerely acknowledged.

June, 2011 KD Tripathi


Contents

1. Introduction, Routes of Drug Administration ............................................................ 3


Introduction 3
Routes of Drug Administration 5

2. Pharmacokinetics ............................................................................................................. 10
Drug Transport 11
Drug Absorption 14
Drug Distribution 16
Drug Biotransformation (Metabolism) 20
Drug Excretion 25
Kinetics of Elimination 26

3. Pharmacodynamics .......................................................................................................... 31
Principles of Drug Action 31
Mechanism of Drug Action 31
Combined Effect of Drugs 45
Drug Dosage 48
Factors Modifying Drug Action 50

4. Adverse Drug Effects ...................................................................................................... 56

5. Drugs Acting on Autonomic Nervous System .......................................................... 67


(General Considerations, Cholinergic and Anticholinergic Drugs)
General Considerations 67
Cholinergic Drugs (Cholinomimetic, Parasympathomimetic) 72
viii Essentials of Pharmacology for Dentistry

Anticholinesterases 74
Anticholinergic Drugs (Parasympatholytic) 76
Drugs Acting on Autonomic Ganglia 80

6. Drugs Acting on Autonomic Nervous System .......................................................... 81


(Adrenergic and Antiadrenergic Drugs)
Adrenergic Transmission 81
Adrenergic Drugs (Sympathomimetics) 83
Antiadrenergic Drugs (Adrenergic Receptor Antagonists) 90

7. Autacoids and Related Drugs ....................................................................................... 98


Histamine 98
H1 Antagonists (Conventional Antihistaminics) 101
5-hydroxytryptamine (5-HT, Serotonin) 105
Drug Therapy of Migraine 107
Prostaglandins and Leukotrienes (Eicosanoids) 109
Platelet Activating Factor (PAF) 115

8. General Anaesthetics and Skeletal Muscle Relaxants ........................................ 117


General Anaesthetics 117
Preanaesthetic Medication 125
Skeletal Muscle Relaxants 126

9. Drugs Acting on Central Nervous System ............................................................... 133


(Sedative-Hypnotics, Alcohols, Antiepileptics and Antiparkinsonian Drugs)
Sedative-hypnotics 133
Ethyl Alcohol (Ethanol) 139
Antiepileptic Drugs 143
Antiparkinsonian Drugs 149

10. Drugs Acting on Central Nervous System ............................................................... 155


(Psychopharmacological Agents)
Psychopharmacological Agents 155
Antipsychotic Drugs (Neuroleptics) 156
Antimanic (Mood Stabilizing) Drugs 160
Antidepressant Drugs 163
Antianxiety Drugs 168

11. Cardiovascular Drugs ................................................................................................... 171


(Drugs Affecting Renin-Angiotensin System, Calcium Channel Blockers,
Drugs for Hypertension, Angina Pectoris and Myocardial Infarction)
Angiotensin 171
Angiotensin Converting Enzyme Inhibitors 173
Calcium Channel Blockers 176
Antihypertensive Drugs 178
Antianginal Drugs 183
Drug Therapy in Myocardial Infarction 188
Contents ix

12. Cardiovascular Drugs ................................................................................................... 190


(Drugs for Heart Failure and Cardiac Arrhythmia)
Cardiac Glycosides 190
Treatment of Congestive Heart Failure 195
Antiarrhythmic Drugs 197

13. Drugs Acting on Kidney ............................................................................................... 203


Relevant Physiology of Urine Formation 203
Diuretics 205
Antidiuretics 212

14. Hormones and Related Drugs .................................................................................... 215


(Anterior Pituitary Hormones, Antidiabetic Drugs, Corticosteroids)
Introduction 215
Anterior Pituitary Hormones 216
Antidiabetic Drugs 219
Insulin 220
Oral Hypoglycaemic Drugs 224
Corticosteroids 228

15. Hormones and Related Drugs .................................................................................... 235


(Sex Hormones, Contraceptives, Drugs Acting on Uterus)
Androgens (Male Sex Hormones) 235
Estrogens 237
Progestins 239
Hormonal Contraceptives 241
Uterine Stimulants (Oxytocics, Abortifacients) 243
Uterine Relaxants (Tocolytics) 245

16. Hormones and Related Drugs .................................................................................... 246


(Thyroid Hormone and Thyroid Inhibitors, Hormones Regulating Calcium Balance)
Thyroid Hormone 246
Thyroid Inhibitors 249
Hormones Regulating Calcium 250

17. Drugs Affecting Blood .................................................................................................. 256


Haematinics 256
Coagulants 260
Anticoagulants 264
Fibrinolytics (Thrombolytics) 268
Antifibrinolytics 269
Antiplatelet Drugs (Antithrombotic Drugs) 269
Hypolipidaemic Drugs 271
x Essentials of Pharmacology for Dentistry

18. Drugs for Gastrointestinal Disorders ....................................................................... 274


Drugs for Peptic Ulcer 274
Antiemetics 280
Treatment of Gastroesophageal Reflux Disease 284
Laxatives (Aperients, Purgatives, Cathartics) 285
Treatment of Diarrhoeas 288

19. Drugs for Respiratory Disorders ................................................................................ 291


Drugs for Cough 291
Drugs for Bronchial Asthma 292

20. Vitamins ........................................................................................................................... 299


Fat-soluble Vitamins 300
Water-soluble Vitamins 301

21. Anticancer and Immunosuppressant Drugs ........................................................... 305


Anticancer Drugs 305
Immunosuppressant Drugs 313

22. Antirheumatoid and Antigout Drugs ........................................................................ 317


Antirheumatoid Drugs 317
Drugs Used in Gout 319

23. Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics ............... 325


Analgesic/NSAIDs in Dentistry 339

24. Opioid Analgesics and Antagonists .......................................................................... 341


Opioid Analgesics 341
Complex Action Opioids and Opioid Antagonists 350

25. Local Anaesthetics ......................................................................................................... 354


Uses and Techniques of Local Anaesthesia 361
Local Anaesthesia in Dentistry 362

26. Antimicrobial Drugs: General Considerations ...................................................... 364


Drug Resistance 367
Superinfection 369
Choice of an Antimicrobial Agent 370
Combined Use of Antimicrobials 373
Prophylactic Use of Antimicrobials 375
Contents xi

27. Sulfonamides, Cotrimoxazole, Quinolones and Nitroimidazoles ..................... 379


Sulfonamides 379
Cotrimoxazole 381
Quinolones 382
Nitroimidazoles 387

28. Beta-Lactam Antibiotics ............................................................................................... 390


Penicillins 390
Cephalosporins 399
Monobactams 404
Carbapenems 404

29. Tetracyclines, Chloramphenicol and Aminoglycoside Antibiotics .................. 405


Tetracyclines 405
Chloramphenicol 410
Aminoglycoside Antibiotics 413
30. Macrolide and Other Antibacterial Antibiotics ..................................................... 420
Macrolide Antibiotics 420
Miscellaneous (Lincosamide, Glycopeptide, Oxazolidinone, Polypeptide) Antibiotics 423
Urinary Antiseptics 427

31. Antitubercular and Antileprotic Drugs .................................................................... 428


Antitubercular Drugs 428
Treatment of Tuberculosis 432
Antileprotic Drugs 435
Multidrug Therapy of Leprosy 436
32. Antifungal and Antiviral Drugs ................................................................................. 438
Antifungal Drugs 438
Antiviral Drugs 444
Treatment of HIV Infection 449
Prophylaxis of HIV Infection 450
33. Antiprotozoal and Anthelmintic Drugs ................................................................... 452
Antimalarial Drugs 452
Antiamoebic Drugs 460
Drugs for Giardiasis and Drugs for Trichomoniasis 462
Drugs for Leishmaniasis 463
Anthelmintic Drugs 463

34. Antiseptics, Disinfectants and Other Locally Acting Drugs .............................. 469
Antiseptics and Disinfectants 469
Locally Acting Drugs 476

35. Drugs and Aids with Specific Application in Dental Disorders ....................... 477
Antiplaque and Antigingivitis Agents 477
Antibiotics in Periodontal Disease 479
xii Essentials of Pharmacology for Dentistry

Anticaries Drugs 480


Desensitizing Agents 483
Obtundants 484
Mummifying Agents 484
Bleaching Agents 485
Disclosing Agents 485
Dentifrices 486
36. Drug Interactions ........................................................................................................... 488
Mechanisms of Drug Interactions 489
Drug Interactions in Dentistry 491

Index............................................................................................................................................ 495
List of Abbreviations
A-I/II/III Angiotensin I/II/III BHP Benign hypertrophy of prostate
AA Amino acid BMD Bone mineral density
AB Antibody BMR Basal metabolic rate
ABC ATP binding cassettee (trasporter) BP Blood pressure
AC Adenylyl cyclase BPN Bisphosphonate
ACE Angiotensin II converting enzyme BRM Biologic response modifier
ACh Acetylcholine BSA Body surface area
AChE Acetylcholinesterase BuChE Butyryl cholinesterase
ACT Artemisinin combination therapy BW Body weight
ACTH Adrenocorticotropic hormone BZD Benzodiazepine
AD Alzheimer’s disease
ADH Antidiuretic hormone C-10 Decamethonium
ADP Adenosine diphosphate CA Catecholamine
Adr Adrenaline CaBP Calcium binding protein
AF Atrial fibrillation CAD Coronary artery disease
AFl Atrial flutter CAM Calmodulin
AG Antigen cAMP 3', 5' Cyclic adenosine monophosphate
AIDS Acquired immunodeficiency syndrome cap Capsule
AIP Aldosterone induced protein CAse Carbonic anhydrase
ALA Alanine CBS Colloidal bismuth subcitrate
AMA Antimicrobial agent CCB Calcium channel blocker
AMB Amphotericin B CD Collecting duct
amp Ampoule cGMP 3', 5' Cyclic guanosine monophosphate
AMP Adenosine monophosphate CGRP Calcitonin gene-related peptide
ANC Acid neutralizing capacity CH Cholesterol
ANS Autonomic nervous system ChE Cholinesterase
ANUG Acute necrotizing ulcerative gingivitis CHE Cholesterol ester
AP Action potential CHF Congestive heart failure
APD Action potential duration CI Cardiac index
APF Acidulated phosphate fluoride CL Clearance
aPTT Activated partial thromboplastin time CLcr Creatinine clearance
ARB Angiotensin receptor blocker Clo Clofazimine
ARC AIDS related complex CMI Cell-mediated immunity
ARV Antiretrovirus CMV Cytomegalovirus
5-ASA 5-Amino salicyclic acid CNS Central nervous system
Asc LH Ascending limb of Loop of Henle c.o. Cardiac output
AT-III Antithrombin III CoEn-A Coenzyme-A
ATP Adenosine triphosphate COMT Catechol-O-methyl transferase
ATPase Adenosine triphosphatase COX Cyclooxygenase
A-V Atrioventricular CPS Complex partial seizures
AVP Arginine vasopressin CPZ Chlorpromazine
AZT Zidovudine CRF Corticotropin releasing factor
CSF Cerebrospinal fluid
B12 Vitamin B12 CTZ Chemoreceptor trigger zone
BCNU Bischloroethyl nitrosourea (Carmustine) CVS Cardiovascular system
BCRP Breast cancer resistance protein CWD Cell wall deficient
BD Twice daily CYP450 Cytochrome P450
xiv Essentials of Pharmacology for Dentistry
DA Dopamine GDP Guanosine diphosphate
DA-B 12 Deoxyadenosyl cobalamin GERD Gastroesophageal reflux disease
DAG Diacyl glycerol g.f.r. Glomerular filtration rate
DAT Dopamine transporter GH Growth hormone
DCI Dichloroisoproterenol g.i.t. Gastrointestinal tract
dDAVP Desmopressin GITS Gastrointestinal therapeutic system
DDS Diamino diphenyl sulfone (Dapsone) GLP-1 Glucagon-like peptide-1
DEC Diethyl carbamazine citrate GLUT Glucose transporter
DHE Dihydroergotamine GnRH Gonadotropin releasing hormone
DHFA Dihydro folic acid G-6-PD Glucose-6-phosphate dehydrogenase
DHFRase Dihydrofolate reductase GTCS Generalised tonic-clonic seizures
DHP Dihydropyridine GTN Glyceryl trinitrate
DI Diabetes insipidus GTP Guanosine triphosphate
DIT Diiodotyrosine
dl Decilitre H Isoniazid (Isonicotinic acid hydrazide)
DLE Disseminated lupus erythematosus HAART Highly active antiretroviral therapy
DMARD Disease modifying antirheumatic drug Hb Haemoglobin
DMCM Dimethoxyethyl-carbomethoxy-β-carboline HCG Human chorionic gonadotropin
DMPA Depot medroxyprogesterone acetate HDL High density lipoprotein
DMPP Dimethyl phenyl piperazinium 5-HIAA 5-Hydroxyindole acetic acid
DNA Deoxyribonucleic acid HETE Hydroxyeicosa tetraenoic acid
DOCA Desoxy corticosterone acetate HIV Human immunodeficiency virus
dopa Dihydroxyphenyl alanine HMG-CoA Hydroxymethyl glutaryl coenzyme A
DOSS Dioctyl sulfosuccinate HPA axis Hypothalamo-pituitary-adrenal axis
DOTS Directly observed treatment short course HPETE Hydroperoxy eicosatetraenoic acid
DPP-4 Dipeptidyl peptidase-4 hr Hour
DRC Dose-response curve HR Heart rate
DT Distal tubule HRT Hormone replacement therapy
d-TC d-Tubocurarine 5-HT 5-Hydroxytryptamine
5-HTP 5-Hydroxytryptophan
E Ethambutol HVA Homovanillic acid
EACA Epsilon amino caproic acid
e.c.f. Extracellular fluid ICSH Interstitial cell stimulating hormone
ECG Electrocardiogram IDL Intermediate density lipoprotein
EDRF Endothelium dependent relaxing factor IGF Insulin-like growth factor
EDTA Ethylene diamine tetraacetic acid IL Interleukin
EEG Electroencephalogram ILEU Isoleucine
β-END β-Endorphin i.m. Intramuscular
EPEC Enteropathogenic E. coli INH Isonicotinic acid hydrazide
EPO Erythropoietin INR International normalized ratio
ERP Effective refractory period i.o.t. Intraocular tension
EPSP Excitatory postsynaptic potential IP3 Inositol trisphosphate
ER Estrogen receptor IPSP Inhibitory postsynaptic potential
ES Extrasystole Iso Isoprenaline
ESR Erythrocyte sedimentation rate IU International unit
ETEC Enterotoxigenic E. coli i.v. Intravenous
Etm Ethionamide

FA Folic acid JAK Janus-kinase


5-FC 5-Flucytosine
FEV1 Forced expiratory volume in 1 second KTZ Ketoconazole
FFA Free fatty acid
FQ Fluoroquinolone LA Local anaesthetic
FSH Follicle stimulating hormone LC-3-KAT Long chain 3-ketoacyl-CoA thiolase
5-FU 5-Fluorouracil LDL Low density lipoprotein
LES Lower esophageal sphincter
GABA Gamma amino butyric acid leu-ENK Leucine enkephalin
GC Guanylyl cyclase LH Luteinizing hormone
Abbreviations xv
liq Liquid OATP Organic anion transporting polypeptide
LMW Low molecular weight OC Oral contraceptive
LOX Lipoxygenase OCD Obsessive-compulsive disorder
LSD Lysergic acid diethylamide OCT Organic cation transporter
LT Leukotriene OD Once daily
ORS Oral rehydration salt (solution)
MAC Minimal alveolar concentration
ORT Oral rehydration therapy
MAC Mycobacterium avium complex
MAO Monoamine oxidase
PABA Paraamino benzoic acid
MAPKinase Mitogen activated protein kinase
PAE Postantibiotic effect
max Maximum
2-PAM Pralidoxime
MBC Minimum bactericidal concentration
PAF Platelet activating factor
MBL Multibacillary leprosy
PAS Paraamino salicylic acid
MDI Manic depressive illness
PBPs Penicillin binding proteins
MDR Multidrug resistant
PBL Paucibacillary leprosy
MDT Multidrug therapy (of leprosy)
PD Parkinson’s disease
met-ENK Methionine enkephalin
PDE Phosphodiesterase
mEq milliequivalent
PF Purkinje fibre
Mf Microfilariae
PFOR Pyruvate: ferredoxin oxidoreductase
MFP Monofluorophosphate
PG Prostaglandin
MHC Major histocompatibility complex
PGI 2 Prostacyclin
MI Myocardial infarction
P-gp P-glycoprotein
MIC Minimal inhibitory concentration
PI Protease inhibitor
min Minimum
PIP 2 Phosphatidyl inositol-4, 5-bisphosphate
MIT Monoiodo tyrosine
PKA Protein kinase: cAMP dependent
MLCK Myosin light chain kinase
PKC Protein kinase C
6-MP 6-Mercaptopurine
PL A Phospholipase A
MRP2 Multidrug resistance associated protein 2
PL C Phospholipase C
MRSA Methicillin resistant Staphylococcus aureus
PnG Penicillin G
Mtx Methotrexate
POMC Pro-opio melanocortin
MW Molecular weight
PP Partial pressure
PPARγ Paroxysome proliferator-activated receptor γ
NA Noradrenaline PPH Postpartum haemorrhage
NABQI N-acetyl-p-benzoquinoneimine PPI Proton pump inhibitor
NADP Nicotinamide adenine dinucleotide ppm Part per million
phosphate PPNG Penicillinase producing N. gonorrhoeae
NADPH Reduced nicotinamide adenine dinucleotide Prl Prolactin
phosphate PSVT Paroxysmal supra-ventricular tachycardia
NAG N-acetyl glucosamine PT Proximal tubule
NAM N-acetyl muramic acid PTCA Percutaneous transluminal coronary
NANC Nonadrenergic noncholinergic angioplasty
NaSSA Noradrenergic and specific serotonergic PTH Parathyroid hormone
antidepressant PTP Post-tetanic potentiation
NAT N-acetyl transferase
NEE Norethindrone enanthate QID Four times a day
NET Norepinephrine transporter
NFAT Nuclear factor of activated T-cell R Rifampin (Rifampicin)
NIS Na+ iodide symporter RAS Renin-angiotensin system
NLEP National leprosy eradication programme RBP Retinol binding protein
NMDA N-methyl-D-aspartate REM Rapid eye movement (sleep)
NNRTI Nonnucleoside reverse transcriptase inhibitor RIMA Reversible inhibitor of MAO-A
NPY Neuropeptide-Y rINN Recommended international nonproprietary
NR Nicotinic receptor name
N-REM Non-rapid eye movement (sleep) RMP Resting membrane potential
NRTI Nucleoside reverse transcriptase inhibitor RNA Ribonucleic acid
NSAID Nonsteroidal antiinflammatory drug RNTCP Revised National Tuberculosis Control
NTS Nucleus tractus solitarius Programme
xvi Essentials of Pharmacology for Dentistry
RP Refractory period TG Triglyceride
RTF Resistance transfer factor 6-TG 6-Thioguanine
THC Tetrahydrocannabinol
S Streptomycin THFA Tetrahydro folic acid
SA Sinoatrial (node) THR Threonine
SAARD Slow acting antirheumatic drug TIAs Transient ischaemic attacks
SABE Subacute bacterial endocarditis TNF-α Tumour necrosis factor α
s.c. Subcutaneous t.p.r. Total peripheral resistance
SCh Succinylcholine t-PA Tissue plasminogen activator
SERM Selective estrogen receptor modulator
TR Thyroid hormone receptor
SERT Serotonin transporter
TRH Thyrotropin releasing hormone
SGA Second generation antihistaminic
TSH Thyroid stimulating hormone
s.l. Sublingual
TTS Transdermal therapeutic system
SLC Solute carrier (transporter)
TX Thromboxane
SLE Systemic lupus erythematosus
SMON Subacute myelo-optic neuropathy
U Unit
SNRI Serotonin and noradrenaline reuptake
UDP Uridine diphosphate
inhibitor
UFH Unfractionated heparin
s.o.s. as required
UGT UDP-glucuronosyl transferase
SPS Simple partial seizures
UT Urea transporter
SR Sustained release
SRS-A Slow reacting substance of anaphylaxis V Volume of distribution
SSRIs Selective serotonin reuptake inhibitors VAL Valine
STAT Signal transducer and activator of VF Ventricular fibrillation
transcription Vit Vitamin
susp Suspension VLDL Very low density lipoprotein
SWS Slow wave sleep VMA Vanillyl mandelic acid
syr Syrup VRE Vancomycin resistant enterococci
VRSA Vancomycin resistant Staphylococcus aureus
t½ Half-life VRUT Vasopressin regulated urea transporter
T3 Triiodothyronine VT Ventricular tachycardia
T4 Thyroxine
tab Tablet WPW Wolff-Parkinson-White syndrome
TB Tubercle bacilli
TCAs Tricyclic antidepressants Z Pyrazinamide
TDS Three times a day ZE syndrome Zollinger-Ellison syndrome
1
Introduction, Routes of
Drug Administration

INTRODUCTION chemically characterized and a vast variety of


highly potent and selective new drugs have been
Pharmacology
developed. The mechanism of action including
Pharmacology is the science of drugs (Greek: molecular target of many drugs has been
Pharmacon—drug; logos—discourse in). In a broad elucidated. This has been possible due to prolific
sense, it deals with interaction of exogenously growth of pharmacology which forms the
administered chemical molecules (drugs) with backbone of rational therapeutics.
living systems. It encompasses all aspects of The two main divisions of pharmacology are
knowledge about drugs, but most importantly pharmacodynamics and pharmacokinetics.
those that are relevant to effective and safe use for
medicinal purposes. Pharmacodynamics (Greek: dynamis—power) —
In the context of dental practice, a broad What the drug does to the body.
understanding of pharmacology with emphasis This includes physiological and biochemical
on certain aspects is imperative because: effects of drugs and their mechanism of action
• Dentists have to prescribe/use drugs, albeit at organ system/subcellular/macromolecular
from a limited range, for the treatment of levels, e.g. adrenaline → interaction with adreno-
dental conditions. ceptors → G-protein mediated stimulation of cell
membrane bound adenylyl cyclase → increased
• Many dental patients concurrently suffer
intracellular cyclic 3’,5’AMP → cardiac stimu-
from other medical conditions, e.g. diabetes,
lation, hepatic glycogenolysis and hypergly-
hypertension, arthritis, etc. for which they
caemia, etc.
may be taking drugs that may have dental
implications or may interact with drugs Pharmacokinetics (Greek: Kinesis—movement) —
prescribed by the dentist. What the body does to the drug.
• The dentist may have to deal with a medical This refers to movement of the drug in and
emergency arising on the dental chair. alteration of the drug by the body; includes
For thousands of years most drugs were crude absorption, distribution, binding/localization/
natural products of unknown composition and storage, biotransformation and excretion of the
limited efficacy. Only the overt effects of these drug, e.g. paracetamol is rapidly and almost
substances on the body were known, that too completely absorbed orally attaining peak blood
rather imprecisely; but how the same were levels at 30-60 min; 25% bound to plasma proteins,
produced was entirely unknown. Over the past widely and almost uniformly distributed in the
100 years or so, drugs have been purified, body (volume of distribution ~ 1 L/kg); extensively
4 Introduction, Routes of Drug Administration
metabolized in the liver, primarily by glucuronide Drugs, in general, can thus be divided into:
and sulfate conjugation into inactive metabolites
Pharmacodynamic agents These are designed
which are excreted in urine; has a plasma half-
to have pharmacodynamic effects in the recipient.
life (t½) of 2–3 hours and a clearance value of
5 ml/kg/min. Chemotherapeutic agents These are designed to
I

inhibit/kill invading parasite/malignant cell and


Drug (French: Drogue—a dry herb) It is the single
SECTION

have no/minimal pharmacodynamic effects in the


active chemical entity present in a medicine that is recipient.
used for diagnosis, prevention, treatment/cure of
a disease. The WHO (1966) has given a more Pharmacy It is the art and science of compoun-
comprehensive definition—“Drug is any substance ding and dispensing drugs or preparing suitable
or product that is used or is intended to be used to dosage forms for administration of drugs to man
modify or explore physiological systems or or animals. It includes collection, identification,
pathological states for the benefit of the recipient.” purification, isolation, synthesis, standardization
The term ‘drugs’ is being also used to mean and quality control of medicinal substances. The
addictive/abused substances. However, this res- large scale manufacture of drugs is called Phar-
tricted and derogatory sense usage is unfortunate maceutics. It is primarily a technological science.
degradation of a time honoured term, and ‘drug’
Toxicology It is the study of poisonous effect of
should refer to a substance that has some thera-
drugs and other chemicals (household, environ-
peutic/diagnostic application.
mental pollutant, industrial, agricultural, homi-
Some other important aspects of pharmacology
cidal) with emphasis on detection, prevention and
are:
treatment of poisonings. It also includes the study
Pharmacotherapeutics It is the application of of adverse effects of drugs, since the same
pharmacological information together with know- substance can be a drug or a poison, depending
ledge of the disease for its prevention, mitigation on the dose.
or cure. Selection of the most appropriate drug,
dosage and duration of treatment in accordance
Drug nomenclature
with the specific features of a patient are a part of
pharmacotherapeutics. A drug generally has three categories of names:
Clinical pharmacology It is the scientific study (a) Chemical name It describes the substance
of drugs in man. It includes pharmacodynamic chemically, e.g. 1-(Isopropylamino)-3-(1-naphthy-
and pharmacokinetic investigation in healthy loxy) propan-2-o1 for propranolol. This is cumber-
volunteers and in patients; evaluation of efficacy some and not suitable for use in prescribing. A code
and safety of drugs and comparative trials with name, e.g. RO 15-1788 (later named flumazenil)
other forms of treatment; surveillance of patterns may be assigned by the manufacturer for con-
of drug use, adverse effects, etc. venience and simplicity before an approved name
The aim of clinical pharmacology is to generate is coined.
data for optimum use of drugs and for practice of
(b) Nonproprietary name It is the name accepted
medicine to be ‘evidence based’.
by a competent scientific body/authority, e.g. the
Chemotherapy It is the treatment of systemic United States Adopted Name (USAN) or the
infection/malignancy with specific drugs that British Approved Name (BAN). The nonproprie-
have selective toxicity for the infecting organism/ tary names of newer drugs are kept uniform by an
malignant cell with no/minimal effects on the host agreement to use the ‘recommended International
cells. Nonproprietary Name (rINN)’ only. However,
Routes of Drug Administration 5

many older drugs have more than one nonpro- ROUTES OF DRUG ADMINISTRATION
prietary names, e.g. meperidine (USA) and
Most drugs can be administered by a variety of
pethidine (UK, India) for the same drug. Until the
routes. The choice of appropriate route in a given
drug is included in a pharmacopoeia, the
situation depends both on drug as well as patient-

CHAPTER
nonproprietary name may also be called the
related factors. Mostly common sense consi-
approved name. After its appearance in the official
derations, feasibility and convenience dictate the
publication, it becomes the official name.
route to be used.
In common parlance, the term generic name is
used in place of nonproprietary name. Etymolo- Factors governing choice of route
gically this is incorrect: ‘generic’ should be
1. Physical and chemical properties of the drug
applied to the chemical or pharmacological group

1
(solid/liquid/gas; solubility, stability, pH,
(or genus) of the compound, e.g. aminoglycoside
irritancy).
antibiotics, tricyclic antidepressants, etc.; but has
2. Site of desired action—localized and appro-
become synonymous with nonproprietary name
achable or generalized and not approachable.
due to wide usage and official acceptance.
3. Rate and extent of absorption of the drug from
(c) Proprietary (Brand) name It is the name assig- different routes.
ned by the manufacturer(s) and is his property or 4. Effect of digestive juices and first pass
trade mark. One drug may have multiple pro- metabolism on the drug.
prietary names, e.g. ALTOL, ATCARDIL, ATECOR, 5. Rapidity with which the response is desired
ATEN, BETACARD, LONOL, TENOLOL, TENORMIN for (routine treatment or emergency).
atenolol from different manufacturers. Brand 6. Accuracy of dosage required (i.v. and
names are designed to be catchy, short, easy to inhalational can provide fine tuning).
remember and often suggestive, e.g. LOPRESOR 7. Condition of the patient (unconscious, vomi-
suggesting drug for lowering blood pressure. ting).
Brand names generally differ in different countries,
e.g. timolol maleate eyedrops are marketed as Routes can be broadly divided into those for
TIMOPTIC in the USA but as GLUCOMOL in India. (a) local action and (b) systemic action.
Even the same manufacturer may market the same
drug under different brand names in different LOCAL ROUTES
countries. In addition, combined formulations have
These routes can only be used for localized lesions
their own multiple brand names. This is respon-
at accessible sites and for drugs whose systemic
sible for much confusion in drug nomenclature.
absorption from these sites is minimal, slow or
There are many arguments for using the
absent. Thus, high concentrations are attained at
nonproprietary name in prescribing: uniformity,
the desired site without exposing the rest of the
convenience, economy and better comprehension
body. Systemic side effects or toxicity are conse-
(propranolol, sotalol, timolol, pindolol, meto-
quently absent or minimal. For drugs (in suitable
prolol, acebutolol, atenolol are all β blockers, but
dosage forms) that are absorbed from these sites/
their brand names have no such similarity).
routes, the same can serve as a systemic route of
However, when it is important to ensure
administration. The local routes are:
consistency of the product in terms of quality and
bioavailability, etc. and especially when official 1. Topical This refers to external application
control over quality of manufactured products is of the drug to the surface for localized action. It is
not rigorous, it is better to prescribe by the often more convenient and efficient mode of
dependable brand name. delivering the drug to skin, oropharyngeal/nasal
6 Introduction, Routes of Drug Administration
mucosa, eyes, ear canal, anal canal, vagina, etc. Limitations of oral route of administration
Nonabsorbable drugs given orally for action on
g.i. mucosa (sucralfate, neomycin), inhalation of • Action is slower and thus not suitable for
drugs for action on bronchial mucosa (cromolyn emergencies.
sodium) and irrigating solutions/jellys (povidone • Unpalatable drugs (chloramphenicol) are
I

iodine, lidocaine) applied to urethra are other difficult to administer; drug may be filled in
SECTION

forms of topical medication. In dental practice capsules to circumvent this.


antiseptics, astringents, haemostatics are often • May cause nausea and vomiting (emetine).
applied as paints, toothpastes, mouthwashes, • Cannot be used for uncooperative/uncons-
gargles or lozenges. cious/vomiting patient.
• Certain drugs are not absorbed (strepto-
2. Deeper tissues Certain deep areas can be mycin). Absorption of some drugs is erratic.
approached by using a syringe and needle, but • Others are destroyed by digestive juices
the drug should be such that systemic absorption (penicillin G, insulin) or in liver (glyceryl
is slow, e.g. infiltration around a nerve or trinitrate, testosterone, lidocaine) by high first
intrathecal injection (lidocaine, amphotericin B), pass metabolism.
intraarticular injection (hydrocortisone acetate),
retrobulbar injection (hydrocortisone acetate).
3. Arterial supply Close intra-arterial injection Absorption is relatively rapid—action can be
is used for contrast media in angiography; produced in minutes. Though it is somewhat
anticancer drugs can be infused in femoral or inconvenient, one can spit the drug after the
brachial artery to localize the effect for limb desired effect has been obtained. The chief
malignancies. advantage is that liver is bypassed and drugs with
high first pass metabolism can be absorbed directly
into systemic circulation. Drugs given sublin-
SYSTEMIC ROUTES
gually are—glyceryl trinitrate, buprenorphine,
The drug administered through systemic routes desamino-oxytocin.
is intended to be absorbed into bloodstream and
3. Rectal
distributed all over, including the site of action,
Certain irritant and unpleasant drugs can be put
through circulation (see Fig. 1.1).
into rectum as suppositories or retention enema
1. Oral for systemic effect. This route can also be used
Oral ingestion is the oldest and commonest mode when the patient is having recurrent vomiting.
of drug administration. It is safer, more con- However, it is rather inconvenient and embar-
venient, does not need assistance, noninvasive, rassing; absorption is slower, irregular and often
often painless, the medicament need not be sterile unpredictable (diazepam solution is dependably
and so is cheaper. Both solid dosage forms absorbed from rectum in children). Drug absorbed
(powders, tablets, capsules, spansules, dragees, into external haemorrhoidal veins (about 50%)
moulded tablets, gastrointestinal therapeutic bypasses liver, but not that absorbed into internal
systems—GITs) and liquid dosage forms (elixirs, haemorrhoidal veins. Rectal inflammation can
syrups, emulsions, mixtures) can be given orally. result from irritant drugs. Indomethacin, diaze-
pam, ergotamine and a few other drugs are
2. Sublingual (s.l.) or buccal
sometimes given rectally.
The tablet or pellet containing the drug is placed
under the tongue or crushed in the mouth and 4. Cutaneous
spread over the buccal mucosa. Only lipid-soluble Highly lipid-soluble drugs can be applied over
and non-irritating drugs can be so administered. the skin for slow and prolonged absorption. The
Routes of Drug Administration 7

CHAPTER
1

Fig. 1.1: Vascular pathway of drugs absorbed from various systemic routes of administration and
sites of first pass metabolism
Note: All drug administered orally is subjected to first pass metabolism in intestinal wall and liver, while
approximately half of that absorbed from rectum passes through liver. Drug entering from any systemic
route is exposed to first pass metabolism in lungs, but its extent is minor for most drugs.
8 Introduction, Routes of Drug Administration
(drug is subjected to little first pass metabolism)
and side effects. They are also more convenient—
many patients prefer transdermal patches to oral
tablets of the same drug; patient compliance is
better. Local irritation and erythema occurs in
I

some, but is generally mild; can be minimized by


SECTION

changing the site of application each time by


rotation. Discontinuation has been necessary in
Fig. 1.2: Illustration of a transdermal drug delivery system 2 to 7% cases.
5. Inhalation
liver is also bypassed. The drug can be incorpo- Volatile liquids and gases are given by inhalation
rated in an ointment and applied over specified for systemic action, e.g. general anaesthetics.
area of skin. Absorption takes place from the vast surface of
alveoli—action is very rapid. When administra-
Transdermal therapeutic systems These are
tion is discontinued, the drug diffuses back and
devices in the form of adhesive patches of various
is rapidly eliminated in expired air. Thus, control-
shapes and sizes (5–20 cm2) which deliver the
led administration is possible with moment-to-
contained drug at a constant rate into systemic
moment adjustment. Irritant vapours (ether) cause
circulation via the stratum corneum (Fig. 1.2).
inflammation of respiratory tract and increase
The drug (in solution or bound to a polymer) is
secretion.
held in a reservoir between an occlusive backing
film and a rate controlling micropore membrane, 6. Nasal
the undersurface of which is smeared with an The mucous membrane of the nose can readily
adhesive impregnated with priming dose of the absorb many drugs; digestive juices and liver are
drug that is protected by another film to be peeled bypassed. However, only certain drugs like GnRH
off just before application. The drug is delivered agonists and desmopressin applied as a spray or
at the skin surface by diffusion for percutaneous nebulized solution have been used by this route.
absorption into circulation. The micropore This route is being tried for some other peptide
membrane is such that rate of drug delivery to skin drugs like insulin.
surface is less than the slowest rate of absorption
7. Parenteral
from skin. This offsets any variation in the rate of
(Par—beyond, enteral—intestinal)
absorption according to the properties of different
This refers to administration by injection which
sites. As such, drug is delivered at constant and
takes the drug directly into the tissue fluid or blood
predictable rate irrespective of site of application:
without having to cross the intestinal mucosa. The
usually chest, abdomen, upper arm, lower back,
limitations of oral administration are circum-
buttock or mastoid region are utilized.
vented. Drug action is faster and surer (valuable
Transdermal patches of glyceryl trinitrate, in emergencies). Gastric irritation and vomiting
fentanyl, nicotine and estradiol are available in are not provoked. Parenteral route can be emplo-
India, while those of isosorbide dinitrate, yed even in unconscious, uncooperative or vomi-
hyoscine, and clonidine are available in other ting patient. There are no chances of interference
countries. These have been designed to last for 1 by food or digestive juices. Liver is bypassed.
to 7 days in case of different drugs and are becoming Disadvantages of parenteral routes are—the
increasingly popular, because they provide preparation has to be sterilized and is costlier, the
smooth plasma concentrations of the drug without technique is invasive and painful, assistance of
fluctuations; minimize interindividual variations another person is mostly needed (though self-
Routes of Drug Administration 9

injection is possible, e.g. insulin by diabetics), (ii) Intramuscular (i.m.) The drug is injected in
there are chances of local tissue injury and in one of the large skeletal muscles—deltoid, triceps,
general it is more risky. The important parenteral gluteus maximus, rectus femoris, etc. Muscle is
routes are: less richly supplied with sensory nerves (mild

CHAPTER
irritants can be injected) and is more vascular
(i) Subcutaneous (s.c.) The drug is deposited
(absorption is faster). It is less painful, but self-
in the loose subcutaneous tissue which is richly injection is often impracticable—deep penetration
supplied by nerves (irritant drugs cannot be is needed. Depot preparations can be injected by
injected) but is less vascular (absorption is slower). this route.
Self-injection is possible because deep penetration
is not needed. This route should be avoided in (iii) Intravenous (i.v.) The drug is injected as a

1
shock patients who are vasoconstricted—absorp- bolus (Greek: bolos-lump) or infused slowly over
tion will be delayed. Repository (depot) prepara- hours in one of the superficial veins. The drug
tions—oily solutions or aqueous suspensions can directly reaches into the bloodstream and effects
be injected for prolonged action. Some special are produced immediately (great value in emer-
forms of this route are: gency). The intima of veins is insensitive and drug
gets diluted with blood, therefore, even highly
(a) Dermojet In this method needle is not used; a irritant drugs can be injected i.v., but hazards are—
high velocity jet of drug solution is projected from thrombophlebitis of the injected vein and necrosis
a microfine orifice using a gun-like implement. of adjoining tissues if extravasation occurs. These
The solution passes through the superficial layers complications can be minimized by diluting the
and gets deposited in the subcutaneous tissue. It drug or injecting it into a running i.v. line. Only
is essentially painless and suited for mass aqueous solutions (not suspensions) can be
inoculations. injected i.v. and there are no depot preparations
for this route. The dose of the drug required is
(b) Pellet implantation The drug as solid pellet is smallest (bioavailability is 100%) and even large
introduced with a trochar and cannula. This volumes can be infused. One big advantage with
provides sustained release of the drug over weeks this route is—in case response is accurately
and months, e.g. DOCA, testosterone. measurable (e.g. BP) and the drug short acting
(c) Sialistic (nonbiodegradable) and biodegradable (e.g. sodium nitroprusside), titration of the dose
implants Crystalline drug is packed in tubes/ with the response is possible. However, this is the
capsules made of suitable materials and implan- most risky route—vital organs like heart, brain,
etc. get exposed to high concentrations of the drug.
ted under the skin. Slow and uniform leaching of
the drug occurs over months providing constant (iv) Intradermal injection The drug is injected
blood levels. The nonbiodegradable implant has into the skin raising a bleb (e.g. BCG vaccine,
to be removed later on but not the biodegradable sensitivity testing) or scarring/multiple puncture of
one. This has been tried for hormones and the epidermis through a drop of the drug is done.
contraceptives (e.g. NORPLANT). This route is employed for specific purposes only.
2
Pharmacokinetics

Pharmacokinetics is the quantitative study of Biological membrane This is a bilayer (about


drug movement in, through and out of the body. 100 Å thick) of phospholipid and cholesterol
The overall scheme of pharmacokinetic processes molecules, the polar groups of these are oriented
is depicted in Fig. 2.1. Intensity of response is at the two surfaces and the nonpolar hydrocarbon
related to concentration of the drug at the site of chains are embedded in the matrix, with adsor-
action, which in turn is dependent on its pharma- bed extrinsic and intrinsic protein molecules
cokinetic properties. Pharmacokinetic considera- (Fig. 2.2). The proteins are able to freely float
tions, therefore, determine the route(s) of through the membrane: associate and organize
or vice versa. Some of the intrinsic ones, which
administration, dose, latency of onset, time of peak
extend through the full thickness of the mem-
action, duration of action and thus frequency of
brane, surround fine aqueous pores. Paracellular
administration of a drug.
spaces or channels also exist between certain
All pharmacokinetic processes involve trans- epithelial/endothelial cells. Other adsorbed
port of the drug across biological membranes. proteins have enzymatic or carrier properties.

Fig. 2.1: Schematic depiction of pharmacokinetic processes


Transport of Drugs 11

CHAPTER
2
Fig. 2.2: Illustration of the organisation of
biological membrane
Fig. 2.3: Illustration of passive diffusion and filtration across
Drugs are transported across the membranes by: the lipoidal biological membrane with aqueous pores
(a) Passive diffusion and filtration.
(b) Specialized transport.
pKa is the negative logarithm of acidic disso-
Passive diffusion ciation constant of the weak electrolyte. If the
The drug diffuses across the membrane in the concentration of ionized drug [A¯ ] is equal to the
direction of its concentration gradient, the concentration of unionized drug [HA], then—
membrane playing no active role in the process. [A¯ ]
This is the most important mechanism for —–— = 1
[HA]
majority of drugs; drugs are foreign substances
since log 1 is 0, under this condition
and specialized mechanisms are developed by
the body for normal metabolites only. pH = pKa ...(2)
Lipid-soluble drugs diffuse by dissolving in Thus, pKa is numerically equal to the pH at which
the lipoidal matrix of the membrane (Fig. 2.3), the the drug is 50% ionized.
rate of transport being proportional to lipid : water If pH is increased by 1, then—
partition coefficient of the drug. A more lipid-
soluble drug attains higher concentration in the log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10
membrane and diffuses quickly. Also, greater the Similarly, if pH is reduced by 1, then—
difference in the concentration of the drug on two [A¯ ]/[HA] = 1/10
sides of the membrane, faster is its diffusion.
Thus, weakly acidic drugs, which form
Influence of pH Most drugs are weak electro- salts with cations, e.g. sod. phenobarbitone, sod.
lytes, i.e. their ionization is pH dependent sulfadiazine, pot. penicillin-V, etc. ionize more at
(contrast strong electrolytes which are nearly alkaline pH and 1 scale change in pH causes 10-
completely ionized at acidic as well as alkaline fold change in ionization.
pH). The ionization of a weak acid HA is given Weakly basic drugs, which form salts with
by the equation: anions, e.g. atropine sulfate, ephedrine HCl,
[A¯ ] chloroquine phosphate, etc. conversely ionize more
pH = pKa + log —–— ...(1)
[HA] at acidic pH. Ions being lipid insoluble, do not
12 Pharmacokinetics
Filtration
Filtration is passage of drugs through aqueous
pores in the membrane or through paracellular
spaces. This can be accelerated if hydrodynamic
flow of the solvent is occurring under hydrostatic
I

or osmotic pressure gradient, e.g. across most


SECTION

capillaries including glomeruli. Lipid-insoluble


drugs cross biological membranes by filtration if
their molecular size is smaller than the diameter
of the pores (Fig. 2.3). Majority of cells (intestinal
mucosa, RBC, etc.) have very small pores (4 Å)
and drugs with MW > 100 or 200 are not able to
penetrate. However, capillaries (except those in
Fig. 2.4: Influence of pH difference on two sides of a
biological membrane on the distribution of a weakly acidic brain) have large paracellular spaces (40 Å) and
drug with pKa = 6 most drugs (even albumin) can filter through these
(see Fig. 2.8A). As such, diffusion of drugs across
capillaries is dependent on rate of blood flow
diffuse and a pH difference across a membrane
through them rather than on lipid-solubility of
can cause differential distribution of weakly
the drug or pH of the medium.
acidic and weakly basic drugs on the two sides
(Fig. 2.4). Specialized transport
Implications of this consideration are: This can be carrier mediated or by pinocytosis.
(a) Acidic drugs, e.g. aspirin (pKa 3.5) are largely Carrier transport
unionized at acid gastric pH and are absorbed All cell membranes express a host of transmem-
from stomach, while bases, e.g. atropine (pKa 10) brane proteins which serve as carriers or
are largely ionized and are absorbed only when transporters for physiologically important ions,
they reach the intestines. nutrients, metabolites, transmitters, etc. across the
(b) The unionized form of acidic drugs which membrane. At some sites, certain transporters also
crosses the surface membrane of gastric mucosal translocate xenobiotics, including drugs and their
cell, reverts to the ionized form within the cell metabolites. In contrast to channels, which open
(pH 7.0) and then only slowly passes to the for a finite time and allow passage of specific ions,
extracellular fluid. This is called ion trapping, i.e. transporters combine transiently with their
a weak electrolyte crossing a membrane to substrate (ion or organic compound)—undergo a
encounter a pH from which it is not able to escape conformational change carrying the substrate to
easily. This may contribute to gastric mucosal cell the other side of the membrane where the substrate
damage caused by aspirin. dissociates and the transporter returns back to its
(c) Basic drugs attain higher concentration original state (Fig. 2.5). Carrier transport is specific
intracellularly (pH 7.0 vs 7.4 of plasma). for the substrate (or the type of substrate, e.g. an
(d) Acidic drugs are ionized more in alkaline organic anion), saturable, competitively inhibited
urine—do not back diffuse in the kidney tubules by analogues which utilize the same transporter,
and are excreted faster. Accordingly, basic drugs and is much slower than the flux through
are excreted faster if urine is acidified. channels. Depending on requirement of energy,
Lipid-soluble nonelectrolytes (e.g. ethanol, carrier transport is of two types:
diethyl-ether) readily cross biological membranes a. Facilitated diffusion The transporter, belong-
and their transport is pH independent. ing to the super-family of solute carrier (SLC)
Transport of Drugs 13

transporters, operates passively without needing from the gut by the aromatic amino acid
energy and translocates the substrate in the transporter. In addition, the body has developed
direction of its electrochemical gradient, i.e. from some relatively nonselective transporters, like
higher to lower concentration (Fig. 2.5A). It mearly P-glycoprotein (P-gp), to deal with xenobiotics.

CHAPTER
facilitates permeation of a poorly diffusible Active transport can be primary or secondary
substrate, e.g. the entry of glucose into muscle and depending on the source of the driving force.
fat cells by the glucose transporter GLUT 4. i. Primary active transport Energy is obtained
b. Active transport It requires energy, is directly by the hydrolysis of ATP (Fig. 2.5B). The
inhibited by metabolic poisons, and transports transporters belong to the superfamily of ATP
the solute against its electrochemical gradient
binding cassettee (ABC) transporters whose intra-
(low to high), resulting in selective accumulation

2
cellular loops have ATPase activity.
of the substance on one side of the membrane. P-glycoprotein is the most well known primary active
Drugs related to normal metabolites can utilize transporter. Others of pharmacological significance are
the transport processes meant for these, e.g. multidrug resistance associated protein 2 (MRP 2) and
levodopa and methyl dopa are actively absorbed breast cancer resistance protein (BCRP).

Fig. 2.5: Illustration of different types of carrier mediated transport across biological membrane
ABC—ATP-binding cassettee transporter; SLC—Solute carrier transporter; M—Membrane
A. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient
(high to low) and does not require energy
B. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrate
against its concentration gradient (low to high)
C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhill
movement of another substrate ‘B’ in the same direction
D. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhill
movement of another substrate ‘B’ in the opposite direction
14 Pharmacokinetics
ii. Secondary active transport In this type of Area of absorbing surface Larger it is, faster is
active transport effected by another set of SLC the absorption.
transporters, the energy to pump one solute is
Vascularity of the absorbing surface Blood circu-
derived from the downhill movement of another
lation removes the drug from the site of absorption
solute (mostly Na+). When the concentration
I

and maintains the concentration gradient across


gradients are such that both the solutes move in
the absorbing surface. Increased blood flow
SECTION

the same direction (Fig. 2.5C), it is called symport


hastens drug absorption just as wind hastens
or cotransport, but when they move in opposite
drying of clothes.
directions (Fig. 2.5D), it is termed antiport or
exchange transport. Metabolic energy (from Route of administration This affects drug absorp-
hydrolysis of ATP) is spent in maintaining high tion, because each route has its own peculiarities.
transmembrane electrochemical gradient of the
Oral
second solute.
The organic anion transporting polypeptide (OATP)
The effective barrier to orally administered drugs
and organic cation transporter (OCT), highly expressed in is the epithelial lining of the gastrointestinal tract,
liver canaliculi and renal tubules, are secondary active which is lipoidal. Nonionized lipid-soluble
transporters important in the metabolism and excretion drugs, e.g. ethanol are readily absorbed from
of drugs and metabolites (especially glucuronides). The
Na+,Cl– dependent neurotransmitter transporters for
stomach as well as intestine at rates proportional
serotonin and dopamine (SERT and DAT) are active SLC to their lipid : water partition coefficient. Acidic
transporters that are targets for action of drugs like tricyclic drugs, e.g. salicylates, barbiturates, etc. are
antidepressants. predominantly unionized in the acid gastric juice
Pinocytosis It is the process of transport across the cell and are absorbed from stomach, while basic
in particulate form by formation of vesicles. This is applicable drugs, e.g. morphine, quinine, etc. are largely
to proteins and other big molecules, and contributes little
ionized and are absorbed only on reaching the
to transport of most drugs.
duodenum. However, even for acidic drugs
ABSORPTION absorption from stomach is slower, because the
Absorption is the movement of drug from its site mucosa is thick, covered with mucus and the
of administration into the circulation. Not only surface area is small. Thus, faster gastric emptying
the fraction of the administered dose that gets accelerates drug absorption in general. Dissolu-
absorbed, but also the rate of absorption is tion is a surface phenomenon, therefore, particle
important. Except when given i.v., the drug has size of the drug in solid dosage form governs rate
to cross biological membranes; absorption is of dissolution and in turn rate of absorption.
governed by the above described principles. Other Presence of food dilutes the drug and retards
factors affecting absorption are: absorption. Further, certain drugs form poorly
absorbed complexes with food constituents, e.g.
Aqueous solubility Drugs given in solid form tetracyclines with calcium present in milk.
must dissolve in the aqueous biophase before they Moreover, food delays gastric emptying. Thus,
are absorbed. For poorly water-soluble drugs most drugs are absorbed better if taken in empty
(aspirin, griseofulvin) rate of dissolution governs stomach. Highly ionized drugs, e.g. gentamicin,
rate of absorption. Obviously, a drug given as neostigmine, are poorly absorbed when given
watery solution is absorbed faster than when the orally.
same is given in solid form or as oily solution. Certain drugs are degraded in the gastrointes-
Concentration Passive transport depends on tinal tract, e.g. penicillin G by acid, insulin by
concentration gradient; drug given as concen- peptidases, and are ineffective orally. Enteric
trated solution is absorbed faster than from dilute coated tablets (having acid resistant coating) and
solution. sustained release preparations (drug particles
Drug Absorption 15

coated with slowly dissolving material) can be occlusive dressing which increases hydration of
used to overcome acid lability, gastric irritancy the skin. Organophosphate insecticides coming
and brief duration of action. in contact with skin can produce systemic toxicity.
Absorption of a drug can be affected by other Abraded surfaces readily absorb drugs.

CHAPTER
concurrently ingested drugs. This may be a Cornea is permeable to lipid soluble, unioni-
luminal effect: formation of insoluble complexes, zed physostigmine but not to highly ionized
e.g. tetracyclines with iron preparations and neostigmine. Similarly, mucous membranes of
antacids, ciprofloxacin with sucralfate. This can mouth, rectum, vagina absorb lipophilic drugs.
be minimized by administering the two drugs at
2–3 hour intervals. Alteration of gut flora by BIOAVAILABILITY
antibiotics may disrupt the enterohepatic cycling

2
Bioavailability refers to the rate and extent of
of oral contraceptives and digoxin. Drugs can also
absorption of a drug from a dosage form as
alter absorption by gut wall effects: altering motility
determined by its concentration-time curve in
(anticholinergics, tricyclic antidepressants,
blood or by its excretion in urine (Fig. 2.6). It is a
opioids, metoclopramide) or causing mucosal
measure of the fraction (F ) of administered dose
damage (neomycin, methotrexate, vinblastine).
of a drug that reaches the systemic circulation in
Subcutaneous and intramuscular the unchanged form. Bioavailability of drug
By these routes the drug is deposited directly in injected i.v. is 100%, but is frequently lower after
the vicinity of the capillaries. Lipid-soluble drugs oral ingestion because—
pass readily across the whole surface of the (a) the drug may be incompletely absorbed.
capillary endothelium. Capillaries being highly (b) the absorbed drug may undergo first pass
porous do not obstruct absorption of even large metabolism in intestinal wall/liver or be excreted
lipid-insoluble molecules or ions (see Fig. 2.8A). in bile.
Very large molecules are absorbed through
lymphatics. Thus, many drugs not absorbed orally
are absorbed parenterally. Absorption from s.c.
site is slower than that from i.m. site, but both are
generally faster and more consistent/predictable
than oral absorption. Application of heat and
muscular exercise accelerate drug absorption by
increasing blood flow, while vasoconstrictors, e.g.
adrenaline injected with the drug (local anaes-
thetic) retard absorption. Many depot prepara-
tions, e.g. benzathine penicillin, protamine zinc
insulin, depot progestins, etc. can be given by these
routes.
Topical sites (skin, cornea, mucous membranes)
Systemic absorption after topical application
depends primarily on lipid solubility of drugs. Fig. 2.6: Plasma concentration-time curves depicting
However, only few drugs significantly penetrate bioavailability differences between three preparations of a
intact skin. Glyceryl trinitrate, fentanyl and drug containing the same amount
Note that formulation B is more slowly absorbed than A,
estradiol (see p. 8) have been used in this manner.
and though ultimately both are absorbed to the same extent
Absorption can be promoted by rubbing the drug (area under the curve same), B may not produce therapeutic
incorporated in an olegenous base or by use of effect; C is absorbed to a lesser extent—lower bioavailability.
16 Pharmacokinetics
Incomplete bioavailability after s.c. or i.m. injection DISTRIBUTION
is less common, but may occur due to local Once a drug has gained access to the bloodstream,
binding of the drug. it gets distributed to other tissues that initially
Oral formulation of a drug from different had no drug, concentration gradient being in the
manufacturers or different batches from the same direction of plasma to tissues. The extent of dis-
I

manufacturer may have the same amount of the tribution of a drug depends on its lipid solubility,
SECTION

drug (chemically equivalent) but may not yield ionization at physiological pH (dependent on
same blood levels—biologically inequivalent. Two pKa), extent of binding to plasma and tissue
preparations of a drug are considered bioequivalent proteins and differences in regional blood flow.
when the rate and extent of bioavailability of the Movement of drug proceeds until an equilibrium
drug from them is not significantly different under is established between unbound drug in the
suitable test conditions. plasma and in the tissue fluids. Subsequently,
Before a drug administered orally in solid there is a parallel decline in both due to
dosage form can be absorbed, it must break into elimination.
individual particles of the active drug (disinte- Apparent volume of distribution (V) Presuming
gration). Tablets and capsules contain a number that the body behaves as a single homogeneous
of other materials—diluents, stabilizing agents, compartment with volume V into which the drug
binders, lubricants, etc. The nature of these as well gets immediately and uniformly distributed
as details of the manufacture process, e.g. force
used in compressing the tablet, may affect dose administered i.v.
V = ——————————– ...(3)
disintegration. The released drug must then dissolve plasma concentration
in the aqueous gastrointestinal contents. The rate Since in the example shown in Fig. 2.7 the drug
of dissolution is governed by the inherent does not actually distribute into 20 L of body
solubility, particle size, crystal form and other water, with the exclusion of the rest of it, this is
physical properties of the drug. Differences in only an apparent volume of distribution which
bioavailability may arise due to variations in can be defined as “the volume that would
disintegration and dissolution rates.
Differences in bioavailability are seen mostly
with poorly soluble and slowly absorbed drugs.
Reduction in particle size increases the rate of
absorption of aspirin (microfine tablets). The
amount of griseofulvin and spironolactone in the
tablet can be reduced to half if the drug particle is
microfined. There is no need to reduce the particle
size of freely water-soluble drugs, e.g.
paracetamol.
Bioavailability variation assumes practical
significance for drugs with low safety margin
(digoxin) or where dosage needs precise control
(oral hypoglycaemics, oral anticoagulants). It may
also be responsible for success or failure of an
Fig. 2.7: Illustration of the concept of apparent volume of
antimicrobial regimen.
distribution (V)
However, for a large number of drugs bioavaila- In this example, 1000 mg of drug injected i.v. produces
bility differences are negligible and the risks of steady-state plasma concentration of 50 mg/L, apparent
changing formulation have often been exaggerated. volume of distribution is 20 L.
Drug Distribution 17

accommodate all the drug in the body, if the termination of drug action. Greater the lipid
concentration throughout was the same as in solubility of the drug, faster is its redistribution.
plasma.” Thus, it describes the amount of drug Anaesthetic action of thiopentone injected i.v. is
present in the body as a multiple of that contained terminated in a few minutes due to redistribution.

CHAPTER
in a unit volume of plasma. Considered together A relatively short (6-8 hr) hypnotic action due to
with drug clearance, this is a very useful pharma- redistribution is exerted by oral diazepam or
cokinetic concept. nitrazepam despite their elimination half-life of
Lipid-insoluble drugs do not enter cells— > 30 hr. However, when the same drug is given
V approximates extracellular fluid volume, e.g. repeatedly or by continuous i.v. infusion over long
streptomycin, gentamicin 0.25 L/kg. periods, the low perfusion high capacity sites get
Distribution is not only a matter of dilution progressively filled up and the drug becomes

2
but also binding and sequestration. Drugs longer acting.
extensively bound to plasma proteins are largely
Penetration into brain and CSF The capillary
restricted to the vascular compartment and have
endothelial cells in brain have tight junctions and
low values, e.g. diclofenac and warfarin (99%
lack large intercellular pores. Further, an invest-
bound) V = 0.15 L/kg.
ment of neural tissue (Fig. 2.8B) covers the
Drugs sequestrated in other tissues may have
capillaries. Together they constitute the so-called
V much more than total body water or even body
blood-brain barrier. A similar blood-CSF barrier is
mass, e.g. digoxin 6 L/kg, chlorpromazine 25 L/
located in the choroid plexus where capillaries
kg, morphine 3.5 L/kg, because most of the drug
are lined by choroidal epithelium having tight
is present in other tissues, and plasma concen-
junctions. Both these barriers are lipoidal and
tration is low.
limit the entry of nonlipid-soluble drugs, e.g.
Pathological states, e.g. congestive heart
gentamicin, neostigmine, etc. Only lipid-soluble
failure, uraemia, cirrhosis of liver, etc. can alter
drugs, therefore, are able to penetrate and have
the V of many drugs by altering distribution of
action on the central nervous system. Efflux
body water, permeability of membranes, binding
transporters like P-glycoprotein present in brain
proteins or by accumulation of metabolites that
and choroidal vessels extrude many drugs that
displace the drug from binding sites.
enter brain by other processes. Dopamine does
not enter brain, but its precursor levodopa does;
Factors governing volume of drug distribution
as such, the latter is used in parkinsonism.
• Lipid : water partition coefficient of the drug Inflammation of meninges or brain increases
• pKa value of the drug permeability of these barriers.
• Degree of plasma protein binding There is also an enzymatic blood-brain bar-
• Affinity for different tissues rier; monoamine oxidase (MAO), cholinesterase
• Fat : lean body mass ratio and some other enzymes are present in the
• Diseases like CHF, uraemia, cirrhosis capillary walls or in the cells lining them. They
do not allow catecholamines, 5-HT, acetylcholine,
Redistribution Highly lipid-soluble drugs get etc. to enter brain in the active form.
initially distributed to organs with high blood The blood-brain barrier is deficient at the CTZ
flow, i.e. brain, heart, kidney, etc. Later, less in the medulla oblongata (even lipid-insoluble
vascular but more bulky tissues (muscle, fat) take drugs are emetic) and at certain periventricular
up the drug—plasma concentration falls and the sites—(anterior hypothalamus). Exit of drugs from
drug is withdrawn from brain, etc. If the site of the CSF and brain, however, is not dependent on
action of the drug was in one of the highly lipid solubility and is rather unrestricted. Bulk
perfused organs, redistribution results in flow of CSF (along with the drug dissolved in it)
18 Pharmacokinetics
I
SECTION

Fig. 2.8: Passage of drugs across capillaries


A. Usual capillary with large intercellular pores through which even large lipid-
insoluble molecules diffuse
B. Capillary constituting blood-brain or blood-CSF barrier. Tight junctions between
capillary endothelial cells and investment of glial processes or choroidal epithelium
do not allow passage of nonlipid-soluble molecules/ions

occurs through the arachnoid villi. Further, non- (even small chemical change can markedly alter
specific organic ion transport processes (similar protein binding), for example:
to those in renal tubule) operate at the choroid Flurazepam 10% Alprazolam 70%
plexus. Lorazepam 90% Diazepam 99%
Passage across placenta Placental membra- Increasing concentrations of the drug can pro-
nes are lipoidal and allow free passage of gressively saturate the binding sites; fractional
lipophilic drugs while restricting hydrophilic binding may be lower when large amounts of the
drugs. The placental efflux P-glycoprotein also drug are given. The generally expressed percen-
serves to limit foetal exposure to maternally tage binding refers to the usual therapeutic plasma
administered drugs. However, restricted amounts concentrations of a drug. The clinically significant
of nonlipid-soluble drugs, when present in high implications of plasma protein binding are:
concentration or for long periods in maternal
(i) Highly plasma protein bound drugs are
circulation, gain access to the foetus. Thus, it is
largely restricted to the vascular compartment and
an incomplete barrier and almost any drug taken
tend to have lower volumes of distribution.
by the mother can affect the foetus or the new-
(ii) The bound fraction is not available for action.
born (drug taken just before delivery, e.g.
However, it is in equilibrium with the free drug in
morphine).
plasma and dissociates when the concentration
Plasma protein binding of the latter is reduced due to elimination. Plasma
Most drugs possess physicochemical affinity for protein binding thus tantamounts to temporary
plasma proteins. Acidic drugs generally bind to storage of the drug.
plasma albumin and basic drugs to α1 acid (iii) High degree of protein binding generally
glycoprotein. Binding to albumin is quantitatively makes the drug long acting, because bound
more important. Extent of binding depends on fraction is not available for metabolism or
the individual compound; no generalization for excretion, unless it is actively extracted by liver or
a pharmacological or chemical class can be made kidney tubules. Glomerular filtration does not
Drug Distribution 19

Drugs highly bound to plasma protein well as get metabolized or excreted; the new
steady-state free drug concentration is only mar-
To Albumin To α1-acid ginally higher unless the displacement extends
glycoprotein to tissue binding or there is concurrent inhibition

CHAPTER
of metabolism and/or excretion. The overall
Barbiturates β-blockers
impact of many displacement interactions is
Benzodiazepines Bupivacaine
minimal; clinical significance being attained only
NSAIDs Lignocaine
in case of highly bound drugs with limited volume
Valproic acid Disopyramide
of distribution (many acidic drugs bound to
Phenytoin Imipramine
albumin) and where interaction is more complex.
Penicillins Methadone
Moreover, two highly bound drugs do not

2
Sulfonamides Prazosin
necessarily displace each other—their binding
Tetracyclines Quinidine
sites may not overlap, e.g. probenecid and
Warfarin Verapamil
indomethacin are highly bound to albumin but
reduce the concentration of the free form in the do not displace each other. Similarly, acidic drugs
efferent vessels because water is also filtered. do not generally displace basic drugs and vice
Active tubular secretion, however, removes the versa. Some clinically important displacement
drug without the attendant solvent → concen- interactions are:
tration of free drug falls → bound drug dissociates • Salicylates displace sulfonylureas.
and is eliminated resulting in a higher renal • Indomethacin, phenytoin displace war-
clearance value of the drug than the total renal farin.
blood flow (See Fig. 2.10). The same is true of active • Sulfonamides and vit K displace bilirubin
transport of highly extracted drugs in liver. (kernicterus in neonates).
Plasma protein binding in this situation acts as a • Salicylates displace methotrexate.
carrier mechanism and hastens drug elimination, (vi)In hypoalbuminaemia, binding may be redu-
e.g. excretion of penicillin; metabolism of ced and high concentrations of free drug may be
lidocaine. Highly protein bound drugs are not attained, e.g. phenytoin and furosemide. Other
removed by haemodialysis and need special diseases may also alter drug binding, e.g.
techniques for treatment of poisoning. phenytoin and pethidine binding is reduced in
(iv) The generally expressed plasma concentra- uraemia; propranolol binding is increased in
tions of the drug refer to bound as well as free pregnant women and in patients with
drug. Degree of protein binding should be taken inflammatory disease (acute phase reactant α1
into account while relating these to concentrations acid-glycoprotein increases).
of the drug that are active in vitro, e.g. MIC of an Tissue storage Drugs may also accumulate in
antimicrobial. specific organs or get bound to specific tissue
(v) One drug can bind to many sites on the constituents, e.g.—
albumin molecule. Conversely, more than one Drugs sequestrated in various tissues are diffe-
drug can bind to the same site. This can give rise rentially distributed, tend to have large volume of
to displacement interactions among drugs bound distribution and long duration of action. Some
to the same site(s); the drug bound with higher may exert local toxicity due to high concentration,
affinity will displace that bound with lower e.g. tetracyclines on bone and teeth, chloroquine
affinity. If just 1% of a drug that is 99% bound is on retina, emetine on heart and skeletal muscle.
displaced, the concentration of free form will be Drugs may also selectively bind to specific
doubled. This, however, is often transient because intracellular organelle, e.g. tetracycline to mito-
the displaced drug will diffuse into the tissues as chondria, chloroquine to nuclei.
20 Pharmacokinetics
phenicol, propranolol and its active metabolite
Drugs concentrated in tissues
4-hydroxypropranolol.
Skeletal muscle, — digoxin, emetine (to (ii) Active metabolite from an active drug Many
heart muscle proteins). drugs have been found to be partially converted
to one or more active metabolite (see box); the
I

Liver — chloroquine, tetracyclines,


emetine, digoxin. effects observed are the sum total of that due to
SECTION

Kidney — digoxin , chloroquine, the parent drug and its active metabolite(s).
emetine.
(iii) Activation of inactive drug Few drugs are
Thyroid — iodine. inactive as such and need conversion in the
Brain — chlorpromazine, body to one or more active metabolite(s). Such a
acetazolamide, isoniazid. drug is called a prodrug. The prodrug may offer
Retina — chloroquine (to advantages over the active form in being more
nucleoproteins). stable, having better bioavailability or other
Iris — ephedrine, atropine (to desirable pharmacokinetic properties or less side
melanin). effects and toxicity. Some prodrugs are activated
Bone and teeth — tetracyclines, heavy metals selectively at the site of action.
(to mucopolysaccharides
of connective tissue), Active drug Active metabolite
bisphosphonates.
Adipose tissue — thiopentone, ether, mino- Allopurinol — Alloxanthine
cycline, DDT dissolve in Procainamide — N-acetyl-procainamide
neutral fat due to high Primidone — Phenobarbitone,
lipid solubility; remain phenylethylmalonamide
stored due to poor blood Cefotaxime — Deacetyl cefotaxime
supply of fat. Diazepam — Desmethyl-diazepam,
oxazepam
Digitoxin — Digoxin
BIOTRANSFORMATION Imipramine — Desipramine
(Metabolism) Amitriptyline — Nortriptyline
Codeine — Morphine
Biotransformation means chemical alteration of Morphine — Morphine-6-glucuronide
the drug in the body. It is needed to render Spironolactone — Canrenone
nonpolar (lipid soluble) compounds polar (lipid Losartan — E 3174
insoluble) so that they are not reabsorbed in the
renal tubules and are excreted. Most hydrophilic Biotransformation reactions can be classified
drugs, e.g. gentamicin, neostigmine, decametho- into:
(a) Nonsynthetic/Phase I reactions: a functional
nium, etc. are not biotransformed and are excreted
group may be generated/exposed—metabolite
unchanged.
may be active or inactive.
The primary site for drug metabolism is liver;
(b) Synthetic/Conjugation/ Phase II reactions—
others are—kidney, intestine, lungs and plasma.
metabolite is mostly inactive except few drugs,
Biotransformation of drugs may lead to the
e.g. morphine-6-glucuronide.
following.
Nonsynthetic reactions
(i) Inactivation Most drugs and their active
metabolites are rendered inactive or less active, (i) Oxidation This reaction involves addition
e.g. lidocaine, ibuprofen, paracetamol, chloram- of oxygen/negatively charged radical or removal
Drug Metabolism 21

mercaptopurine are oxidized by mitochondrial


Prodrug Active form
or cytoplasmic enzymes.
Levodopa —
Dopamine
(ii) Reduction This reaction is the converse of
Enalapril —
Enalaprilat
oxidation and involves cytochrome P-450 enzymes

CHAPTER
α-Methyldopa α-Methylnorepinephrine

working in the opposite direction. Drugs prima-
Dipivefrine —
Epinephrine rily reduced are chloramphenicol, halothane and
Proguanil —
Cycloguanil warfarin.
Bacampicillin —
Ampicillin
Sulfasalazine —
5-Aminosalicylic acid (iii) Hydrolysis This is cleavage of drug mole-
cule by taking up a molecule of water.
Acyclovir —
Acyclovir triphosphate

2
Cyclophos- —
Aldophosphamide, esterase
phamide phosphoramide mustard, → Acid + Alcohol
Ester + H2O ————→
acrolein Similarly, amides and polypeptides are hydro-
Mercaptopurine — Methylmercaptopurine lyzed by amidases and peptidases. Hydrolysis
ribonucleotide occurs in liver, intestines, plasma and other
tissues. Examples are choline esters, procaine,
of hydrogen/positively charged radical. Oxida- lidocaine, procainamide, pethidine, oxytocin.
tions are the most important drug metabolizing
reactions. Various oxidation reactions are: Synthetic reactions
hydroxylation; oxygenation at C, N or S atoms; These involve conjugation of the drug or its phase
N or O-dealkylation, oxidative deamination, etc. I metabolite with an endogenous substrate, gene-
In many cases, the initial insertion of oxygen rally derived from carbohydrate or amino acid, to
atom into the drug molecule produces short lived form a polar highly ionized organic acid, which
highly reactive quinone/epoxide/superoxide is easily excreted in urine or bile.
intermediates which then convert to more stable (i) Glucuronide conjugation This is the most
compounds. important synthetic reaction carried out by a
Oxidative reactions are mostly carried out by group of UDP-glucuronosyl transferases (UGTs).
a group of monooxygenases in the liver, which in Compounds with a hydroxyl or carboxylic acid
the final step involve a cytochrome P-450 haemo- group are easily conjugated with glucuronic acid
protein, NADPH, cytochrome P-450 reductase which is derived from glucose. Examples are
and molecular O2. More than 100 cytochrome P- chloramphenicol, aspirin, morphine, metroni-
450 (CYP-450) isoenzymes differing in their dazole. Not only drugs but endogenous substrates
affinity for various substrates (drugs), have been like bilirubin, steroidal hormones and thyroxine
identified. The CYP-450 isoenzymes important utilize this pathway. Drug glucuronides excreted
in drug metabolism are CYP3A4, CYP2D6, in bile can be hydrolyzed by bacteria in the gut—
CYP2C8/9, CYP2C19, CYP1A2. the liberated drug is reabsorbed and undergoes
The relative amount of different cytochrome P-450s the same fate. This enterohepatic cycling of the
differs among species and among individuals of the same
species. These differences largely account for the marked drug prolongs its action, e.g. phenolphthalein,
interspecies and interindividual differences in rate of oral contraceptives.
metabolism of drugs.
(ii) Acetylation Compounds having amino or
Barbiturates, phenothiazines, paracetamol, hydrazine residues are conjugated with the help
steroids, phenytoin, benzodiazepines, theophyl- of acetyl coenzyme-A, e.g. sulfonamides, isonia-
line and many other drugs are oxidized in this zid, PAS, hydralazine. Multiple genes control
way. Some other drugs, e.g. adrenaline, alcohol, the N-acetyl transferases (NATs) and rate of
22 Pharmacokinetics
acetylation shows genetic polymorphism (slow Only few drugs are metabolized by enzymes
and fast acetylators). of intermediary metabolism, e.g. alcohol by dehy-
(iii) Methylation The amines and phenols can drogenase, allopurinol by xanthine oxidase,
be methylated; methionine and cysteine acting as succinylcholine and procaine by plasma choli-
methyl donors, e.g. adrenaline, histamine, nico- nesterase, adrenaline by monoamine oxidase.
I

tinic acid. Majority of drugs are acted on by relatively


SECTION

nonspecific enzymes which are directed to types


(iv) Sulfate conjugation The phenolic com- of molecules rather than to specific drugs. The
pounds and steroids are sulfated by sulfotrans- same enzyme can metabolize many drugs. The
ferases (SULTs), e.g. chloramphenicol, adrenal drug metabolizing enzymes are divided into two
and sex steroids. types:
(v) Glycine conjugation Salicylates and other
Microsomal These are located on smooth
drugs having carboxylic acid group are conju-
endoplasmic reticulum (a system of microtubules
gated with glycine, but this is not a major pathway
inside the cell), primarily in liver, also in kidney,
of metabolism.
intestinal mucosa and lungs. The monooxyge-
(vi) Glutathione conjugation Forming a mercap- nases, cytochrome P 450, UGTs, etc. are micro-
turate is normally a minor pathway. However, it somal enzymes.
serves to inactivate highly reactive quinone or They catalyze most of the oxidations, reduc-
epoxide intermediates formed during metabolism tions, hydrolysis and glucuronide conjugation.
of certain drugs, e.g. paracetamol. When a large Microsomal enzymes are inducible by drugs, diet
amount of such intermediates are formed (in and other agencies.
poisoning or after enzyme induction), glutathio-
Nonmicrosomal These are present in the cyto-
ne supply falls short—toxic adducts are formed
plasm and mitochondria of hepatic cells as well
with tissue constituents → tissue damage.
as in other tissues including plasma. The flavo-
(vii) Ribonucleoside/nucleotide synthesis It protein oxidases, esterases, amidases and conju-
is important for the activation of many purine gases are nonmicrosomal. Reactions catalyzed
and pyrimidine antimetabolites used in cancer are:
chemotherapy. Some oxidations and reductions, many hydro-
Most drugs are metabolized by many lytic reactions and all conjugations except
pathways, simultaneously or sequentially as glucuronidation.
illustrated in Fig. 2.9. As such, a variety of The nonmicrosomal enzymes are not inducible
metabolities of a drug may be produced. but many show genetic polymorphism (acetyl
transferase, pseudocholinesterase).
Both microsomal and nonmicrosomal enzy-
mes are deficient in the newborn, especially
premature, making them more susceptible to many
drugs, e.g. chloramphenicol, opioids. This deficit
is made up in first few months, more quickly in
case of oxidation and other phase I reactions than
in case of glucuronide and other conjugations
taking 3 or more months.
Amount and kind of drug metabolizing enzy-
mes is controlled genetically and is also altered
Fig. 2.9: Simultaneous and/or sequential metabolism
of a drug by phase I and phase II reactions by environmental factors. Thus, marked inter-
Drug Metabolism 23

species and interindividual differences are seen. Because enzyme inhibition occurs by direct
Up to 6-fold difference in the rate of metabolism effect on the enzyme, it has a fast time course
of a drug among normal human adults may be (within hours) compared to enzyme induction (see
observed. This is one of the major causes of below).

CHAPTER
individual variation in drug response.
Metabolism of drugs with high hepatic
Hofmann elimination This refers to inactivation extraction is dependent on liver blood flow (blood
of the drug in the body fluids by spontaneous flow limited metabolism). Propranolol reduces rate
molecular rearrangement without the agency of of lidocaine metabolism by decreasing hepatic
any enzyme, e.g. atracurium. blood flow.

2
INHIBITION OF DRUG METABOLISM MICROSOMAL ENZYME INDUCTION
One drug can competitively inhibit the meta- Many drugs, insecticides and carcinogens interact
bolism of another if it utilizes the same enzyme or with DNA and increase the synthesis of micro-
cofactors. However, such interactions are not as somal enzyme protein, especially cytochrome P-
common as one would expect, because often 450 and glucuronyl transferase. As a result, rate
different drugs are substrates for different CYP- of metabolism of inducing drug itself and/or other
450 isoenzymes. Moreover, a drug may inhibit drugs is increased.
one isoenzyme while being itself a substrate of
another isoenzyme, e.g. quinidine is metabolized Different inducers are relatively selective for
by CYP3A4 but inhibits CYP2D6. Also most certain cytochrome P-450 enzyme families, e.g.:
drugs, at therapeutic concentrations are • Anticonvulsants including phenobarbitone,
metabolized by non-saturation kinetics, i.e. the rifampin, glucocorticoids induce CYP3A
enzyme is present in excess. Clinically significant isoenzymes.
inhibition of drug metabolism occurs in case of • Phenobarbitone also induces CYP2B1 and
drugs having affinity for the same isoenzyme, rifampin also induces CYP2D6.
especially if they are metabolized by saturation • Isoniazid and chronic alcohol consumption
kinetics or if kinetics changes from first order to induce CYP2E1.
zero order over the therapeutic range (capacity • Polycyclic hydrocarbons like 3-methylcholan-
limited metabolism). Obviously, inhibition of drug threne and benzopyrene found in cigarette
metabolism occurs in a dose-related manner and smoke, charcoalbroiled meat and industrial
can precipitate toxicity of the object drug (whose pollutants induce CYP1A isoenzymes.
metabolism has been inhibited). • Other important enzyme inducers are: chloral
Drugs that inhibit drug metabolizing hydrate, griseofulvin, DDT.
enzymes
Since different CYP isoenzymes are involved in
Allopurinol Diltiazem the metabolism of different drugs, every inducer
Omeprazole Amiodarone increases biotransformation of certain drugs
Erythromycin Propoxyphene but not that of others. However, phenobarbitone
Clarithromycin Isoniazid like inducers of CYP3A and CYP2D6 affect the
Chloramphenicol Cimetidine metabolism of a large number of drugs, because
Ketoconazole Quinidine these isoenzymes act on many drugs. On the
Itraconazole Metronidazole other hand, induction by polycyclic hydrocarbons
Ciprofloxacin Disulfiram is limited to a few drugs (like theophylline)
Sulfonamides Verapamil because CYP1A isoenzyme metabolizes only few
Fluoxetine Ritonavir drugs.
24 Pharmacokinetics
Induction involves microsomal enzymes in warfarin, tolbutamide, imipramine, oral
liver as well as other organs and increases the contraceptives, chloramphenicol, doxycycline,
rate of metabolism by 2–4-fold. Induction takes theophylline, griseofulvin.
4–14 days to reach its peak and is maintained till
Possible uses of enzyme induction
the inducing agent is being given. Thereafter, the
I

1. Congenital nonhaemolytic jaundice: pheno-


enzymes return to their original value over 1 to 3
barbitone causes rapid clearance of jaundice.
SECTION

weeks.
2. Cushing’s syndrome: phenytoin may reduce
Consequences of microsomal the manifestations.
enzyme induction 3. Chronic poisonings.
1. Decreased intensity and/or duration of action 4. Liver disease.
of drugs that are inactivated by metabolism, e.g.
failure of contraception with oral contraceptives. FIRST PASS (PRESYSTEMIC) METABOLISM
2. Increased intensity of action of drugs that are This refers to metabolism of a drug during its
activated by metabolism. Acute paracetamol toxi- passage from the site of absorption into the sys-
city is due to one of its metabolites—toxicity occurs temic circulation. All orally administered drugs
at lower doses in patients receiving enzyme are exposed to drug metabolizing enzymes in the
inducers. intestinal wall and liver (where they first reach
3. Tolerance—if the drug induces its own through the portal vein). Presystemic metabolism
metabolism (autoinduction), e.g. carbamazepine, of limited magnitude can also occur in the skin
rifampin. (transdermally administered drug) and in lungs
4. Some endogenous substrates (steroids, bili- (for drug reaching venous blood through any
rubin) are also metabolized faster. route). The extent of first pass metabolism differs
5. Precipitation of acute intermittent porphyria: for different drugs (Table 2.1) and is an important
enzyme induction increases porphyrin synthesis determinant of oral bioavailability.
by derepressing δ-aminolevulenic acid synthe-
tase. Attributes of drugs with high first pass
6. Intermittent use of an inducer may interfere metabolism
(a) Oral dose is considerably higher than sub-
with adjustment of dose of another drug pres-
lingual or parenteral dose.
cribed on regular basis, e.g. oral anticoagulants,
(b) There is marked individual variation in the
oral hypoglycaemics, antiepileptics, antihyper-
oral dose due to differences in the extent of first
tensives.
pass metabolism.
Drugs whose metabolism is significantly (c) Oral bioavailability is apparently increased
affected by enzyme induction are—phenytoin, in patients with severe liver disease.

Table 2.1: Extent of first pass metabolism of some important drugs

Low Intermediate High


not given orally high oral dose
Phenobarbitone Aspirin Isoprenaline Propranolol
Tolbutamide Quinidine Lidocaine Alprenolol
Theophylline Desipramine Hydrocortisone Verapamil
Pindolol Nortriptyline Testosterone Salbutamol
Isosorbide Chlorpromazine Glyceryl trinitrate
mononitrate Pentazocine Morphine
Metoprolol Pethidine
Drug Excretion 25
(d) Oral bioavailability of a drug is increased if inadvertently receives the drug. Most drugs enter
another drug competing with it in first pass breast milk by passive diffusion. As such, more
metabolism is given concurrently, e.g. chlorpro- lipid soluble and less protein bound drugs cross
mazine and propranolol. better. Milk has a lower pH (7.0) than plasma,

CHAPTER
basic drugs are somewhat more concentrated in
EXCRETION it. However, the total amount of drug reaching
the infant through breastfeeding is generally small
Excretion is the passage out of systemically
and majority of drugs can be given to lactating
absorbed drug. Drugs and their metabolites are
mothers without ill effects on the infant. Never-
excreted in:
theless, it is advisable to administer any drug to a
1. Urine Through the kidney. It is the most lactating women only when essential.

2
important channel of excretion for majority of
drugs (see below). RENAL EXCRETION
2. Faeces Apart from the unabsorbed fraction, The kidney is responsible for excreting all water-
most of the drug present in faeces is derived from soluble substances. The amount of drug or its
bile. Organic acids (especially drug glucuroni- metabolites ultimately present in urine is the sum
des), organic bases and steroids are actively trans- total of glomerular filtration, tubular reabsorp-
ported into bile by liver through separate non- tion and tubular secretion (Fig. 2.10).
specific active transport mechanisms (OATP,
MRP2, OCT, P-gP, etc.). Relatively larger mole- Net renal (glomerular filtration + tubular
=
cules (MW > 300) are preferentially eliminated in excretion secretion) – tubular reabsorption
the bile. Most of the drug, including that released Glomerular filtration Glomerular capillaries
by deconjugation of glucuronides by bacteria in have pores larger than usual; all nonprotein bound
intestines is reabsorbed (enterohepatic cycling) drug (whether-lipid soluble or insoluble) presen-
and ultimate excretion occurs in urine. Drugs that ted to the glomerulus is filtered. Thus, glomerular
attain high concentrations in bile are erythro- filtration of a drug depends on its plasma protein
mycin, ampicillin, rifampin, tetracycline, oral binding and renal blood flow. Glomerular
contraceptives, phenolphthalein. filtration rate (g.f.r.), normally ~ 120 mL/min,
Certain drugs are excreted directly in colon, declines progressively after the age of 50 and is
e.g. anthracene purgatives, heavy metals. low in renal failure.
3. Exhaled air Gases and volatile liquids Tubular reabsorption This depends on lipid
(general anaesthetics, alcohol) are eliminated by solubility and ionization of the drug at the existing
lungs, irrespective of their lipid solubility. urinary pH. Lipid-soluble drugs filtered at the
Alveolar transfer of the gas/vapour depends on glomerulus back diffuse passively in the tubules
its partial pressure in the blood. Lungs also serve because 99% of glomerular filtrate is reabsorbed,
to trap and extrude any particulate matter injected but nonlipid-soluble and highly ionized drugs
i.v. are unable to do so. Thus, rate of excretion of such
drugs, e.g. aminoglycoside antibiotics, quaternary
4. Saliva and sweat These are of minor impor-
ammonium compounds parallels g.f.r. (or
tance for drug excretion. Lithium, pot. iodide,
creatinine clearance). Changes in urinary pH affect
rifampin and heavy metals are present in these
tubular reabsorption of drugs that are partially
secretions. Most of the saliva along with the drug
ionized—
in it, is swallowed and meets the same fate as
• Weak bases ionize more and are less reabsor-
orally taken drug.
bed in acidic urine.
5. Milk The excretion of drug in milk is not • Weak acids ionize more and are less reabsor-
important for the mother, but the suckling infant bed in alkaline urine.
26 Pharmacokinetics
This principle is utilized for facilitating elimina- sulfinpyrazone, nitrofurantoin, methotrexate,
tion of drug in poisoning, i.e. urine is alkalinized drug glucuronides, etc.
in barbiturate and salicylate poisoning.
(b) Organic base transport (through OCT) for
Tubular secretion This is the active transfer of thiazides, quinine, procainamide, choline, cimeti-
organic acids and bases by two separate classes
I

dine, amiloride, etc.


of nonspecific transporters (OATP and OCT) Inherently both transport processes are bi-
SECTION

which operate in the proximal tubules. In directional, i.e. they can transport their substrates
addition efflux transporters P-gp and MRP2 are from blood to tubular fluid and vice versa. How-
located in luminal membrane of proximal tubular ever, for drugs and their metabolites (exogenous
cells. If renal clearance of a drug is greater than substances) secretion into the tubular lumen
120 mL/min (g.f.r.), additional tubular secretion predominates, whereas an endogenous substrate
can be assumed to be occurring. like uric acid is predominantly reabsorbed.
Active transport of the drug across tubules Drugs utilizing the same active transport com-
reduces the concentration of its free form in the pete with each other. Probenecid is an organic
tubular vessels and promotes dissociation of acid which has high affinity for the tubular OATP.
protein bound drug, which again is secreted (Fig. It blocks the active transport of both penicillin
2.10). Thus, protein binding, which is a hinde- and uric acid, but whereas the net excretion of the
rance for glomerular filtration of the drug, is not former is decreased, that of the latter is increased.
so (may even be facilitatory) to excretion by This is because penicillin is primarily secreted
tubular secretion. while uric acid is primarily reabsorbed. Many
(a) Organic acid transport (by OATP) for drug interactions occur due to competition for
penicillin, probenecid, uric acid, salicylates, tubular secretion, e.g.
(i) Salicylates block uricosuric action of probene-
cid and sulfinpyrazone and decrease tubular
secretion of methotrexate.
(ii) Probenecid decreases the concentration of
nitrofurantoin in urine, increases the duration of
action of penicillin/ampicillin and impairs
secretion of methotrexate.
(iii) Quinidine decreases renal and biliary clea-
rance of digoxin by inhibiting efflux carrier P-gp.
Tubular transport mechanisms are not well
developed at birth. As a result, duration of action
of many drugs, e.g. penicillin, cephalosporins,
aspirin is longer in neonates. These systems
mature during infancy. Ranal function again
progressively declines after the age of 50 years.
The renal clearance of many drugs is substan-
tially lower in the elderly above 75 years of age.

KINETICS OF ELIMINATION
The knowledge of kinetics of elimination of a drug
Fig. 2.10: Schematic depiction of glomerular filtration, tubular
reabsorption and tubular secretion of drugs
provides the basis for, as well as serves to devise
FD—free drug; BD—bound drug; UD—unionized drug; ID— rational dosage regimens and to modify them
ionized drug, Dx—highly secreted organic acid (or base) drug according to individual needs. There are three
Kinetics of Elimination 27
fraction of the drug present in the body is
eliminated in unit time.
Few drugs, however, saturate eliminating
mechanisms and are handled by—

CHAPTER
Zero order (linear) kinetics The rate of elimi-
nation remains constant irrespective of drug
concentration, CL decreases with increase in
concentration; or a constant amount of the drug is
eliminated in unit time, e.g. ethyl alcohol.
The elimination of some drugs approaches

2
saturation over the therapeutic range, kinetics
changes from first order to zero order at higher
Fig. 2.11: Illustration of the concept of drug clearance. A
fraction of the drug molecules present in plasma are removed doses. As a result, plasma concentration increases
on each passage through the organs of elimination. In the disproportionately with increase in dose (see Fig.
case shown, it requires 50 mL of plasma to account for the 2.13) as occurs in the case of phenytoin,
amount of drug being eliminated every minute: clearance is tolbutamide, theophylline, warfarin.
50 mL/min
Plasma half-life The plasma half-life (t½) of a
fundamental pharmacokinetic parameters, viz. drug is the time taken for its plasma concentration
bioavailability (F), volume of distribution (V) and to be reduced to half of its original value.
clearance (CL) which must be understood. The Taking the simplest case of a drug which has
first two have already been considered. rapid one compartment distribution and first
Drug elimination is the sum total of metabolic order elimination, and is given i.v., a semilog
inactivation and excretion. As depicted in Fig. plasma concentration-time plot as shown in Fig.
2.1, drug is eliminated only from the central 2.12 is obtained. The plot has two slopes:
compartment (blood) which is in equilibrium with (i) initial rapidly declining (α) phase—due to
peripheral compartments including the site of distribution.
action. Depending upon the ability of the body to (ii) later less declined (β) phase—due to
eliminate a drug, a certain fraction of the central elimination.
compartment may be considered to be totally At least two half-lives (distribution t½ and
‘cleared’ of that drug in a given period of time to elimination t½) can be calculated from the two
account for elimination over that period. slopes. The elimination half-life derived from the
β slope is simply called the ‘half-life’ of the drug.
Clearance (CL) The clearance of a drug is the Mathematically, elimination t½ is
theoretical volume of plasma from which the drug ln2
is completely removed in unit time (analogy crea- t½ = —— ...(5)
tinine clearance, Fig. 2.11). It can be calculated as k
Where ln2 is the natural logarithm of 2 (or 0.693)
CL = Rate of elimination/C ...(4) and k is the elimination rate constant of the drug, i.e.
where C is the plasma concentration. the fraction of the total amount of drug in the body
For majority of drugs the processes involved which is removed per unit time. For example, if 2
in elimination are not saturated over the clini- g of the drug is present in the body and 0.1 g is
cally obtained concentrations, they follow: eliminated every hour, then k = 0.1/2 = 0.05. It is
First order (exponential) kinetics The rate of calculated as:
elimination is directly proportional to drug con- CL
k = —– ...(6)
centration, CL remains constant; or a constant V
28 Pharmacokinetics
Repeated drug administration
When a drug is repeated at relatively short inter-
vals, it accumulates in the body until elimination
balances input and a steady-state plasma concen-
I

tration (Cpss) is attained—


SECTION

dose rate
Cpss = ————— ...(8)
CL
From this equation it is implied that doubling the
dose rate would double the average Cpss and so
on. Further, if the therapeutic plasma concen-
tration of the drug has been worked out and its
CL is known, the dose rate needed to achieve the
target Cpss can be determined—
dose rate = target Cpss × CL ...(9)
After oral administration, often only a fraction (F)
of the dose reaches systemic circulation in the
Fig. 2.12: Semilog plasma concentration-time plot of a drug active form. In such a case—
eliminated by first order kinetics after intravenous injection
target Cpss CL
V
therefore, t½ = 0.693 × —— ...(7) dose rate = ———————— ...(10)
CL F
As such, half-life is a derived parameter from two The dose rate-Cpss relationship is linear only in
variables V and CL both of which may change case of drugs eliminated by first order kinetics.
independently. It, therefore, is not an exact index For drugs (e.g. phenytoin) which follow Michaelis
of drug elimination. Nevertheless, it is a simple Menten kinetics, elimination changes from first
and useful guide to the sojourn of the drug in the order to zero order kinetics over the therapeutic
body, i.e. after range. Increase in their dose beyond saturation
1 t½ – 50% drug is eliminated. levels causes an increase in Cpss which is out of
2 t½ – 75% (50 + 25) drug is eliminated. proportion to the change in dose rate (Fig. 2.13).
3 t½ – 87.5% (50 + 25 + 12.5) drug is eliminated. In their case:
4 t½ – 93.75% (50 + 25 + 12.5 + 6.25) drug is (Vmax) (C)
eliminated. Rate of drug elimination = ————— ...(11)
Thus, nearly complete drug elimination occurs Km + C
in 4–5 half-lives. where C is the plasma concentration of the drug,
For drugs eliminated by— Vmax is the maximum rate of drug elimination,
First order kinetics—t½ remains constant because and Km is the plasma concentration at which
V and CL do not change with dose. elimination rate is half maximal.
Zero order kinetics—t½ increases with dose
because CL progressively decreases as dose is Plateau principle
increased. When a constant dose of a drug is repeated before
the expiry of 4 t½, it would achieve higher peak
Half-life of some representative drugs
concentration, because some remnant of the
Aspirin 4 hr Digoxin 40 hr previous dose will be present in the body. This
Penicillin-G 30 min Metronidazole 8 hr continues with every dose until progressively
Doxycycline 20 hr Phenobarbitone 90 hr increasing rate of elimination (which increases
Kinetics of Elimination 29

CHAPTER
2
Fig. 2.14: Plateau principle of drug accumulation on repeated
Fig. 2.13 Relationship between dose rate and average oral dosing
steady-state plasma concentration of drugs eliminated by Note. The area of the two shaded portions is equal.
first order and Michaelis Menten (zero order) kinetics

lithium, some antimicrobials, etc. or those given


with increase in concentration) balances the
to prevent an event, it is best to aim at achieving a
amount administered over the dose interval. certain plasma concentration which has been
Subsequently, plasma concentration plateaus defined to be in the therapeutic range; such data
and fluctuates about an average steady-state level. are now available for most drugs of this type.
This is known as the plateau principle of drug Drugs with short t½ (up to 2–3 hr) adminis-
accumulation. Steady state is reached in 4–5 half- tered at conventional intervals (6–12 hr) achieve
lives unless dose interval is very much longer than the target levels only intermittently and fluctua-
t½ (Fig. 2.14). tions in plasma concentration are marked. In case
The amplitude of fluctuations in plasma of many drugs (penicillin, ampicillin, chloramp-
concentration at steady state depends on the dose henicol, erythromycin, propranolol) this, how-
interval relative to t½, i.e. the difference between ever, is therapeutically acceptable.
the maximum and minimum levels is less if For drugs with longer t½ a dose that is
smaller doses are repeated more frequently (dose sufficient to attain the target concentration after
rate remaining constant). Dosage intervals are single administration, if repeated will accumu-
generally a compromise between what amplitude late according to plateau principle and produce
of fluctuations is clinically acceptable (loss of toxicity later on. On the other hand, if the dosing
efficacy at troughs and side effects at peaks) and is such as to attain target level at steady state, the
what frequency of dosing is convenient. However, therapeutic effect will be delayed by about 4 half-
if the dose rate is changed, a new average Cpss is lives (this may be clinically unacceptable). Such
attained over the next 4–5 half-lives. When the drugs are often administered by initial loading
drug is administered orally (absorption takes and subsequent maintenance doses.
some time), average Cpss is approximately 1/3rd
Loading dose This is a single or few quickly
of the way between the minimal and maximal
repeated doses given in the beginning to attain tar-
levels in a dose interval.
get concentration rapidly. It may be calculated as—
Target level strategy For drugs whose effects target Cp × V
are not easily quantifiable and safety margin is Loading dose = —————— ...(12)
not big, e.g. anticonvulsants, antidepressants, F
30 Pharmacokinetics
Thus, loading dose is governed only by V and not 1. By prolonging absorption from site of
by CL or t½. administration
(a) Oral Sustained release tablets, spansule
Maintenance dose This dose is one that is to be capsules, etc.; drug particles are coated with resins,
repeated at specified intervals after the attainment plastic materials or other substances which
I

of target Cpss so as to maintain the same by balan- temporally disperse release of the active ingredient
SECTION

cing elimination. The maintenance dose rate is in the g.i.t. The controlled release tablet/capsule
computed by equation (10) and is governed by CL preparation utilizes a semipermeable membrane
(or t½) of the drug. If facilities for measurement of to control the release of drug from the dosage form.
drug concentration are available, attainment of Such preparations prolong the action by 4 to 6
target level in a patient can be verified sub- hours and no more because in that time drug
sequently and dose rate adjusted if required. particles reach the colon.
Such two phase dosing provides rapid thera- (b) Parenteral The s.c. and i.m. injection of drug
peutic effect with long-term safety; frequently in insoluble form (benzathine penicillin, lente
applied to digoxin, chloroquine, doxycycline, etc. insulin) or as oily solution (depot progestins);
However, if there is no urgency, maintenance doses pellet implantation, sialistic and biodegradable
can be given from the beginning. implants can provide for its absorption over a
couple of days to several months or even years.
PROLONGATION OF DRUG ACTION
Inclusion of a vasoconstrictor with the drug also
It is sometimes advantageous to modify a drug in delays absorption (adrenaline with local anaes-
such a way that it acts for a longer period. By thetics).
doing so:
(i) Frequency of administration is reduced— (c) Transdermal drug delivery systems The drug
more convenient. impregnated in adhesive patches, strips or as
ointment applied on skin is becoming popular,
(ii) Improved patient compliance—a single
e.g. glyceryl trinitrate.
morning dose is less likely to be forgotten/omitted
than a 6 or 8 hourly regimen. 2. By increasing plasma protein binding
(iii) Large fluctuations in plasma concentration Drug congeners have been prepared which are
are avoided—side effects related to high peak highly bound to plasma protein and are slowly
plasma level just after a dose would be minimized released in the free active form, e.g. sulfadoxine.
(e.g. nifedipine); better round-the-clock control of 3. By retarding rate of metabolism Small
blood sugar, etc. chemical modification can markedly affect the rate
(iv) Drug effect could be maintained overnight of metabolism without affecting the biological
without disturbing sleep, e.g. antiasthmatics, action, e.g. addition of ethinyl group to estradiol
anticonvulsants, etc. makes it longer acting and suitable for use as oral
However, all drugs do not need to be made contraceptive. Inhibition of specific enzyme by
long acting, e.g. those used for brief therapeutic one drug can prolong the action of another drug,
effect (sleep inducing hypnotic, headache remedy) e.g. allopurinol inhibits degradation of 6-mer-
or those with inherently long duration of action captopurine; ritonavir boosts the action of indina-
(digoxin, amlodipine, doxycycline, omeprazole). vir, cilastatin protects imipenem from degradation
Drugs with t½ < 4 hr are suitable for controlled in kidney.
release formulations, while there is no need of 4. By retarding renal excretion The tubular
such formulations for drugs with t½ >12 hr. secretion of drug being an active process, can be
Methods utilized for prolonging drug action are suppressed by a competing substance, e.g. pro-
summarized below. Some of these have already benecid prolongs duration of action of penicillin
been described. and ampicillin.
3

Pharmacodynamics

Pharmacodynamics is the study of drug effects. 3. Irritation This connotes a nonselective,


It attempts to elucidate the complete action-effect often noxious effect and is particularly applied
sequence and the dose-effect relationship. to less specialized cells (epithelium, connective
Modification of the effects of one drug by another tissue). Mild irritation may stimulate associated
drug and by other factors is also an aspect of function, but strong irritation results in inflam-
pharmacodynamics. mation, corrosion, necrosis and morphological
damage. This may result in diminution or loss
PRINCIPLES OF DRUG ACTION of function.
Drugs (except those gene based) do not impart 4. Replacement This refers to the use of natu-
new functions to any system, organ or cell; they ral metabolites, hormones or their congeners in
only alter the pace of ongoing activity. The basic deficiency states, e.g. levodopa in parkinsonism,
types of drug action can be broadly classed as: insulin in diabetes mellitus, iron in anaemia.
1. Stimulation It refers to selective enhance- 5. Cytotoxic action Selective cytotoxic action
ment of the level of activity of specialized cells, for invading parasites or cancer cells, attenuating
e.g. adrenaline stimulates heart, pilocarpine them without significantly affecting the host cells
stimulates salivary glands. However, excessive is utilized for cure/palliation of infections and
stimulation is often followed by depression of neoplasms, e.g. penicillin, chloroquine, zido-
that function, e.g. high dose of picrotoxin, a vudine, cyclophosphamide, etc.
central nervous system (CNS) stimulant,
produces convulsions followed by coma and MECHANISM OF DRUG ACTION
respiratory depression.
Only a handful of drugs act by virtue of their
2. Depression It means selective diminution simple physical or chemical property; examples
of activity of specialized cells, e.g. barbiturates are:
depress CNS, quinidine depresses heart, local • Bulk laxatives—physical mass
anaesthetics depress nerve conduction. • Charcoal—adsorptive property
Certain drugs stimulate one type of cells but • Mannitol—osmotic activity
depress the other, e.g. acetylcholine stimulates • 131I and other radioisotopes—radioactivity
intestinal smooth muscle but depresses SA node • Antacids—neutralization of gastric HCl
in heart. Thus, most drugs cannot be just classed • Pot. permanganate—oxidizing property
as stimulants or depressants. • Dimercaprol—chelation of heavy metals.
32 Pharmacodynamics
Majority of drugs produce their effects by
interacting with a discrete target biomolecule,
which usually is a protein. This also confers
selectivity of action to the drug. Functional
proteins that are targets of drug action can be
I

grouped into four basic categories, viz. enzymes,


SECTION

ion channels, transporters and receptors (Fig. 3.1).


However, a few drugs do act on other proteins
(e.g. colchicine, vinca alkaloids, taxanes bind to
the structural protein tubulin) or on nucleic acids
(alkylating agents).

I. ENZYMES
Almost all biological reactions are carried out
under catalytic influence of enzymes; hence,
enzymes are a very important target of drug
action. Drugs can either increase or decrease the
rate of enzymatically mediated reactions. How-
ever, in physiological systems enzyme activities
are often optimally set. Thus, stimulation of
enzymes by drugs, that are truly foreign
substances, is unusual. Enzyme stimulation is
relevant to some natural metabolites only, e.g.
pyridoxine acts as a cofactor and increases
decarboxylase activity. Several enzymes are
stimulated through receptors and second
messengers, e.g. adrenaline stimulates hepatic
glycogen phosphorylase enzyme through β
receptors and cyclic AMP (second messenger).
Stimulation of an enzyme increases its affinity
for the substrate so that rate constant (kM) of the
reaction is lowered (Fig. 3.2).
Apparent increase in enzyme activity can also
occur by enzyme induction, i.e. synthesis of more
enzyme protein. This cannot be called stimulation
because the kM does not change. Many drugs
induce microsomal enzymes (see p. 23).
Inhibition of enzymes is a common mode of
drug action.
A. Nonspecific inhibition Many chemicals Fig. 3.1: Four major types of biomacromolecular
targets of drug action
and drugs are capable of denaturing proteins.
(A) Enzyme; (B) Transmembrane ion channel;
They alter the tertiary structure of any enzyme (C) Membrane bound transporter; (D) Receptor (see
with which they come in contact and thus inhibit text for description)
Mechanism of Drug Action 33

it. Heavy metal salts, strong acids and alkalies, • Allopurinol competes with hypoxanthine for
alcohol, formaldehyde, phenol inhibit enzymes xanthine oxidase.
nonspecifically. Such inhibitors are too dama- • Carbidopa and methyldopa compete with
ging to be used systemically. levodopa for dopa decarboxylase.

CHAPTER
B. Specific inhibition Many drugs inhibit a A nonequilibrium type of enzyme inhibition can
particular enzyme without affecting others. Such also occur with drugs which react with the same
inhibition is either competitive or noncompeti- catalytic site of the enzyme but either form strong
tive. covalent bonds or have such high affinity for the
(i) Competitive (equilibrium type) The drug enzyme that the normal substrate is not able to
being structurally similar competes with the displace the inhibitor, e.g.

3
normal substrate for the catalytic binding site of • Organophosphates react covalently with the
esteretic site of the enzyme cholinesterase.
the enzyme (Fig. 3.1A), so that a new equilibrium
• Methotrexate has 50,000 times higher affinity
is achieved in the presence of the drug. Such
for dihydrofolate reductase than the normal
inhibitors increase the kM but the Vmax remains
substrate DHFA.
unchanged (Fig. 3.2), i.e. higher concentration
of the substrate is required to achieve ½ maximal In these situations, kM is increased and Vmax is
reaction velocity, but if substrate concentration reduced.
is sufficiently increased, it can displace the drug
(ii) Noncompetitive The inhibitor reacts with
and the same maximal reaction velocity can be
an adjacent site and not with the catalytic site,
attained. Examples are:
but alters the enzyme in such a way that it loses
• Physostigmine and neostigmine compete
its catalytic property. Thus, kM is unchanged but
with acetylcholine for cholinesterase.
Vmax is reduced. Examples are:
• Sulfonamides compete with PABA for
bacterial folate synthetase. Noncompetitive Enzyme
inhibitor
Acetazolamide — Carbonic anhydrase
Aspirin, — Cyclooxygenase
indomethacin
Disulfiram — Aldehyde
dehydrogenase
Omeprazole — H+ K+ ATPase
Digoxin — Na+ K+ ATPase
Theophylline — Phosphodiesterase
Propylthiouracil — Peroxidase in thyroid
Lovastatin — HMG-CoA reductase
Fig. 3.2: Effect of enzyme induction, stimulation and
inhibition on kinetics of the reaction II. ION CHANNELS
Vmax—Maximum velocity of reaction; Vmax (s) of stimulated
enzyme; Vmax (i)—in presence of noncompetitive inhibitor; Proteins which act as ion selective channels
kM—rate constant of the reaction; kM (s)—of stimulated participate in transmembrane signaling and
enzyme; kM (i)—in presence of competitive inhibitor regulate intracellular ionic composition. This
Note: Enzyme induction and noncompetitive inhibition do
not change the affinity of the enzyme (kM is unaltered),
makes them a common target of drug action.
whereas enzyme stimulation and competitive inhibition Drugs can affect ion channels either through
respectively decrease and increase the kM. specific receptors (ligand gated ion channels,
34 Pharmacodynamics
G-protein operated ion channels, see p. 37, 38 and or structural proteins, etc. but act through speci-
39), or by directly binding to the channel and fic regulatory macromolecules which control
affecting ion movement through it, e.g. local these effectors. These macromolecules or the sites
anaesthetics which physically obstruct voltage on them which bind and interact with the drug
sensitive Na+ channels (see Ch. 25). In addition, are called ‘receptors’.
I

certain drugs modulate the opening and closing Receptor It is defined as a macromolecule or
SECTION

of channels, e.g.: binding site located on the surface or within the


• Nifedipine blocks L-type of voltage sensitive effector cell that serves to recognize and initiate
Ca2+ channel. the response to a signal molecule or drug, but
• Nicorandil opens ATP-sensitive K+ channels. itself has no other function. In this sense, effectors
• Sulfonylurea hypoglycaemics inhibit pan- (enzymes, channels, transporters, etc.) which
creatic ATP- sensitive K+ channels. bind and interact directly with a drug are not
• Amiloride inhibits renal epithelial Na+ referred to as receptors; e.g. xanthine oxidase is
channels. not called the receptor for allopurinol.
The following terms are used in describing drug-
III. TRANSPORTERS receptor interaction.
Several substrates are translocated across mem- Agonist An agent which activates a receptor to
branes by binding to specific transporters produce an effect similar to that of the physio-
(carriers) which either facilitate diffusion in the logical signal molecule.
direction of the concentration gradient or pump Inverse agonist An agent which activates a
the metabolite/ion against the concentration receptor to produce an effect in the opposite
gradient using metabolic energy (see Fig. 2.5). direction to that of the agonist.
Many drugs produce their action by directly
interacting with the carrier protein to inhibit the Antagonist An agent which prevents the action
ongoing physiological transport of the of an agonist on a receptor or the subsequent
metabolite/ion. Examples are: response but does not have any effect of its own.
• Desipramine blocks neuronal reuptake of Partial agonist An agent which activates a
noradrenaline by inhibiting NET. receptor to produce submaximal effect but
• Fluoxetine selectively inhibits neuronal 5-HT antagonizes the action of a full agonist.
transporter SERT. Ligand (Latin: ligare—to bind) Any molecule
• Reserpine blocks the granular reuptake of which attaches selectively to particular receptors
noradrenaline and 5-HT by vesicular amine or sites. The term only indicates affinity or ability
transporter. to bind without regard to functional change:
• Furosemide inhibits the Na+-K+-2Cl¯ cotrans- agonists and competitive antagonists are both
porter in the ascending limb of loop of Henle. ligands of the same receptor.
• Hydrochlorothiazide inhibits the Na+-Cl¯
symporter in the early distal tubule. Basic evidences for drug action
• Probenecid inhibits active transport of through receptors
organic acids (uric acid, penicillin) in renal (i) Many drugs exhibit structural specificity of action, i.e. a
tubules by organic anion transporter (OAT). specific chemical configuration is associated with a particular
action, e.g. isopropyl substitution on the ethylamine side chain
of sympathetic drugs produces compounds with marked
IV. RECEPTORS cardiac and bronchial activity—most β adrenergic agonists
and antagonists have this substitution.
A large number of drugs do not bind directly to Further, many drugs have shown stereospecificity in
the effectors like enzymes, channels, transporters action, e.g. levo noradrenaline is 10 times more potent than
Mechanism of Drug Action 35

dextro noradrenaline; d-propranolol is about 100 times less K1


potent in blocking β receptors than the l-isomer, but both
D+R DR S E ...(2)
are equipotent local anaesthetics.
Thus, the cell must have some mechanism to recognize K2
a particular chemical configuration and three-dimensional
Depending on the agonist, DR could generate a

CHAPTER
structure.
stronger or weaker S, probably as a function of
(ii) Competitive antagonism is seen between specific
the conformational change brought about by the
agonists and antagonists. Langley in 1878 was so impressed
by the mutual antagonism among two alkaloids pilocarpine agonist in the receptor.
and atropine that he proposed that both reacted with the Agonists have both affinity and maximal
same ‘receptive substance’ on the cell.
intrinsic activity (IA = 1), e.g. adrenaline,
(iii) It was calculated by Clark that adrenaline and histamine, morphine.

3
acetylcholine produce their maximal effect on frog’s heart
by occupying only 1/6,000th of the cardiac cell surface— Competitive antagonists have affinity but no
thus, special regions of reactivity to such drugs must be intrinsic activity (IA = 0), e.g. propranolol, atro-
present on the cell. pine, chlorpheniramine, naloxone.
Receptor occupation theory Partial agonists have affinity and submaximal
After studying quantitative aspects of drug intrinsic activity (IA between 0 and 1), e.g.
action, Clark (1937) propounded a theory of drug dichloroisoproterenol on β adrenergic receptor
action based on occupation of receptors by and pentazocine on opioid receptor.
specific drugs and that the pace of a cellular
Inverse agonists have affinity but intrinsic acti-
function can be altered by interaction of these
vity with a minus sign (IA between 0 and –1),
receptors with drugs (small molecular ligands).
e.g. DMCM on benzodiazepine receptor.
He perceived the interaction between the two
molecular species, viz. drug (D) and receptor (R)
to be governed by the law of mass action, and the The two-state receptor model
effect (E) to be a direct function of the drug- An alternative ‘two-state receptor’ model of drug
receptor complex (DR) formed: action has also been proposed which does not
K1 envisage intrinsic activity to be an independent
D+R DR E ...(1) attribute of the drug. Instead, the receptor is
K2 believed to exist in two interchangeable states
Subsequently, it has been realized that occupa- Ra (active) and Ri (inactive) which are in
tion of the receptor is essential but not itself equilibrium. The agonist binds preferentially to
sufficient to elicit a response; the agonist must the Ra state and tilts the equilibrium to generate
also be able to activate (induce a conformational a response, while the competitive antagonist
change in) the receptor. The ability to bind with binds to Ra and Ri with equal affinity so that the
the receptor designated as affinity, and the equilibrium is not altered and no response is
capacity to induce a functional change in the generated. However, fewer Ra are available to
receptor designated as intrinsic activity (IA) or bind the agonist. Further, inverse agonist is
efficacy are independent properties. Competitive believed to preferentially bind to Ri, while partial
antagonists occupy the receptor but do not agonist is supposed to have only slightly higher
activate it. Moreover, certain drugs are partial affinity for Ra than for Ri. Several evidences
agonists which occupy and submaximally support this model.
activate the receptor. An all or none action is not
a must at the receptor. A theoretical quantity(S) Nature of receptors
denoting strength of stimulus imparted to the Receptors are regulatory macromolecules, mostly
cell was interposed in the Clark’s equation: proteins, though nucleic acids may also serve as
36 Pharmacodynamics
receptors. They are no longer hypothetical. muscarinic (M) and nicotinic (N) types of
Hundreds of receptor proteins have been isolated, cholinergic receptors and their subtypes (M1,
purified, cloned and their primary amino acid M2....M5), α and β adrenergic receptors and their
(AA) sequence has been worked out. Molecular subtypes (α1, α2), (β1, β2, β3). This receptor
cloning has also helped in obtaining the receptor diversity has been exploited in producing more
I

protein in larger quantity to study its structure selective and more targeted newer drugs.
SECTION

and properties, and in subclassifying receptors.


The surface receptors with their coupling and ACTION-EFFECT SEQUENCE
effector proteins are considered to be floating in ‘Drug action’ and ‘drug effect’ are often loosely
a sea of membrane lipids; the folding, orientation used interchangeably, but are not synonymous.
and topography of the system being determined Drug action It is the initial combination of the
by interactions between the lipophilic and hydro- drug with its receptor resulting in a conforma-
philic domains of the peptide chains with solvent tional change in the latter (in case of agonists),
molecules (water on one side and lipids on the or prevention of conformational change through
other). Nonpolar portions of the AA chain tend exclusion of the agonist (in case of antagonists).
to bury within the membrane, while polar groups
tend to come out in the aqueous medium. In such
Drug effect It is the ultimate change in biolo-
gical function brought about as a consequence
a delicately balanced system, it is not difficult to
of drug action, through a series of intermediate
visualize that a small molecular ligand binding
steps (transducer).
to one site in the receptor molecule could be
Receptors subserve two essential functions,
capable of tripping the balance (by altering
viz, recognition of the specific ligand molecule
distribution of charges, etc.) and bringing about
and transduction of the signal into a response.
conformational changes at distant sites. Majority
Accordingly, the receptor molecule has a ligand
of receptor molecules are made up of several non-
binding domain (spatially and energetically
identical subunits (heteropolymeric), and agonist
suitable for binding the specific ligand) and an
binding has been shown to bring about changes
effector domain (Fig. 3.3.) which undergoes a func-
in their quaternary structure or relative align- tional conformational change. These domains
ment of the subunits, e.g. on activation the have now actually been identified in some
subunits of nicotinic receptor move apart opening receptors. The perturbation in the receptor
a centrally located cation channel (see Fig. 3.3). molecule is variously translated into the response.
Many drugs act upon physiological receptors The sequential relationship between drug action,
which mediate responses to transmitters, hormo- transducer and drug effect can be seen in Fig. 3.5.
nes, autacoids and other endogenous signal
molecules; examples are cholinergic, adrenergic, Transducer mechanisms
histaminergic, steroid, leukotriene and other
Considerable progress has been made in the
receptors. In addition, now some truly drug
understanding of transducer mechanisms which
receptors have been described for which there are
in most instances have been found to be highly
no known physiological ligands, e.g. benzo-
complex multistep processes that provide for
diazepine receptor, sulfonylurea receptor.
amplification and integration of concurrently
Subtypes of receptors It has been found that received extra- and intracellular signals at each
most receptors exist in multiple types and step. These mechanisms of translation of receptor
subtypes, differing in their affinity for various activation into functional response can be grou-
agonists and antagonists, ligand binding, tissue ped into four major categories. Receptors falling
distribution, transducer pathway used and in one category have also been found to possess
molecular composition. Illustrative examples are considerable structural homology, and may be
Mechanism of Drug Action 37

CHAPTER
3
Fig. 3.3: Diagrammatic representation of direct receptor mediated operation of membrane ion channel
In case of nicotinic cholinergic receptor, the molecule (8 nm in diameter) is composed of 5 subunits (2α +β + γ + δ) enclosing
a cylindrical ion channel. Normally the channel is closed (A). When two molecules of acetylcholine bind to the two α subunits
(B), all subunits move apart opening the central pore to 0.7 nm, enough to allow passage of partially hydrated Na+ ions.
Anions are blocked from passage through the channel by positive charges lining it.
In other cases, K+, Ca2+ or Cl¯ ions move through the channel depending on its ion selectivity.

considered to belong to one super family of


receptors.
1. G-protein coupled receptors These are a
large family of cell membrane receptors which
are linked to the effector (enzyme/channel/car-
rier protein) through one or more GTP-activated
proteins (G-proteins) for response effectuation.
All such receptors have a common pattern of
structural organization (Fig. 3.4). The molecule
has 7 α-helical membrane spanning hydrophobic
amino acid (AA) segments which run into 3
extracellular and 3 intracellular loops. The ago-
nist- binding site is located somewhere between
the helices on the extracellular face, while
Fig. 3.4: Diagrammatic representation of G-protein
another recognition site formed by cytosolic seg- coupled receptor molecule
ments binds the coupling G-protein. The G- The receptor consists of 7 membrane spanning helical
proteins float in the membrane with their segments of hydrophobic amino acids. The intervening
exposed domain lying in the cytosol, and are segments connecting the helices form 3 loops on either side
of the membrane. The amino terminus of the chain lies on
heterotrimeric in composition (α, β and γ
the extracellular face, while the carboxy terminus is on the
subunits). In the inactive state GDP is bound to cytosolic side. The approximate location of the agonist and
their exposed domain; activation through the G-protein-binding sites is indicated.
38 Pharmacodynamics
receptor leads to displacement of GDP by GTP. (b) Phospholipase C: IP3-DAG pathway Activa-
The activated α-subunit carrying GTP dissociates tion of phospholipase C (PLc) hydrolyzes the
from the other two subunits and either activates membrane phospholipid phosphatidyl inositol
or inhibits the effector. The βγ subunits have also 4, 5-bisphosphate (PIP2) to generate the second
been shown to modulate certain effectors like messengers inositol 1,4,5-trisphosphate (IP3) and
I

receptor operated K+ channels, adenylyl cyclase diacylglycerol (DAG), IP3 mobilizes Ca2+ from
SECTION

(AC) and phospholipase C. intracellular organellar depots and DAG enhan-


ces protein kinase C (PKc) activation by Ca2+ (Fig.
The α-subunit has GTPase activity: the bound 3.6). Cytosolic Ca2+ (third messenger in this set-
GTP is slowly hydrolyzed to GDP: the α-subunit ting) is a highly versatile regulator acting through
then dissociates from the effector to rejoin its calmodulin (CAM), PKc and other effectors—
other subunits, but not before the effector has mediates/modulates contraction, secretion/
been activated/inhibited for a few seconds and transmitter release, neuronal excitability, intra-
the signal has been amplified. cellular movements, membrane function, meta-
There are three major effector pathways bolism, cell proliferation, etc. Like AC, the PLc
(Table 3.1) through which G-protein coupled can also be inhibited through inhibitory G-protein
receptors function: when directionally opposite responses would be
(a) Adenylyl cyclase: cAMP pathway Activation expected.
of AC results in intracellular accumulation of
(c) Channel regulation The activated G-proteins
second messenger cAMP which functions mainly
can also open or close ionic channels specific for
through cAMP-dependent protein kinase (PKA).
Ca2+, K+ or Na+ without the intervention of second
The PKA phosphorylates and alters the function messengers like cAMP or IP3, and bring about
of many enzymes, ion channels, transporters and hyperpolarization/depolarization/changes in
structural proteins to manifest as increased intracellular Ca2+; e.g. Gs opens Ca2+ channels in
contractility/impulse generation (heart, Fig. 3.5), myocardium and skeletal muscles, while Gi
relaxation (smooth muscle), glycogenolysis, lipo- and Go open K+ channels in heart and smooth
lysis, inhibition of secretion/mediator release, muscle as well as close neuronal Ca2+ channels.
modulation of junctional transmission, hormone Physiological responses like changes in inotropy,
synthesis, etc. The reverse occurs when AC is chronotropy, transmitter release, neuronal
inhibited through inhibitory Gi-protein. activity and smooth muscle relaxation follow.

Table 3.1: Major functional pathways of G-protein coupled receptor transduction

Adenylylcyclase: cAMP Phospholipase Channel regulation


IP3-DAG
↑ ↓ Ca2+↑ Ca2+↓ K+↑
Adrenergic-β Adrenergic-α2 Adrenergic-α1 Adrenergic-β1 Dopamine-D2 Adrenergic-α2
Histamine-H2 Muscarinic-M2 Histamine-H1 (Heart, GABA-B Muscarinic-M2
Dopamine-D1 Dopamine-D2 Muscarinic-M1, M3 Sk. muscle) Opioid-κ Dopamine-D2
Glucagon 5-HT1 5-HT2 Adenosine-A1 5-HT1A
FSH & LH GABA-B Vasopressin-Oxytocin Somatostatin GABA-B
ACTH Opioid-μ, δ Bradykinin-B2 Opioid-μ, δ
TSH Angiotensin Angiotensin Adenosine-A1
Prostaglandin-EP2 Prostaglandin-EP3 Prostaglandin-FP, EP1, EP3
Prostacyclin-IP Somatostatin Thromboxane-TP
Adenosine-A2 Adenosine-A1 Leukotriene
Cholecystokinin-Gastrin
PAF
Mechanism of Drug Action 39

CHAPTER
3
Fig. 3.5: The action-effect sequence of β adrenergic receptor activation in myocardial cell
Adrenaline (Adr) binds to β-adrenergic receptor (β-R) on the cell surface inducing a conformational change which permits
interaction of the G-protein binding site with the stimulatory G-protein (Gs). The activated Gs now binds GTP (in place of
GDP), causing its active subunit to dissociate and inturn activate the enzyme adenylyl cyclase (AC) located on the cytosolic
side of the membrane: ATP is hydrolyzed to cAMP which phosphorylates and thus activates cAMP-dependent protein
kinase (PKA). The PKA phosphorylates many functional proteins including troponin and phospholamban, so that they interact
with Ca2+, respectively resulting in increased force of contraction and faster relaxation. Calcium is made available by entry
from outside (direct activation of myocardial membrane Ca2+ channels by Gs and through their phosphorylation by PKA) as
well as from intracellular stores.
Action of acetylcholine (ACh) on muscarinic M2 receptor (M2–R), also located in the myocardial membrane, can similarly
activate an inhibitory G-protein (Gi) which can oppose the activation of AC by Gs.

Receptors found to regulate ionic channels (inhibitory), excitatory AA (kainate, NMDA or


through G-proteins are listed in Table 3.1. N-methyl-D-aspartate, quisqualate) and 5-HT3
2. Receptors with intrinsic ion channel These receptors fall in this category.
cell surface receptors enclose ion selective The receptor is usually a pentameric protein; all subunits, in
addition to large intra- and extracellular segments, generally
channels (for Na+, K+, Ca2+ or Cl¯) within their have four membrane spanning domains in each of which
molecules. Agonist binding opens the channel the AA chain traverses the width of the membrane six times.
(Fig. 3.3) and causes depolarization/hyperpo- The subunits are thought to be arranged round the channel
like a rosette and the α subunits usually bear the agonist-
larization/changes in cytosolic ionic composi- binding sites.
tion, depending on the ion that flows through. Certain receptor operated ion channels also have
The nicotinic cholinergic, GABA-A, glycine secondary ligands which bind to an allosteric site and
40 Pharmacodynamics
a single transmembrane stretch of peptide chain.
There are two major subgroups of such receptors:
(a) Those having intrinsic tyrosine/serine
protein-kinase activity or guanylyl cyclase acti-
vity which generates cGMP as second messenger.
I

(b) Those without intrinsic enzymatic activity,


SECTION

but bind a JAK-STAT-Kinase on activation.


The general scheme of operation of these two
subgroups of enzyme-linked receptors is illus-
trated respectively in Fig. 3.7A and 3.7B.
Examples of protein kinase receptors are insulin
and various growth factors receptors, while those
of JAK-STAT-Kinase binding receptors are cyto-
kine, interferon and growth hormone receptors.
The enzyme-linked receptors transduce
Fig. 3.6: The important steps of phospholipase C(PLc) responses in a matter of minutes to few hours.
pathway of response effectuation (in smooth muscle)
4. Receptors regulating gene expression
The agonist, e.g. histamine binds to its H1 receptor (H1 R) and
(Transcription factors) In contrast to the above
activates the G-protein Gq, which in turn activates membrane
bound phospholipase C (PLc) that hydrolyzes phosphatidyl 3 classes of receptors, these are intracellular
inositol 4, 5-bisphosphate (PIP2), a membrane bound phos- cytoplasmic (as in case of steroidal hormones)
pholipid. The products inositol 1, 4, 5-trisphosphate (IP3) and or nuclear (in case of thyroid hormone) soluble
diacylglycerol (DAG) act as second messengers. The primary
proteins which respond to lipid-soluble chemical
action of IP3 is facilitation of Ca2+ mobilization from intracellular
organellar pools, while DAG in conjunction with Ca2+ activates messengers that penetrate the cell (Fig. 3.8). The
protein kinase C (PKc) which phosphorylates and alters the receptor protein (specific for each hormone/
activity of a number of functional and structural proteins. regulator) is inherently capable of binding to
Cytosolic Ca2+ is a veritable messenger: combines with
specific genes, but is kept inhibited till the
calmodulin (CAM) to activate myosin light chain kinase (MLCK)
inducing contraction, and another important regulator calcium- hormone binds near its carboxy terminus and
calmodulin protein kinase (CCPK). Several other effectors are exposes the DNA binding regulatory segment
regulated by Ca2+ in a CAM dependent or independent manner. located in the middle of the molecule. Attachment
modulate the gating of the channel by the primary ligand, e.g.
of the receptor protein to the genes facilitates their
the benzodiazepine receptor modulates GABAA gated expression so that specific mRNA is synthesized
Cl¯channel. on the template of the gene. This mRNA moves
to the ribosomes and directs synthesis of specific
Thus, in these receptors, agonists directly operate
proteins which regulate the activity of target cells.
ion channels, without the intervention of any
All steroidal hormones (glucocorticoids, minera-
coupling protein or second messenger. The onset
locorticoids, androgens, estrogens, progeste-
and offset of responses through this class of
rone), thyroxine, vit D and vit A function in this
receptors is the fastest.
manner. This transduction mechanism is the
3. Enzyme-linked receptors This class of slowest in its time course of action.
receptors have a subunit with enzymatic
property or bind a JAK (Janus-Kinase) enzyme Receptor regulation
on activation. The agonist-binding site and the Receptors exist in a dynamic state; their density
catalytic site lie respectively on the outer and and efficacy is subject to regulation by the level
inner face of the plasma membrane (Fig. 3.7). of ongoing activity and other physiopathological
These two domains are interconnected through influences. In tonically active systems, prolonged
Mechanism of Drug Action 41

CHAPTER
3
Fig. 3.7: Models of enzyme-linked receptors
A. Intrinsic tyrosine protein kinase receptor: On binding the peptide hormone to the extracellular domains, the monomeric
receptors move laterally in the membrane and form diamers. Dimerization activates tyrosine-protein kinase (t-Pr-K) activity
of the intracellular domains so that they phosphorylate tyrosine (t) residues on each other, as well as on several SH2 domain
substrate proteins (SH2-Pr). The phosphorylated substrate proteins then perform downstream signaling function.
B. JAK-STAT kinase binding receptor: The intracellular domain of these receptors lacks intrinsic protein kinase activity.
Signal molecule binding to the extracellular domain induces receptor dimerization which activates the intracellular domain
to bind free moving JAK (Janus Kinase) molecules. The activated JAK phosphorylate tyrosine residues on the receptor
which then binds another protein STAT (signal transducer and activator of transcription). Tyrosine residues of STAT
also get phosphorylated by JAK. The phosphorylated STAT dimerize, dissociate from the receptor and move to the
nucleus to regulate transcription of target genes.

deprivation of the agonist (by denervation or (ii) Decreased synthesis/increased destruction of


continued use of an antagonist or a drug which the receptor (down regulation): refractoriness deve-
reduces input) results in supersensitivity of the lops over weeks or months and recedes slowly.
receptor as well as the effector system to the Receptor downregulation is particularly exhi-
agonist. This has clinical relevance in clonidine bited by the tyrosine protein kinase receptors.
and CNS depressant/opioid withdrawal syn- Sometimes response to all agonists which act
dromes, sudden discontinuation of propranolol through different receptors but produce the same
in angina pectoris, etc. The mechanisms involved overt effect (e.g. histamine and acetylcholine both
may be unmasking of receptors or their proli- contract intestinal smooth muscle) is decreased
feration (up regulation) or accentuation of signal by exposure to any one of these agonists (hetero-
amplification by the transducer. logous desensitization), showing that mecha-
Conversely, continued intense receptor nisms of response effectuation have become less
stimulation causes desensitization or refractori- efficient. However, often desensitization is limi-
ness: the receptor becomes less sensitive to the ted to agonists of the receptor being repeatedly
agonist. This can be easily demonstrated experi- activated (homologous desensitization).
mentally (Fig. 3.9); clinical examples are
Functions of receptors These can be summa-
bronchial asthma patients treated continuously
rized as:
with β-adrenergic agonists and parkinsonian
(a) To propagate regulatory signals from outside
patients treated with high doses of levodopa. The
to within the effector cell when the molecular
changes may be brought about by:
species carrying the signal cannot itself penetrate
(i) Masking or internalization of the receptor the cell membrane.
(the receptor becomes inaccessible to the (b) To amplify the signal.
agonist). In this case refractoriness develops as (c) To integrate various extracellular and intra-
well as fades quickly. cellular regulatory signals.
42 Pharmacodynamics
I
SECTION

Fig. 3.8: Operational scheme of intracellular (glucocorticoid) receptor


The glucocorticoid (G) penetrates the cell membrane and binds to the glucocorticoid receptor (GR) protein that normally
resides in the cytoplasm in association with 3 other proteins, viz. heat shock protein 90 (HSP90), HSP70 and immunophilin
(IP). The GR has a steroid-binding domain near the carboxy terminus and a mid-region DNA-binding domain having two
‘zinc fingers’, each made up of a loop of amino acids with chelated zinc ion. Binding of the steroid to GR dissociates the
complexed proteins (HSP90, etc.) removing their inhibitory influence on it. A dimerization region that overlaps the steroid-
binding domain is exposed, promoting dimerization of the occupied receptor. The steroid bound receptor diamer translocates
to the nucleus and interacts with specific DNA sequences called ‘glucocorticoid responsive elements’ (GREs) within the
regulatory region of appropriate genes. The expression of these genes is consequently altered resulting in promotion (or
suppression) of their transcription. The specific mRNA thus produced is directed to the ribosome where the message is
translated into a specific pattern of protein synthesis, which in turn modifies cell function.
Dose-Response Relationship 43

CHAPTER
3
Fig. 3.10: Dose-response and log dose-response curves

where E is the observed effect at a dose [D] of


Fig. 3.9: Illustration of the phenomenon of desensitization
the drug, Emax is the maximal response, KD is
the dissociation constant of the drug-receptor
Contractile responses of frog’s rectus abdominis muscle to
acetylcholine. Note that shortly after exposure to a high (100-
complex, which is equal to the dose of drug at
fold) dose of the agonist, the response is markedly which half maximal response is produced. If the
attenuated, but is regained if sufficient time is allowed to dose is plotted on a logarithmic scale, the curve
elapse. becomes sigmoid and a linear relationship bet-
ween log of dose and the response is seen in the
(d) To adapt to short-term and long-term intermediate (30-70% response) zone, as can be
changes in the regulatory melieu and maintain predicted from equation (3). This is not peculiar
homeostasis. to drugs. In fact, all stimuli are graded biologi-
cally by the fractional change in stimulus
DOSE-RESPONSE RELATIONSHIP intensity, e.g. 1 kg and 2 kg weights held in two
When a drug is administered systemically, the hands can be easily differentiated, but not 10 kg
dose-response relationship has two components: and 11 kg weights; though the absolute
dose-plasma concentration relationship and plasma difference remains 1 kg, there is a 100% fractional
concentration-response relationship. The former is change in the former case but only 10% change
determined by pharmacokinetic considerations in the latter case. In other words, response is
and ordinarily, descriptions of dose-response proportional to an exponential function (log) of
relationship refer to the latter, which can be more the dose.
easily studied in vitro.
The log dose-response curve (DRC) can be
Generally, the intensity of response increases
characterized by its shape (slope and maxima)
with increase in dose (or more precisely concen-
and position on the dose axis.
tration at the receptor) and the dose-response
curve is a rectangular hyperbola (Fig. 3.10). This
Drug potency and efficacy
is because drug-receptor interaction obeys law
of mass action, accordingly— The position of DRC on the dose axis is the index
of drug potency which refers to the amount of
Emax × [D]
E = ————— ...(3) drug needed to produce a certain response. A
KD + [D] DRC positioned rightward indicates lower
44 Pharmacodynamics
(a) Aspirin is less potent as well as less effica-
cious analgesic than morphine.
(b) Pethidine is less potent but equally
efficacious analgesic as morphine.
(c) Furosemide is less potent but more
I

efficacious diuretic than metolazone.


SECTION

(d) Diazepam is more potent but less efficacious


CNS depressant than pentobarbitone.
Depending on the type of drug, both higher
efficacy (as in the case of furosemide: acts even
in renal failure), or lower efficacy (as in the case
of diazepam: safety in overdose) could be
clinically advantageous.
The slope of the DRC is also important. A
steep slope indicates that a moderate increase in
dose will markedly increase the response (dose
needs individualization), while a flat one implies
Fig. 3.11: Illustration of drug potency and drug efficacy.
Dose-response curve of four drugs producing the same that little increase in response will occur over a
qualitative effect wide dose range (standard doses can be given to
Note: most patients). Hydralazine has a steep, while
Drug B is less potent but equally efficacious as drug A.
hydrochlorothiazide has a flat DRC of anti-
Drug C is less potent and less efficacious than drug A, but
equally potent and less efficacious than drug B. hypertensive effect (Fig. 3.12).
Drug D is more potent than drugs A, B, & C, but less efficacious
than drugs A & B, and equally efficacious as drug C.
Selectivity Drugs seldom produce just one
action: the DRCs for different effects of a drug

potency (Fig. 3.11). Relative potency is often


more meaningful than absolute potency, e.g. if
10 mg of morphine = 100 mg of pethidine,
morphine is 10 times more potent than
pethidine. However, a higher potency, in itself,
does not confer clinical superiority unless the
potency for therapeutic effect is selectively
increased over potency for adverse effect.
The upper limit of DRC is the index of drug
efficacy and refers to the maximal response that
can be elicited by the drug, e.g. morphine pro-
duces a degree of analgesia not obtainable with
any dose of aspirin—morphine is more effica-
cious than aspirin. Efficacy is a more decisive
factor in the choice of a drug.
Often, the terms ‘drug potency’ and ‘drug effi-
cacy’ are used interchangeably, but these are not
Fig. 3.12: Steep and flat dose-response curves, illustrated
synonymous and refer to different characteris- by antihypertensive effect of hydralazine and hydrochloro-
tics of the drug. The two can vary independently: thiazide
Combined Effect of Drugs 45

CHAPTER
3
Fig. 3.13: Illustration of drug selectivity Fig. 3.14: Illustrative dose-response curves for therapeutic
Log dose-response curves of salbutamol for broncho- effect and adverse effect of the same drug
dilatation (A) and cardiac stimulation (D)
Log dose-response curves of isoprenaline for broncho-
dilatation (B) and cardiac stimulation (C). may be capable of inducing a higher therapeutic
response (have higher efficacy), but develop-
may be different. The extent of separation of ment of intolerable adverse effects may preclude
DRCs of a drug for different effects is a measure use of higher doses, e.g. prednisolone in
of its selectivity, e.g. the DRCs for bronchodila- bronchial asthma.
tation and cardiac stimulation (Fig. 3.13) are
Risk-benefit ratio This term is very frequently
quite similar in case of isoprenaline but far apart
used, and conveys a judgement on the estimated
in case of salbutamol—the latter is a more
harm (adverse effects, inconvenience) vs
selective bronchodilator drug.
expected advantages (relief of symptoms, cure,
The gap between the therapeutic effect DRC
reduction of complications/mortality, improve-
and the adverse effect DRC defines the safety
ment in quality of life). A drug should be
margin or the therapeutic index of a drug. In
prescribed only when the benefits outweigh the
experimental animals, therapeutic index is often
risks. However, risk-benefit ratio can hardly ever
calculated as:
be accurately measured for each instance of drug
median lethal dose use. The physician has to rely on data from use
Therapeutic index = —————————– of drugs in large populations (pharmacoepide-
median effective dose
miology) and his own experience of the drug and
LD50 the patient.
or ——–
ED50
But this is irrelevant in the clinical set up where COMBINED EFFECT OF DRUGS
the therapeutic range is bounded by the dose When two or more drugs are given simulta-
which produces minimal therapeutic effect and neously or in quick succession, they may be
the dose which produces maximal acceptable either indifferent to each other or exhibit syner-
adverse effect (Fig. 3.14). Because of inter- gism or antagonism. The interaction may take
individual variability, the effective dose of a drug place at pharmacokinetic level (see Ch. 2) or at
for one subject may be toxic for the other. A drug pharmacodynamic level.
46 Pharmacodynamics
SYNERGISM Supraadditive drug combinations
(Greek: Syn—together; ergon—work)
Drug pair Basis of potentiation
When the action of one drug is facilitated or
increased by the other, they are said to be syner- Acetylcholine + Inhibition of break
I

gistic. In a synergistic pair both the drugs can physostigmine down


have action in the same direction or given alone
SECTION

Levodopa + carbidopa/ Inhibition of peri-


one may be inactive but still enhance the action benserazide pheral metabolism
of the other when given together. Synergism can Adrenaline + cocaine/ Inhibition of
be: desipramine neuronal uptake
(a) Additive The effect of the two drugs are in Sulfamethoxazole + Sequential blockade
the same direction and simply add up: trimethoprim
effect of drugs A + B = effect of drug A + effect Antihypertensives Tackling two
of drug B (enalapril+ contributory factors
Examples are— hydrochlorothiazide)
Aspirin + paracetamol : as analgesic/ Tyramine + MAO Increasing release-
antipyretic inhibitors able CA store
Nitrous oxide + ether : as general
anaesthetic
other. Depending on the mechanism involved,
Amlodipine + : as antihypertensive
antagonism may be:
atenolol
Glibenclamide + : as hypoglycaemic (a) Physical antagonism Based on the physi-
metformin cal property of the drugs, e.g. charcoal adsorbs
alkaloids and can prevent their absorption—
Side effects of components of an additive pair
used in alkaloidal poisonings.
may be different—do not add up. Thus, the
combination is better tolerated than higher dose (b) Chemical antagonism The two drugs react
of one component. chemically and form an inactive product, e.g.
• KMnO4 oxidizes alkaloids—used for gastric
(b) Supra-additive (potentiation) The effect of
lavage in poisoning.
combination is greater than the individual effects
• Tannins + alkaloids—insoluble alkaloidal
of the components:
tannate is formed.
effect of drug A + B > effect of drug A + • Chelating agents (BAL, Cal. disod. edetate)
effect of drug B complex metals (As, Pb).
• Nitrites form methaemoglobin which reacts
This is always the case when one component with cyanide radical.
given alone produces no effect, but enhances the
effect of the other. Examples are given in the box. Drugs may react when mixed in the same
syringe or infusion bottle:
ANTAGONISM • Thiopentone sod. + succinylcholine chloride
When one drug decreases or abolishes the action • Penicillin-G sod. + succinylcholine chloride
of another, they are said to be antagonistic: • Heparin + penicillin/tetracyclines/strepto-
mycin/hydrocortisone
effect of drugs A + B < effect of drug A +
effect of drug B. (c) Physiological / functional antagonism The
Usually, in an antagonistic pair one drug is two drugs act on different receptors or by different
inactive as such but decreases the effect of the mechanisms, but have opposite overt effects on
Combined Effect of Drugs 47

the same physiological function, i.e. have


pharmacological effects in opposite direction, e.g.
• Histamine and adrenaline on bronchial
muscles and BP.
• Hydrochlorothiazide and triamterene on

CHAPTER
urinary K+ excretion.
• Glucagon and insulin on blood sugar level.
(d) Receptor antagonism One drug (antagonist)
blocks the receptor action of the other (agonist).
This is a very important mechanism of drug

3
action, because physiological signal molecules
act through their receptors, blockade of which
can produce specific and often profound
pharmacological effects. Receptor antagonists are
selective (relatively), i.e. an anticholinergic will
oppose contraction of intestinal smooth muscle
induced by cholinergic agonists, but not that
induced by histamine or 5-HT (they act through
a different set of receptors). Receptor antagonism
can be competitive or noncompetitive.
Competitive antagonism (equilibrium type) The
antagonist is chemically similar to the agonist,
competes with it (Fig. 3.15A, D) and binds to the
same site to the exclusion of the agonist
molecules. Because the antagonist has affinity
but no intrinsic activity, no response is produced.
Since antagonist binding is reversible and
depends on the relative concentration of the
agonist and antagonist molecules, higher
concentration of the agonist progressively
overcomes the block—a parallel shift to the right
of the agonist DRC with no suppression of
maximal response is obtained (Fig. 3.16a). The
extent of shift is dependent on the affinity and
concentration of the antagonist. Fig. 3.15: Illustration of sites of action of agonists and
A partial agonist (Fig. 3.15C), having affinity antagonists (A), and the action of full agonist (B), partial
for the same receptor, also competes with and agonist (C), competitive antagonist (D) and noncompetitive
antagonizes a full agonist, while producing a antagonist (E) on the receptor
submaximal response of its own. are uncoupled. Because the agonist and the anta-
Noncompetitive antagonism The antagonist is gonist are combining with different sites, there
chemically unrelated to the agonist, binds to a is no competition between them—even high
different allosteric site altering the receptor in agonist concentration is unable to reverse the
such a way that it is unable to combine with the block completely. Increasing concentrations of
agonist (Fig. 3.15E), or unable to transduce the the antagonist progressively flatten the agonist
response, so that the downstream chain of events DRC (Fig. 3.16b).
48 Pharmacodynamics
I
SECTION

Fig. 3.16: Dose-response curves showing competitive (a) and noncompetitive (b) antagonism
A—agonist, B—competitive antagonist, C—noncompetitive antagonist

Nonequilibrium (competitive) antagonism antagonist of adrenaline at the α adrenergic


Certain antagonists bind to the receptor with receptors.
strong (covalent) bonds or dissociate from it Features of competitive and noncompetitive
slowly so that agonist molecules are unable to antagonism are compared in the box.
reduce receptor occupancy of the antagonist
molecules—law of mass action cannot apply— DRUG DOSAGE
an irreversible or nonequilibrium antagonism is ‘Dose’ is the appropriate amount of a drug
produced. The agonist DRC is shifted to the right needed to produce a certain degree of response
and the maximal response is lowered (if spare in a patient. Accordingly, dose of a drug has to
receptors are few). Since flattening of agonist be qualified in terms of the chosen response, e.g.
DRC is a feature of noncompetitive antagonism; the analgesic dose of aspirin for headache is
nonequilibrium antagonism has also been called 0.3–0.6 g, its antiplatelet dose is 75–150 mg/day,
‘a type of noncompetitive antagonism’. while its anti-inflammatory dose for rheumatoid
Phenoxybenzamine is a nonequilibrium arthritis is 3–5 g per day. Similarly, there could

Competitive (equilibrium type) Noncompetitive

1. Antagonist binds with the same receptor Binds to another site of receptor
as the agonist
2. Antagonist resembles chemically with Does not resemble
the agonist
3. Parallel rightward shift of agonist DRC Flattening of agonist DRC
4. The same maximal response can be Maximal response is suppressed
attained by increasing dose of agonist (unsurmountable antagonism)
(surmountable antagonism)
5. Intensity of response depends on the concen- Maximal response depends only on the concentration
tration of both agonist and antagonist of antagonist
6. Examples: ACh—Atropine Diazepam—Bicuculline
Morphine—Naloxone
Drug Dosage 49

be prophylactic dose, a therapeutic dose or a toxic Fixed dose ratio combination preparations
dose of the same drug. A large number of pharmaceutical preparations
The dose of a drug is governed by its inherent contain two or more drugs in a fixed dose ratio.
potency, i.e. the concentration at which it should
Advantages offered by these are:

CHAPTER
be present at the target site, and its pharmaco-
kinetic characteristics. In addition, it is modified 1. Convenience, better patient compliance and
by a number of factors (see below). However, may be cost saving—when all the compo-
different strategies are adopted for individua- nents present in a formulation are actually
lizing drug dosage. needed by the patient.
1. Standard dose The same dose is appro- 2. Certain drug combinations are synergistic,

3
priate for most patients—individual variations e.g. sulfamethoxazole + trimethoprim; levo-
are minor or the drug has a wide safety margin dopa + carbidopa/benserazide; combination
so that enough can be given to cover them, e.g. oral contraceptives.
oral contraceptives, penicillin, chloroquine, 3. The therapeutic effect of two components
mebendazole, amantadine. being same may add up while the side effects
being different may not.
2. Regulated dose The drug modifies a finely
regulated body function which can be easily 4. The side effect of one component may be
measured. The dosage is accurately adjusted by counteracted by the other, e.g. a thiazide + a
repeated measurement of the affected physiolo- potassium sparing diuretic.
gical parameter, e.g. antihypertensives, hypogly- 5. Combined formulation ensures that a single
caemics, anticoagulants, diuretics, general drug will not be taken. This is important in
anaesthetics. the treatment of tuberculosis and HIV-AIDS.
3. Target level dose (see p. 29) The response Before prescribing a combination, the physician
is not easily measurable but has been demon- must consider whether any of the ingredients is
strated to be obtained at a certain range of drug unnecessary; if it is, the combination should not
concentration in plasma. An empirical dose be prescribed.
aimed at attaining the target level is given in the
beginning and adjustments are made later by There are many inbuilt disadvantages of fixed
measuring the plasma concentration or by obser- dose ratio combinations:
ving the patient at relatively long intervals, e.g. • The patient may not actually need all the
antidepressants, antiepileptics, digoxin, lithium, drugs present in a combination: he is sub-
theophylline. jected to additional side effects and expense
(often due to ignorance of the physician about
4. Titrated dose The dose needed to produce
the exact composition of the combined
maximal therapeutic effect cannot be given
formulations).
because of intolerable adverse effects. Optimal
• The dose of most drugs needs to be adjusted
dose is arrived at by titrating it with an
acceptable level of adverse effect. Low initial and individualized. When a combined for-
dose and upward titration (in most non-critical mulation is used, this cannot be done without
situations) or high initial dose and downward altering the dose of the other component(s).
titration (in critical situations) can be practised. • The time course of action of the components
Often, a compromise between submaximal may be different.
therapeutic effect but tolerable side effects can • Altered renal or hepatic function of the patient
be struck, e.g. anticancer drugs, corticosteroids, may differently affect the pharmacokinetics
levodopa. of the components.
50 Pharmacodynamics
• Adverse effect, when it occurs, cannot be patient. However, final adjustments have to be
easily ascribed to the particular drug causing made by observing the response in a given patient
it. on a given occasion.
• Contraindication to one component (allergy,
These factors modify drug action either:
other conditions) contraindicates the whole
I

preparation. (a) Quantitatively The plasma concentration


SECTION

• Confusion of therapeutic aims and false sense and/or the action of the drug is increased or
of superiority of two drugs over one is decreased. Most of the factors introduce this type
fostered, especially in case of antimicrobials of change and can be dealt with by adjustment
whose combinations should be avoided. of drug dosage.
Corticosteroids should never be combined (b) Qualitatively The type of response is altered,
with any other drug meant for internal use. e.g. drug allergy or idiosyncrasy. This is less
common but often precludes further use of that
Thus, only a handful of fixed dose ratio combi-
drug in the affected patient.
nations are rational and justified, while far too
many are available and vigorously promoted. The various factors are discussed below—
1. Body size It influences the concentration
FACTORS MODIFYING DRUG ACTION
of the drug attained at the site of action. The
Variation in response to the same dose of a drug average adult dose refers to individuals of
between different patients and even in the same medium built. For exceptionally obese or lean
patient on different occasions is a rule rather than individuals and for children dose may be
exception. One or more of the following cate- calculated on body weight (BW) basis:
gories of differences among individuals are
BW (kg)
responsible for the variations in drug response: Individual dose = ———— × average adult dose
70
(1) Individuals differ in pharmacokinetic hand-
ling of drugs: attain varying plasma/target site In the case of few drugs, doses are calculated
concentration of the drug. This is more marked more appropriately on the basis of body surface
for drugs disposed by metabolism (e.g. pro- area (BSA).
pranolol) than for drugs excreted unchanged 2. Age The dose of a drug for children is often
(e.g. atenolol). calculated from the adult dose
(2) Variations in number or state of receptors, Age
coupling proteins or other components of Child dose = ———— × adult dose ... (Young’s
response effectuation. Age + 12
formula)
(3) Variations in neurogenic/hormonal tone or Age
Child dose = –—— × adult dose ...(Dilling’s
concentrations of specific constituents, e.g. atro- 20
formula)
pine tachycardia depends on vagal tone, propra-
nolol bradycardia depends on sympathetic tone, Ideal % of
captopril hypotension depends on body Na+ Age BW (kg) Adult dose
status. 6 months 7.5 22
A multitude of host and environmental factors 1 year 10 25
influence drug response. Though individual 3 years 14 33
variation cannot be totally accounted for by these 5 years 18 40
factors, their understanding can guide choice of 7 years 23 50
appropriate drug and dose for an individual 12 years 37 75
Factors Modifying Drug Action 51

It can also be calculated (more accurately) on BW 3. Sex Females have smaller body size and
basis, and for many drugs, manufacturers give require doses that are on the lower side of the
dosage recommendations on mg/kg basis. range. Subjective effects of drugs may differ in
Average figures for children are given in the box. females because of their mental makeup. A num-

CHAPTER
However, infants and children are not small ber of antihypertensives (clonidine, methyldopa,
adults. They have important physiological diffe- β-blockers, diuretics) interfere with sexual func-
rences from adults. tion in males but not in females. Gynaecomastia
Children are growing and are susceptible to is a side effect (of ketoconazole, metoclopramide,
special adverse effects of drugs, e.g. suppression chlorpromazine, digitalis) that can occur only in
of growth can occur with corticosteroids; men. Ketoconazole causes loss of libido in men
but not in women. Obviously, androgens are

3
tetracyclines get deposited in growing teeth and
unacceptable to women and estrogens to men.
discolour/deform them. Dystonic reactions to
In women consideration must also be given to
phenothiazines are more common in children.
menstruation, pregnancy and lactation.
Elderly In the elderly, renal function progres- Drugs given during pregnancy can affect the
sively declines (intact nephron loss) and drug foetus (see Ch. 4). There are marked physiological
doses have to be reduced, e.g. daily dose of changes during pregnancy, especially in the
streptomycin is 0.75 g after 50 years and 0.5 g third trimester, which can alter drug disposition.
after 70 years of age compared to 1 g for young (i) Gastrointestinal motility is reduced →
adults. There is also a reduction in the hepatic delayed absorption of orally administered
microsomal drug metabolizing activity and liver drugs.
blood flow: the oral bioavailability of drugs with (ii) Plasma and extracellular fluid volume
high hepatic extraction is generally increased, expands—volume of drug distribution
but the overall effects on drug metabolism are may increase.
not uniform. Other affected aspects of drug (iii) While plasma albumin level falls, that of
handling are slower absorption due to reduced α1 acid glycoprotein increases—the
motility of and blood flow to intestines, lesser unbound fraction of acidic drugs increases
plasma protein binding due to lower plasma but that of basic drugs decreases.
albumin, increased or decreased volume of (iv) Renal blood flow increases markedly—
distribution of lipophilic and hydrophilic drugs polar drugs are eliminated faster.
respectively. The responsiveness of β adrenergic (v) Hepatic microsomal enzymes undergo
receptors to both agonists and antagonists is induction—many drugs are metabolized
reduced in the elderly and sensitivity to other faster.
drugs also may be altered. Due to prostatism in Thus, the overall effect on drug disposition
elderly males, even mild anticholinergic activity is complex and often difficult to predict.
of the drug can accentuate bladder voiding 4. Species and race There are many examp-
difficulty. Elderly are also likely to be on multiple les of differences in responsiveness to drugs
drug therapy for hypertension, ischaemic heart among different species.
disease, diabetes, arthritis, etc. which increases Among human beings some racial diffe-
many fold the chances of drug interactions. They rences have been observed, e.g. blacks require
are more prone to develop postural instability higher and mongols require lower concentra-
(e.g. on standing from dental chair), giddiness tions of atropine and ephedrine to dilate their
and mental confusion. In general, the incidence pupil. β-blockers are less effective as antihyper-
of adverse drug reactions is much higher in the tensive in blacks. Indians tolerate thiacetazone
elderly. better than whites. Considering the widespread
52 Pharmacodynamics
use of chloramphenicol in India and Hong Kong, 7. Environmental factors and time of admi-
relatively few cases of aplastic anaemia have nistration Several environmental factors affect
been reported compared to its incidence in the drug responses. Exposure to insecticides, carci-
west. Similarly, quiniodochlor related cases of nogens, tobacco smoke and consumption of
subacute myelooptic neuropathy (SMON) occu- charcoal broiled meat are well known to induce
I

rred in epidemic proportion in Japan, but there drug metabolism. Type of diet and temporal
SECTION

is no confirmed report of its occurrence in India relation between drug ingestion and meals can
despite extensive use. alter drug absorption. Subjective effect of a drug
may be markedly affected by the setup in which
5. Genetics The dose of a drug to produce the
it is taken. It has been shown that corticosteroids
same effect may vary by 4 to 6-fold among
taken as a single morning dose cause less pitui-
different individuals. This is mainly because of
tary-adrenal suppression. Local anaesthetics have
differing rates of drug metabolism, because the
been found to produce more prolonged dental
amount and isoform pattern of drug metabo-
anaesthesia when injected in the afternoon than in
lizing enzymes is genetically controlled. There
the morning.
are also differences in target organ sensitivity,
transporters, ion channels, etc. The study of 8. Psychological factor Efficacy of a drug can
genetic basis for variability in drug response is be affected by patient’s beliefs, attitudes and
called Pharmacogenetics;while Pharmacogenomics expectations. This is particularly applicable to
is the use of genetic information to guide the centrally acting drugs, e.g. a nervous and anxious
choice of drug and its dose on an individual patient requires more general anaesthetic; alco-
basis. A continuous variation with Gaussian hol generally impairs performance but if punish-
frequency distribution is seen in the case of most ment (which induces anxiety) is introduced, it
drugs. However, there are some specific genetic may actually improve performance.
defects which lead to discontinuous variation in
Placebo This is an inert substance which is
drug responses, e.g.
given in the garb of a medicine. It works by psy-
(i) Atypical pseudocholinesterase—prolong- chological rather than pharmacological means
ed succinylcholine apnoea. and often produces responses equivalent to the
(ii) G-6-PD deficiency—haemolysis with pri- active drug. Some individuals are more sug-
maquine and other oxidizing drugs like gestible and easily respond to a placebo—
sulfonamides, dapsone, quinine, nalidixic ‘placebo reactors’. Placebos are used in two
acid, nitrofurantoin and menadione, etc. situations:
(iii) Acetylator polymorphism—isoniazid neu- 1. As a control device in clinical trial of drugs
ropathy, procainamide and hydralazine (dummy medication).
induced lupus in slow acetylators. 2. To treat a patient who, in the opinion of the
(iv) CYP2D6 abnormality causes poor meto- physician, does not require an active drug.
prolol/debrisoquin metabolizer status.
Placebo is a Latin word meaning ‘I shall
(v) Precipitation of an attack of angle closure
please’. A patient responds to the whole thera-
glaucoma by mydriatics in individuals
peutic setting; placebo-effect largely depends on
with narrow iridocorneal angle.
the physician-patient relationship.
6. Route of administration Route of adminis- Placebos do induce physiological responses,
tration governs the speed and intensity of drug e.g. they can release endorphins in brain—caus-
response (see Ch. 1). Parenteral administration ing analgesia. Naloxone, an opioid antagonist,
is often resorted to for more rapid, more blocks placebo analgesia. Placebo effects can thus
pronounced and more predictable drug action. supplement pharmacological effects. However,
Factors Modifying Drug Action 53

placebo effects are highly variable even in the Even the action of certain drugs can be
same individual, e.g. a placebo may induce sleep altered in liver disease, e.g.
on the first night but not subsequently. Thus, it • The sensitivity of brain to depressant action
has a very limited role in practical therapeutics. of morphine and barbiturates is markedly

CHAPTER
Substances commonly used as placebo are increased in cirrhotics—normal doses can
lactose tablets/capsules and distilled water produce coma.
injection. • Brisk diuresis can precipitate mental changes
9. Pathological states Not only drugs modify in patients with impending hepatic encep-
disease processes, several diseases can influence halopathy because diuretics cause hypo-
drug disposition and drug action: kalemic alkalosis which favours conversion
of NH+4 to NH3 → enters brain more easily.

3
Gastrointestinal diseases These can alter • Oral anticoagulants can markedly increase
absorption of orally administered drugs. The prothrombin time because clotting factors are
changes are complex and drug absorption may already low.
increase or decrease, e.g. in coeliac disease
absorption of amoxicillin is decreased but that Hepatotoxic drugs should be avoided in liver
of cephalexin and cotrimoxazole is increased. disease.
Nonsteroidal antiinflammatory drugs can Kidney disease It markedly affects pharmaco-
aggravate peptic ulcer disease. kinetics of many drugs as well as alters the effects
Liver disease Liver disease (especially cirrho- of some drugs.
sis) can influence drug disposition in several Clearance of drugs that are primarily
ways: excreted unchanged (aminoglycosides, digoxin,
(i) Bioavailability of drugs having high first phenobarbitone) is reduced parallel to the
pass metabolism (see Ch. 2) is increased due decrease in creatinine clearance (CLcr). Loading
to loss of hepatocellular function and dose of such a drug is not altered (unless edema
portocaval shunting. is present), but maintenance doses should be
(ii) Serum albumin is reduced—protein bind- reduced or dose interval prolonged proportio-
ing of acidic drugs (diclofenac, warfarin, nately. A rough guideline is given in the box:
etc.) is reduced and more drug is present
in the free form. CLcr (patient) Dose rate to be reduced to
(iii) Metabolism and elimination of some drugs
(morphine, lidocaine, propranolol) is 50–70 ml/min 70%
decreased: their dose should be reduced. 30–50 ml/min 50%
Alternative drugs that do not depend on 10–30 ml/min 30%
hepatic metabolism for elimination and/ 5–10 ml/min 20%
or have shorter t½ should be preferred, e.g.
oxazepam or lorazepam in place of Dose rate of drugs only partly excreted
diazepam; atenolol as β-blocker. unchanged in urine also needs reduction, but to
(iv) Prodrugs needing hepatic metabolism for lesser extents. If the t½ of the drug is prolonged,
activation, e.g. prednisone, bacampicillin attainment of steady-state plasma concentration
are less effective and should be avoided. with maintenance doses is delayed proportio-
The changes are complex and there is no nately.
simple test (like creatinine clearance for renal Plasma proteins, especially albumin, are
disease) to guide the extent of alteration in drug often low or altered in structure in patients with
disposition; kinetics of different drugs is affected renal disease—binding of acidic drugs is reduced
to different extents. but that of basic drugs is not much affected.
54 Pharmacodynamics
The permeability of blood-brain barrier is (iii) Retarding drug elimination as a result of
increased in renal failure; opiates, barbiturates, decreased perfusion and congestion of liver,
phenothiazines, benzodiazepines, etc. produce reduced glomerular filtration rate and increased
more CNS depression. Pethidine should be tubular reabsorption; dosing rate of drugs may
avoided because its metabolite norpethidine can need reduction.
I

accumulate on repeated dosing and cause (iv) The decompensated heart is more sensitive
SECTION

seizures. The target organ sensitivity may also to digitalis.


be increased. Antihypertensive drugs produce
Thyroid disease The hypothyroid patients are
more postural hypotension in patients with renal
more sensitive to digoxin, morphine and other
insufficiency.
CNS depressants. Hyperthyroid patients are
Certain drugs worsen the existing clinical relatively resistant to inotropic action but more
condition in renal failure, e.g. tetracyclines prone to arrhythmic action of digoxin. The
have an antianabolic effect and accentuate clearance of digoxin is roughly proportional to
uraemia; nonsteroidal antiinflammatory drugs the thyroid function, but this only partially
cause more fluid retention; potentially nephro- accounts for the observed changes in sensitivity.
toxic drugs, e.g. aminoglycosides, tetracyclines Other examples of modification of drug
(except doxycycline), sulfonamides (crystalluria), response by pathological states are:
cyclosporine, vancomycin should be avoided. • Antipyretics lower body temperature only
when it is raised (fever).
Antimicrobials needing dose reduction in • Thiazides induce more marked diuresis in
renal failure edematous patients.
Even in mild failure Only in severe failure • Myocardial infarction patients are more prone
to adrenaline and digitalis induced cardiac
Aminoglycosides Cotrimoxazole
arrhythmias.
Cephalexin Carbenicillin
• Myasthenics are very sensitive to curare.
Ethambutol Cefotaxime
• Schizophrenics tolerate large doses of pheno-
Vancomycin Norfloxacin
thiazines.
Amphotericin B Ciprofloxacin
• Head injury patients are prone to go into
Acyclovir Metronidazole
respiratory failure with normal doses of
morphine.
Thiazide diuretics tend to reduce g.f.r.: are • Atropine, imipramine, furosemide can cause
ineffective in renal failure and can worsen urae- urinary retention in individuals with prostatic
mia. Potassium-sparing diuretics are contraindi- hypertrophy.
cated; can cause hyperkalaemia → cardiac • Hypnotics given to a patient in severe pain
depression. may cause mental confusion and delirium.
Congestive heart failure It can alter drug • Cotrimoxazole produces a much higher inci-
kinetics by— dence of adverse reactions in AIDS patients.
(i) Decreasing drug absorption from g.i.t. due 10. Other drugs Drugs can modify the response
to mucosal edema and splanchnic vasocons- to each other by pharmacokinetic or pharmaco-
triction. dynamic interaction between them. The number
(ii) Modifying volume of distribution which can of reported interactions is already too large to
increase for some drugs due to expansion of remember. However, knowledge of drugs and
extracellular fluid volume or decrease for others patients at particular risk and the mechanism
as a result of decreased tissue perfusion. underlying the interaction can avoid most
Factors Modifying Drug Action 55

iatrogenic disasters. That two drugs interact does • Tolerance occurs to analgesic and euphoric
not necessarily mean that their concurrent use action of morphine but not to its constipating
is contraindicated: many can be used together and miotic actions.
with dose adjustments or some other measures. Cross tolerance It is the development of tole-

CHAPTER
Many drug interactions have already been rance to pharmacologically related drugs, e.g.
considered (see pharmacokinetics and combined alcoholics are relatively tolerant to barbiturates
effect of drugs). Drug interactions relevant to and general anaesthetics. Closer the two drugs
dental practice are given in Ch. 36. are, more complete is the cross tolerance between
them, e.g.
11. Cumulation Any drug will cumulate in the
There is partial cross tolerance between
body if rate of administration is more than rate

3
morphine and barbiturates but complete cross
of elimination. However, slowly eliminated tolerance between morphine and pethidine.
drugs are particularly liable to cause cumulative
Mechanisms responsible for development of
toxicity, e.g. prolonged use of chloroquine causes
tolerance are incompletely understood. How-
retinal damage.
ever, tolerance may be:
Full loading dose of digoxin should not be given (i) Pharmacokinetic/drug disposition tole-
if patient has received it within the past week. rance—the effective concentration of the
drug at the site of action is decreased, mostly
12. Tolerance It refers to the requirement of due to enhancement of drug elimination
higher dose of a drug to produce a given response. on chronic use, e.g. barbiturates, carbama-
Tolerance is a widely occurring adaptive biolo- zepine, amphetamine.
gical phenomenon. Drug tolerance may be: (ii) Pharmacodynamic/cellular tolerance—
Natural The species/individual is inherently drug action is lessened; cells of the target
less sensitive to the drug, e.g. rabbits are tolerant organ become less responsive, e.g. morp-
to atropine, black races are tolerant to mydriatics. hine, barbiturates, nitrates. This may be due
to downregulation of receptors (see p. 41),
Acquired This occurs by repeated use of a drug weakening of response effectuation or other
in an individual who was initially responsive. compensatory homeostatic mechanisms
Body is capable of developing tolerance to most (e.g. antihypertensives).
drugs, but the phenomenon is very easily
Tachyphylaxis (Tachy-fast, phylaxis-protection)
recognized in the case of CNS depressants. An is rapid development of tolerance—doses of a
uninterrupted presence of the drug in the body drug repeated in quick succession result in
favours development of tolerance. However, marked reduction in response. This is usually
significant tolerance does not develop to atropine, seen with indirectly acting drugs, e.g. ephedrine,
digitalis, cocaine, sodium nitroprusside, etc. tyramine, nicotine: they act by releasing
Tolerance need not develop equally to all actions catecholamines in the body, synthesis of which
of a drug; consequently, therapeutic index of a is unable to match the rate of release: stores get
drug may increase or decrease with prolonged depleted. Other mechanisms like slow dissocia-
use, e.g.: tion of the drug from its receptor, internalization
• Tolerance develops to sedative action of chlor- of receptor, homeostatic adaptation, etc. may
promazine but not to its antipsychotic action. also be involved.
• Tolerance occurs to the sedative action of Drug resistance It refers to tolerance of micro-
phenobarbitone but not to its antiepileptic organisms to inhibitory action of antimicrobials,
action. e.g. Staphylococci to penicillin (see Ch. 26).
4
Adverse Drug Effects

Adverse effect is ‘any undesirable or unintended Unpredictable (Type B) reactions These are
consequence of drug administration’. It is a broad based on peculiarities of the patient and not on
term, includes all kinds of noxious effect—trivial, the drug’s known actions; include allergy and
serious or even fatal. idiosyncrasy. They are less common, often non-
All drugs are capable of producing adverse dose related, generally more serious and require
effects and whenever a drug is given a risk is withdrawal of the drug. Some of these reactions
taken. The magnitude of risk has to be considered can be predicted and prevented if their genetic
along with the magnitude of expected therapeutic basis is known and suitable test to characterize
benefit in deciding whether to use or not to use a the individual’s phenotype is performed.
particular drug in a given patient, e.g. even risk of Severity of adverse drug reactions has been
bone marrow depression may be justified in graded as:
treating cancer while mild drowsiness caused by
Minor: No therapy, antidote or prolongation of
an antihistaminic in treating common cold may
hospitalization is required.
be unacceptable.
Adverse effects may develop promptly or only Moderate: Requires change in drug therapy,
after prolonged medication or even after stoppage specific treatment or prolongs hospital stay by at
of the drug. Adverse effects are not rare; an least one day.
incidence of 10–25% has been documented in Severe: Potentially life threatening, causes perma-
different clinical settings. They are more common nent damage or requires intensive medical treat-
with multiple drug therapy and in the elderly. ment.
Adverse effects have been classified in many Lethal: Directly or indirectly contributes to death
ways. One may divide them into: of the patient.
Predictable (Type A) reactions (mechanism Prevention of adverse effects to drugs Adverse
based adverse reactions) these are based on drug effects can be minimized but not altogether
pharmacological properties of the drug, i.e. they eliminated by observing the following practices:
are augmented but qualitatively normal response 1. Avoid all inappropriate use of drugs in the
to the drug; include side effects, toxic effects context of patient’s clinical condition.
and consequences of drug withdrawal. They are 2. Use appropriate dose, route and frequency
more common, dose related and mostly preven- of drug administration based on patient’s
table and reversible. specific variables.
Toxic Effects 57

3. Elicit and take into consideration previous 3. Toxic effects


history of drug reactions.
These are the result of excessive pharmacological
4. Elicit history of allergic diseases and
action of the drug due to overdosage or prolon-
exercise caution (drug allergy is more
ged use. Overdosage may be absolute (acciden-
common in patients with allergic diseases).

CHAPTER
tal, homicidal, suicidal) or relative (i.e. usual dose
5. Rule out possibility of drug interactions
when more than one drug is prescribed. of gentamicin in presence of renal failure). Toxic
6. Adopt correct drug administration effects are predictable and dose related. They
technique (e.g. NSAIDs not to be given on result from functional alteration (high dose of atro-
empty stomach). pine causing delirium) or drug induced tissue
7. Carry out appropriate laboratory damage (hepatic necrosis from paracetamol

4
monitoring (e.g. prothrombin time with overdosage). The CNS, CVS, kidney, liver, lung,
warfarin, serum drug levels with lithium). skin and blood forming organs are most com-
The adverse drug effects may be categorized monly involved in drug toxicity.
into: Toxicity may result from extension of the
therapeutic effect itself, e.g. hypoglycaemia due
1. Side effects to insulin, bleeding due to heparin.
These are unwanted but often unavoidable phar- Another action may be responsible for toxi-
macodynamic effects that occur at therapeutic city, e.g.
doses. They can be predicted from the pharma- Morphine (analgesic) causes respiratory failure
cological profile of a drug and are known to occur in overdosage.
in a given percentage of drug recipients. Reduction Gentamicin (antibacterial) in high dose causes
in dose generally ameliorates the symptoms. vestibular damage.
A side effect may be based on the same action
Poisoning Poisoning may result from large
as the therapeutic effect, e.g. atropine is used in
doses of drugs because ‘it is the dose which
preanaesthetic medication for its antisecretory
distinguishes a drug from a poison’. Poison is a
action—produces dryness of mouth as a side
‘substance which endangers life by severely
effect; antiinflammatory as well as gastric mucosal
affecting one or more vital functions’. Not only
damaging effects of NSAIDs are due to inhibition
drugs but other household and industrial chemi-
of prostaglandin synthesis.
cals, insecticides, etc. are frequently involved in
Side effect may also be based on a different
poisonings. Specific antidotes such as receptor
facet of action, e.g. promethazine produces
sedation which is unrelated to its antiallergic antagonists, chelating agents or specific antibodies
action. An effect may be therapeutic in one context are available for a few poisons. General supportive
but side effect in another context, e.g. codeine used and symptomatic treatment is all that can be done
for cough produces constipation as a side effect, for others, and this is also important for poisons
but the latter is its therapeutic effect in traveller’s which have a selective antagonist.
diarrhoea. These measures are:
1. Resuscitation and maintenance of vital
2. Secondary effects
functions
These are indirect consequences of a primary a. Ensure patent airway, adequate ventilation,
action of the drug, e.g. suppression of bacterial give artificial respiration/100% oxygen
flora by tetracyclines paves the way for superin- inhalation as needed.
fections; corticosteroids weaken host defence b. Maintain blood pressure and heart beat by
mechanisms so that latent tuberculosis gets fluid and crystalloid infusion, pressor
activated. agents, cardiac stimulants, etc, as needed.
58 Adverse Drug Effects
c. Maintain body temperature. • One tablet of aspirin may cause gastric
d. Maintain blood sugar level by dextrose bleeding.
infusion, especially in patients with altered
sensorium. 5. Idiosyncrasy
2. Termination of exposure (decontamination) by It is genetically determined abnormal reactivity
I

removing the patient to fresh air (for inhaled to a chemical. Certain adverse effects of some drugs
SECTION

poisons), washing the skin and eyes (for poisons are largely restricted to individuals with a
entering from the surface), induction of emesis particular genotype (see p. 52). In addition, certain
with syrup ipecac or gastric lavage (for ingested uncharacteristic or bizarre drug effects due to
poisons). Emesis should not be attempted in peculiarities of an individual (for which no
comatose or haemodynamically unstable patient. definite genotype has been described) are included
among idiosyncratic reactions, e.g.:
3. Prevention of absorption of ingested poisons • Barbiturates cause excitement and mental
A suspension of 20–40 g (1g/kg) of activated confusion in some individuals.
charcoal, which has large surface area and can • Chloramphenicol produces non-dose-related
adsorb many chemicals, should be administered serious aplastic anaemia in rare individuals.
in 200 ml of water. However, strong acids and
alkalies, metallic salts, iodine, cyanide, caustics, 6. Drug allergy
alcohol, hydrocarbons and other organic solvents It is an immunologically mediated reaction
are not adsorbed by charcoal. producing stereotype symptoms which are unre-
4. Hastening elimination of the poison by lated to the pharmacodynamic profile of the drug,
inducing diuresis (furosemide, mannitol) or and can occur even with much smaller doses.
altering urinary pH (alkalinization for acidic This is also called drug hypersensitivity; but does
drugs, e.g. barbiturates). However, excretion of not refer to increased response which is called
many poisons is not enhanced by forced diuresis supersensitivity.
Allergic reactions occur only in a small
and it is generally not employed now. Haemo-
proportion of the population exposed to the drug
dialysis and haemoperfusion (passage of blood
and cannot be produced in other individuals at
through a column of charcoal or adsorbant resin)
any dose. Prior sensitization is needed and a
are more efficacious procedures. latent period of at least 1–2 weeks is required after
the first exposure. The drug or its metabolite acts
4. Intolerance as antigen (AG) or more commonly hapten
(incomplete antigen: drugs have small molecules
It is the appearance of characteristic toxic effects
which become antigenic only after binding with
of a drug in an individual at therapeutic doses. It
an endogenous protein) and induce production
is the converse of tolerance and indicates a low
of antibody (AB)/sensitized lymphocytes. Pre-
threshold of the individual to the action of a drug. sence of AB to a drug is not necessarily followed
These are individuals who fall on the extreme left by allergy to it. Chemically related drugs often
side of the Gaussian frequency distribution curve show cross sensitivity. One drug can produce
for sensitivity to the drug. Examples are: different types of allergic reactions in different
• A single dose of triflupromazine induces individuals, while widely different drugs can
muscular dystonias in some individuals, produce the same reaction. The course of drug
especially children. allergy is variable; an individual previously
• Only few doses of carbamazepine may cause sensitive to a drug may subsequently tolerate it
ataxia in some people. without a reaction and vice versa.
Drug Allergy 59

Mechanism and Types of Allergic Reactions generate an inflammatory response, e.g. contact
dermatitis, some rashes, fever, photosensitization.
A. Humoral The reaction generally takes > 12 hours to develop.
Type-I (anaphylactic) reactions Reaginic anti- Dentists may develop contact dermatitis by repeated

CHAPTER
bodies (IgE) are produced which get fixed to the handling of local anaesthetics; though this is now
mast cells. On exposure to the drug, AG: AB rare due to replacement of procaine by lidocaine
reaction takes place on the mast cell surface (see and use of surgical gloves.
Fig. 7.2) releasing mediators like histamine, 5-HT,
leukotrienes, especially LT-C4 and D4, prostaglan- Treatment of Drug Allergy
dins, PAF, etc. resulting in urticaria, itching, The offending drug must be immediately stopped.
Most mild reactions (like skin rashes) subside by

4
angioedema, bronchospasm, rhinitis or anaphy-
lactic shock. The manifestations occur quickly themselves and do not require specific treatment.
after challenge and are called immediate hyper- Antihistamines (H1) are beneficial in some type I
sensitivity. This is the only type of allergic drug reactions (urticaria, rhinitis, swelling of lips, etc.)
reaction that the dentist may have to treat himself. and some skin rashes. In case of anaphylactic
shock or angioedema of larynx, the resuscitation
Type-II (cytolytic) reactions Drug + component council of UK has recommended the following
of a specific tissue cell act as AG. The resulting measures:
antibodies (IgG, IgM) bind to the target cells; on • Put the patient in reclining position, admini-
reexposure AG: AB reaction takes place on the ster oxygen at high flow rate and perform
surface of these cells, complement is activated and cardiopulmonary resuscitation if required.
cytolysis occurs, e.g. thrombocytopenia, agranulo- • Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000
cytosis, aplastic anaemia, haemolysis, organ solution) i.m.; repeat every 5–10 min in case
damage (liver, kidney, muscle), systemic lupus the patient does not improve or improvement
erythematosus. is transient. This is the only life-saving
measure. Adrenaline should not be injected
Type-III (retarded, Arthus) reactions These are
i.v. (can itself be fatal) unless shock is
mediated by circulating antibodies (predominan-
immediately life threatening. If adrenaline is
tly IgG, mopping AB). AG: AB complexes bind
to be injected i.v., it should be diluted to
complement and precipitate on vascular endo- 1:10,000 or 1:100,000 and infused slowly with
thelium giving rise to a destructive inflammatory constant monitoring.
response. Manifestations are rashes, serum sick- • Administer a H1 antihistaminic (chlorpheni-
ness (fever, arthralgia, lymphadenopathy), poly- ramine 10–20 mg) i.m./slow i.v. It may have
arteritis nodosa, Stevens-Johnson syndrome adjuvant value.
(erythema multiforme, arthritis, nephritis, myo- • Intravenous glucocorticoid (hydrocortisone
carditis, mental symptoms). The reaction usually sod. succinate 100–200 mg) should be added
subsides in 1–2 weeks. in severe/recurrent cases. It acts slowly, but
is specially valuable for prolonged reactions
B. Cell mediated and in asthmatics.
Type-IV (delayed hypersensitivity) reactions Adrenaline followed by a short course of gluco-
These are mediated through production of corticoids is indicated for bronchospasm atten-
sensitized T-lymphocytes carrying receptors for ding drug hypersensitivity. Glucocorticoids are
the AG. On contact with AG, these T cells produce the only drugs effective in type II, type III and type
lymphokines which attract granulocytes and IV reactions.
60 Adverse Drug Effects

Drugs frequently causing allergic reactions 8. Drug dependence


Drugs capable of altering mood and feelings are
Penicillins Local anaesthetics
liable to repetitive use to derive euphoria, with-
Cephalosporins Salicylates
Sulfonamides Carbamazepine drawal from reality, social adjustment, etc. Drug
I

Tetracyclines Allopurinol dependence is a state in which use of drugs for


personal satisfaction is accorded a higher priority
SECTION

Quinolones ACE inhibitors


Antitubercular drugs Methyldopa than other basic needs, often in the face of known
Phenothiazines Hydralazine risks to health.
There is a lot of confusion in terminology and
Skin tests (intradermal, patch) or intranasal definitions; the following may serve to describe
tests may forewarn in case of Type I hypersen- different aspects of the problem.
sitivity but not in case of other types. However,
these tests are not entirely reliable—false positive Psychological dependence It is said to have
and false negative results are not rare. developed when the individual believes that
optimal state of wellbeing is achieved only
7. Photosensitivity through the actions of the drug. It may start as
It is a cutaneous reaction resulting from drug liking for the drug effects and may progress to
induced sensitization of the skin to UV radiation. compulsive drug use in some individuals. The
The reactions are of two types: intensity of psychological dependence may vary
from desire to craving. Obviously, certain degree
(a) Phototoxic Drug or its metabolite accumu-
of psychological dependence accompanies all
lates in the skin, absorbs light and undergoes a
patterns of self-medication.
photochemical reaction followed by a photobio-
logical reaction resulting in local tissue damage Reinforcement is the ability of the drug to produce
(sunburn like), i.e. erythema, edema, blistering effects that make the user wish to take it again.
followed by hyperpigmentation and desquama- Certain drugs (opioids, cocaine) are strong
tion. The shorter wavelengths (290–320 nm, UV- reinforcers, while others (benzodiazepines) are
B) are responsible. Drugs involved in acute weak reinforcers. Faster the drug acts, more
phototoxic reactions are tetracyclines (especially reinforcing it is.
demeclocycline) and tar products. Drugs causing
chronic and low-grade sensitization are nalidixic Physical dependence It is an altered physio-
acid, fluoroquinolones, sulfones, sulfonamides, logical state produced by repeated administra-
phenothiazines, thiazides, amiodarone. This type tion of a drug which necessitates the continued
of reaction is more common than photoallergic presence of the drug to maintain physiological
reaction. equilibrium. Discontinuation of the drug results
(b) Photoallergic Drug or its metabolite induces in a characteristic withdrawal (abstinence) syndrome.
a cell-mediated immune response which on Since the essence of the process is adaptation of
exposure to light of longer wavelengths (320–400 the nervous system to function normally in the
nm, UV-A) produces a papular or eczematous presence of the drug, it has been called
contact dermatitis like picture. Rarely antibodies ‘neuroadaptation’.
mediate photoallergy and the reaction takes the Drugs producing physical dependence are—
form of immediate flare and wheal on exposure opioids, barbiturates and other depressants inc-
to sun. Drugs involved are sulfonamides, sul- luding alcohol and benzodiazepines. Stimulant
fonylureas, griseofulvin, chloroquine, chlorpro- drugs, e.g. amphetamines, cocaine produce little
mazine. or no physical dependence.
Teratogenicity 61

Drug abuse Refers to use of a drug by self-medi- (ii) Severe hypertension and sympathetic over-
cation in a manner and amount that deviates from activity may occur shortly after disconti-
the approved medical and social patterns in a nuing clonidine.
given culture at a given time. The term conveys (iii) Worsening of angina pectoris or myocardial
infarction may result from stoppage of β

CHAPTER
social disapproval of the manner and purpose of
drug use. For regulatory agencies, drug abuse refers blockers.
to any use of an ilicit drug. (iv) Frequency of seizures may increase on
sudden withdrawal of an antiepileptic.
Drug addiction It is a pattern of compulsive These manifestations are also due to adaptive
drug use characterized by overwhelming invol- changes and can be minimized by gradual
vement with the use of a drug. Procuring the drug withdrawal.

4
and using it takes precedence over other activities.
Even after withdrawal most addicts tend to 10. Teratogenicity
relapse. Physical dependence, though a strong It refers to the capacity of a drug to cause foetal
impetus for continued drug use, is not an essential abnormalities when administered to the pregnant
feature of addiction. Amphetamines, cocaine, mother. The placenta does not strictly constitute
cannabis, LSD are drugs which produce a barrier and any drug can cross it to a greater or
addiction but little/no physical dependence. On lesser extent. The embryo is one of the most
the other hand, drugs like nalorphine produce dynamic biological systems, and in contrast to
physical dependence without imparting addic- adults, drug effects on embryo are often irrever-
tion in the sense that there is little drug seeking sible. The thalidomide disaster (1958–61) resul-
behaviour. ting in thousands of babies born with phocomelia
(seal-like limbs) and other defects focused
Drug habituation It denotes less intensive attention to this type of adverse effect.
involvement with the drug, so that its withdrawal
produces only mild discomfort. Consumption of Drugs can affect the foetus at three stages—
tea, coffee, tobacco, social drinking are regarded (i) Fertilization and implantation—conception to
habituating, physical dependence is absent. 17 days—failure of pregnancy which often
Basically, habituation and addiction imply goes unnoticed.
different degrees of psychological dependence (ii) Organogenesis—18 to 55 days of gestation—
and it may be difficult to draw a clearcut line of most vulnerable period, deformities are pro-
distinction between the two. Therefore, it is better duced.
to avoid using these terms in describing drug (iii) Growth and development—56 days onwards
dependence and related conditions. — developmental and functional abnorma-
lities can occur, e.g. ACE inhibitors can cause
9. Drug withdrawal reactions hypoplasia of organs, especially lungs and
kidneys; NSAIDs may induce premature
Apart from drugs that are usually recognized as closure of ductus arteriosus.
producing dependence, sudden interruption of The type of malformation depends on the drug as
therapy with certain other drugs also results in well as stage of exposure to the teratogen. The
adverse consequences, mostly in the form of proven human teratogens are listed in the box.
worsening of the clinical condition for which the Other drugs may be low grade teratogens and
drug was being used, e.g.: it is almost impossible to declare a drug to be
(i) Acute adrenal insufficiency may be precipi- absolutely safe during pregnancy. The US-FDA
tated by abrupt cessation of corticosteroid has graded the documentation of risk for causing
therapy. birth defects into five categories (see box).
62 Adverse Drug Effects

Human teratogenic drugs

Drug Abnormality
Thalidomide phocomelia, multiple defects
Anticancer drugs cleft palate, hydrocephalus, multiple defects,
I

(methotrexate) foetal death


SECTION

Androgens virilization; limb, esophageal, cardiac defects


Progestins virilization of female foetus
Stilboestrol vaginal carcinoma in teenage female offspring
Tetracyclines discoloured and deformed teeth, retarded bone growth
Warfarin depressed nose; eye and hand defects, growth retardation
Phenytoin hypoplastic phalanges, cleft lip/palate, microcephaly
Phenobarbitone various malformations
Carbamazepine neural tube defects, other abnormalities
Valproate sod. spina bifida and other neural tube defects
Alcohol low IQ baby, growth retardation, foetal alcohol syndrome
ACE inhibitors hypoplasia of organs, growth retardation, foetal loss
Lithium foetal goiter, cardiac and other abnormalities
Antithyroid drugs foetal goiter and hypothyroidism
Indomethacin/aspirin premature closure of ductus arteriosus
Isotretinoin craniofacial, heart and CNS defects

Risk category of drugs during pregnancy

Category Examples
A Adequate studies in pregnant women have failed to demonstrate Inj. Mag. sulfate,
a risk to the foetus thyroxine
B Adequate human studies are lacking, but animal studies have failed to Penicillin V,
demonstrate a risk to the foetus amoxicillin,
or cefactor,
Adequate studies in pregnant women have failed to demonstrate a risk erythromycin,
to the foetus, but animal studies have shown an adverse effect on the paracetamol,
foetus lignocaine
C No adequate studies in pregnant women and animal studies are lacking or Morphine,
have shown and adverse effect on foetus, but potential benefit may warrant codeine,
use of the drug in pregnant women despite potential risk atropine,
corticosteroids,
adrenaline,
thiopentone,
bupivacaine
D There is evidence of human foetal risk, but the potential benefits from use Aspirin,
of the drug may be acceptable despite the potential risk phenytoin,
carbamazepine,
valproate,
lorazepam
X Studies in animals or humans have demonstrated foetal abnormalities, and Estrogens,
potential risk clearly outweighs possible benefit isotretinoin,
ergometrine
Drug-induced Diseases 63

It is, therefore, wise to avoid all drugs during to develop. Drugs implicated in these adverse
pregnancy unless compelling reasons exist for effects are—anticancer drugs, radioisotopes,
their use regardless of the assigned pregnancy estrogens, tobacco.
category, or presumed safety. Only emergency
dental treatment should be undertaken during

CHAPTER
12. Drug-induced diseases
the most vulnerable period of organogenesis.
These are also called iatrogenic (physician-indu-
11. Carcinogenicity and mutagenicity ced) diseases, and are functional disturbances
(disease) caused by drugs which persist even after
It refers to capacity of a drug to cause cancer and the offending drug has been withdrawn and
genetic defects respectively. Usually, oxidation largely eliminated, e.g.:

4
of the drug results in the production of reactive Peptic ulcer by salicylates and corticosteroids.
intermediates which affect genes and may cause Parkinsonism by phenothiazines and other
structural changes in the chromosomes. Chemi- antipsychotics.
cal carcinogenesis is a well-recognized pheno- Hepatitis by isoniazid.
menon but generally takes several (10–40) years DLE by hydralazine.
5
Drugs Acting on Autonomic
Nervous System
General Considerations,
Cholinergic and Anticholinergic Drugs

ORGANIZATION OF AUTONOMIC parasympathetic innervation. The general layout


NERVOUS SYSTEM of ANS is depicted in Fig. 5.1 and the important
differences between its two subdivisions are given
The autonomic nervous system (ANS) functions
in Table 5.1.
largely below the level of consciousness and
The enteric plexus of nerves receives inputs
controls visceral functions. Like the somatic
from both sympathetic and parasympathetic
nervous system, the ANS consists of afferents,
divisions, but in addition functions indepen-
centre and efferents.
dently to integrate bowel movements as well as
Autonomic afferents are carried in the visceral
regulate secretion and absorption. As such, it has
nerves, most of which are mixed nerves. They
also been labelled as a distinct ‘enteric nervous
mediate visceral pain and visceral reflexes
system’.
(cardiovascular, respiratory, vasomotor, etc.).
The highest seat regulating autonomic func-
tions is in hypothalamus—posterior and lateral NEUROHUMORAL TRANSMISSION
nuclei are primarily sympathetic while anterior Neurohumoral transmission implies that nerves
and medial nuclei are primarily parasympathetic. transmit their message across synapses and
Many autonomic centres (pupillary, vagal, neuroeffector junctions by the release of humoral
respiratory, etc.) are located in the mid-brain and (chemical) messengers.
the medulla in relation to the cranial nerves. The
lateral column in the thoracic spinal cord contains
cells which give rise to the sympathetic outflow. Steps in neurohumoral transmission
The motor limb of the ANS is anatomically I. Impulse conduction The resting transmem-
divided into sympathetic and parasympathetic. brane potential (70 mV negative inside) is
In general, these subdivisions are functionally established by high K+ permeability of axonal
antagonistic and most organs receive both membrane and high axoplasmic concentration of
sympathetic and parasympathetic innervation. this ion coupled with low Na+ permeability and its
The level of activity of the innervated organ at a active extrusion from the neurone. Stimulation or
given moment is the algebraic sum of sympathetic arrival of an electrical impulse causes a sudden
and parasympathetic tone. However, most blood increase in Na+ conductance → depolarization
vessels, spleen, sweat glands and hair follicles and overshoot (reverse polarization: inside
receive only sympathetic, while ciliary muscle, becoming 20 mV positive) occurs; K+ ions then
gastric and pancreatic glands receive only move out in the direction of their concentration
68 Drugs Acting on ANS
II
SECTION

Fig. 5.1: The general outlay of autonomic nervous system. The transmitter released and the
primary postjunctional receptor subtype is shown at each synapse/neuroeffector junction
N = Nicotinic, M = Muscarinic, α = α adrenergic, β = β adrenergic

gradient and repolarization is achieved. Ionic Ranvier in myelinated fibre) and the AP is
distribution is normalized during the refractory propagated without decrement.
period by the activation of Na+ K+ pump. The action
potential (AP) thus generated sets up local circuit II. Transmitter release The transmitter (exci-
currents which activate ionic channels at the next tatory or inhibitory) is stored in prejunctional
excitable part of the membrane (next node of nerve endings within ‘synaptic vesicles’ (Fig. 5.2).

Table 5.1: Differences between sympathetic and parasympathetic divisions of the autonomic nervous system

Sympathetic Parasympathetic
1. Origin Dorso-lumbar (T1 to L2 or L3) Cranio-sacral (III, VII, IX, X; S2-S4)
2. Distribution Wide Limited to head, neck and trunk
3. Ganglia Away from the organs supplied On or close to the organ supplied
4. Postgang. fibre Long Short
5. Pre: post ganglionic 1: 20 to 1: 100 1: 1 to 1: 2 (except in enteric
fibre ratio plexuses)
6. Transmitter Noradrenaline (major) Acetylcholine
(neuroeffector) Acetylcholine (minor)
7. Stability of transmitter NA stable, diffuses for wider actions ACh—rapidly destroyed locally
8. Important function Tackling stress and emergency Assimilation of food, conservation of energy
ANS: General Considerations 69

Fig. 5.2: Diagrammatic representation of steps in excitatory and inhibitory neurohumoral transmission:

CHAPTER
EPSP = Excitatory postsynaptic potential; IPSP = Inhibitory postsynaptic potential

Nerve impulse promotes fusion of vesicular and causes depolarization followed by K+ efflux. These
axonal membranes, through Ca2+ entry which ionic movements are passive as the flow is down
fluidizes membranes. All contents of the vesicle the concentration gradients.
(transmitter, enzymes and other proteins) are
IPSP Increase in permeability to smaller ions,
extruded (exocytosis) in the junctional cleft.
i.e. K+ and Cl¯ (hydrated K+ ion is smaller than

5
The release process can be modulated by the
transmitter itself and by other agents through hydrated Na+ ion) only, so that K+ moves out and
activation of specific receptors located on the pre- Cl¯ moves in (in the direction of their concen-
junctional membrane, e.g. noradrenaline (NA) tration gradients) resulting in hyperpolarization.
release is inhibited by NA (α2 receptors), dopamine, In addition, a trophic influence on junctional
adenosine, prostaglandins and enkephalins while morphology and functional status is exerted by
isoprenaline (β2 receptors) and angiotensin (AT1 the background basal release of the transmitter.
receptor) increase NA release. Similarly, α2 and IV. Postjunctional activity A suprathreshold
muscarinic agonists inhibit acetylcholine (ACh) EPSP generates a propagated postjunctional AP
release at autonomic neuroeffector sites (but not in which results in nerve impulse (in neurone),
ganglia and skeletal muscles). contraction (in muscle) or secretion (in gland).
III. Transmitter action on postjunctional mem- An IPSP stabilizes the postjunctional membrane
brane The released transmitter combines with and resists depolarizing stimuli.
specific receptors on the postjunctional membrane V. Termination of transmitter action Following
and depending on its nature induces an
its combination with the receptor, the transmitter
excitatory postsynaptic potential (EPSP) or an
is either locally degraded (e.g. ACh) or is taken
inhibitory postsynaptic potential (IPSP).
back into the prejunctional neurone by active
EPSP Increase in permeability to all cations → uptake as well as diffuses away (e.g. NA, GABA).
Na+ or Ca2+ influx (through fast or slow channels) Rate of termination of transmitter action governs
70 Drugs Acting on ANS
the rate at which responses can be transmitted
across a junction (1 to 1000/sec).

Cotransmission
It has now become apparent that the classical ‘one
neurone—one transmitter’ model is an over
simplification. Many peripheral and central
neurones have been shown to release more than
one active substance when stimulated. In the ANS,
besides the primary transmitters ACh and NA,
neurones have been found to elaborate purines
(ATP, adenosine), peptides (vasoactive intestinal
peptide or VIP, neuropeptide-Y or NPY, substance
P, enkephalins, somatostatin, etc.), nitric oxide
and prostaglandins as cotransmitters. The
cotransmitter is stored in the same neurone but in
distinct synaptic vesicles or locations (Fig. 5.3).
However, ATP is stored with NA in the same
vesicle. On being released by the nerve impulse, Fig. 5.3: Cotransmission
II

The cotransmitter is stored in the prejunctional nerve terminal


the cotransmitter may serve to regulate the pre- along with the primary transmitter, but in separate vesicles
synaptic release of the primary transmitter and/ (in some cases in the same vesicle itself). Nerve impulse
SECTION

or postsynaptic sensitivity to it (neuromodulator releases both the transmitters concurrently. Acting on its
role). The cotransmitter may also serve as an alter- own receptors, the cotransmitter modifies responsiveness
of the effector to the primary transmitter or substitutes for it.
native transmitter in its own right and/or exert a Cotransmitter may also act on prejunctional receptors and
trophic influence on the synaptic structures. modulate release of the transmitters

CHOLINERGIC TRANSMISSION
Synthesis, storage and destruction of ACh
Acetylcholine (ACh) is a major neurohumoral
transmitter at autonomic as well as somatic sites The cholinergic neuronal mechanisms are sum-
(Table 5.2). marized in Fig. 5.4.

Table 5.2: Sites of cholinergic transmission and type of receptor involved

Site Type of receptor Selective agonist Selective antagonist


1. a. All postganglionic parasymp. ⎫
b. Few postganglionic symp (sweat ⎬ Muscarinic Muscarine Atropine
glands, some blood vessels) ⎭

2. a. Ganglia (both symp. and ⎫


parasymp). ⎬ Nicotinic (NN) DMPP* Hexamethonium
b. Adrenal medulla ⎭
3. Skeletal muscles Nicotinic (NM) PTMA** d-tubocurarine
4. CNS (cortex, basal ganglia, spinal Muscarinic Muscarine/ Atropine
cord and other sites) Oxotremorine
Nicotinic Carbachol d-tubocurarine
* DMPP—Dimethyl phenyl piperazinium
** PTMA—Phenyl trimethyl ammonium
Cholinergic Transmission 71

present in the axoplasm. Most of the ACh is stored


in ionic solution within small synaptic vesicles,
but some free ACh is also present in the cytoplasm
of cholinergic terminals.
Release of ACh from nerve terminals occurs
in small quanta—amount contained in individual
vesicles is extruded by exocytosis. In response
to a nerve AP synchronous release of multiple
quanta triggers postjunctional events. Imme-
diately after release, ACh is hydrolyzed by the
enzyme cholinesterase and choline is recycled.
A specific (Acetylcholinesterase—AChE or true
cholinesterase) and a nonspecific (Butyrylcholi-
nesterase—BuChE or pseudocholinesterase) type
of enzyme occurs in the body.
Acetylcholine
Cholinesterase

Choline + Acetate

CHAPTER
Fig. 5.4: Cholinergic neuronal mechanisms Acetylcholinesterase is strategically located at
Minus sign indicates inhibition while bold arrow indicates all cholinergic sites and serves to hydrolyze ACh
active transport.
Ch = Choline, ACh = Acetylcholine, ChA = Choline acetylase,
instantaneously (in μS). Pseudocholinesterase is
AChE = Acetylcholinesterase, Anti-ChE = Anticholinesterase, a relatively nonspecific esterase present in plasma,
M = Muscarinic receptor, N = Nicotinic receptor, HC3 = liver and some other tissues; hydrolyzes ACh
Hemicholinium, BoT = Botulinus toxin, Vsa = Vesamicol slowly and probably serves to metabolize ingested
esters.

5
Acetylcholine is synthesized locally in the choli-
nergic nerve endings by the following pathway— Cholinoceptors
ATP + Acetate + CoEn-A
Two classes of receptors for ACh are recognized
—muscarinic and nicotinic; the former is a G pro-
Acetate activating reaction tein coupled receptor, while the latter is a ligand
Acetyl CoEn-A gated cation channel.
CHOLINE
Choline acetylase
Muscarinic These receptors are selectively
stimulated by muscarine and selectively blocked
ACETYLCHOLINE + CoEn-A
by atropine. They are located primarily on
CH3 O autonomic effector cells in heart, blood vessels,
| || Cl¯ eye, smooth muscles and glands of gastrointes-
CH3—N+—CH2—CH2—O—C—CH 3
tinal, respiratory and urinary tracts, sweat glands,
|
CH3 etc. and in the CNS. Subsidiary muscarinic
receptors are also present in autonomic ganglia
Acetylcholine chloride where they appear to play a modulatory role by
inducing a long-lasting late EPSP.
Choline is actively taken up by the axonal
membrane and acetylated with the help of ATP Subtypes of muscarinic receptor The muscarinic
and coenzyme-A by the enzyme cholineacetylase receptors have been divided into 5 subtypes M1,
72 Drugs Acting on ANS
M2, M3, M4 and M5. Out of these, the first 3 have cholinergic receptors (cholinergic agonists) or by
been functionally characterized. increasing availability of ACh at these sites
M1: The M1 is primarily a neuronal receptor located on (anticholinesterases).
ganglion cells and central neurones: especially in cortex,
hippocampus and corpus striatum. It plays a major role
in mediating gastric secretion and relaxation of lower ACTIONS (of ACh as prototype)
esophageal sphincter (LES) caused by vagal stimulation.
Depending on the type of receptor through which
M2: Cardiac muscarinic receptors are predominantly M2
and mediate vagal bradycardia. Autoreceptors on
it is mediated the peripheral actions of ACh may
cholinergic nerve endings are also of M2 subtype. be classified as muscarinic or nicotinic. The
M3: Visceral smooth muscle contraction and glandular central actions are not so classifiable and are
secretions are elicited through M3 receptors, which also described separately.
mediate vasodilatation through EDRF release. Together
the M2 and M3 receptors mediate most of the well-recognized
muscarinic actions including contraction of LES.
A. Muscarinic actions

Nicotinic These receptors are selectively acti- 1. Heart ACh hyperpolarizes the SA nodal cells
vated by nicotine and blocked by tubocurarine or and decreases their rate of diastolic depolari-
hexamethonium. These are rosette-like pentameric zation. As a result, rate of impulse generation is
structures (see Fig. 3.3) which enclose a ligand reduced—bradycardia or even cardiac arrest may
gated cation channel: their activation causes occur.
opening of the channel and rapid flow of cations At the A-V node and His-Purkinje fibres
II

resulting in depolarization and an action poten- refractory period (RP) is increased and conduction
tial. On the basis of location and selective agonists is slowed: P-R interval increases and partial to
SECTION

and antagonists, two subtypes NM and NN are complete A-V block may be produced. The force of
recognized. atrial contraction is markedly reduced and RP of atrial
fibres is abbreviated. Due to nonuniform vagal
NM: These are present at skeletal muscle endplate: are
selectively stimulated by phenyl trimethyl ammonium innervation, the intensity of effect on RP and
(PTMA) and blocked by tubocurarine. They mediate skeletal conduction of different atrial fibres varies—
muscle contraction. inducing inhomogeneity and predisposing to
NN: These are present on ganglionic cells (sympathetic as atrial fibrillation or flutter.
well as parasympathetic), adrenal medullary cells, in spinal Ventricular contractility is also decreased but
cord and certain areas of brain. They are selectively stimu- the effect is not marked.
lated by dimethyl phenyl piperazinium (DMPP), blocked
by hexamethonium, and constitute the primary pathway 2. Blood vessels All blood vessels are dilated,
of transmission in ganglia.
though only few (skin of face, neck) receive
cholinergic innervation. Thus, fall in BP and
CHOLINERGIC DRUGS flushing, especially in the blush area occurs.
(Cholinomimetic, Parasympathomimetic)
Muscarinic receptors (M3) are present on vascular
These are drugs which produce actions similar endothelial cells: vasodilatation is primarily
to that of ACh, either by directly interacting with mediated through the release of an endothelium-
dependent relaxing factor (EDRF) which is nitric
CHOLINERGIC AGONISTS oxide (NO).
Choline esters Alkaloids Stimulation of cholinergic nerves to the penis
Acetylcholine Muscarine causes erection by releasing NO and dilating
Methacholine Pilocarpine cavernosal vessels through M3 receptors.
Carbachol Arecoline However, this response is minimal with injected
Bethanechol cholinomimetic drugs.
Cholinergic Drugs 73

3. Smooth muscle Smooth muscle in most The important features of other cholinesters
organs is contracted. Tone and peristalsis in the are summarized in Table 5.3.
gastrointestinal tract is increased and sphincters
relax → abdominal cramps and evacuation of Table 5.3: Properties of choline esters
bowel.
Choline ester Hydrolysis by Actions Selective
Peristalsis in ureter is increased. The detrusor
AChE BuChE Musc. Nico. action on
muscle contracts while the bladder trigone and
sphincter relaxes → voiding of bladder. Acetylcholine ++ + + + Nonselective
Bronchial muscles constrict, asthmatics are Methacholine + – + ± CVS
highly sensitive → dyspnoea, precipitation of an Carbachol – – + + g.i.t., bladder
attack of bronchial asthma. Bethanechol – – + – g.i.t., bladder
4. Glands Secretion from all parasympathe-
tically innervated glands is increased—sweating,
salivation, lacrimation, tracheobronchial and Uses Choline esters are rarely if ever used
gastric secretion. The effect on pancreatic and clinically. ACh is not used because of evanescent
intestinal glands is not marked. Secretion of milk and nonselective action. Bethanechol has been used
and bile is not affected. in postoperative/postpartum nonobstructive
urinary retention, neurogenic bladder, congenital
5. Eye Contraction of circular muscle of iris → megacolon and gastroesophageal reflux.

CHAPTER
miosis.
Contraction of ciliary muscle → spasm of accom-
modation, increased outflow facility, reduction CHOLINOMIMETIC ALKALOIDS
in intraocular tension (especially in glaucomatous Pilocarpine It is obtained from the leaves of
patients).
Pilocarpus microphyllus and other species. It has
B. Nicotinic actions prominent muscarinic actions but stimulates

5
1. Autonomic ganglia Both sympathetic and ganglia as well—mainly through ganglionic mus-
parasympathetic ganglia are stimulated. This carinic receptors.
effect is manifested at higher doses. High dose of Pilocarpine causes marked sweating, sali-
ACh given after atropine causes tachycardia and vation and increase in other secretions. The cardio-
rise in BP. vascular effects of pilocarpine are complex.
Applied to the eye, it penetrates cornea and
2. Skeletal muscles Iontophoretic application
promptly causes miosis, ciliary muscle contrac-
of ACh to muscle endplate causes contraction of
tion and fall in intraocular tension lasting 4–8
the fibre. Intraarterial injection of high dose can
hours. Pilocarpine is used in the eye as 0.5–4%
cause twitching and fasciculations, but i.v.
drops, primarily in open angle glaucoma. It has
injection is generally without any effect (due to
rapid hydrolysis of ACh). also been used orally for xerostomia, but is not
available commercially for this purpose.
C. CNS actions Muscarine It occurs in poisonous mushrooms Amanita
muscaria and Inocybe species and has only muscarinic
ACh injected i.v. does not penetrate blood-brain actions. It is not used therapeutically but is of toxicological
barrier and no central effects are seen. However, importance in mushroom poisoning.
direct injection into the brain, or other cholinergic Arecoline It is found in betel nut Areca catechu. It has
drugs which enter brain, produce a complex muscarinic as well as nicotinic actions including prominent
pattern of stimulation followed by depression. CNS effects.
74 Drugs Acting on ANS
ANTICHOLINESTERASES carbamylated enzyme (reversible inhibitors)
reacts slowly and the phosphorylated enzyme
Anticholinesterases (anti-ChEs) are agents which
(irreversible inhibitors) reacts extremely slowly
inhibit ChE, protect ACh from hydrolysis—
or not at all. The half-life of reactivation of
produce cholinergic effects in vivo and potentiate
ACh both in vivo and in vitro. Some anti- ChEs have carbamylated enzyme (about 30 min) is less than
additional direct action on cholinergic receptors. that of synthesis of fresh enzyme protein, while
that of phosphorylated enzyme is more than the
Reversible regeneration time. Thus, apparently reversible and
Carbamates Acridine irreversible enzyme inhibition is obtained, though
Physostigmine (Eserine) Tacrine the basic pattern of inhibitor-enzyme interaction
Neostigmine remains the same.
Pyridostigmine
Edrophonium Pharmacological actions
Rivastigmine, Donepezil The actions of anti-ChEs are qualitatively similar
to that of directly acting cholinoceptor stimulants.
Irreversible However, relative intensity of action on
Organophosphates Carbamates muscarinic, ganglionic, skeletal muscle and CNS
Dyflos (DFP) Carbaryl* (SEVIN) sites varies among the different agents.
Echothiophate Propoxur* (BAYGON) Lipid-soluble agents (physostigmine and
Malathion* *Insecticides organophosphates) have more marked musca-
II

Diazinon* (TIK-20) £
Nerve gases for
£ £ £ rinic and CNS effects; stimulate ganglia but action
Tabun , Sarin , Soman chemical warfare
SECTION

on skeletal muscles is less prominent.


Anti-ChEs are either esters of carbamic acid or Lipid-insoluble agents (neostigmine and other
derivatives of phosphoric acid. quaternary ammonium compounds) produce
O O more marked effect on the skeletal muscles (direct
|| R2 R2 || action on muscle endplate cholinoceptors as
R1—O—C—N P—R1 well), stimulate ganglia, but muscarinic effects
R3 R3 are less prominent. They do not penetrate CNS
Carbamates Organophosphates and have no central effects.
After treatment with anti-ChEs, the ACh
In carbamates R1 may have a nonpolar tertiary released by a single nerve impulse in skeletal
amino N, e.g. in physostigmine, rendering the muscle is not immediately destroyed—rebinds to
compound lipid soluble. In others, e.g. neostig- the same receptor and diffuses to act on neigh-
mine, R1 has a quaternary N+—rendering it lipid bouring receptors as well as on prejunctional
insoluble. All organophosphates are highly lipid fibres → repetitive firing → twitching and
soluble except echothiophate which is water fasciculations. Force of contraction in partially
soluble. curarized and myasthenic muscles is increased.
The anti-ChEs react with the enzyme essen- Higher doses cause persistent depolarization of
tially in the same way as ACh. The carbamates endplates resulting in blockade of neuromuscular
and phosphates respectively carbamylate and transmission → weakness and paralysis.
phosphorylate the esteratic site of the enzyme. The cardiovascular effects of anti-ChEs are
Whereas the acetylated enzyme (produced complex: depend on the agent and its dose.
momentarily when ACh reacts with ChE) reacts Smooth muscles and glands of the gastrointes-
with water extremely rapidly and the esteratic tinal, respiratory, urinary tracts and in the eye
site is freed in a fraction of a millisecond, the are stimulated.
Anticholinesterases 75

Pharmacokinetics 5. Postoperative decurarization: To reverse the effect


Physostigmine is rapidly absorbed from g.i.t. and of muscle relaxants.
parenteral sites. Applied to the eye, it penetrates 6. Postoperative paralytic ileus/urinary retention.
cornea freely. It crosses blood-brain barrier and is 7. Cobra bite: To antagonize the curare-like action
disposed after hydrolysis by ChE. of cobra neurotoxin.
8. Belladonna poisoning: Physostigmine is the
Neostigmine and congeners are poorly absorbed drug of choice for poisoning with atropine and
orally; oral dose is 20–30 times higher than other anticholinergic drugs.
parenteral dose. They do not effectively penetrate 9. Alzheimer’s disease: This is a neurodegenera-
cornea or cross blood-brain barrier. tive disorder affecting primarily the cholinergic
neurones in the brain. The relatively cerebroselec-
Organophosphates are absorbed from all sites
tive anti-ChEs tacrine, rivastigmine, donepezil
including intact skin and lungs. They are
and galantamine afford some symptomatic
hydrolyzed as well as oxidized in the body and
improvement.
little is excreted unchanged.
Uses ANTICHOLINESTERASE POISONING
1. Glaucoma: It is a progressive form of optic nerve Anticholinesterases are easily available and
damage associated with raised intraocular extensively used as agricultural and household
tension (i.o.t.). Miotics like pilocarpine and insecticides; accidental as well as suicidal and
physostigmine lower i.o.t. by different mecha-

CHAPTER
homicidal poisoning is common.
nisms in the two principal types of glaucoma: Local muscarinic manifestations at the site of
Open angle (chronic simple) glaucoma: Miotics exposure (skin, eye, g.i.t.) occur immediately and
increase the tone of ciliary muscle which pulls on are followed by complex systemic effects due to
and improves the outflow facility of trabecular muscarinic, nicotinic and central actions.
meshwork. However, they are now 3rd line drugs
to ocular β blockers, latanoprost (PGF2α analogue), Treatment

5
brimonidine (α2 agonist clonidine congener),
dorzolamide (ocular carbonic anhydrase 1. Termination of further exposure to the
inhibitor) and dipivefrine (prodrug of adrenaline). poison—fresh air, wash the skin and mucous
Angle closure (narrow angle, acute congestive) membranes with water, gastric lavage
glaucoma: Miotics contract sphincter pupillae according to need.
2. Maintain patent airway, positive pressure
muscle changing the direction of forces in the iris
respiration if it is failing.
to lessen its contact with the lens → pupillary
3. Supportive measures—maintain BP, hydra-
block is removed and iridocorneal angle is freed.
tion, control of convulsions with judicious use
2. To reverse the effect of mydriatic : After refraction
of diazepam.
testing.
4. Specific antidotes—
3. To prevent/break adhesions between iris and lens/
cornea: A miotic is alternated with a mydriatic. (a) Atropine It is highly effective in counter-
4. Myasthenia gravis: It is an autoimmune acting the muscarinic symptoms, but higher doses
disorder due to development of antibodies to the are required to antagonize the central effects. It
muscle endplate nicotinic receptors resulting in does not reverse peripheral muscular paralysis
weakness and easy fatigability. Neostigmine and which is a nicotinic action.
its congeners improve muscle contraction by (b) Cholinesterase reactivators Oximes are used
preserving ACh as well as by directly depolarizing to restore neuromuscular transmission in case
the endplate. of organophosphate anti-ChE poisoning. They
76 Drugs Acting on ANS
provide more reactive OH groups which react The natural alkaloids are found in plants of
with phosphorylated enzyme to form oxime the solanaceae family: atropine in Atropa
phosphonate and release free cholinesterase. belladonna and Datura stramonium, hyoscine in
Pralidoxime is the most commonly used oxime. Hyoscyamus niger. The levo-isomers are much more
active than the dextroisomers. Atropine is racemic
ANTICHOLINERGIC DRUGS while scopolamine is l-hyoscine.
(Muscarinic receptor antagonists,
Atropinic, Parasympatholytic) PHARMACOLOGICAL ACTIONS
(Atropine as prototype)
Conventionally, anticholinergic drugs are those
which block actions of ACh on autonomic effec- The actions of atropine can be largely predicted
tors and in the CNS exerted through muscarinic from knowledge of parasympathetic responses.
receptors. Though nicotinic antagonists also block Prominent effects are seen in organs which
certain actions of ACh, they are generally referred normally receive strong parasympathetic tone. It
to as ‘ganglion blockers’ and ‘neuromuscular blocks all subtypes of muscarinic receptors.
blockers’.
Atropine, the prototype drug of this class, is 1. CNS Atropine has an overall CNS stimulant
highly selective for muscarinic receptors, but action. However, these effects are not appreciable
some of its synthetic substitutes do possess signi- at low doses which mainly produce peripheral
ficant nicotinic blocking property in addition. effects because of restricted entry of atropine into
All anticholinergic drugs are competitive anta- the brain.
II

gonists. • Atropine stimulates many medullary centres


SECTION

—vagal, respiratory, vasomotor.


CLASSIFICATION • It depresses vestibular excitation and has
antimotion sickness property.
1. Natural alkaloids Atropine, Hyoscine • By blocking the relative cholinergic overactivity
(Scopolamine). in basal ganglia, it suppresses tremor
2. Semisynthetic derivatives Homatropine,
and rigidity of parkinsonism.
Atropine methonitrate, Hyoscine butyl
• High doses cause cortical excitation, restless-
bromide, Ipratropium bromide, Tiotropium
ness, disorientation, hallucinations and
bromide.
delirium followed by respiratory depression
3. Synthetic compounds
and coma.
(a) Mydriatics: Cyclopentolate, Tropicamide.
Hyoscine differs from atropine in producing
(b) Antisecretory-antispasmodics:
(i) Quaternary compounds: Propantheline, depressant (drowsiness, amnesia, fatigue) effects
Oxyphenonium, Clidinium, Glycopyr- at low doses.
rolate. 2. CVS
(ii) Tertiary amines: Dicyclomine, Valetha- Heart The most prominent effect of atropine is
mate, Pirenzepine. to cause tachycardia. It is due to blockade of M2
(c) Vasicoselective: Oxybutynin, Flavoxate, Toltero- receptors on SA node through which vagal tone
dine. decreases HR. Higher the existing vagal tone—
(d) Antiparkinsonian: Trihexyphenidyl (Benzhe-
more marked is the tachycardia (maximum in
xol), Procyclidine, Biperiden.
young adults, less in children and elderly). On
In addition, many other classes of drugs, i.e. i.m./s.c. injection, transient initial bradycardia
tricyclic antidepressants, phenothiazines, anti- often occurs. Earlier believed to be due to vagal
histamines, disopyramide possess significant centre stimulation, it is now thought to be caused
antimuscarinic actions. by blockade of muscarinic autoreceptors (M1) on
Anticholinergic Drugs 77

vagal nerve endings augmenting ACh release.


Atropine abbreviates refractory period of A-V
node and facilitates A-V conduction, especially if
it has been depressed by high vagal tone. P-R
interval is shortened.
BP Since cholinergic impulses are not involved
in maintenance of vascular tone, atropine does
not have any consistent or marked effect on BP.
Tachycardia and vasomotor centre stimulation
tend to raise BP while histamine release and direct
vasodilator action (at high doses) tend to lower
BP.
Atropine blocks vasodepressor action of choli-
nergic agonists.
3. Eye The autonomic control of iris muscles
and the action of mydriatics as well as miotics is
illustrated in Fig. 5.5. Topical instillation of
atropine causes mydriasis, abolition of light reflex

CHAPTER
and cycloplegia lasting 7–10 days. This results
in photophobia and blurring of near vision.
The ciliary muscles recover somewhat earlier than
sphincter pupillae. The intraocular tension tends
to rise, especially in narrow angle glaucoma;
conventional systemic doses produce minor

5
ocular effects.
4. Smooth muscles All visceral smooth musc-
les that receive parasympathetic motor innerva-
tion are relaxed by atropine (M3 blockade). Tone
and amplitude of contractions of stomach and
intestine are reduced; the passage of chyme is
slowed—constipation may occur, spasm may be
relieved. However, peristalsis is only incompletely
suppressed because it is primarily regulated by
Fig. 5.5: Autonomic control of pupil (A); and site of
local reflexes and other neurotransmitters (5-HT, action of mydriatics (B) and miotics (C)
enkephalin, etc.).
Atropine causes bronchodilatation and redu-
ces airway resistance, especially in COPD and Atropine has a relaxant action on ureter and
asthma patients. Inflammatory mediators like urinary bladder; urinary retention can occur in
histamine, PGs and kinins increase vagal activity older males with prostatic hypertrophy. However,
in addition to their direct action on bronchial the same can be beneficial for increasing bladder
muscle and glands. Atropine attenuates their action capacity and controlling detrusor hyperreflexia
by antagonizing the reflex vagal component. in neurogenic bladder/enuresis. Relaxation of
78 Drugs Acting on ANS
biliary tract is less marked and effect on uterus is functions. Most of these differ only marginally
minimal. from the natural alkaloids.
5. Glands Atropine markedly decreases sweat, Hyoscine butyl bromide and atropine methonitrate are
quaternary derivatives which do not produce CNS effects
salivary, tracheobronchial and lacrimal secretion
and are used mainly for colics and functional g.i. disorders.
(M3 blockade). Skin and eyes become dry, talking
and swallowing may be difficult. Ipratropium bromide is given by inhalation in bronchial
asthma and chronic obstructive pulmonary disease
Atropine decreases secretion of acid, pepsin (COPD). Unlike atropine, it does not depress mucociliary
and mucus in the stomach, but the primary action clearance by bronchial epithelium. Tiotropium bromide is a
is on volume of secretion so that pH of gastric long acting and more broncho-selective congener of
contents may not be elevated unless diluted by ipratropium.
food. Relatively higher doses are needed and Propantheline, oxyphenonium, clidinium are synthetic qua-
atropine is less efficacious than H2 blockers in ternary anticholinergics mainly used as antisecretory-
antispasmodic.
reducing acid secretion. Intestinal and pancreatic
secretions are not significantly reduced. Bile Glycopyrrolate acts rapidly and is almost exclusively
production is not under cholinergic control, so not employed parenterally before and during anaesthesia.
affected. Dicyclomine has additional direct smooth muscle relaxant
and antiemetic properties; has been used in morning sick-
6. Body temperature Rise in body temperature ness, motion sickness, irritable bowel and dysmenorrhoea.
occurs at higher doses. It is due to both inhibition
II

Valethamate This antispasmodic-anticholinergic is mostly


of sweating as well as stimulation of temperature used to hasten dilatation of cervix during labour.
regulating centre in the hypothalamus. Children
SECTION

Oxybutynin, tolterodine and flavoxate are relatively


are highly susceptible to atropine fever. vasicoselective anticholinergics with direct smooth muscle
The sensitivity of different organs and tissues to relaxant property; used for detrusor instability, urinary
frequency and urge incontinence.
atropine varies and can be graded as—
Saliva, sweat, bronchial secretion > eye, bron- Pirenzepine is a selective M1 antimuscarinic which inhibits
gastric secretion with few atropinic side effects.
chial muscle, heart > smooth muscle of intestine,
bladder > gastric glands and smooth muscle. Homatropine, cyclopentolate, tropicamide are used exclusively
as mydriatic and cycloplegic. They have quicker and briefer
action than atropine.
PHARMACOKINETICS
Trihexyphenidyl, procyclidine and biperiden have more
Atropine and hyoscine are rapidly absorbed from prominent central antimuscarinic action: are used in
g.i.t. Applied to eyes, they freely penetrate cornea. parkinsonism.
Passage across blood-brain barrier is somewhat
restricted. About 50% of atropine is metabolized USES (of atropine and its congeners)
in liver and rest is excreted unchanged in urine. It 1. Preanaesthetic medication: To check increa-
has a t½ of 3–4 hours. Hyoscine is more sed salivary and tracheobronchial secretions due
completely metabolized and has better blood-brain to irritant general anaesthetics, prevent reflex
barrier penetration. laryngospasm and to block vagal reflexes.
Atropine and glycopyrrolate are occasionally
ATROPINE SUBSTITUTES employed to prevent salivation during dental
Many semisynthetic derivatives of belladonna procedures and oral surgery.
alkaloids and a large number of synthetic com- 2. Abdominal cramps/colics, ureteric colic,
pounds have been introduced with the aim of functional g.i. disorders. Use of atropinic drugs
producing more selective action on certain in peptic ulcer is now obsolete.
Anticholinergic Drugs 79

3. To relieve urinary frequency and urgency in Dry, flushed and hot skin (especially over face
neurogenic disorders, enuresis in children. and neck), fever, difficulty in micturition, a scarlet
4. Pulmonary embolism: Atropine benefits by rash may appear.
reducing reflex respiratory secretions. Dilated pupil, photophobia, blurring of near
5. Bronchial asthma and COPD: Inhaled vision, palpitation.
ipratropium bromide and tiotropium bromide are Excitement, psychotic behaviour, ataxia, delirium,
particularly useful in COPD and as adjuvant to hallucinations.
inhaled β2 agonists in severe/refractory bronchial Hypotension, weak and rapid pulse, cardiovas-
asthma. cular collapse with respiratory depression.
6. As mydriatic and cycloplegic for refraction Convulsions and coma occur only in severe
testing and fundoscopy: tropicamide is preferred poisoning.
because of quickest and briefest action. The long-
lasting mydriatic-cycloplegic action of atropine Treatment If poison has been ingested, gastric
is very valuable for giving rest to intraocular lavage should be done with tannic acid (KMnO4
muscles in iritis, iridocyclitis, choroiditis, keratitis is ineffective in oxidizing atropine). The patient
and corneal ulcer. should be kept in a dark quiet room. Cold spon-
7. To block vagal bradycardia in selected cases ging or ice bags are applied for reducing body
of myocardial infarction and digitalis toxicity. temperature. Physostigmine 1–3 mg s.c. or i.v.
8. Parkinsonism: Central anticholinergics reduce antagonizes both central and peripheral effects.

CHAPTER
tremor and rigidity by counteracting unbalanced It may be repeated 4–6 hourly. Neostigmine is less
cholinergic activity in striatum. satisfactory.
9. Motion sickness: Hyoscine is highly effective, Other general measures (maintenance of blood
especially valuable for vigorous motions. volume, artificial respiration, diazepam to control
Dicyclomine is used in milder cases. convulsions) should be taken as appropriate.
10. Atropine is the specific antidote for anti-
Contraindications Atropinic drugs are absolu-
cholinesterase and early mushroom poisoning

5
(due to muscarine). It is also used to block the tely contraindicated in individuals with a narrow
muscarinic side effects of neostigmine. iridocorneal angle—may precipitate acute con-
gestive glaucoma. However, marked rise in
intraocular tension is rare in patients with wide
SIDE EFFECTS AND TOXICITY
angle glaucoma.
Side effects are quite common with the use of Caution is advocated in elderly males with
atropine and its congeners; are due to facets of its prostatic hypertrophy—urinary retention can
action other than for which it is being used. They occur.
cause inconvenience but are rarely serious.
The dental implication is that xerostomia
Interactions
(due to reduced salivary flow) caused by atro-
pinic drugs can promote dental caries and oral 1. Absorption of most drugs is slowed because
candidiasis. atropine delays gastric emptying. Extent of
Belladonna poisoning may occur due to drug digoxin and tetracycline absorption may be
overdose or consumption of seeds and berries of increased due to longer transit time in the g.i.t.
belladonna/datura plant. Children are highly 2. Antihistaminics, tricyclic antidepressants,
susceptible. Manifestations are due to exagge- phenothiazines, disopyramide, pethidine
rated pharmacological actions. have anticholinergic property—additive side
Dry mouth, difficulty in swallowing and talking. effects occur with atropinic drugs.
80 Drugs Acting on ANS
DRUGS ACTING ON AUTONOMIC become available for treatment of nicotine dependence
and as an aid to smoking cessation.
GANGLIA
Varenicline It is a NN subtype selective nicotinic receptor
Acetylcholine is the primary excitatory neuro- partial agonist recently approved as an aid to smoking
transmitter in both sympathetic and parasym- cessation.
pathetic ganglia.
Ganglion blocking agents
Drugs can either stimulate or block the ganglia. A. Competitive blockers
Quaternary ammonium compounds
Ganglionic stimulants Hexamethonium
Pentolinium
Selective nicotinic Nonselective/muscarinic
Amines (secondary/tertiary)
agonists agonists
Mecamylamine
Nicotine (small dose) Acetylcholine Pempidine
Lobeline Carbachol
Monosulfonium compound
Dimethyl phenyl Pilocarpine
Trimethaphan camforsulfonate
piperazinium iodide Anticholinesterases
(DMPP) MCN 343-A B. Persistent depolarising blockers
Tetramethyl ammonium Nicotine (large dose)
(TMA) Anticholinesterases (large dose)
Varenicline
The competitive ganglion blockers were used in
Nicotine (from Nicotiana tabacum) is important in the the 1950s for hypertension and peptic ulcer,
context of smoking or chewing tobacco, but there is no
II

clinical application of ganglionic stimulants, because no but have been totally replaced now because they
useful purpose can be served by stimulating both produce a number of intolerable side effects.
SECTION

sympathetic and parasympathetic ganglia concurrently.


There is at present no clinical relevance of
Nicotine transdermal and nicotine chewing gum have ganglion blockers.
6
Drugs Acting on Autonomic
Nervous System
Adrenergic and Antiadrenergic Drugs

ADRENERGIC TRANSMISSION
Adrenergic (more precisely ‘Noradrenergic’)
transmission is restricted to the sympathetic
division of the ANS. There are three closely related
endogenous catecholamines (CAs).
Noradrenaline (NA) It acts as transmitter at post-
ganglionic sympathetic sites (except sweat
glands, hair follicles and some vasodilator fibres)
and in certain areas of brain.
Adrenaline (Adr) It is secreted by adrenal medulla
and may have a transmitter role in the brain.
Dopamine (DA) It is a major transmitter in basal
ganglia, limbic system, CTZ, anterior pituitary,
etc. and in a limited manner in the periphery.
1. Synthesis of CAs Catecholamines are
synthesized from the amino acid phenylalanine
as depicted in Fig. 6.1. Synthesis of NA occurs in
all adrenergic neurones, while that of Adr occurs
only in the adrenal medullary cells and probably
requires high concentration of glucocorticoids Fig. 6.1: Steps in the synthesis of catecholamines
through intra-adrenal portal circulation for
induction of the methylating enzyme. complex with ATP (in a ratio of 4:1) which is
adsorbed on a protein chromogranin. The
2. Storage of CAs NA is stored in synaptic
cytoplasmic pool of CAs is kept low by the
vesicles or ‘granules’ within the adrenergic
enzyme monoamine oxidase (MAO) present on
nerve terminal (see Fig. 6.4). The granular
the outer surface of mitochondria.
membrane actively takes up DA from the
cytoplasm and the final step of synthesis of NA 3. Release of CAs The nerve impulse coupled
takes place inside the granule which contains release of CA takes place by exocytosis (see p. 69)
dopamine β-hydroxylase. NA is then stored as a and all the granular contents (NA or Adr, ATP,
82 Drugs Acting on ANS
dopamine β hydroxylase, chromogranin) are it is very important in maintaining the NA content
poured out. The release is modulated by pre- of the neurone. This uptake is inhibited by
synaptic receptors, of which α2 inhibitory control reserpine resulting in depletion of CAs.
is dominant. An extraneuronal uptake (uptake-2) of CAs involving
Indirectly acting sympathomimetic amines (tyramine, a different transporter also occurs into nonneural cells.
etc.) also induce release of NA, but they do so by This is not inhibited by cocaine and is of minor importance.
displacing NA from the nerve ending binding sites and by
exchange diffusion utilizing norepinephrine transporter 5. Metabolism of CAs The pathways of meta-
(NET) which is the carrier of uptake-1 (see below). This process bolism of CAs are depicted in Fig. 6.2. Part of the
is not exocytotic and does not require Ca2+. NA leaking out from vesicles into cytoplasm as
4. Uptake of CAs There is a very efficient well as that taken up by axonal transport is first
mechanism by which NA released from the nerve attacked by MAO, while that which diffuses into
circulation is first acted upon by catechol-o-
terminal is recaptured. This occurs in two steps—
methyl transferase (COMT) in liver and other
Axonal uptake An active amine pump (NET) is tissues. The other enzyme can subsequently act
present at the neuronal membrane which to produce vanillylmandelic acid (VMA). The
transports NA at a higher rate than Adr (uptake- major metabolites excreted in urine are VMA and
1). The indirectly acting sympathomimetic amines 3-methoxy-4-hydroxy phenylethylene glycol (a
also utilize this pump for entering the neurone. reduced product) along with some metanephrine,
This uptake is the most important mechanism for normetanephrine and 3,4 dihydroxy mandelic
terminating the postjunctional action of NA and acid. These metabolites are mostly conjugated
II

is inhibited by cocaine, desipramine and its with glucuronic acid or sulfate before excretion
congeners. in urine. However, metabolism does not play an
SECTION

important role in terminating the action of


Vesicular uptake The membrane of intracellular
endogenous CAs.
vesicles has another amine pump which trans-
ports CA from the cytoplasm to the interior of 6. Adrenergic receptors Adrenergic receptors
vesicle. The vesicular NA is constantly leaking are membrane bound G-protein coupled receptors
out into the axoplasm and is recaptured by this which function primarily by increasing or
mechanism. This carrier also takes up DA formed decreasing the intracellular production of second
in the axoplasm for further synthesis to NA. Thus, messengers cAMP or IP3/DAG. In some cases, the

Fig. 6.2: Metabolism of catecholamines


Adrenergic Transmission 83
Table 6.1: Differences between α and β adrenergic receptors
α β
1. Rank order of potency of agonists Adr > NA > Iso Iso > Adr > NA
2. Antagonist Phenoxybenzamine Propranolol
+
3. Effector pathway IP3/DAG↑, cAMP ↓, K channel ↑ cAMP↑, Ca2+ channel ↑

CHAPTER
Fig. 6.3: Dose-response curves of 3 catecholamines adrenaline (Adr), noradrenaline (NA) and
isoprenaline (Iso) on isolated aortic strip and isolated bronchial smooth muscle illustrating two
distinct rank orders of potencies respectively for α and β adrenergic receptors

activated G-protein itself operates K+ or Ca2+ antagonist. The α2 subtype is present both pre-

6
channels, or increases prostaglandin production. and postjuctionally. It is selectively activated by
Ahlquist (1948), on the basis of two distinct clonidine and blocked by yohimbine.
rank order of potencies of adrenergic agonists (Fig. The adrenergic neuronal mechanisms and
6.3), classified adrenergic receptors into two types action of drugs which modify them are depicted in
α and β. This classification was then confirmed by Fig. 6.4. A summary of drugs acting through
the development of selective α and β adrenergic adrenergic neuronal mechanisms is presented in
antagonists. Important features of α and β Table 6.2.
receptors are given in Table 6.1.
On the basis of relative organ specificity of ADRENERGIC DRUGS
selective agonists and antagonists, the β receptors (Sympathomimetics)
were further subdivided into β1 (cardiac) and β2 These are drugs with actions similar to that of Adr
(bronchial, vascular, uterine) subtypes. The β1 or of sympathetic stimulation.
receptors are preferentially activated by dobuta- Direct sympathomimetics They act directly as
mine and blocked by metoprolol, while β2 agonists on α and/or β adrenoceptors —Adr, NA,
receptors are selectively activated by salbutamol isoprenaline (Iso), phenylephrine, methoxamine,
and blocked by α-methyl propranolol. xylometazoline, salbutamol and many others.
Similarly, subtypes of α adrenoceptor have
also been identified. The α1 subtype is located Indirect sympathomimetics They act on adre-
only postjunctionally. Phenylephrine and nergic neurone to release NA which then acts on
prazosin respectively are its selective agonist and the adrenoceptors—tyramine, amphetamine.
84 Drugs Acting on ANS
II
SECTION

Fig. 6.4: Schematic representation of adrenergic neurotransmission and its modification by drugs
TYR—tyrosine; α M-p-TYR—α methyl-p-tyrosine; α M-DOPA—α methyl dopa; MAO— monoamineoxidase;
MAOI—monoamine oxidase inhibitor; COMT—catechol-o-methyl transferase; DOH-MA—dihydroxy mandelic
acid, NMN—nor-metanephrine; VMA—vanillylmandelic acid

Mixed action sympathomimetics They act direc- receptor subtype, wherever defined, has been
tly as well as indirectly—ephedrine, dopamine, mentioned in parenthesis. The actions of a
mephentermine. particular sympathomimetic amine depend on its
relative activity at different types of adrenergic
receptors.
ACTIONS
Adr : α1 + α2 + β1 + β2
The peripheral actions of Adr in most tissues NA: α1 + α2 + β1 but no β2 action
have been clearly differentiated into those Iso: β1 + β2 but no α action
mediated by α or β receptors depending on the
predominant receptor type present in a given Important actions of Adr, NA and isoprenaline
tissue. These are tabulated in Table 6.3. The are compared in Table 6.4.
Adrenergic Drugs 85
Table 6.2: Summary of drug action through modification of adrenergic transmission

Step/site Action Drug Response


1. Synthesis of NA Inhibition α-methyl-p-tyrosine Depletion of NA
Utilisation of α-methyl dopa Replacement of NA by
same synthetic α-methyl NA (false
pathway transmitter)
2. Axonal uptake Blockade Cocaine, desipramine, Potentiation of NA
guanethidine (endo-and exogenous),
inhibition of tyramine
3. Granular uptake Blockade Reserpine Depletion of NA
(degraded by MAO)
4. Nerve impulse Inhibition Guanethidine, Loss of transmission
coupled release bretylium
of NA
5. Granular NA Displacement Guanethidine Initially sympathomimetic,
depletion later
6. Membrane NA pool Exchange diffusion Tyramine, ephedrine Indirect sympathomimetic
7. Metabolism MAO inhibition Nialamide Potentiation of NA (slight),
tranylcypromine —of tyramine (marked)
COMT inhibition Tolcapone, Potentiation of NA (slight)

CHAPTER
entacapone
8. Receptors Mimicking Phenylephrine α1 sympathomimetic
Clonidine α2–inhibition of NA release,
↓ sympathetic outflow
Isoprenaline β1 + β2 —sympathomimetic
Salbutamol β 2—sympathomimetic
Blockade Phenoxybenzamine α1 + α2—blockade

6
Prazosin α1—blockade
Yohimbine α2—blockade
Propranolol β1 + β2—blockade
Metoprolol β 1—blockade

The overall actions are — is reduced. All cardiac actions are predominantly
1. Heart Adr increases heart rate by increa- β1 receptor mediated.
sing automaticity of SA node. It also activates When BP rises markedly, reflex bradycardia
latent pacemakers in A-V node and Purkinje fibres; occurs due to stimulation of vagus— this is the
arrhythmias can occur with high doses that raise usual response seen when NA is injected i.v.
BP markedly. Certain anaesthetics (chloroform,
halothane) sensitize the heart to the arrhythmic 2. Blood vessels Both vasoconstriction (α)
action of Adr. Idioventricular rate is increased in and vasodilatation (β2) can occur depending on
patients with complete heart block. the drug, its dose and vascular bed. Constriction
Force of cardiac contraction is increased. predominates in cutaneous, mucous membrane
Cardiac output and oxygen consumption of the and renal beds. Vasoconstriction occurs through
heart are markedly enhanced. both α1 and α2 receptors. Dilatation predominates
Conduction velocity through A-V node, bun- in skeletal muscles, liver and coronaries. The
dle of His, atrial and ventricular fibres is direct effect on cerebral vessels is not prominent—
increased; partial A-V block may be overcome. blood flow through this bed parallels change in
Refractory period (RP) of all types of cardiac cells BP.
86 Drugs Acting on ANS

Table 6.3: Adrenergic responses mediated through α and β receptors

α actions β actions
1. Constriction of arterioles and veins → rise in Dilatation of arterioles and veins → fall in BP (β2)
BP (mainly α1)
2. Heart—little action, arrhythmia at high dose Cardiac stimulation (β1), ↑ rate, force and conduction
(α1) velocity
3. — Bronchodilatation (β2)
4. Contraction of radial muscles of iris → No effect on iris and ciliary muscle
mydriasis (α1), decreased aqueous secretion Enhanced aqueous secretion
5. Intestinal relaxation, contraction of sphincters Intestinal relaxation (β2)
6. Bladder trigone—contraction Detrusor—relaxation
7. Uterus—contraction Relaxation (β2)
8. Splenic capsule—contraction Relaxation (β2) (slight)
9. Neuromuscular transmission facilitated, Active state—prolonged in fast contracting muscle,
↑ ACh release abbreviated in slow contracting muscle; tremors (β2)
10. Insulin secretion inhibited (α2) (dominant) Augmented insulin (mild) and glucagon secretion (β2)
11. Liver—glycogenolysis (α in some species) Liver—glycogenolysis (β2) → hyperglycaemia
Muscle—glycogenolysis (β2) → hyperlactacidaemia
Fat—lipolysis (β3) → increased blood FFA, calorigenesis
II

12. — Renin release from kidney (β1)


SECTION

13. Male sex organs—ejaculation —


14. Salivary gland—K+ and water secretion (α1) Ptylin secretion
15. — ADH secretion from posterior pituitary (β1)
16. Nictitating membrane—contraction (in —
animals)

Action is most marked on arterioles; larger When an α blocker has been given, only fall in BP
arteries and veins are affected at higher doses. is seen—vasomotor reversal of Dale.
3. BP The effect depends on the amine, its dose 4. Respiration Adr and Isoprenaline but not NA
and rate of administration. are potent bronchodilators (β2). This action is more
• NA causes rise in systolic, diastolic and mean marked when the bronchi are constricted. Adr can
BP; it does not cause vasodilatation (no directly stimulate respiratory centre (RC), but
β2 action), peripheral resistance increases this action is seldom manifest at clinically used
consistently due to α action. doses.
• Isoprenaline causes rise in systolic but marked
5. Eye Mydriasis occurs due to contraction of
fall in diastolic BP (β1—cardiac stimulation,
radial muscles of iris (α1), but this is minimal after
β2— vasodilatation). The mean BP generally
topical application because Adr penetrates cornea
falls.
poorly. The intraocular tension tends to fall,
• Adr given by slow i.v. infusion or s.c. injection
especially in wide angle glaucoma due to both
causes rise in systolic but fall in diastolic BP;
reduction in aqueous formation and facilitation of
peripheral resistance decreases because vas-
outflow.
cular β2 receptors are more sensitive than
α receptors. Mean BP generally rises. Pulse 6. GIT In isolated preparations of gut relaxation
pressure is increased. occurs through activation of both α and β
Adrenergic Drugs 87
receptors. In intact animals and man, peristalsis Table 6.4: Comparative effects of adrenaline,
is reduced and sphincters are constricted, but the noradrenaline and isoprenaline
effects are brief and of no clinical import.
Adr NA Iso
7. Bladder Detrusor is relaxed (β) and trigone 1. Heart rate ↑ ↓ ↑↑
is constricted (α): both actions tend to hinder 2. Cardiac output ↑↑ – ↑↑
micturition. 3. BP—Systolic ↑↑ ↑↑ ↑
Diastolic ↓↑ ↑↑ ↓↓
8. Uterus Adr can both contract or relax uterine
Mean ↑ ↑↑ ↓
muscle through respectively α and β receptors;
4. Blood flow
effect varies with hormonal and gestational
Skin and mm ↓ ↓ –
status. Human uterus at term of pregnancy is
Sk. muscle ↑↑ –, ↓ ↑
relaxed by Adr; while at other times, its
Kidney ↓ ↓ –
contractions are enhanced.
Liver ↑↑ – ↑
9. Skeletal muscle Adr facilitates neuromus- Coronary ↑ ↑ ↑
cular transmission. However, incomplete fusion 5. Bronchial muscle ↓↓ – ↓↓
of individual muscle fibre contractions along with 6. Intestinal muscle ↓↓ ↓ ↓
enhanced firing of muscle spindles is responsible 7. Blood sugar ↑↑ –, ↑ ↑
for the tremors produced by β2 agonists.
10. CNS Adr, in clinically used doses, does not Administration CAs are absorbed from the

CHAPTER
produce any marked CNS effects because of poor intestine but are rapidly degraded by MAO and
penetration in brain, but restlessness, apprehen- COMT present in the intestinal wall and liver.
sion and tremor may occur. Activation of α2 They are thus orally inactive. For systemic effects
receptors in the brainstem results in decreased Adrenaline (epinephrine) is administered by s.c. or
sympathetic outflow → fall in BP and brady- i.m. injection in a dose of 0.2–0.5 mg; action lasts
cardia. 0.5–2 hours. In dental practice, it is used as a local

6
11. Metabolic Adr produces glycogenolysis— vasoconstrictor added to lidocaine in a concentration
hyperglycaemia, hyperlactacidaemia (β2); lipoly- of 1 in 200,000 to 100,000 for dental anaesthesia.
sis—rise in plasma free fatty acid (FFA), calori- ADRENALINE 1 mg/ml inj.; in XYLOCAINE with
genesis (β2 + β3) and transient hyperkalaemia ADRENALINE: Lidocaine 21.3 mg + Adrenaline 0.005
followed by hypokalaemia due to direct action on mg per ml inj, 30 ml vial.
liver, muscle and adipose tissue cells. In addition, Noradrenaline (norepinephrine, levarterenol) is
metabolic effects result from reduction of insulin administered only by slow i.v. infusion at the rate
(α2) and augmentation of glucagon (β2) secretion. of 2–4 μg/min, for raising BP in emergency
Biochemical mediation of adrenergic responses situations.
β actions The β actions are mediated through cAMP (see
Fig. 3.5). Adr activates membrane bound enzyme adenylyl Adverse effects and contraindications
cyclase through a regulatory protein Gs → ATP is broken
• Transient restlessness, palpitation, anxiety,
down to cAMP at the inner face. This in turn phosphorylates
a number of intracellular cAMP-dependent protein kinases tremor, pallor may occur after s.c./i.m. injection
and initiates a series of reactions. of Adr.
α actions The mediation of α actions is varied and less • Marked rise in BP leading to cerebral haemor-
well defined. Vascular and other muscle contractions are rhage, ventricular tachycardia/fibrillation,
mediated through IP3/DAG production and mobilization angina, myocardial infarction are the
of intracellular Ca2+. In other tissues, inhibition of cAMP
production and hyperpolarization through K+ channel
hazards of large doses or inadvertant i.v.
activation mediates the α adrenergic responses. injection of Adr.
88 Drugs Acting on ANS
• Adr is contraindicated in hypertensive, hyper- β2) agonist. The D1 receptors in renal and
thyroid and angina patients. mesenteric blood vessels are the most sensitive: i.v.
• Adr mixed local anaesthetic should be used very infusion of low dose of DA dilates these vessels
cautiously for dental anaesthesia in patients with increasing g.f.r. and Na+ excretion. Moderately
heart disease. high doses produce a positive inotropic effect on
• It should not be given during anaesthesia the heart. Vasoconstriction (α1 action) occurs only
with halothane (risk of arrhythmias) and to when large doses are infused. At doses normally
patients receiving β blockers (marked rise in infused i.v. (0.2–1 mg/min), it raises cardiac
BP can occur). output and systolic BP with little effect on diastolic
BP. This is useful in cardiogenic and septic shock.
THERAPEUTIC CLASSIFICATION OF
ADRENERGIC DRUGS
Dobutamine A derivative of DA, but not a D1 or
D2 receptor agonist. Though it acts on both α and
I. Pressor agents β adrenergic receptors, the only prominent action
Noradrenaline Phenylephrine of clinically employed doses (2-8 μg/kg/min i.v.
Ephedrine Methoxamine infusion) is increase in force of cardiac contraction
Dopamine Mephentermine and output. It is used as an inotropic agent in
II. Cardiac stimulants pump failure accompanying myocardial infarc-
Adrenaline Dobutamine tion, cardiac surgery, and for short-term manage-
Isoprenaline ment of severe congestive heart failure.
II

III. Bronchodilators Ephedrine It is an alkaloid obtained from


SECTION

Isoprenaline Terbutaline Ephedra vulgaris. Mainly acts indirectly but has


Salbutamol Bambuterol some direct action on α and β receptors also.
(Albuterol) Salmeterol Repeated injections produce tachyphylaxis,
Formoterol primarily because the neuronal pool of NA
available for displacement is small. It is resistant
IV. Nasal decongestants to MAO, therefore, effective orally. It crosses to
Phenylephrine Naphazoline brain and causes stimulation.
Xylometazoline Pseudoephedrine Ephedrine is now occasionally used in mild
Oxymetazoline Phenyl propanolamine chronic bronchial asthma and for hypotension
V. CNS stimulants during spinal anaesthesia.
Amphetamine Methamphetamine Amphetamines These are synthetic compounds
Dexamphetamine having the same pharmacological profile as
VI. Anorectics ephedrine; orally active with long duration (4–6
Fenfluramine Sibutramine hr). The CNS actions are more prominent;
Dexfenfluramine maximal selectivity is exhibited by dextroamphe-
tamine and methamphetamine, which in the
VII. Uterine relaxant and vasodilators usual doses produce few peripheral effects.
Ritodrine Salbutamol The central effects include alertness, increased
Isoxsuprine Terbutaline concentration and attention span, euphoria,
talkativeness, increased work capacity. Fatigue is
Salient features of important adrenergic drugs are
allayed. Athletic performance is improved tempo-
summarized below:
rarily followed by deterioration. It is one of the
Dopamine (DA) It is a dopamine (D1 and D2 drugs included in the ‘dope test’ for athletes. The
receptors) as well as adrenergic α and β1 (but not reticular activating system is stimulated resulting
Adrenergic Drugs 89
in wakefulness and postponement of sleep depri- without producing significant cardiac stimula-
vation induced physical disability. But this is tion. β2 selectivity is only relative. Salbutamol
short lived and may be accompanied by anxiety, has β2:β1 action ratio of about 10 . They are
restlessness, tremor, dysphoria and agitation. primarily used in bronchial asthma (see Ch. 19).
Amphetamines stimulate respiratory centre, Occasionally ritodrine is employed to depress
especially if it has been depressed. Hunger is sup- uterine contractions and delay premature labour.
pressed as a result of inhibition of hypothalamic The most important side effect is muscle
feeding centre. Peripheral effects on heart and BP tremor.
are not significant at the usual doses, but tone of
vesical sphincter is definitely increased. NASAL DECONGESTANTS
Amphetamines are drugs of abuse and are
These are α agonists which on topical appli-
capable of producing marked psychological but
cation as dilute solution (0.05–0.1%) produce
little or no physical dependence. Amphetamine
local vasoconstriction. The imidazoline com-
abusers are generally teenagers seeking thrill or
pounds—xylometazoline and oxymetazoline are
kick which is obtained on rapid i.v. injection. High
relatively selective α2 agonist (like clonidine).
doses produce euphoria, marked excitement
They have a longer duration of action (12 hr) than
which may progress to mental confusion, deli-
ephedrine. Rise in BP can occur in hypertensives
rium, hallucinations and an acute psychotic state.
after nasal instillation.
Repeated use is likely to produce long-lasting
behavioural abnormalities; psychosis may be Phenylpropanolamine (PPA) Chemically and

CHAPTER
precipitated. pharmacologically similar to ephedrine; causes
Phenylephrine It is a selective α1 agonist, has vasoconstriction and has some amphetamine
negligible β action. It raises BP by causing vaso- like CNS effects. It is included in a large number of
constriction. Topically, it is used as a nasal oral cold/decongestant combination remedies,
decongestant and for producing mydriasis when though it has been banned in the USA because of
cycloplegia is not required. It is also a constituent possible risk of haemorrhagic stroke when used

6
of orally administered nasal decongestant pre- as appetite suppressant in relatively larger doses.
parations.
Methoxamine Another selective α1 stimulant ANORECTIC AGENTS
with no β actions; occasionally used as a pressor A number of drugs related to amphetamine have
agent. been developed which inhibit feeding centre but
have little/no CNS stimulant action or abuse
Mephentermine It produces both cardiac stimu-
liability. All of them act by inhibiting the reuptake
lation and vasoconstriction by directly activating
of NA/DA or 5-HT, enhancing monoaminergic
α and β adrenergic receptors as well as by
transmission in the brain.
releasing NA. Administered orally as well as
Fenfluramine and its dextroisomer dexfenflu-
parenterally, it is used to prevent and treat hypo-
ramine reduce food seeking behaviour by enhan-
tension due to spinal anaesthesia, shock and other
hypotensive states. cing serotonergic transmission in the hypo-
thalamus, and have no stimulant property. As
such, they were extensively used by slimming
SELECTIVE β2 STIMULANTS
centres, but are banned now due to a possible
These include, salbutamol, terbutaline and its association with cardiac valvular defects and
long acting prodrug bambuterol, salmeterol, pulmonary hypertension.
formoterol and ritodrine. They cause bronchodila- Sibutramine is a newer antiobesity drug which
tation, vasodilatation and uterine relaxation, inhibits both NA and 5-HT reuptake. It reduces
90 Drugs Acting on ANS
appetite and may in addition stimulate thermo- CHF. However, controlled short-term i.v. infusion
genesis resulting in weight loss. The safety of this of DA/dobutamine can tide over acute cardiac
drug too has been questioned, but it is still widely decompensation during myocardial infarction,
used. cardiac surgery and in resistant CHF.

THERAPEUTIC USES 8. Bronchial asthma Adrenergic drugs, espe-


cially β2 stimulants, are the primary drugs for
1. Hypotensive states (shock, spinal anaesthe- relief of reversible airway obstruction (see Ch. 19).
sia, hypotensive drugs) One of the pressor agents
can be used along with volume replacement for 9. Allergic disorders Adr is life saving in
neurogenic and haemorrhagic shock, also as an laryngeal edema and anaphylaxis, and can afford
expedient measure to maintain cerebral circula- quick relief in urticaria, angioedema of mouth/
tion in other hypotensive states. Slow i.v. infusion face, etc., because it is a physiological antagonist
of dopamine is more appropriate, while use of NA of histamine.
is practically obsolete. Adr 0.5 mg injected 10. Mydriatic Phenylephrine is used to facilitate
promptly i.m. is the drug of choice for anaphy-
fundus examination; cycloplegia is not required.
lactic shock (see p 59). It not only raises BP, but
It tends to reduce intraocular tension in wide angle
counteracts bronchospasm/laryngeal edema that
glaucoma. The ester prodrug of Adr dipivefrine is
may accompany. Because of the rapidity and
an adjuvant drug for open angle glaucoma.
profile of action, Adr is the only life-saving
measure. 11. Narcolepsy Narcolepsy is sleep occurring in
II

fits, and is adequately controlled by ampheta-


2. Along with local anaesthetics Adr 1 in
SECTION

100,000 or 1 in 200,000 for infiltration, nerve block mines.


and spinal anaesthesia. Duration of anaesthesia 12. Hyperkinetic children (minimal brain dys-
is prolonged and systemic toxicity of local function, attention deficit hyperkinetic disorder):
anaesthetic is reduced. It is routinely included in Amphetamines have an apparently paradoxical
dental anaesthesia (unless contraindicated); serves to effect to calm down hyperkinetic children. By
reduce bleeding as well. increasing attention span, they improve
3. Control of local bleeding From skin, mucous behaviour and performance in studies.
membranes, tooth socket, epistaxis, etc: compresses 13. Obesity The anorectic drugs can help the
or packs of Adr 1 in 10,000, soaked in cotton can obese to tolerate a reducing diet for short periods.
control arteriolar and capillary bleeding. Their use (for 2–3 months) may be considered in
4. Nasal decongestant In colds, rhinitis, sinusi- severe obesity.
tis, blocked eustachian tube—one of the α- 14. Uterine relaxant Selective β2 stimulants,
agonists is used as nasal drops. especially ritodrine, infused i.v. have been
5. Cardiac arrest (drowning, electrocution, successfully used to postpone labour.
Stokes-Adams syndrome and other causes) Adr 15. Insulin hypoglycaemia Adr may be used as
injected i.v. may be used to stimulate the heart an expedient measure, but glucose should be
along with external cardiac massage. given as soon as possible.
6. Partial or complete A-V block Isoprenaline
may be used as temporary measure to maintain ANTIADRENERGIC DRUGS
sufficient ventricular rate. (ADRENERGIC RECEPTOR ANTAGONISTS)
7. Congestive heart failure Adrenergic inotropic These are drugs which antagonize the receptor
drugs are not useful in the routine treatment of action of adrenaline and related drugs. They are
α Adrenergic Blocking Drugs 91
competitive antagonists at α or β or both types of 2. Reflex tachycardia occurs due to fall in mean
adrenergic receptors. arterial pressure and increased release of NA due
to blockade of presynaptic α2 receptors.
α ADRENERGIC BLOCKING DRUGS 3. Nasal stuffiness and miosis result from
These drugs inhibit adrenergic responses media- blockade of α receptors in nasal blood vessels and
ted through the α adrenergic receptors without in radial muscles of iris respectively.
affecting those mediated through β receptors. 4. Intestinal motility is increased due to partial
inhibition of relaxant sympathetic influences—
CLASSIFICATION diarrhoea may occur.
5. Hypotension produced by α blockers can
I. Nonequilibrium type
reduce renal blood flow → g.f.r. is reduced
β-Haloalkylamines—Phenoxybenzamine.
and more complete reabsorption of Na+ and water
II. Equilibrium type (competitive) occurs in the tubules → Na+ retention and
A. Nonselective increase in blood volume. This is accentuated by
(i) Ergot alkaloids—Ergotamine, Ergotoxine. reflex increase in renin release mediated through
(ii) Hydrogenated ergot alkaloids—Dihydroergo- β1 receptors.
tamine (DHE), Dihydroergotoxine. 6. Tone of smooth muscle in bladder trigone,
(iii) Imidazolines—Tolazoline, Phentolamine. sphincter and prostate is reduced by blockade of
(iv) Miscellaneous—Chlorpromazine. α1 receptors (mostly of the α1A subtype) → urine

CHAPTER
flow in patients with benign hypertrophy of
B. α1 selective—Prazosin, Terazosin, Doxazosin, prostate (BHP) is improved.
Tamsulosin, Alfuzosin. 7. Contractions of vas deferens and related
C. α2 selective—Yohimbine. organs which result in ejaculation are coordina-
ted through α receptors—α blockers can inhibit
ejaculation; this may manifest as impotence.
GENERAL EFFECTS OF α BLOCKERS The α blockers have no effect on adrenergically

6
1. Blockade of vasoconstrictor α1 (also α2) recep- induced cardiac stimulation, bronchodilatation,
tors reduces peripheral resistance and causes vasodilatation and most of the metabolic changes,
pooling of blood in capacitance vessels → venous because these are predominantly mediated
return and cardiac output are reduced → fall in through β receptors.
BP. Postural reflex is interfered with → marked Apart from these common effects, most of
hypotension occurs on standing → dizziness and which manifest as side effects, individual α
syncope. Hypovolemia accentuates the hypoten- blockers have some additional actions. Their
sion. Special care must be taken to ensure that pharmacological profile is also governed by their
patients receiving an α blocker (e.g. prazosin for central effects and by the relative activity on α1
hypertension or benign prostatic hypertrophy) do not and α2 receptor subtypes.
suddenly stand up after being supine on the dental Side effects that may occur with any α blocker
chair. Also, these patients are more prone to are—palpitation, postural hypotension, nasal
develop hypotension if they bleed during the blockage, loose motions, fluid retention, inhibi-
tion of ejaculation and impotence.
dental procedure. The α blockers abolish pressor
Distinctive features of important α adrenergic
action of Adr (injected i.v. in animals) which then
blockers are given below:
produces only fall in BP due to β2 mediated
vasodilatation—vasomotor reversal of Dale. Pressor Phenoxybenzamine It cyclizes spontaneously
and other actions of selective α agonists (NA, in the body giving rise to a highly reactive
phenylephrine) are suppressed. ethyleniminium intermediate which reacts with
92 Drugs Acting on ANS
α adrenoceptors and other biomolecules by Tamsulosin is relatively uroselective due to
forming strong covalent bonds. The α blockade is higher affinity for α1A subtype of α1 receptors
of nonequilibrium type and develops gradually which predominate in the bladder base and
(even after i.v. injection). It lasts 3–4 days. prostate. Thus, it does not cause significant
Phenoxybenzamine has been used primarily changes in BP or HR at doses which relieve
in pheochromocytoma; occasionally in secondary urinary symptoms of BHP. Dizziness and
shock and peripheral vascular disease. retrograde ejaculation are the only significant side
Natural and hydrogenated ergot alkaloids The amino
effects. Its modified release (MR) capsule needs
acid alkaloids ergotamine and ergotoxine are partial agonists only once daily dosing.
and antagonists at α adrenergic, serotonergic and dopami-
Yohimbine An alkaloid from West African plant
nergic receptors. The amine alkaloid ergometrine has no α
Yohimbehe. It is a relatively selective α2 blocker with
blocking activity.
short duration of action. It may cause congestion of
The natural ergot alkaloids produce long-lasting
genitals and has been claimed to be an aphrodisiac. This
vasoconstriction which predominates over their α blocking
effect probably is only psychological.
action—peripheral vascular insufficiency and gangrene of
There are no valid indications for clinical use of yohimbine.
toes and fingers occurs in ergotism. Hydrogenation reduces
vasoconstrictor and increases α blocking activity.
Their principal use is in migraine. Dihydroergotoxine USES OF α BLOCKERS
has been used as a cognition enhancer. 1. Pheochromocytoma It is a tumour of adre-
Phentolamine It is a rapidly acting α blocker nal medullary cells. Excess CAs are secreted
with short duration of action (in minutes) which which can cause intermittent or persistent hyper-
II

has been utilized for diagnosis and intraoperative tension. Estimation of urinary CA metabolites
management of pheochromocytoma and for con- (VMA, normetanephrine) is diagnostic. In addi-
SECTION

trol of hypertension due to clonidine withdrawal, tion, a pharmacological test can be performed by
cheese reaction, etc. injecting phentolamine 5 mg i.v. A fall in BP
> 35 mmHg systolic or > 25 mmHg diastolic is
Prazosin It is first of the highly selective α1 indicative of pheochromocytoma.
blockers having α1 : α2 selectivity ratio 1000:1. It Phenoxybenzamine can be used as definitive
blocks sympathetically mediated vasoconstric- therapy for inoperable and malignant tumours. It
tion and produces fall in BP which is attended by is also employed before and during surgical
only mild tachycardia; NA release is not increased removal of the tumour. Alternatively, phentola-
due to absence of α2 blockade. mine drip can be instituted during the operation.
Prazosin dilates arterioles more than veins.
Postural hypotension occurs, especially in the 2. Hypertension Prazosin and other selective
beginning—dizziness and fainting may be α1 blockers are useful antihypertensive drugs, but
caused as ‘first dose effect’. This can be minimized the nonselective α1 + α2 blockers have been a
by starting with a low dose and taking it at failure. However, phentolamine/phenoxybenza-
bedtime. mine are of great value in controlling episodes
Prazosin is primarily used as an anti- of rise in BP during clonidine withdrawal and
hypertensive. Other uses are—LVF, Raynaud’s cheese reaction in patients on MAO inhibitors.
disease and prostatic hypertrophy—blocks α1 3. Benign hypertrophy of prostate (BHP) The
receptors in bladder trigone and prostate and thus urinary obstruction caused by BHP has a static
improves urine flow, reduces residual urine in component due to increased size of prostate and
bladder. a dynamic component due to increased tone of
Terazosin and doxazosin are longer acting smooth muscle in bladder neck and prostatic
congeners of prazosin suitable for once daily urethra. Since this increase in tone is mediated
dosing, particularly in BHP. neurogenically through α1 receptors, their
β Adrenergic Blocking Drugs 93
blockade relaxes these structures, reducing The pharmacology of propranolol is described
dynamic obstruction, increasing urinary flow rate as prototype.
and causing more complete emptying of bladder
in many patients of BHP.
Terazosin, doxazosin and tamsulosin are the
peferred α1 blockers because of once daily dosing.
Tamsulosin appears to cause fewer vascular side
effects because of relative α1A selectivity.
4. Secondary shock Shock due to blood or fluid loss is
accompanied by reflex vasoconstriction. If volume
replacement fails to reverse this, therapy with an α blocker PHARMACOLOGICAL ACTIONS
(phenoxybenzamine i.v.) can help by counteracting
vasoconstriction and improving tissue perfusion, shifting
1. CVS
blood from extravascular to vascular compartment and (a) Heart Propranolol decreases heart rate, force
from pulmonary to systemic circuit. of contraction (at relatively higher doses) and
5. Peripheral vascular diseases The α blockers afford cardiac output (c.o.). The effects on a normal
symptomatic relief when vasoconstriction is prominent as resting subject are not appreciable, but become
in Raynaud’s phenomenon, but not when vascular
obstruction is organic as in Buerger’s disease.
prominent under sympathetic overactivity
(exercise, emotion).
Cardiac work and oxygen consumption are

CHAPTER
β ADRENERGIC BLOCKING DRUGS
reduced as the product of heart rate and aortic
These drugs inhibit adrenergic responses media- pressure decreases. Overall effect in angina
ted through the β receptors. All β blockers are patients is improvement of O2 supply/demand
competitive antagonists. status: exercise tolerance is increased.
Propranolol suppresses ectopic automaticity,
CLASSIFICATION especially if it has been augmented by adrenergic

6
Nonselective (β1 and β2) stimuli. The A-V conduction is delayed. At high
a. Without intrinsic sympathomimetic activity doses, a direct depressant and membrane stabi-
Propranolol, Sotalol, Timolol. lizing (quinidine like) action is exerted, but this
b. With intrinsic sympathomimetic activity contributes little to the antiarrhythmic effect at
Pindolol. usual doses. Propranolol blocks cardiac stimulant
c. With additional α blocking property action of adrenergic drugs but not that of digoxin,
Labetalol, Carvedilol. methylxanthines or glucagon.
Cardioselective (β1) (b) Blood vessels Propranolol blocks vasodila-
Metoprolol, Atenolol, Acebutolol, Bisoprolol, tation and fall in BP evoked by isoprenaline and
Esmolol, Betaxolol, Celiprolol, Nebivolol. enhances the rise in BP caused by Adr—there is
Another system classifies β blockers into 3 generations:

First generation Second generation Third generation


(older, nonselective) (β1 selective) (with additional α blocking
and/or vasodilator property)
Propranolol Metoprolol Labetalol
Timolol Atenolol Carvedilol
Sotalol Acebutolol Celiprolol
Pindolol Bisoprolol Nebivolol
Esmolol
94 Drugs Acting on ANS
re-reversal of vasomotor reversal that is seen after propranolol therapy may reduce carbohydrate
α blockade. It has no direct effect on blood vessels tolerance by decreasing insulin release.
and there is little acute change in BP. On
6. Skeletal muscle Propranolol inhibits adre-
prolonged administration, BP gradually falls in
nergically provoked tremor. This is a peri-
hypertensive subjects but not in normotensives. pheral action exerted directly on muscle fibre
Total peripheral resistance (t.p.r.) is increased through β2 receptors.
initially (due to blockade of β mediated vaso-
dilatation) and c.o. is reduced so that there is little 7. Eye Instillation of β blockers reduces
change in BP. With continued treatment, secretion of aqueous humor: i.o.t. is lowered. There
resistance vessels gradually adapt to chronically is no consistent effect on pupil size or accom-
reduced c.o. and t.p.r. decreases—both systolic modation.
and diastolic BP fall. This is considered to be the
most likely explanation of the antihypertensive PHARMACOKINETICS
action. Other mechanisms that may contribute are:
Propranolol is well absorbed after oral adminis-
(i) Reduced NA release from sympathetic termi- tration, but has low bioavailability due to high
nals. first pass metabolism in liver. Oral: parenteral dose
(ii) Decreased renin release from kidney (β1 ratio of up to 40:1 has been found.
mediated). Metabolism of propranolol is dependent on
(iii) Central action reducing sympathetic outflow. hepatic blood flow. Chronic use of propranolol
II

2. Respiratory tract Propranolol increases itself decreases hepatic blood flow—oral bio-
availability is increased and its t½ is prolonged.
SECTION

bronchial resistance by blocking β2 receptors. The


effect is hardly discernible in normal individuals Metabolites of propranolol, one of which is active,
because sympathetic bronchodilator tone is are excreted in urine.
minimal. In asthmatics, however, the condition
is consistently worsened and a severe attack may INTERACTIONS
be precipitated. 1. Additive depression of sinus node and A-V
conduction with digitalis and verapamil—
3. CNS No overt central effects are produced cardiac arrest can occur.
by propranolol. However, subtle behavioural 2. Propranolol delays recovery from hypoglycae-
changes, forgetfulness, increased dreaming and mia due to insulin and oral antidiabetics.
nightmares have been reported with long-term Warning signs of hypoglycaemia mediated
use of relatively high doses. through sympathetic stimulation (tachycardia,
4. Local anaesthetic Propranolol is as potent tremor) are suppressed.
a local anaesthetic as lidocaine, but is not 3. Phenylephrine, ephedrine and other α
clinically used for this purpose because of its agonists present in cold remedies can cause
irritant property. marked rise in BP in β blocked subjects.
4. Though only low concentrations of Adr are
5. Metabolic Propranolol blocks adrenergi- added to lidocaine for dental anaesthesia, it may
cally induced lipolysis and consequent increase produce some pressor action in patients receiving
in plasma free fatty acid levels. Plasma trigly- nonselective β blockers.
ceride level and LDL/HDL ratio is increased. It 5. Indomethacin and other NSAIDs attenuate
also inhibits glycogenolysis—recovery from the antihypertensive action of β blockers.
insulin action is delayed. Though there is no effect 6. Propranolol retards lidocaine metabolism by
on normal blood sugar level, prolonged reducing hepatic blood flow.
β Adrenergic Blocking Drugs 95
ADVERSE EFFECTS AND 2. Less interference with carbohydrate meta-
CONTRAINDICATIONS bolism.
3. Lower incidence of cold hands and feet.
1. Propranolol can accentuate myocardial insuffi-
4. No/less deleterious effect on blood lipid
ciency and worsen CHF. However, when compen-
profile.
sation has been restored, careful addition of a β1
5. Ineffective in suppressing essential tremor.
blocker is now established therapy to prolong
survival. 6. Less liable to impair exercise capacity.
2. Bradycardia: resting HR may be reduced to Partial agonistic (intrinsic sympathomimetic)
60/min or less. action (in pindolol, acebutolol). They themselves
3. Propranolol worsens chronic obstructive lung activate β1 and/or β2 receptors submaximally.
disease; can precipitate life-threatening attack of 1. Bradycardia and depression of contractility
bronchial asthma: contraindicated in asthmatics. at rest are not prominent.
4. Propranolol exacerbates variant (vasospastic) 2. Withdrawal is less likely to exacerbate hyper-
angina due to unopposed α mediated coronary tension or angina.
constriction. 3. Not effective in migraine prophylaxis—they
5. Carbohydrate tolerance may be impaired in dilate cerebral vessels.
prediabetics. 4. Less suitable for secondary prophylaxis of MI.
6. Plasma lipid profile is altered on long-term
use. Salient features of important β blockers are given

CHAPTER
7. Withdrawal of propranolol after chronic use below:
should be gradual, otherwise rebound hyper- 1. Sotalol Nonselective β blocker that has
tension, worsening of angina and even sudden additional K+ channel blocking and class III
death can occur. antiarrhythmic property.
8. Propranolol is contraindicated in partial and
complete heart block: arrest may occur. 2. Timolol It is a β blocker used topically in
9. Tiredness and reduced exercise capacity. the eye for glaucoma.

6
10. Cold hands and feet due to blockade of Betaxolol and Levobunolol are other β blockers employed
vasodilator β2 receptors. topically for glaucoma.
11. Side effects not overtly due to β blockade are— 3. Pindolol A potent β blocker with prominent
g.i.t. upset, lack of drive, nightmares, forgetfulness, intrinsic sympathomimetic activity.
rarely hallucinations. Male patients more fre-
quently complain of sexual distress. 4. Metoprolol It is the prototype of cardio-
selective (β1) blockers. Its potency to block cardiac
OTHER β BLOCKERS stimulation is similar to propranolol, but nearly
A number of β blockers have been developed 50 times higher dose is needed to block isoprenaline
having some special features. The associated induced vasodilatation. It is less likely to worsen
properties along with their significance can be asthma and it may be preferred in diabetics
summarized as: receiving insulin or oral hypoglycaemics.
Cardioselectivity (in metoprolol, atenolol, acebu- 5. Atenolol A relatively selective β1 blocker
tolol, bisoprolol, nebivolol). having low lipid solubility. It is incompletely
These drugs are more potent in blocking cardiac absorbed orally, but first pass metabolism is not
(β1) than bronchial (β2) receptors. Their features significant. Because of longer duration of action,
are: once daily dose is often sufficient. It is one of the
1. Lower propensity to cause bronchoconstric- most commonly used β blockers for hypertension
tion. and angina.
96 Drugs Acting on ANS
6. Esmolol It is an ultrashort acting β1 blocker (i) May limit infarct size by reducing O2 con-
devoid of partial agonistic or membrane stabili- sumption—marginal tissue which is
zing actions. It is inactivated by esterases in blood; partially ischaemic may survive.
plasma t½ is < 10 min; action lasts 15–20 min (ii) May prevent arrhythmias including ventri-
after terminating i.v. infusion—degree of β block- cular fibrillation.
ade can be titrated by regulating rate of infusion. However, β blockers can be given to only those
Esmolol has been used to terminate supra- patients not in shock or cardiac failure. In
ventricular tachycardia, episodic atrial fibrillation megatrials such therapy has been found to reduce
or flutter, arrhythmia during anaesthesia, to mortality by 20–25%.
reduce HR and BP during and after cardiac
surgery, and in early treatment of myocardial 5. Congestive heart failure Although β blockers
infarction. can worsen heart failure, several studies have
reported beneficial haemodynamic effects of low
7. Nebivolol This cardioselective β blocker also doses of β1 blockers in selected patients with
acts as a nitric oxide (NO) donor: produces dilated cardiomyopathy. Introduced gradually
vasodilatation and has the potential to improve and maintained for long term, these drugs retard
endothelial function. the progression of CHF and prolong life. The
USES benefit may result from antagonism of deleterious
effects of sympathetic overactivity on myocar-
1. Hypertension β blockers are relatively mild
dium. Certain β1 blockers used appropriately
II

antihypertensives. All agents, irrespective of asso-


along with other measures under expert super-
ciated properties, are nearly equally effective. They
vision is now considered standard therapy for
SECTION

are one of the first choice drugs because of good


most mild-to-moderate CHF patients.
patient acceptability and cardioprotective
potential (see Ch. 11). 6. Dissecting aortic aneurysm β blockers help
by reducing cardiac contractile force and aortic
2. Angina pectoris All β blockers benefit angina
of effort. Taken on a regular schedule, they dec- pulsation.
rease frequency of attacks and increase exercise 7. Pheochromocytoma β blockers may be
tolerance (see Ch. 11). added to α blockers to control tachycardia and
3. Cardiac arrhythmias β blockers suppress arrhythmia.
extrasystoles and tachycardias, especially those 8. Thyrotoxicosis Propranolol rapidly controls
mediated adrenergically (during anaesthesia, symptoms (palpitation, nervousness, tremor,
digitalis induced)—may be used i.v. for this fixed stare, severe myopathy and sweating)
purpose. Esmolol is an alternative drug for without significantly affecting thyroid status. It
paroxysmal supraventricular tachycardia (see is used preoperatively and while awaiting res-
Ch. 12). ponse to antithyroid drugs/radioactive iodine.
4. Myocardial infarction (MI) In relation to MI, 9. Migraine Propranolol is the most effective
β blockers are used for two purposes: drug for chronic prophylaxis of migraine (see
(a) Secondary prophylaxis of MI: there is now firm p. 109).
evidence of benefit. Long-term use after recovery
from MI has been found to decrease subsequent 10. Anxiety Propranolol exerts an apparent
mortality by 20%. antianxiety effect, especially under conditions
(b) Myocardial salvage during evolution of MI: which provoke nervousness and panic, e.g.
administered i.v. within 4–6 hours of an attack examination, unaccustomed public appearance,
followed by continued oral therapy. β blockers— etc. This is probably due to blockade of peripheral
α + β Adrenergic Blockers 97
manifestations of anxiety (palpitation, tremor) Labetalol is 5 times more potent in blocking
which have a reinforcing effect on anxiety. β than α receptors. As such, effects of a low dose
resemble those of propranolol alone; while at high
11. Essential tremor Nonselective β blockers
doses, they are like a combination of propranolol
have an established place in treating essential
and prazosin. It causes fall in BP which is
tremor.
attended by no change or slight decrease in heart
12. Glaucoma Timolol and other ocular β rate.
blockers are one of the first choice drugs for Labetalol is orally effective but undergoes
chronic simple (wide angle) glaucoma; also used considerable first pass metabolism. It is a
as adjuvant in angle closure glaucoma. moderately potent hypotensive and is specially
13. Hypertrophic obstructive cardiomyopathy The useful in pheochromocytoma, clonidine with-
subaortic region is hypertrophic. β blockers drawal; can also be used in essential hyper-
improve c.o. in these patients during exercise, by tension. Most important side effect is postural
reducing left ventricular outflow obstruction. hypotension, though other side effects of α and β
blockers can also occur.
α + β ADRENERGIC BLOCKERS Carvedilol It is a β1 + β2 + α1 adrenoceptor
Labetalol It is the first adrenergic antagonist blocker; produces vasodilatation due to α1
capable of blocking both α and β receptors. The blockade as well as calcium channel blockade,
β blocking potency is about 1/3rd that of propra- and has antioxidant property. It has been used in

CHAPTER
nolol, while the α blocking potency is about hypertension and is the β blocker especially
1/10th of phentolamine. employed as cardioprotective in CHF.

6
7

Autacoids and Related Drugs

Autacoid This term is derived from Greek: HISTAMINE


autos—self, akos—healing substance or remedy.
Histamine, meaning ‘tissue amine’ (histos—
These are diverse substances produced by a wide
tissue) is almost ubiquitously present in animal
variety of cells in the body, having intense
tissues and in certain plants, e.g. stinging nettle.
biological activity, but generally act locally (e.g.
within inflammatory pockets) at the site of Histamine is present mostly within storage
synthesis and release. granules of mast cells. Tissues rich in histamine
They have also been called ‘local hormones’. are skin, gastric and intestinal mucosa, lungs, liver
However, they differ from ‘hormones’ in two and placenta. Nonmast cell histamine occurs in
important ways—hormones are produced by brain, epidermis, gastric mucosa and growing
specific cells, and are transported through circu- regions. Turnover of mast cell histamine is slow,
lation to act on distant target tissues. while that of nonmast cell histamine is fast.
Autacoids are involved in a number of phy- Histamine is also present in blood, most body
siological and pathological processes (especially secretions, venoms and pathological fluids.
inflammation and immunological reaction). Synthesis, storage and destruction Histamine
They even serve as transmitters or modulators is β imidazolylethylamine. It is synthesized
in the nervous system, but their role at many sites locally from the amino acid histidine and
is not precisely known. A number of useful drugs degraded rapidly by oxidation and methylation
act by modifying their action or metabolism. The (Fig. 7.1). In mast cells, histamine (positively
classical autacoids are— charged) is held by an acidic protein and heparin
Amine autacoids Histamine, 5-Hydroxytryp- (negatively charged) within intracellular
tamine (Serotonin).
Lipid-derived autacoids Prostaglandins, Leuko-
trienes, Platelet activating factor.
Peptide autacoids Plasma kinins (Bradykinin,
Kallidin), Angiotensin.
In addition, cytokines (interleukins, TNFα,
GM-CSF, etc.) and several peptides like gastrin,
somatostatin, vasoactive intestinal peptide
and many others may be considered as
autacoids. Fig. 7.1: Synthesis and degradation of histamine
Histamine 99

classified into H1 and H2. A third H3 receptor,


which serves primarily as an autoreceptor
controlling histamine release from neurones in
brain, has been lately identified, but is not of clini-
cal importance. The important features of H1 and
H2 histamine receptors are given in Table 7.1.

PHARMACOLOGICAL ACTIONS
1. Blood vessels Histamine causes marked
dilatation of smaller blood vessels, including
arterioles, capillaries and venules. On s.c. injec-
tion flushing, especially in the blush area, heat,
increased heart rate and cardiac output, with
little or no fall in BP are produced. Rapid i.v.
injection causes fall in BP which has an early
short-lasting H1 and a slow but more persistent
H2 component. Dilatation of cranial vessels
causes pulsatile headache.
Like many other autacoids and ACh, vasodi-

CHAPTER
latation caused by histamine is partly (H1 compo-
Fig. 7.2: Mechanism of antigen-antibody reaction induced nent) indirect, mediated through ‘endothelium-
release of histamine from mast cell dependent relaxing factor’ (EDRF): the receptor
being located on the endothelial cells. H2 receptors
In sensitized atopic individual, specific reaginic (IgE) antibody
is produced and gets bound to Fc epsilon receptor I (FcεRI) mediating vasodilatation are located directly on
on the surface of mast cells. On challenge, the antigen the vascular smooth muscle. Histamine also

7
bridges IgE molecules resulting in transmembrane activation causes increased capillary permeability due to
of a tyrosine-protein kinase (t-Pr-K) which phosphorylates separation of endothelial cells → exudation of
and activates phospholipaseCγ. Phosphatidyl inositol
bisphosphate (PIP2) is hydrolysed and inositol trisphosphate
plasma. This is primarily a H1 response.
(IP3) is generated which triggers intracellular release of Ca2+. Injected intradermally, it elicits the triple response
The Ca2+ ions induce fusion of granule membrane with consisting of:
plasma membrane of the mast cell resulting in exocytotic Red spot: due to intense capillary dilatation.
release of granule contents. In the granule, positively charged
histamine (Hist+) is held complexed with negatively charged
Wheal: due to exudation of fluid from
protein (Prot–) and heparin (Hep–) molecules. Cationic capillaries and venules.
exchange with extracellular Na+ (and Ca2+) sets histamine Flare: i.e. redness in the surrounding
free to act on the target cells. area due to arteriolar dilatation
mediated by axon reflex.
granules. When the granules are extruded by
2. Heart Direct effects of histamine on in situ
exocytosis, Na+ ions in e.c.f. exchange with
heart are not prominent, but the isolated heart
histamine to release it free (Fig. 7.2). Increase in
is stimulated.
intracellular cAMP inhibits histamine release.
Histamine is inactive orally because liver 3. Visceral smooth muscle Histamine
degrades all histamine that is absorbed from the causes bronchoconstriction; guineapigs and
intestines. patients of asthma are highly sensitive. Large
doses cause abdominal cramps and colic by
Histamine receptors Analogous to adrenergic increasing intestinal contractions. Other visceral
α and β receptors, histaminergic receptors are smooth muscles are not much affected.
100 Autacoids and Related Drugs

Table 7.1: Distinctive features of H1 and H2 histaminergic receptors

H1 H2
1. Selective agonists 2-Methyl histamine (8:1) 4-Methyl histamine (1:170)
(relative selectivity H1: H2) 2-Pyridylethylamine(30:1) Dimaprit (1:2000)
2-Thiazolyl ethylamine (90: 1 ) Impromidine (1:10,000)

2. Selective antagonists Mepyramine (6000:1) Cimetidine (1: 500)


(relative selectivity H1: H2) Chlorpheniramine (15000:1) Ranitidine ( l : >500)

3. Receptor type G-protein coupled G-protein coupled

4. Effector pathway PIP2 hydrolysis → IP3/DAG : Adenylyl cyclase activation —


Release of Ca2+ from intracellular stores; cAMP ↑ — phosphorylation of
Protein Kinase-C activation specific proteins

5. Distribution in body: a) Smooth muscle (intestine, airway, a) Gastric glands — acid secretion
actions mediated uterus) — contraction b) Blood vessels (smooth
b) Blood vessels muscle) — dilatation
i) Endothelium: Release of EDRF, c) Heart
PGI2 — vasodilatation. Atria: +ive chronotropy
widening of gap junctions — Ventricles: +ive inotropy
increased capillary permeability d) Uterus (rat)—relaxation
ii) Smooth muscle — vasoconstriction. e) Brain — transmitter
II

c) Afferent nerve endings — stimulation


d) Ganglionic cell — stimulation.
SECTION

e) Adrenal medulla — release of CAs.


f) Brain—transmitter.

PIP2 — Phosphatidyl inositol bisphosphate; IP3 — Inositol trisphosphate; DAG — Diacylglycerols:


EDRF— Endothelium dependent relaxing factor: PGI2 — Prostacyclin;
CAs — Catecholamines: cAMP —Cyclic 3', 5' adenosine monophosphate; ACh — acetylcholine

4. Glands Histamine causes marked increase administration produces rise in BP, cardiac
in gastric secretion—primarily of acid but also stimulation, behavioural arousal, hypothermia,
of pepsin (see Ch. 18). This is a direct action vomiting and ADH release.
exerted on parietal cells through H2 receptors
and is mediated by increased cAMP generation, PATHOPHYSIOLOGICAL ROLES
which in turn activates the membrane proton 1. Gastric secretion Histamine has dominant
pump (H+ K+ ATPase). physiological role in mediating secretion of HCl
5. Sensory nerve endings Itching occurs when in the stomach (see Fig. 18.1). Histamine is
histamine is injected i.v. or intracutaneously. released locally under the influence of all stimuli
Higher concentrations injected more deeply that evoke gastric secretion (feeding, vagal
cause pain. stimulation, cholinergic drugs and gastrin) and
activates the proton pump (K+H+ATPase)
6. Autonomic ganglia and adrenal medulla through H2 receptors to secrete HCl.
These are stimulated and release of Adr occurs,
2. Allergic phenomena Released from mast cells
which can cause a secondary rise in BP.
following AG : AB reaction, histamine is causative
7. CNS Histamine does not penetrate blood- in urticaria, angioedema, bronchoconstriction
brain barrier—no central effects are seen on and anaphylactic shock. The H1 antagonists are
i.v. injection. However, intracerebroventricular effective in controlling these manifestations to a
H1 Antagonists 101

considerable extent, except asthma and to a lesser are well controlled. Anaphylactic fall in BP is
extent anaphylactic fall in BP in which leuko- only partially prevented. Asthma in man is
trienes (especially LTD4) and PAF appear to be practically unaffected.
more important. Histamine is not involved in 3. CNS The older antihistamines produce
delayed or retarded type of allergic reactions. variable degree of CNS depression. This appears
3. As transmitter Histamine is believed to be to depend on the compound’s ability to penetrate
the afferent transmitter which initiates the sen- blood-brain barrier and its affinity for the central
sation of itch and pain at sensory nerve endings. (compared to peripheral) H1 receptors. Individual
In the brain, it is involved in maintaining susceptibility to different agents varies consi-
wakefulness; (H1 antihistaminics owe their derably, but an overall grading of the sedative
sedative action to blockade of this function) and property is presented in Table 7.2. Some indivi-
appears to regulate many other functions. duals also experience stimulant effects like
restlessness and insomnia. Excitement and con-
4. Inflammation Histamine has been implica-
vulsions are frequently seen at toxic doses. The
ted as a mediator of vasodilatation and other
second generation antihistaminics are practically
changes that occur during inflammation. It may
nonsedating.
also regulate microcirculation according to the
Certain (see below) H1 antihistamines are
local needs.
effective in preventing motion sickness. Prome-
5. Headache Histamine has been implicated thazine also controls vomiting of pregnancy and

CHAPTER
in certain vascular headaches, but there is no other causes.
conclusive evidence. Promethazine and a few other antihistami-
Histamine has no therapeutic use. nics reduce tremor, rigidity and sialorrhoea of
parkinsonism. Anticholinergic and sedative
H1 ANTAGONISTS properties underlie the benefit. Some H1 anti-
(Conventional antihistaminics) histamines are used as antitussives (see Ch. 19).

7
These drugs competitively antagonize actions of 4. Anticholinergic action Many H1 blockers in
histamine at the H1 receptors. addition antagonize muscarinic actions of ACh.
The anticholinergic action can be graded as:
Pharmacological actions
High Low Minimal/Absent
Qualitatively all H1 antihistaminics have similar
actions, but there are quantitative differences, Promethazine Chlorpheniramine Fexofenadine
Diphenhydramine Hydroxyzine Astemizole
especially in the sedative property. Dimenhydrinate Triprolidine Loratadine
1. Antagonism of histamine They effectively Pheniramine Cyclizine Cetirizine
Cyproheptadine Mizolastine
block histamine induced bronchoconstriction,
contraction of intestinal and other smooth muscle
5. Local anaesthetic Some drugs have strong
and triple response—especially wheal, flare and
while others have weak membrane stabilizing
itch. Fall in BP produced by low doses of hista-
property. However, they are not used clinically
mine is blocked, but additional H2 antagonists
as local anaesthetic because they cause irritation
are required for complete blockade of higher
when injected s.c.
doses. Action of histamine on gastric secretion is
Membrane stabilizing activity also confers
singularly not affected by these drugs.
antiarrhythmic property to these compounds.
2. Antiallergic action Many manifestations of
immediate hypersensitivity (type I reactions) are 6. BP Most antihistaminics cause a fall in BP
suppressed. Urticaria, itching and angioedema on i.v. injection (direct smooth muscle
102 Autacoids and Related Drugs

Table 7.2: Clinical classification, doses and preparations of H1 antihistaminics

Drug Dose and route Preparations


I. HIGHLY SEDATIVE
Diphenhydramine 25–50 mg oral BENADRYL 25 mg cap., 12.5 mg/5 ml syr.
Dimenhydrinate 25–50 mg oral, DRAMAMINE 16 mg/5 ml syr, 50 mg tab
Promethazine 25–50 mg oral, PHENERGAN 10, 25 mg tab., 5 mg/ml elixer,
i.m. (1 mg/kg) 25 mg/ml inj
Hydroxyzine 25–50 mg oral, ATARAX 10, 25 mg tab., 10 mg/5 ml syr, 6 mg/ml
i.m. drops, 25 mg/ml inj.

II. MODERATELY SEDATIVE


Pheniramine 20–50 mg oral, AVIL 25 mg, 50 mg tab, 15 mg/5 ml syr,
i.m. 22.5 mg/ml inj.
Cyproheptadine 4 mg oral PRACTIN, CIPLACTIN 4 mg tab., 2 mg/5 ml syrup,
Meclozine (Meclizine) 25–50 mg oral In DILIGAN 12.5 mg + niacin 50 mg tab
Cinnarizine 25–50 mg oral STUGERON, VERTIGON 25 and 75 mg tab.

III. MILD SEDATIVE


Chlorpheniramine 2–4 mg (0.1 mg/kg) PIRITON, CADISTIN 4 mg tab
oral, i.m.
II

Dexchlorpheniramine 2 mg oral POLARAMINE 2 mg tab, 0.5 mg/5 ml syr


Triprolidine 2.5–5 mg oral ACTIDIL 2.5 mg tab.
SECTION

Mebhydroline 100–300 mg oral INCIDAL 50 mg (base) tab.


Cyclizine 50 mg oral MAREZINE 50 mg tab.
Clemastine 1-2 mg oral TAVEGYL 1 mg tab, 0.5 mg/5 ml syr.

IV. SECOND GENERATION ANTIHISTAMINICS


Fexofenadine 120–180 mg oral ALLEGRA, ALTIVA, FEXO 120, 180 mg tab
Astemizole 10 mg oral STEMIZOLE, HISTALONG, STEMIZ, 5 mg,
10 mg tab., 1 mg/ml susp.
Loratadine 10 mg oral LORFAST, LORIDIN, LORMEG, 10 mg tab,
1 mg/ml susp.
Desloratadine 5 mg oral DESLOR, LORDAY 5 mg tab
Cetirizine 10 mg oral ALERID, CETZINE, ZIRTIN, SIZON 10 mg tab,
5 mg/5 ml syr.
Levocetirizine 5-10 mg oral LEVOSIZ, LEVORID, TECZINE 5, 10 mg tab.
Azelastine 4 mg oral AZEP NASAL SPRAY 0.14 mg per puff nasal spray
0.28 mg intranasal
Mizolastine 10 mg oral ELINA 10 mg tab
Ebastine 10 mg oral EBAST 10 mg tab

relaxation). However, this is not evident on oral urine. They are widely distributed in the body
administration. and enter brain. The newer compounds pene-
Pharmacokinetics The classical H1 antihistami- trate brain poorly. Duration of action of most
nics are well absorbed from oral and parenteral agents is 4–6 hours, except astemizole, lorata-
routes, metabolized in the liver and excreted in dine, cetirizine and fexofenadine which act for
H1 Antagonists 103

12–24 hours or more. On repeated use, many extent of involvement of histamine (acting
antihistamines induce their own metabolism. through H1 receptors) in the disease state. Their
Side effects and toxicity Side effects with first principal indications are:
generation H1 antihistaminics are frequent, but (i) Allergic rhinitis and conjunctivitis, hay
are generally mild. Individuals show marked fever, pollinosis—control sneezing, runny
differences in susceptibility to side effects with but not blocked nose, and red, watering,
different drugs. Some tolerance to side effects itchy eyes.
develops on repeated use. (ii) Urticaria, dermographism, atopic eczema.
Sedation, diminished alertness and concen- (iii) Acute allergic reactions to drugs and foods.
tration, light headedness, motor incoordination, They have poor antipruritic, antiemetic and
fatigue and tendency to fall asleep are the most antitussive actions.
common. Objective testing shows impairment of A life-threatening adverse effect due to overdose or drug
psychomotor performance. Patients should be interaction occurred with some SGAs. Terfenadine, the first
SGA introduced clinically, was found to cause polymorphic
cautioned not to operate motor vehicles or ventricular tachycardia (Torsades de pointes) in a few patients.
machinery requiring constant attention. Alcohol The risk was markedly increased in liver disease or when
synergises in producing these effects as do other erythromycin, clarithromycin, ketoconazole or itraconazole
CNS depressants. Few individuals become rest- (inhibitors of CYP 3A4) were given concurrently. This adverse
effect occurs due to blockade of cardiac K+ channels by high
less, nervous and are unable to sleep. Second concentrations of terfenadine (but not by its active metabolite).
generation compounds are largely free of CNS Similar incidences have been reported with astemizole and

CHAPTER
effects. are possible with ebastine, but not with other SGAs.
Dryness of mouth, alteration of bowel movement, Terfenadine has been withdrawn by the manufacturers.
urinary hesitancy and blurring of vision can be Fexofenadine It is the active metabolite of
ascribed to anticholinergic property. terfenadine that does not block delayed rectifier
Epigastric distress and headache are also K+ channels in the heart—does not prolong QTc
common. interval. Therefore, it has been introduced as a

7
Local application can cause contact dermatitis. substitute of terfenadine free of arrhythmogenic
potential.
SECOND GENERATION ANTIHISTAMINICS
Astemizole It has slow onset (2–4 hr) and long
The second generation antihistaminics (SGAs) duration (2–5 days) of action. An active
may be defined as those H1 receptor blockers metabolite is produced whose t½ is 12–19 days.
marketed after 1980 which have one or more of Astemizole is better used for maintenance
the following properties: therapy and is not suitable for rapid control of
• Absence of CNS depressant property. symptoms. In perennial rhinitis it has shown
• Higher H1 selectivitiy: no anticholinergic side good efficacy. However, it shares the ventricular
effects. tachycardia producing potential of terfenadine.
• Additional antiallergic mechanisms apart
Loratadine Another long-acting selective peri-
from histamine blockade.
pheral H1 antagonist which lacks CNS depres-
These newer drugs have the advantage of not
sant effects and is faster acting than astemizole.
impairing psychomotor performance (driving,
Good efficacy has been reported in urticaria and
etc. need not be contraindicated), produce no
atopic dermatitis.
subjective effects, no sleepiness, do not potentiate
Desloratadine is the active metabolite of
alcohol or benzodiazepines. Some patients do
loratadine with similar properties.
complain of sedation, but incidence is similar to
placebo. However, they have a narrow spectrum Cetirizine This nonsedating antihistamine in
of therapeutic usefulness which is limited by the addition inhibits release of histamine and
104 Autacoids and Related Drugs

cytotoxic mediators from platelets as well as eosi- 3. Pruritides Though relief is often incomplete,
nophil chemotaxis during the secondary phase older antihistaminics remain the first choice
of the allergic response. Thus, it may benefit drugs for idiopathic pruritus.
allergic disorders by other actions as well. It is 4. Common cold Antihistaminics do not affect
indicated in upper respiratory allergies, polli-
the course of the illness but may afford symptoma-
nosis, urticaria and atopic dermatitis; also used
tic relief by anticholinergic (reduce rhinorrhoea)
as adjuvant in seasonal asthma.
and sedative actions. The newer nonsedating anti-
Its active R(–) enantiomer has been marketed
histamines are less effective in this respect.
as Levocetirizine, claimed to produce fewer side
effects. 5. Motion sickness Promethazine, diphenhy-
dramine, dimenhydrinate and cyclizine have
Azelastine This newer H1 blocker has good prophylactic value in milder types of motion
topical activity. Given by nasal spray for seasonal
sickness; should be taken one hour before
and perennial allergic rhinitis it provides quick
starting journey. Promethazine can also be used
symptomatic relief lasting 12 hr. Stinging in the
in morning sickness, drug induced and post-
nose and altered taste perception are the local
operative vomiting.
side effects.
6. Vertigo Cinnarizine is the H1 antihistamine
USES having additional anticholinergic, anti-5-HT,
sedative and vasodilator properties which has
The uses of H1 antihistaminics are based on their
II

been widely used in vertigo. It inhibits vestibular


ability to block certain effects of histamine relea- sensory nuclei in the inner ear, possibly by
SECTION

sed endogeneously, as well as on sedative and reducing stimulated influx of Ca2+ from endo-
anticholinergic properties. lymph into the vestibular sensory cells.
1. Allergic disorders They do not suppress 7. Preanaesthetic medication Promethazine
AG: AB reaction, but block the effects of released has been used, especially in children, for its
histamine—are only palliative. They effectively anticholinergic and sedative properties.
control certain immediate type of allergies, e.g. 8. Cough Antihistaminics like chlorphenira-
itching, urticaria, seasonal hay fever, allergic mine, diphenhydramine, promethazine are
conjunctivitis and angioedema of lips, eyelids, constituents of many popular cough remedies.
etc. However, their action is slow—Adr alone is
They have no selective cough suppressant action,
life saving in laryngeal angioedema. Similarly,
but may afford symptomatic relief by sedative
they cannot be relied upon in anaphylactic shock
and anticholinergic action.
and have a secondary place to Adr. Benefits are
less marked in perennial vasomotor rhinitis, 9. Parkinsonism Promethazine and some others
atopic dermatitis and chronic urticarias. afford mild symptomatic relief in early cases—
Certain newer compounds like cetirizine have based on anticholinergic and sedative property.
adjuvant role in seasonal asthma. 10. Acute muscle dystonia Caused by antieme-
Type I hypersensitivity reactions to drugs tic-antipsychotic drugs is promptly relieved by
(except asthma and anaphylaxis) are suppressed. parenteral promethazine or hydroxyzine. This
Some skin rashes also respond. is again based on central anticholinergic action
2. Other conditions involving histamine They of the drugs.
afford symptomatic relief in insect bite and 11. As sedative, hypnotic, anxiolytic Antihista-
ivy poisoning. Abnormal dermographism is mines with CNS depressant action have been
suppressed. They have prophylactic value in used as sedative and to induce sleep, but are not
blood/saline infusion induced rigor. as dependable as benzodiazepines. Prometha-
5-Hydroxytryptamine 105
zine, commonly used to sedate children, has pro- synthesize but acquire 5-HT by uptake during
duced severe respiratory depression in some passage through intestinal blood vessels. Again,
young children. It is contraindicated below 2 years like CAs, 5-HT is stored within storage vesicles
age. and its uptake at the vesicular membrane is
inhibited by reserpine.
H2 antagonists They are primarily used in
peptic ulcer and other gastric hypersecretory Serotonergic (5-HT) receptors
states (see Ch. 18).
Four families of 5-HT receptors (5-HT1, 5-HT2,
5-HT3, 5-HT4-7) comprising of 14 receptor
5-HYDROXYTRYPTAMINE
subtypes have so far been recognized. However,
(5-HT, Serotonin)
only some of these have been functionally
Serotonin was the name given to the vasocons- correlated or their selective agonists/antagonists
trictor substance which appeared in serum when defined. Knowledge of subtypes of 5-HT recep-
blood clotted, and was shown to be 5-hydroxytry- tors has assumed importance because some
ptamine (5-HT). About 90% of body’s content of newly developed therapeutically useful drugs
5-HT is localized in the intestines; most of the can only be described as 5-HT receptor subtype
rest is in platelets and brain. It is also found in selective agonists or antagonists.
wasp and scorpion sting and widely distributed
in invertebrates and plants (banana, pear, Important 5-HT receptor subtypes
pineapple, tomato, stinging nettle, cowhage).

CHAPTER
5-HT1 : Autoreceptors; inhibit serotonergic
neural activity in brain.
Synthesis, storage and destruction
5-HT1A—present in raphe nuclei and
5-HT is β-aminoethyl-5-hydroxyindole. It is syn- hippocampus; buspirone appears to
thesized from the amino acid tryptophan and exert antianxiety action through these
degraded primarily by MAO and to a small receptors.

7
extent by a dehydrogenase (Fig. 7.3). 5-HT1B/1D—Constricts cranial blood
Like NA, 5-HT is actively taken up by an vessels and inhibits release of
amine pump serotonin transporter (SERT) which inflammatory neuropeptides in them;
operates at the membrane of platelets (therefore, sumatriptan controls migraine
5-HT does not circulate in free form in plasma) through these receptors.
and serotonergic nerve endings. It is inhibited 5-HT2A : Most important postjunctional
by tricyclic antidepressants. Platelets do not receptor mediating direct actions of 5-
HT like vascular and visceral smooth
muscle contraction, platelet aggre-
gation, neuronal activation in brain;
ketanserin blocks these receptors.
5-HT3 : Depolarizes neurones by gating cation
channels; elicits reflex effects of 5-
HT—emesis, gut peristalsis, brady-
cardia, transient hypotension, apnoea,
pain, itch; ondansetron acts as
antiemetic by blocking these receptors.
5-HT4 : Mediate intestinal secretion, augmen-
tation of peristalsis. Renzapride is a
Fig. 7.3: Synthesis and degradation of
selective 5-HT4 agonist.
5-hydroxytryptamine (5-HT)
106 Autacoids and Related Drugs

All 5-HT receptors (except 5-HT3) are G 6. Migraine: probably involved in initiating
protein coupled receptors which function constriction of cranial vessels and inducing
through decreasing (5-HT1) or increasing (5-HT4, neurogenic inflammation of vessel wall.
5-HT6, 5-HT7) cAMP production or by generating 7. Haemostasis by promoting platelet aggre-
IP3/DAG (5-HT2) as second messengers. The 5- gation and blood vessel retraction.
HT3 is a ligand gated cation (Na+, K+) channel 8. Vasospastic disorders like Raynaud’s
which on activation elicits fast depolarization. phenomenon and variant angina.
9. Carcinoid syndrome: mediates bowel
Actions hypermotility and bronchoconstriction.
5-HT is a potent depolarizer of nerve endings. 5-HT ANTAGONISTS
It thus exerts direct as well as reflex and indirect
effects. Tachyphylaxis is common with repeated The ability to antagonize at least some actions
doses of 5-HT. The overall effects, therefore, are of 5-HT is found in many classes of drugs, e.g.
often variable; important ones are: ergot derivatives (ergotamine, LSD, 2-bromo
1. Constriction of larger arteries and veins, but LSD, methysergide), adrenergic α blockers
dilatation of arterioles: variable and phasic effect (phenoxybenzamine), antihistaminics (cypro-
on BP. heptadine, cinnarizine), chlorpromazine, mor-
2. Isolated heart is stimulated, but in the intact phine, etc., but these are nonselective and interact
animal bradycardia due to coronary chemoreflex with several other receptors as well. Drugs that
II

predominates. have been used as 5-HT antagonists and some


3. Enhanced peristalsis and secretion in gut → newer subtype selective agents are:
SECTION

diarrhoea.
1. Cyproheptadine It primarily blocks 5-HT2A
4. Inhibition of gastric acid and pepsin
receptors and has additional H1 antihistaminic,
secretion; augmentation of mucus production:
anticholinergic and sedative properties. Like
ulceroprotective.
other antihistaminics, it has been used in
5. Activation of afferent nerve endings—
allergies and is a good antipruritic. It increases
tingling or pricking sensation, pain; cardiovas-
appetite and has been recommended in children
cular and respiratory reflexes are elicited.
and poor eaters to promote weight gain.
6. Proaggregatory action on platelets.
The anti-5-HT activity of cyproheptadine has
been utilized in controlling intestinal manifes-
Pathophysiological roles ascribed to 5-HT are:
tations of carcinoid and postgastrectomy dump-
1. Neurotransmitter in brain, especially raphe
nuclei, substantia nigra, limbic system, cortex, ing syndromes.
etc; involved in sleep, temperature regulation, 2. Methysergide Methysergide is a potent 5-HT2A/2C and
cognitive function, behavior and mood, weak 5-HT1 antagonist. It has been used for migraine pro-
phylaxis, carcinoid and postgastrectomy dumping syndrome.
vomiting and pain perception.
3. Ketanserin It has 5-HT2 receptor blocking property
2. Regulation of gut peristalsis by 5-HT with negligible action on 5-HT1, 5-HT3 and 5-HT4 receptors
containing neurones on enteric plexuses and and no partial agonistic activity.
enterochromaffin cells. Ketanserin is an effective antihypertensive, but α1
3. Precursor of melatonin in pineal gland: adrenergic blockade appears to be causative rather than 5-
HT2A blockade.
regulation of biological clock.
4. Control of anterior pituitary hormone 4. Clozapine In addition to being a dopami-
function by hypothalamus. nergic antagonist (weaker than the typical
5. Nausea and vomiting, especially that evoked neuroleptics), this atypical antipsychotic is a
by cancer chemotherapy/radiotherapy. 5-HT2A/2C blocker (see Ch. 10).
Drug Therapy of Migraine 107
5. Risperidone This atypical antipsychotic is Dihydroergotamine (DHE) Hydrogenation of
a combined 5-HT2A + dopamine D2 antagonist, ergotamine reduces serotonergic and α-adrener-
similar to clozapine. gic agonistic actions, but enhances α-receptor
blocking property. Consequently, DHE is a less
6. Ondansetron It is the prototype of selective
potent vasoconstrictor.
5-HT3 antagonists that have shown remarkable
efficacy in controlling nausea and vomiting Dihydroergotoxine (Codergocrine) This hydro-
following administration of highly emetic genated mixture of ergotoxine group of alkaloids
anticancer drugs and radiotherapy (see Ch. 18). is a more potent α blocker and a very weak
vasoconstrictor. It has been advocated for
ERGOT ALKALOIDS treatment of dementia.
Ergot is a fungus Claviceps purpurea which grows on rye, Bromocriptine The 2 bromo derivative of ergo-
millet and some other grains. Epidemics of ergot poisoning cryptine is a relatively selective dopamine D2
(ergotism), due to consumption of contaminated grains, have
been recorded from the beginning of history. It still occurs
agonist on pituitary lactotropes (inhibits pro-
in epidemic and sporadic forms. Dry gangrene of hands and lactin release), in striatum (antiparkinsonian)
feet which become black (as if burnt) is the most prominent and in CTZ (emetic—but less than ergotamine).
feature. Miscarriages occur in women and cattle. A
convulsive type is also described. Ergometrine (Ergonovine) This amine ergot
Ergot contains a host of pharmacologically alkaloid has a very weak agonistic and prac-
active substances—alkaloids, LSD, histamine, tically no antagonistic action on α adrenergic

CHAPTER
ACh, tyramine and other amines, sterols, etc. receptors: vasoconstriction is not significant.
Partial agonistic action on 5-HT receptors has
Ergot alkaloids are tetracyclic indole contain- been demonstrated in uterus, placental and
ing compounds which may be considered as deri- umbilical blood vessels. The most prominent
vatives of lysergic acid. They are divided into— action is contraction of myometrium. It is used
(a) Amine alkaloid Ergometrine (Ergonovine): exclusively in obstetrics (see Ch. 15).

7
which is oxytocic.
(b) Amino acid alkaloids Ergotamine, Ergotoxine DRUG THERAPY OF MIGRAINE
(mixture of ergocristine + ergocornine + Migraine is a mysterious disorder characterized by pulsating
ergocryptine): that are vasoconstrictor and headache, usually restricted to one side, which comes in
α adrenergic blocker. attacks lasting 4–48 hours and is often associated with nausea,
vomiting, sensitivity to light and sound, vertigo, loose
The ergot alkaloid-related compounds have
motions and other symptoms. Two major types are—migraine
diverse pharmacological properties. They act as with aura (classical migraine) in which headache is preceded
agonists, partial agonists and antagonists on by visual or other neurological symptoms, and migraine
certain subtypes of α adrenergic, serotonergic without aura (common migraine). Pulsatile dilatation of
and dopaminergic receptors: activity differing certain large cranial vessels is the immediate cause of pain.
The pathogenic mechanisms are not well understood. Some
depending on the tissue and the compound. triggering event appears to produce neurogenic
inflammation of the affected blood vessel wall which is
Ergotamine It acts as a partial agonist and
amplified by retrograde transmission in the afferent
antagonist at α adrenergic and all subtypes of nerves and release of mediators like 5-HT, neurokinin,
5-HT1 and 5-HT2 receptors, produces sustained substance P, calcitonin gene-related peptide (CGRP), nitric
vasoconstriction, visceral smooth muscle con- oxide, etc.
Changes in blood/urinary levels of 5-HT and its
traction, vasomotor centre depression and
metabolites during migraine attack, its precipitation by 5-
antagonizes the action of NA and 5-HT on HT releasers and efficacy of drugs having actions in the
smooth muscles. It is a potent emetic (through serotonergic system to prevent/abort/terminate migraine
CTZ) and moderately potent oxytocic. attacks suggests a pivotal role of 5-HT in this disorder.
108 Autacoids and Related Drugs

Drug therapy of migraine


Severity Drug therapy
Mild : Simple analgesics/NSAIDs or their combinations (± antiemetic)
Moderate : NSAIDs combinations/ergot alkaloids/sumatriptan (+ antiemetic)
Severe : Ergot alkaloids/sumatriptan/rizatriptan (+ antiemetic)
+ Prophylaxis • Propranolol/other β blockers
• Amitriptyline/other tricyclic antidepressants
• Flunarizine/other Ca2+ channel blockers
• Valproate/topiramate
• Methysergide/cyproheptadine

Drug therapy of migraine has to be individua- vomiting and other features are more prominent
lized: severity and frequency of attacks and and the patient is functionally impaired.
response of individual patients to various drugs Simple analgesics are usually not effective,
determine the choice. The strategy mostly but stronger NSAIDs or their combinations men-
adopted is summarized in the box. tioned above are beneficial in many cases. The
remaining patients are treated with an ergot
Mild migraine Cases having fewer than one
II

preparation or sumatriptan. Antiemetics are


attack per month of throbbing but tolerable
almost regularly needed. Prophylactic therapy
headache lasting up to 8 hours which does not
SECTION

is advised only when attacks are more frequent


incapacitate the individual may be classified as
than 2 to 3 per month.
mild migraine.
(i) Simple analgesics like paracetamol (500 Severe migraine These patients suffer more
mg) or aspirin (300–600 mg) taken at the first than 2 to 3 attacks per month of severe throbbing
indication of an attack and repeated 4–6 hourly headache lasting 12–48 hours, often accom-
abort and suppress most mild attacks. panied by vertigo, vomiting and other
(ii) Nonsteroidal antiinflammatory drugs symptoms; the subject is grossly incapacitated
(NSAIDs) and their combinations Drugs like during the attack.
ibuprofen (400–800 mg 8 hourly), diclofenac (50 Analgesics/NSAIDs and their combinations
mg 8 hourly), mephenamic acid (500 mg 8 hourly), usually do not afford adequate relief—specific
either alone or combined with paracetamol/ drugs like ergot alkaloids/sumatriptan have to
codeine/diazepam/diphenhydramine/caffeine be prescribed along with antiemetics. Prophylac-
are found more satisfactory by some patients. tic regimens lasting 6 months or more are recom-
Drugs are taken only till the attack passes off. mended.
Taken in the prodromal stage they also have a
Ergotamine It is the most effective ergot
prophylactic effect.
alkaloid for migraine. Given early in attack, relief
(iii) Antiemetics Metoclopramide (10 mg
is often dramatic and lower doses suffice, but
oral/i.m.) is frequently used. Domperidone (10–
when pain has become severe—larger doses are
20 mg oral) and prochlorperazine (10–25 mg
needed and control may be achieved only after
oral/i.m.) are also effective.
a few hours.
Moderate migraine Migraine may be labelled Ergotamine probably acts by constricting the
as moderate when the throbbing headache is dilated cranial vessels. It has also been shown
more intense, lasts for 6–24 hours, nausea/ to reduce neurogenic inflammation and leakage
Prostaglandins and Leukotrienes 109
of plasma in duramater that occurs due to moderate-to-severe migraine when more than
retrograde stimulation of perivascular afferent 2 to 3 attacks occur per month. Diverse classes
nerves. These actions appear to be mediated of drugs are used but none is effective in all cases,
through partial agonism at 5-HT1B/1D receptors and none abolishes the attacks totally.
in and around cranial vessels.
(i) β-Adrenergic blockers Propranolol is the
Dihydroergotamine (DHE) It is nearly as effec- most commonly used drug: reduces frequency
tive as ergotamine and preferred for parenteral as well as severity of attacks in up to 70%
administration because injected DHE is less patients. Effect is generally seen in 4 weeks and
hazardous. Orally, it is a safer alternative to is sustained during prolonged therapy.
ergotamine in patients who respond to this drug.
Ergot alkaloids should be discontinued when (ii) Tricyclic antidepressants Many tricyclic
relief is obtained. They have no prophylactic compounds, of which amitriptyline has been
value. Caffeine 100 mg taken with ergotamine en- most extensively tried, reduce migraine attacks.
hances its absorption from oral and rectal routes It is effective in many patients but produces more
and adds to the cranial vasoconstricting action. side effects than propranolol.
Sumatriptan This novel selective 5-HT1B/1D (iii) Calcium channel blockers Flunarizine is
receptor agonist does not interact with 5-HT2, claimed to be a cerebro-selective Ca2+ channel
5-HT3, 5-HT4-7, α or β adrenergic, dopaminergic, blocker which may benefit migraine by reducing
cholinergic or GABA receptors. Administered at intracellular Ca2+ overload due to brain hypoxia

CHAPTER
the onset of an attack of migraine sumatriptan and other causes. It may reduce frequency of
is as effective and better tolerated than ergo- attacks, but effect on intensity and duration of
tamine. It tends to suppress nausea and vomiting attacks is less marked.
of migraine, while ergotamine accentuates these
symptoms. The antimigraine activity of sumatri- (iv) Anticonvulsants Valproic acid and topira-
ptan has been ascribed to 5-HT1B/1D receptor mate can reduce the frequency of migraine

7
mediated constriction of dilated cranial attacks, but are less effective than propranolol;
extracerebral blood vessels. Like ergotamine, the may be tried when the latter is contraindicated.
triptans have been found to suppress neurogenic The 5-HT antagonists methysergide and
inflammation of cranial vessels. cyproheptadine have less impressive prophy-
lactic effect in migraine and produce more side
Side effects to sumatriptan are usually mild.
effects than propranolol.
Tightness in head and chest, feeling of heat and
other paresthesias in limbs, dizziness, weakness
are short lasting but dose-related side effects. PROSTAGLANDINS AND LEUKOTRIENES
Bradycardia, coronary vasospasm and risk of (Eicosanoids)
myocardial infarction are the serious but Prostaglandins (PGs) and Leukotrienes (LTs) are
infrequent adverse effects. biologically active derivatives of 20 carbon atom
It is contraindicated in patients with ischaemic polyunsaturated essential fatty acids that are
heart disease, hypertension, epilepsy, hepatic or released from cell membrane phospholipids.
renal impairment and during pregnancy. They are the major lipid-derived autacoids.
Rizatriptan is a more potent and slightly faster In the 1930s, human semen was found to contract isolated
acting congener of sumatriptan. uterine and other smooth muscle strips and to cause fall in BP
in animals. The active principle was termed ‘prostaglandin’,
thinking that it was derived from prostate. Only in 1960s, it
Prophylaxis of migraine
was shown to be a mixture of closely related compounds, the
Regular medication to reduce the frequency chemical structures were elucidated and widespread
and/or severity of attacks is recommended for distribution was revealed. In 1970s, it became clear that
110 Autacoids and Related Drugs
aspirin-like drugs act by inhibiting PG synthesis, and that in more types of PGs or LTs. The pathways of
addition to the classical PGs (Es and Fs), thromboxane (TX),
biosynthesis of eicosanoids are summarized in
prostacyclin (PGI) and leukotrienes (LTs) were of great
biological importance. Bergstrom, Samuelsson and Vane got Fig. 7.4.
the Nobel prize in 1982 for their work on PGs and LTs. There are no preformed stores of PGs and
LTs. They are synthesized locally at rates
CHEMISTRY, BIOSYNTHESIS AND governed by the release of arachidonic acid from
DEGRADATION membrane lipids in response to appropriate
stimuli. These stimuli activate hydrolases,
Chemically, PGs may be considered to be deri- including phospholipase A.
vatives of prostanoic acid, though prostanoic acid The cyclooxygenase (COX) pathway generates
does not naturally occur in the body. It has a five
eicosanoids with a ring structure (PGs, TXs,
membered ring and two side chains projecting
prostacyclin) while lipoxygenase (LOX) produces
in opposite directions at right angle to the plane
open chain compounds (LTs). All tissues have
of the ring. There are many series of PGs
COX—can form cyclic endoperoxides PGG2 and
designated A, B, C,..., I, and thromboxanes (TXs)
PGH2 which are unstable compounds. Further
depending on the ring structure and the
course in a particular tissue depends on the type
substituents on it. Each series has members with
of isomerases or other enzymes present in it.
subscript 1, 2, 3 indicating the number of double
PGE2 and PGF2α are the primary prostaglandins.
bonds in the side chains.
Lung and spleen can synthesize the whole range
Leukotrienes are so named because they
II

of COX products. Platelets primarily synthesize


were first obtained from leukocytes (leuko) and
have 3 conjugated double bonds (triene). They TXA2 which is chemically unstable, sponta-
SECTION

have also been similarly designated A, B, C,..., F neously changes to TXB2. Endothelium mainly
and given subscripts 1, 2, 3, 4. generates prostacyclin (PGI2) that is also
In the body PGs, TXs and LTs are all derived chemically unstable and rapidly converts to 6-
keto PGF1α.
Cyclooxygenase is now known to exist in two
isoforms COX-1 and COX-2. While both isoforms
catalyse the same reactions, COX-1 is a consti-
tutive enzyme in most cells—its activity is not
changed once the cell is fully grown. On the other
hand, COX-2 normally present in insignificant
amounts is inducible by cytokines, growth factors
from 5,8,11,14 eicosa tetraenoic acid (arachidonic and other stimuli during the inflammatory
acid). During PG, TX and prostacyclin synthesis, response. It is believed that eicosanoids produced
2 of the 4 double bonds of arachidonic acid get by COX-1 participate in physiological (house
saturated in the process of cyclization, leaving 2 keeping) functions such as secretion of mucus
double bonds in the side chain. Thus, subscript for protection of gastric mucosa, haemostasis and
2 PGs are most important in man, e.g. PGE2, maintenance of renal function, while those
PGF2α, PGI2, TXA2. No cyclization or reduction produced by COX-2 lead to inflammatory and
of double bonds occurs during LT synthesis— other pathological changes. However, certain
the LTs of biological importance are LTB4, LTC4, sites in kidney and brain constitutively express
LTD4. COX-2 which may play physiological role.
Eicosanoids are the most universally distri- Lipoxygenase pathway appears to operate
buted autacoids in the body. Practically, every mainly in the lung, WBC and platelets. Its most
cell and tissue is capable of synthesizing one or important products are the LTs, (generated by
Prostaglandins and Leukotrienes 111

CHAPTER
Fig. 7.4: Biosynthesis of prostaglandins (PG) and leukotrienes (LT). Less active metabolites are shown in italics
TX—Thromboxane, PGI—Prostacyclin; HPETE—Hydroperoxy eicosatetraenoic acid (Hydroperoxy arachidonic acid);
HETE—Hydroxyeicosatetraenoic acid (Hydroxy arachidonic acid); SRS-A—Slow-reacting substance of anaphylaxis

5-LOX) particularly LTB4 (potent chemotactic) induction of COX-2 by cytokines at the site of

7
and LTC4, LTD4 which together constitute the inflammation.
‘slow reacting substance of anaphylaxis’ (SRS-A).
Degradation of arachidonates occurs rapidly
Inhibition of synthesis Synthesis of COX in most tissues, but fastest in the lungs. Most PGs,
products can be inhibited by nonsteroidal TXA2 and prostacyclin have plasma t½ of a few
antiinflammatory drugs (NSAIDs). Aspirin seconds to a few minutes. First a specific carrier
acetylates COX at a serine residue and causes mediated uptake into cells occurs, the side chains
irreversible inhibition, while other NSAIDs are are then oxidized and double bonds are reduced
competitive and reversible inhibitors. Most in a stepwise manner to yield inactive
NSAIDs are nonselective COX-1 and COX-2 metabolites. Metabolites are excreted in urine.
inhibitors, but some newer ones like celecoxib, PGI2 is catabolized mainly in the kidney.
etoricoxib are selective for COX-2.
NSAIDs do not inhibit the production of LTs: PROSTAGLANDINS, THROMBOXANES AND
this may even be increased since all the arachido- PROSTACYCLIN
nic acid becomes available to the LOX pathway.
Glucocorticosteroids inhibit the release of Actions
arachidonic acid from membrane lipids (by The cyclic eicosanoids produce a wide variety of
stimulating production of proteins called annexins actions depending upon the particular PG (or TX
or lipocortins which inhibit phospholipase A2) — or PGI), species on which tested, tissue, hormonal
indirectly reduce production of all eicosanoids— status and other factors. PGs differ in their
PGs, TXs and LTs. Moreover, they inhibit the potency to produce a given action and different
112 Autacoids and Related Drugs

PGs sometimes have opposite effects. Even the 6. Because PGs are present in high concen-
same PG may have opposite effects under tration in semen and can be rapidly absorbed
different circumstances. The actions of important when lodged in the vagina at coitus, it is believed
PGs, PGI2 and TXA2 are summarized in Table 7.3. that they so coordinate movements of the female
genital tract that transport of sperms and
Patho-physiological roles fertilization is facilitated.
Since virtually all cells and tissues are capable 7. Dysmenorrhoea in many women is asso-
of forming PGs, these autacoids have been imp- ciated with increased PG synthesis by the endo-
licated as mediators or modulators of a number metrium. This apparently induces uncoordi-
of physiological processes and pathological nated uterine contractions which compress
states. blood vessels → uterine ischaemia → pain.
1. PGI2 is probably involved in the regulation Aspirin group of drugs are highly effective in
of local vascular tone as a dilator. relieving dysmenorrhoea in most women.
2. PGE2 and PGI2 are believed to be conti- 8. Asthma may be due to an imbalance bet-
nuously produced locally in the ductus ween constrictor PGs (F2a, PGD2, TXA2) and LTs
arteriosus during foetal life—keep it patent. At on one hand and dilator ones (PGE2, PGI2) on
birth their synthesis stops and closure occurs. the other. However, in allergic human asthma,
Aspirin and indomethacin have been found to LTs are more important and COX inhibitors are
induce closure when it fails to occur without any effect in most patients.
II

spontaneously. These PGs may also be impor- 9. PGs may be involved in mediating toxin
tant in maintaining placental blood flow. induced increased fluid movement in secretory
SECTION

3. PGs, along with LTs and other autacoids may diarrhoeas. PGs appear to play a role in the
mediate vasodilatation and exudation at the site growth of colonic polyps and cancer. Association
of inflammation. of low incidence of colon cancer with regular
4. TXA2 (produced by platelets) and PGI2 intake of aspirin is now established.
(produced by vascular endothelium) probably 10. PGs (especially PGI2) appear to be involved
constitute a mutually antagonistic system: in the regulation of gastric mucosal blood flow
preventing aggregation of platelets while in and PGE2 enhances gastric mucus production.
circulation and inducing aggregation on injury, They may be functioning as natural ulcer
when plugging and thrombosis are needed. protectives. The ulcerogenic action of NSAIDs
Aspirin interferes with haemostasis by may be due to loss of this protective influence.
inhibiting platelet aggregation which is due to 11. PGs appear to function as intrarenal
TXA2 production. Before it is deacetylated in regulators of blood flow as well as tubular
liver, aspirin acetylates COX in platelets while reabsorption in kidney. The NSAIDs tend to
they are in portal circulation. Further, platelets retain salt and water. The diuretic action of
are unable to regenerate fresh COX (lack nucleus: furosemide is blunted by indomethacin—indica-
do not synthesize protein), while vessel wall is ting a facilitatory role of PGs by increasing renal
able to do so (fresh enzyme is synthesized within blood flow and/or augmenting inhibition of
hours). Thus, in low doses, aspirin selectively tubular reabsorption.
inhibits TXA2 production and has antithrombotic 12. PGE2 may mediate bacterial or other
effect lasting > 3 days. pyrogen-induced fever and malaise at the level
5. PGs produced by foetal tissues at term of hypothalamus. Aspirin and other inhibitors
probably mediate initiation and progression of of PG synthesis are antipyretic.
labour. Aspirin has been found to delay the ini- 13. PGs may be functioning as neuromodulators
tiation of labour and also prolongs its duration. in the brain by regulating neuronal excitability.
Table 7.3: A summary of the actions of major prostaglandins, prostacyclin and thromboxane

Organ Prostaglandin E2 (PGE2) Prostaglandin F2α (PGF2α) Prostacyclin (PGI2) Thromboxane A2 (TXA2)
1. Blood Vasodilatation, ↓ BP Vasodilatation (mostly), larger veins Vasodilatation (marked and Vasoconstriction
vessels constrict, little effect on BP widespread), ↓ ↓ BP
2. Heart Weak inotropic, reflex Weak inotropic — —
cardiac stimulation
3. Platelets Variable effect — Antiaggregatory Aggregation and
release reaction
4. Uterus Contraction (in vivo), relaxes Contraction (in vivo and in vitro), — —
nongravid human uterus in softening of cervix
vitro, softening of cervix
5. Bronchi Dilatation, inhibit histamine Constriction Dilatation (mild), inhibit Constriction
release histamine release
6. Stomach ↓ acid secretion, — ↓ acid secretion (weak), —
↑ mucus production mucosal vasodilatation
7. Intestine Contracts longitudinal & relaxes Spasmogenic, ↑ fluid & electrolyte Weak spasmogenic, inhibit Weak spasmogenic
circular muscles, ↑ peristalsis, secretion (weak) toxin-induced fluid secretion
↑ Cl¯ & water secretion
8. Kidney Natriuresis, ↓ Cl¯ reabsorp- — Natriuresis, vasodilatation, Vasoconstriction
tion, inhibit ADH action, renin release
vasodilatation, renin release
9. CNS Pyrogenic, variety of effects
on i.c.v. inj.
10. Release ↑ or ↓ ↑ or ↓
of NA
11. Afferent Sensitize to noxious stimuli — Same as PGE2 —
nerves → tenderness
12. Endocrine Release of ant. pituitary Release of gonadotropins & — —
system hormones, steroids, insulin; prolactin, luteolysis (in animals)
TSH-like action
13. Metabolism Antilipolytic, insulin-like action, — — —
mobilization of bone Ca2+
Prostaglandins and Leukotrienes 113

7 CHAPTER
114 Autacoids and Related Drugs

cardiac output and reduction in circulating


volume due to increased capillary permeability.
These LTs markedly increase capillary
permeability and are more potent than histamine
in causing local edema formation.
LTB4 is highly chemotactic for neutrophils
and monocytes. Migration of neutrophils
through capillaries and their clumping at sites
of inflammation in tissues is also promoted by
LTB4.
Role LTs are important mediators of inflam-
mation. They are produced (along with PGs)
Fig. 7.5: Sensitization of nociceptors (pain receptors) to
locally at the site of injury. While LTC4 and D4
mediators of pain by prostaglandins at the inflammatory site cause exudation of plasma, LTB4 attracts the
inflammatory cells which reinforce the reaction.
They may also modulate sympathetic neuro- 5-HPETE and 5-HETE may facilitate local release
transmission in the periphery. of histamine from mast cells.
14. PGs (especially E2 and I2) sensitize afferent
nerve endings to pain inducing chemical and 2. Smooth muscle LTC4 and D4 contract
most smooth muscles. They are potent
II

mechanical stimuli (Fig. 7.5). They irritate


mucous membranes and produce long lasting bronchoconstrictors and induce spastic
SECTION

dull pain on intradermal injection. contraction of g.i.t. at low concentrations.


PGs appear to serve as algesic agents during They also increase mucus secretion in the
inflammation. They cause tenderness and airways.
amplify the action of other algesics. Inhibition of Role The cysteinyl LTs (C4 and D4) are the most
PG synthesis is a major antiinflammatory important mediators of human allergic asthma.
mechanism. They are released along with PGs and other
15. PG F2α lowers i.o.t. by enhancing uveoscleral autacoids during AG: AB reaction in the lungs.
outflow of aqueous humor. Several nonirritating In comparison to other mediators, they are more
PG congeners like latanoprost are first line drugs
potent and are metabolized slowly in the lungs,
for open angle glaucoma.
exert a long lasting action. LTs may also be
responsible for abdominal colics during systemic
LEUKOTRIENES
anaphylaxis.
The straight chain lipoxygenase products of
3. Afferent nerves Like PGE2 and I2, the LTB4
arachidonic acid are produced by a more limited
also sensitizes afferents carrying pain impulses—
number of tissues (LTB4 mainly by neutrophils;
contributes to pain and tenderness of inflam-
LTC4 and LTD4—the cysteinyl LTs—mainly by
mation.
macrophages) but probably they are pathophy-
siologically as important as PGs. PROSTANOID RECEPTORS
PGs, TX and prostacyclin act on their own specific receptors
1. CVS and blood LTC4 and LTD4 injected i.v. located on cell membrane. Five major types of prostanoid
evoke a brief rise in BP followed by a more receptors have been designated, each after the natural PG
prolonged fall. The fall in BP is not due to for which it has the greatest affinity. All prostanoid receptors
are G-protein coupled receptors which utilize the IP3/DAG
vasodilatation because no relaxant action has or cAMP transducer mechanisms. Some selective antagonists
been seen on blood vessels. It is probably a result of prostanoid receptors have been produced. The prostanoid
of coronary constriction induced decrease in receptors are:
Platelet Activating Factor 115
DP Has greatest affinity for PGD2, but PGE2 also acts on it. 6. Glaucoma: Topical latanoprost (PGF2α ana-
EP Has greatest affinity for PGE2; enprostil is a selective logue) is a first line drug.
agonist. It mediates both smooth muscle contraction and 7. To maintain patency of ductus arteriosus in
relaxation.
neonates with congenital heart disease:
FP Has greatest affinity for PGF2α; fluprostenol is a selective alprostadil (PGE1) i.v. infusion.
agonist. The most prominent effect of activation of this
receptor is smooth muscle contraction mediated through IP3/ 8. To avoid platelet damage during haemo-
DAG formation. dialysis/cardiopulmonary bypass.
IP Has greatest affinity for PGI2; PGE also acts on it and
cicaprost is a selective agonist. It functions by activating PLATELET ACTIVATING FACTOR (PAF)
adenylyl cyclase in platelets (inhibiting aggregation) and
smooth muscles (relaxation). Like eicosanoids, platelet activating factor (PAF)
is a cell membrane- derived polar lipid with
TP Has greatest affinity for TXA2; PGH2 also acts on it. It
utilizes IP3/DAG as second messengers which mediate intense biological activity; discovered in 1970s
platelet aggregation and smooth muscle contraction. and now recognized to be an important signal
molecule. PAF is acetyl-glyceryl ether-
LEUKOTRIENE RECEPTORS phosphoryl choline.
Separate receptors for LTB4 and for the cysteinyl LTs (LTC4, Synthesis and degradation PAF is synthesized from
LTD4) have been defined. Two subtypes cysLT1 and precursor phospholipids present in cell membrane by the
cys LT2 of the cysteinyl LT receptor have been cloned. All following reactions:
LT receptors function through the IP3/DAG transducer

CHAPTER
mechanism. Many cysLT1 receptor antagonists, viz. PAF-acetyl
Montelukast, Zafirlukast, etc. are now valuable drugs for Phospholipase A2 transferase
bronchial asthma (see Ch 19). Membrane
Acyl-glycero- Lyso PAF PAF
phosphocholine
USES Fatty acid Acetyl CoA CoA

Clinical use of PGs and their analogues is rather The second step is rate limiting. Antigen-antibody reaction
restricted because of limited availability, short and a variety of mediators stimulate PAF synthesis on

7
lasting action, cost, side effects and other prac- demand: there are no preformed stores of PAF. In contrast
to eicosanoids, the types of cells which synthesize PAF is
tical considerations. Their approved indications quite limited—mainly WBC, platelets, vascular endothelium
are: and kidney cells.
1. Abortion: Single oral dose of misoprostol after PAF is degraded by reversal of the above reactions and
the product is incorporated back into the membrane.
2 days of mifepristone (antiprogestin) priming is
used to terminate pregnancy of upto 7 weeks Actions PAF has potent actions on many tissues/organs.
duration. Extra or intra amniotic injection of PGE2 Platelets Aggregation and release reaction; also releases
or PGF2α can be used for 2nd trimester abortion. TXA2; i.v. injection results in intravascular thrombosis.
2. Induction/augmentation of labour: Intra- WBC PAF is chemotactic to neutrophils, eosinophils and
vaginal PGE2 or PGF2α are alternative to i.v. monocytes. It stimulates neutrophils to aggregate, to stick
oxytocin, but less reliable. to vascular endothelium and migrate across it to the site of
3. Cervical priming: Low doses of PGE2 applied infection. It also prompts release of lysosomal enzymes and
LTs and generation of superoxide radical by the polymorphs.
in cervical canal/vagina make the cervix soft and
Blood vessels Vasodilatation occurs mediated by release
more compliant for abortion/delivery. of EDRF → fall in BP on i.v. injection.
4. Postpartum haemorrhage: Carboprost (15-
PAF is the most potent agent known to increase vascular
methyl PGF2α) i.v. is an alternative to permeability. Wheal and flare occur at the site of intradermal
ergometrine/oxytocin. injection.
5. Peptic ulcer: Misoprostol (PGE1 analogue) can Visceral smooth muscle Contraction occurs by direct action
be used to heal NSAID-associated peptic ulcer. as well as through release of LTC4, TXA2 and PGs.
116 Autacoids and Related Drugs

Aerosolized PAF is a potent bronchoconstrictor. In addition, some structural analogues of PAF. The PAF antagonists have
it produces mucosal edema, secretion and a delayed and manyfold therapeutic potentials but none has been found
long-lasting bronchial hyper-responsiveness. It also worth marketing. Alprazolam and triazolam antagonize
stimulates intestinal and uterine smooth muscle. some actions of PAF.
Stomach Ulcerogenic: erosions and mucosal bleeding occur Pathophysiological roles PAF has been implicated in
shortly after i.v. injection of PAF. The gastric smooth muscle many physiological processes and pathological states,
contracts. especially those involving cell-to-cell interaction. These are:
Mechanism of action Membrane bound specific PAF 1. Inflammation
receptors have been identified. The PAF receptor is a 2. Bronchial asthma
G-protein coupled receptor which exerts most of the 3. Anaphylactic (and other) shock conditions
actions through intracellular messengers IP3/DAG → Ca2+ 4. Haemostasis and thrombosis
release. 5. Rupture of mature graafian follicle and implantation
6. Labour
PAF antagonists A number of natural and synthetic PAF
7. Ischaemic states of brain, heart and g.i.t., including
receptor antagonists have been investigated. Important
among these are ginkgolide B (from a Chinese plant), and g.i. ulceration.
II
SECTION
8
General Anaesthetics and
Skeletal Muscle Relaxants

GENERAL ANAESTHETICS monary alveoli needed to produce immobility in


response to a painful stimulus (surgical incision)
General anaesthetics (GAs) are drugs which
in 50% individuals. It is accepted as a valid
produce reversible loss of all sensation and
measure of potency of inhalational GAs because
consciousness. The cardinal features of general
it remains fairly constant for a given species even
anaesthesia are:
under varying conditions.
• Loss of all sensation, especially pain The MAC of a number of GAs shows
• Sleep (unconsciousness) and amnesia excellent correlation with their oil/gas partition
• Immobility and muscle relaxation coefficient. However, this only reflects capacity
• Abolition of reflexes. of the anaesthetic to enter into CNS and attain
sufficient concentration in the neuronal mem-
In the modern practice of balanced anaesthesia,
brane, but not the mechanism by which anaes-
these modalities are achieved by using combi-
thesia is produced.
nation of drugs, each drug for a specific purpose.
Recent evidence favours a direct interaction
Anaesthesia has developed as a highly specia-
of the GA molecules with hydrophobic domains
lized science in itself. In dental practice, general
of membrane proteins or the lipid-protein
anaesthesia is employed occasionally; is admini-
interface.
stered and managed by a qualified anaesthetist,
Different anaesthetics may be acting through
and not by the dental surgeon himself.
different molecular mechanisms and various
components of the anaesthetic state involve
Mechanism of general anaesthesia
action at discrete loci in the cerebrospinal axis.
The mechanism of action of GAs is not precisely The principal locus of causation of unconscious-
known. A wide variety of chemical agents pro- ness appears to be in the thalamus or reticular
duce general anaesthesia. Therefore, GA action activating system, amnesia may result from
had been related to some common physicoche- action in hippocampus, while spinal cord is
mical property of the drugs. Mayer and Overton the likely seat of immobility on surgical
(1901) pointed out a direct parallelism between stimulation.
lipid/water partition coefficient of the GAs and Recent findings show that ligand gated ion channels
their anaesthetic potency. (but not voltage sensitive ion channels) are the major
targets of anaesthetic action. The GABAA receptor gated
Minimal alveolar concentration (MAC) is the Cl¯ channel is the most important of these. Many
lowest concentration of the anaesthetic in pul- inhalational anaesthetics, barbiturates, benzodiazepines
118 General Anaesthetics and Skeletal Muscle Relaxants
and propofol potentiate the action of inhibitory trans- anaesthesia becomes light to deep. Most dental/
mitter GABA to open Cl¯ channels. Each of the above
anaesthetics appears to interact with its own specific
surgical procedures are carried out at plane 1 or 2.
binding site on the GABAA receptor-Cl¯ channel complex, IV. Medullary paralysis From cessation of
but none binds to the GABA binding site as such. Action breathing to failure of circulation and death. It is
of glycine (another inhibitory transmitter which also
never attempted.
activates Cl¯ channels) in the spinal cord and medulla
is augmented by barbiturates, propofol and many inhala- These clear-cut stages are not seen now-a-
tional anaesthetics. This action may block responsiveness days with the use of faster acting GAs,
to painful stimuli resulting in immobility of the premedication and employment of many drugs
anaesthetic state. Certain fluorinated anaesthetics and
barbiturates, in addition, inhibit neuronal cation channel
together. The precise sequence of events differs
gated by nicotinic cholinergic receptor which may mediate somewhat with anaesthetics other than ether.
analgesia and amnesia. The modern anaesthetist has to depend on
On the other hand, N2O and ketamine do not affect several other observations to gauge the depth of
GABA or glycine gated Cl¯ channels. Rather they selec-
tively inhibit the excitatory NMDA type of glutamate anaesthesia.
receptor. This receptor gates mainly Ca2+ selective cation • If eyelash reflex is present and patient is
channels in the neurones and their inhibition appears to making swallowing movements—Stage II has
be the primary mechanism of anaesthetic action of
ketamine as well as N2O. The volatile anaesthetics have
not been reached.
little action on this receptor. • Incision of the skin causes reflex increase in
Unlike local anaesthetics which act primarily respiration, BP rise or other effects; insertion
by blocking axonal conduction, the GAs appear of endotracheal tube is resisted and induces
II

to act by depressing synaptic transmission. coughing, vomiting, laryngospasm; tears


appear in eye; passive inflation of lungs is
SECTION

Stages of anaesthesia resisted—anaesthesia is light.


GAs cause an irregularly descending depression • Fall in BP, cardiac and respiratory depression
of the CNS, i.e. the higher functions are lost first are signs of deep anaesthesia.
and progressively lower areas of the brain are In the present-day practice, anaesthesia is
involved, but in the spinal cord lower segments generally kept light; adequate analgesia, amnesia
are affected somewhat earlier than the higher and muscle relaxation are produced by the use
segments. The vital centres located in the of intravenous drugs. Concentrations of inhala-
medulla are paralysed the last as the depth of tional anaesthetics exceeding 1.2 MAC are rarely
anaesthesia increases. Guedel (1920) described used.
four stages with ether anaesthesia.
I. Stage of analgesia From beginning of
anaesthetic inhalation to loss of consciousness; Pharmacokinetics of inhalational anaesthetics
pain is progressively abolished; some minor Inhalational anaesthetics are gases or vapours
procedures can be performed, but it is difficult to that diffuse rapidly across pulmonary alveoli
maintain. and tissue barriers. The depth of anaesthesia
II. Stage of delirium From loss of consciousness depends on the potency of the agent (MAC is an
to beginning of regular respiration; excitement, index of potency) and its partial pressure (PP)
struggling, breath-holding, jerky breathing, in the brain, while induction and recovery
sympathetic stimulation occur. No procedure can depend on the rate of change of PP in the brain.
be carried out. This stage is inconspicuous in
Transfer of the anaesthetic between lung and
modern anaesthesia.
brain depends on a series of tension gradients
III. Surgical anaesthesia From onset of regular
which may be summarized as—
respiration to cessation of spontaneous breathing.
This stage has been divided into 4 planes as Alveoli Blood Brain
Inhalational Anaesthetics 119

Factors affecting the PP of anaesthetic attained which govern induction also govern recovery.
in brain are— Anaesthetics, in general, persist for long periods
1. PP of anaesthetic in the inspired gas Higher in adipose tissue because of their high lipid solu-
the inspired tension more anaesthetic will be bility and low blood flow through fatty tissues.
transferred to the blood hastening induction. Muscles occupy an intermediate position
between brain and adipose tissue. Most GAs are
2. Pulmonary ventilation It governs delivery of
eliminated unchanged. Metabolism is significant
the GA to the alveoli. Hyperventilation will bring
only for halothane which is about 20% meta-
in more anaesthetic per minute and quicken
induction. bolized in liver.

3. Alveolar exchange The GAs diffuse freely Second gas effect and diffusion hypoxia In
across alveoli, but if alveolar ventilation and the initial part of induction, diffusion gradient
perfusion are mismatched (as occurs in emphy- from alveoli to blood is high and larger quantity
sema and other lung diseases) the attainment of of anaesthetic is entering blood. If the inhaled
equilibrium between alveoli and blood will be concentration of anaesthetic is high, substantial
delayed. Induction and recovery both are loss of alveolar gas volume will occur and the
slowed. gas mixture will be sucked in, independent of
4. Solubility of anaesthetic in blood This is the ventilatory exchange—gas flow will be higher
most important property determining induction than tidal volume. This is significant only with

CHAPTER
and recovery. Large amount of an anaesthetic N2O since it is given at 70–80% concentration.
that is highly soluble in blood (ether) must Though it has low solubility in blood, about 1
dissolve before its PP is raised. The rise as well litre/min of N2O enters blood in the first few
as fall of PP in blood and consequently induction minutes—gas flow is 1 litre/min higher than
as well as recovery are slow. Drugs with low minute volume. If another potent anaesthetic, e.g.
blood solubility, e.g. N2O, sevoflurane, desflurane halothane (given at 1–2% concentration) is being

8
induce quickly. given at the same time, it also will be delivered
to blood at a rate 1 litre/min higher than minute
5. Solubility of anaesthetic in tissues Relative
volume and induction will be faster—second gas
solubility of anaesthetic in blood and tissues
effect.
determines its concentration in tissues at
The reverse occurs when N2O is dis-
equilibrium. Most of GAs are equally soluble in
continued after prolonged anaesthesia—N2O
lean tissues as in blood but more soluble in fatty
having low blood solubility rapidly diffuses into
tissue. Anaesthetics with higher lipid solubility
(halothane) continue to enter adipose tissue for alveoli and dilutes the alveolar air—PP of
hours and also leave it slowly. oxygen in alveoli is reduced. The resulting
hypoxia, called diffusion hypoxia, is not of much
6. Cerebral blood flow Brain is a highly per- consequence if cardiopulmonary reserve is
fused organ; as such GAs are quickly delivered normal, but may be dangerous if it is low. This
to it. This can be hastened by CO2 inhalation can be prevented by continuing 100% O2
which causes cerebral vasodilatation—induction inhalation for a few minutes after discontinuing
and recovery are accelerated. N2O, instead of straight away switching over to
Elimination When anaesthetic administration air. Diffusion hypoxia is not significant with
is discontinued, gradients are reversed and the other anaesthetics because they are administered
channel of absorption (pulmonary epithelium) at low concentrations (0.2–4%) and cannot dilute
becomes the channel of elimination. Same factors alveolar air by more than 1–2%.
120 General Anaesthetics and Skeletal Muscle Relaxants

Table 8.1: Physical and anaesthetic properties of inhalational anaesthetics

Anaesthetic Boiling Inflamma- Irritancy Oil: Gas Blood: Gas MAC Induction Muscle
point (°C) bility (odour) partition partition (%) relaxation
coefficient* coefficient*
1. Ether 35 Infl. + +++ 65 12.1 1.9 Slow V. good
Explo. (Pungent)
2. Halothane 50 Noninfl. – 224 2.3 0.75 Interm. Fair
(Pleasant)
3. Isoflurane 48 Noninfl. ± 99 1.4 1.2 Fast Good
(Not pleasant)
4. Desflurane 24 Noninfl. + 19 0.42 6.0 Fast Good
(Unpleasant)
5. Sevoflurane 59 Noninfl. – 50 0.68 2.0 Fast Good
(Pleasant)
6. Nitrous oxide Gas Noninfl. – 1.4 0.47 105 Fast Poor

* At
37oC
MAC—Minimal alveolar concentration; Infl.—Inflammable; Explo.—Explosive; Interm.—Intermediate

Properties of an ideal anaesthetic bilizes>90 individuals (at MAC only 50% are
II

A. For the patient It should be pleasant, non- immobilized), and 2–3 MAC is often lethal.
irritating, should not cause nausea or vomiting. The important physical and anaesthetic
SECTION

Induction and recovery should be fast with no properties of inhalational anaesthetics are
after effects. presented in Table 8.1.
B. For the surgeon It should provide adequate
analgesia, immobility and muscle relaxation. CLASSIFICATION
It should be noninflammable and nonexplosive Inhalational
so that cautery may be used.
Gas Liquids
C. For the anaesthetist Its administration Nitrous oxide Ether
should be easy, controllable and versatile. Halothane
• Margin of safety should be wide—no fall in Isoflurane
BP. Heart, liver and other organs should not Desflurane
be affected. Sevoflurane
• It should be potent so that low concentrations
are needed and oxygenation of the patient Intravenous
does not suffer. Inducing agents Slower acting drugs
• Rapid adjustments in depth of anaesthesia Thiopentone sod. Benzodiazepines
should be possible. Methohexitone sod. Diazepam
• It should be cheap, stable and easily stored. Propofol Lorazepam
• It should not react with rubber tubing or soda Midazolam
lime. Dissociative anaesthesia
The inhalational anaesthetics have a steep con- Ketamine
centration-response relationship: increasing the Opioid analgesia
concentration only by 10% over MAC immo- Fentanyl
Inhalational Anaesthetics 121

INHALATIONAL ANAESTHETICS flammable. Solubility in blood is intermediate—


1. Nitrous oxide (N 2O) It is a colourless, induction is reasonably quick and pleasant.
odourless, heavier than air, noninflammable gas It is a potent anaesthetic. For induction 2–4%
supplied under pressure in steel cylinders. It is and for maintenance 0.5–1% is delivered by the
a nonirritating but low potency anaesthetic; use of a special vaporizer. It is not a good
unconsciousness cannot be produced in all analgesic or muscle relaxant; however, it poten-
individuals without concomittent hypoxia: MAC tiates competitive neuromuscular blockers.
is 105% implying that even pure N2O cannot Halothane causes direct depression of myo-
produce adequate anaesthesia at 1 atmosphere cardial contractility. Cardiac output is reduced
pressure. with deepening anaesthesia. BP starts falling
Nitrous oxide is a good analgesic (even 20% early and parallels the depth. Heart rate is often
produces moderate analgesia) but poor muscle reduced by direct depression of SA nodal auto-
relaxant. Onset of N2O action is quick and maticity and lack of baroreceptor activation even
smooth (but thiopentone is often used for when BP falls. It tends to sensitize the heart to
induction), recovery is rapid. Second gas effect the arrhythmogenic action of Adr. Halothane
and diffusion hypoxia occur with N2O only. causes relatively greater depression of respira-
Post-anaesthetic nausea is not marked. tion; breathing is shallow and rapid. Ventilatory
Nitrous oxide is generally used as a carrier support with added oxygen is frequently
and adjuvant to other anaesthetics. A mixture of required.

CHAPTER
70% N2O + 25–30% O2 + 0.2–2% another potent Pharyngeal and laryngeal reflexes are aboli-
anaesthetic is employed for most surgical shed early and coughing is suppressed while
procedures. bronchi dilate—preferred for asthmatics. It
As the sole agent, N2O (50%) has been used inhibits intestinal and uterine contractions.
with O2 for obstetric analgesia. In dental practice Hepatitis occurs in susceptible individuals
N2O is now used to provide ‘conscious sedation’ (approximately 1 in 10,000) especially after
repeated use. A genetically determined reaction

8
for allaying anxiety and apprehension (see
p. 125). It is nontoxic to liver, kidney and brain. malignant hyperthermia occurs rarely. It is due to
It is cheap and very commonly used. intracellular release of Ca2+ from sarcoplasmic
reticulum through an abnormal RyR calcium
2. Ether (Diethyl ether) It is a highly volatile liquid, channel causing persistent muscle contraction
produces irritating vapours which are inflammable and
explosive. Ether is a potent anaesthetic, produces good and increased heat production.
analgesia and marked muscle relaxation—the dose of About 20% of halothane that enters blood is
competitive neuromuscular blockers should be reduced metabolized in the liver, the rest is exhaled out.
to about 1/3rd. Recovery from halothane anaesthesia is smooth
It is highly soluble in blood—induction is prolonged
and unpleasant with struggling, breath-holding, saliva- and reasonably quick; shivering may occur but
tion and marked respiratory secretions (atropine must nausea and vomiting are rare. Psychomotor per-
be given as premedication to prevent the patient from formance and mental ability remain depressed
drowning in his own secretions). Recovery is slow; post- for several hours after regaining consciousness.
anaesthetic nausea, vomiting and retching are marked.
Ether has gone out of use because of its unpleasant Halothane is a routinely used anaesthetic in
and inflammable properties. However, it is occasionally India, but in affluent countries it has been
used in peripheral areas because it is—cheap, can be given replaced by the newer and costlier congeners.
by open drop method without the need for any equip-
ment, and is relatively safe even in inexperienced hands.
4. Isoflurane (SOFANE) This potent fluorinated
3. Halothane (FLUOTHANE) It is a volatile anaesthetic has properties similar to halothane,
liquid with sweet odour, nonirritant and nonin- but is less soluble in blood—produces rapid
122 General Anaesthetics and Skeletal Muscle Relaxants

induction and recovery. Fall in BP is like than isoflurane but more than desflurane.
halothane, but it tends to increase heart rate. Induction and emergence from anaesthesia are
Isoflurane does not sensitize the heart to fast and rapid changes in depth can be achieved.
adrenergic arrhythmias. Absence of pungency makes it pleasant and
Respiratory depression is prominent and administrable through face mask. Unlike
assistance is usually needed to avoid hyper- desflurane, it poses no problem in induction;
carbia. Secretions are slightly increased. Renal acceptability is good even by pediatric patients.
and hepatic toxicity has not been encountered. Recovery is smooth; orientation, cognitive and
Postanaesthetic nausea and vomiting is low. motor functions are regained almost as quickly
Though slightly irritant, isoflurane has many as with desflurane. Sevoflurane is suitable for
advantages, i.e. better adjustment of depth of both outpatient and inpatient surgery, but its
anaesthesia and low toxicity. It does not provoke high cost and need for high flow open system
seizures and is preferred for neurosurgery. In makes it very expensive to use.
many hospitals it has become the routine
anaesthetic. INTRAVENOUS ANAESTHETICS

5. Desflurane It is a recently developed all INDUCING AGENTS


fluorinated congener of isoflurane which has These are drugs which on i.v. injection produce
gained popularity as an anaesthetic for out- loss of consciousness in one arm-brain circu-
patient surgery in western countries. Its lation time (~11 sec); are generally used for
II

distinctive properties are high volatility, lower induction because of rapidity of onset of action.
oil: gas partition coefficient and very low
SECTION

Anaesthesia is then usually maintained by an


solubility in blood as well as tissues because of inhalational agent. They also serve to reduce the
which induction and recovery are very fast. amount of maintenance anaesthetic. Supple-
Depth of anaesthesia changes rapidly with mented with analgesics and muscle relaxants,
change in inhaled concentration. Postanaesthetic they can also be used as the sole anaesthetic.
cognitive and motor impairment is shortlived—
patient can be discharged a few hours after 1. Thiopentone sod It is an ultrashort acting
surgery. thiobarbiturate, highly soluble in water yielding
Desflurane is less potent than isoflurane; a very alkaline solution, which must be prepared
higher concentration has to be used for freshly before injection. Extravasation of the
induction—irritates air passage—may induce solution or inadvertent intraarterial injection
coughing, breath-holding and laryngospasm produces intense pain—necrosis and gangrene
because of somewhat pungent odour making it may occur.
difficult to use for induction. Degree of respiratory Injected i.v. (3–5 mg/kg) it produces uncons-
depression, muscle relaxation, vasodilatation and ciousness in 15–20 sec. Its undissociated form
fall in BP, as well as maintained cardiac contrac- has high lipid solubility—enters brain almost
tility and coronary circulation are like isoflurane. instantaneously. Initial distribution depends on
Desflurane can serve as a good alternative to organ blood flow—brain gets large amounts.
isoflurane for routine surgery as well, especially However, as other less vascular tissues (muscle,
prolonged operations. fat) gradually take up the drug, blood concen-
tration falls and it back diffuses from the brain;
6. Sevoflurane It is the latest polyfluorinated consciousness is regained in 6–10 min (t½ of
anaesthetic with properties intermediate bet- distribution phase is 3 min).
ween isoflurane and desflurane. Solubility in On repeated injection, the extracerebral sites
blood and tissues as well as potency are less are gradually filled up—lower doses produce
Intravenous Anaesthetics 123
anaesthesia which lasts longer. Its ultimate few patients. Induction apnoea lasting ~1 min
disposal occurs mainly by hepatic metabolism is common. Fall in BP due primarily to vasodila-
(elimination t½ is 7–12 hr). Residual CNS dep- tation occurs consistently and is occasionally
ression may persist for > 12 hr. The patient severe, but short lasting. Bradycardia is also
should not be allowed to leave the hospital frequent.
without an attendant before this time. In subanaesthetic doses it has been used for
Thiopentone is a poor analgesic. Painful sedating intubated patients in intensive care
procedures should not be carried out under its units.
influence unless an opioid or N2O has been
given; otherwise, the patient may struggle, shout SLOWER ACTING DRUGS
and show reflex changes in BP and respiration. 1. Benzodiazepines (BZDs) In addition to
It is a weak muscle relaxant. BP falls preanaesthetic medication, BZDs are now
immediately after injection mainly due to vaso- frequently used for inducing, maintaining and
dilatation, but recovers rapidly. supplementing anaesthesia as well as for cons-
Thiopentone is a commonly used inducing cious sedation. Relatively large doses (diazepam
agent, but seldom employed in dentistry. 0.2–0.5 mg/kg or equivalent) injected i.v. produce
Adverse effects Laryngospasm occurs gene- sedation, amnesia and then unconsciousness in
rally when respiratory secretions or other irri- 5–10 min. If no other anaesthetic or opioid is
given, the patient becomes responsive in 1 hr or

CHAPTER
tants are present, or when intubation is attemp-
ted while anaesthesia is light. This can be so due to redistribution of the drug (distribution
prevented by atropine premedication. t½ of diazepam is 15 min), but amnesia persists
Shivering and delirium may occur during for 2–3 hr and sedation for 6 hr or more. BZDs
recovery. Postanaesthetic nausea and vomiting are poor analgesics : an opioid or N2O is usually
are uncommon. added if the procedure is painful.
By themselves, BZDs do not markedly dep-

8
2. Methohexitone sod. It is a more potent and shorter
ress respiration, cardiac contractility or BP; but
acting thiopentone congener that is more rapidly
metabolized—patient becomes roadworthy earlier. when opioids are also given, these functions are
considerably compromised. They do not provoke
3. Propofol It is an oily liquid employed as a postoperative nausea or vomiting. Involuntary
1% emulsion for i.v. induction and short movements are not stimulated.
duration anaesthesia. Unconsciousness after BZDs are now the preferred drugs for endo-
propofol injection occurs in 15–45 sec and lasts scopies, cardiac catheterization, angiographies,
~10 min. Propofol distributes rapidly (distribu- conscious sedation during local/regional anaes-
tion t½ 2–4 min). Elimination t½ (100 min) is thesia for dental procedures, fracture setting, etc.
much shorter than that of thiopentone due to They are a frequent component of balanced
rapid metabolism. As such, propofol has largely anaesthesia employing several drugs. The
superseded thiopentone. anaesthetic action of BZDs can be rapidly
Intermittent injection or continuous infu- reversed by flumazenil 0.5–2 mg i.v.
sion of propofol has been used for total i.v.
anaesthesia when supplemented by fentanyl. It Diazepam 0.2–0.5 mg/kg by slow undiluted
lacks airway irritancy and is particularly suited injection in a running i.v. drip: this technique
for outpatient surgery because residual impair- reduces the burning sensation in the vein and
ment is less marked and incidence of post- incidence of thromboflebitis.
operative nausea and vomiting is low. Excitatory Lorazepam Three times more potent, slower
effects and involuntary movements are noted in acting and less irritating than diazepam. It
124 General Anaesthetics and Skeletal Muscle Relaxants

distributes more gradually—awakening may be stability. Combined with benzodiazepines, it can


delayed. Amnesia is more profound. obviate the need for inhaled anaesthetics for
Midazolam Water soluble, nonirritating to diagnostic, endoscopic, angiographic, dental and
veins, faster and shorter acting and 3 times more other minor procedures in poor risk patients, as
potent than diazepam. It is being preferred over well as for burn dressing.
diazepam for anaesthetic use and for sedation After i.v. fentanyl (2–4 μg/kg) the patient
of dental patients, intubated and mechanically remains drowsy but conscious and his co-
ventilated patients, etc. operation can be commanded. Respiratory
depression is marked, but predictable; the patient
2. Ketamine It induces a so- called ‘dissociative may be encouraged to breathe and assistance
anaesthesia’—profound analgesia, immobility, may be provided. Heart rate decreases, because
amnesia with light sleep and feeling of dis- fentanyl stimulates vagus. Fall in BP is slight and
sociation from one’s own body and the heart is not sensitized to Adr.
surroundings. The primary site of action is in the Nausea, vomiting and itching often occur
cortex and subcortical areas; not in the reticular during recovery. The opioid antagonist naloxone
activating system. can be used to counteract persisting respiratory
Respiration is not depressed, airway reflexes depression and mental clouding.
are maintained and muscle tone increases. Heart
rate, cardiac output and BP are elevated due to COMPLICATIONS OF GENERAL
sympathetic stimulation. The above effects are
II

ANAESTHESIA
produced within a min and recovery starts after
SECTION

10–15 min, but the patient remains amnesic for A. During anaesthesia
1–2 hr. Emergence delirium, hallucinations and 1. Respiratory depression and hypercarbia.
involuntary movements occur in up to 50% 2. Salivation, respiratory secretions—less
patients, but the injection is not painful. Children problematic now as nonirritant anaesthetics
tolerate the drug better. Its elimination t½ is are mostly used.
3–4 hr. 3. Cardiac arrhythmias, asystole.
Ketamine has been employed for dental and 4. Fall in BP.
other operations on the head and neck, in 5. Aspiration of gastric contents: acid pneumo-
patients who have bled, in asthmatics (relieves nitis.
bronchospasm), in those who do not want to lose 6. Laryngospasm and asphyxia.
consciousness and for short operations. It is good 7. Awareness: dreadful perception and recall of
for repeated use; particularly suitable for burn events during surgery—by use of light anaes-
dressing. Combined with diazepam, it has thesia + analgesics and muscle relaxants.
found use in angiographies, cardiac catheteriza- 8. Delirium, convulsions, excitatory effects.
tion and trauma surgery. It may be dangerous 9. Fire and explosion—rare now due to use of
for hypertensives and in ischaemic heart disease, non-inflammable agents.
but is good for hypovolemic patients. B. After anaesthesia
3. Fentanyl This short acting (30–50 min) 1. Nausea and vomiting.
potent opioid analgesic related to pethidine is 2. Persisting sedation: impaired psychomotor
generally given i.v. at the beginning of painful function.
surgical procedures. It is frequently used to 3. Pneumonia, atelectasis.
supplement anaesthetics in balanced anaes- 4. Organ toxicities: liver, kidney damage.
thesia. This permits use of lower anaesthetic 5. Nerve palsies—due to faulty positioning.
concentrations with better haemodynamic 6. Emergence delirium.
Preanaesthetic Medication 125

7. Cognitive defects: prolonged excess cognitive by relaxation, indifference, slurring of speech,


decline has been observed in some patients, ptosis, etc. Further injection is stopped, after which
especially the elderly. this state lasts for about 1 hour and psychomotor
impairment persists for 6–24 hours; an escort is
DRUG INTERACTIONS
needed to take back the patient home. Flumazenil
1. Patients on antihypertensives given general can be used to reverse the sedation, but repeated
anaesthetics—BP may fall markedly. doses are needed.
2. Neuroleptics, opioids, clonidine and mono- Midazolam (i.v.) is a shorter acting alternative
amine oxidase inhibitors potentiate anaes- to diazepam. Oral diazepam administered 1 hr
thetics. before is also used with the limitation that level of
3. Halothane sensitizes heart to Adr. sedation cannot be titrated. The patient remains
4. If a patient on corticosteroids is to be sedated (not roadworthy) for several hours.
anaesthetized, give 100 mg hydrocortisone
2. Propofol Because of brief action, it has to be
intraoperatively because anaesthesia is a
administered by continuous i.v. infusion
stress—can precipitate adrenal insufficiency.
regulated by infusion pump throughout the
5. Insulin need of a diabetic is increased during
procedure. However, level of sedation can be
GA: switch over to plain insulin even if the
altered during the procedure and recovery is
patient is on oral hypoglycaemics.
relatively quick, permitting early discharge of the
patient.

CHAPTER
CONSCIOUS SEDATION
3. Nitrous oxide The patient is made to breathe
In place of general anaesthesia ‘conscious 100 oxygen through a nose piece or hood and
sedation’ (a monitored state of altered N2O is added in 10% increments (to a maximum
consciousness) can be employed, supplemented of 50%, rarely 70%) till the desired level of sedation
with local anaesthesia, to carry out dental assessed by constant verbal contact is obtained.
procedures/surgery in apprehensive children (or This is maintained till the procedure is performed.

8
adults) and in medically compromised patients. Thereafter, N2O is switched off but 100% O2 is
It allows operative procedure to be performed continued for next 5 min. The patient is generally
with minimal physiologic and psychologic stress. roadworthy within 30–60 min.
Conscious sedation is a technique in which drugs
4. Fentanyl Injected i.v. (1-2 μg/kg every 15-30
are used to produce a state of CNS depression
min), it can be used alone as well as in
(but not unconsciousness) enabling surgical
combination with propofol.
procedure to be carried out while maintaining
communication with the patient who is able to
PREANAESTHETIC MEDICATION
respond to commands and maintain a patent
airway throughout. The difference between Preanaesthetic medication refers to the use of
conscious sedation and anaesthesia is one of drugs before anaesthesia to make it more
degree. The protective airway and other reflexes pleasant and safe. The aims are:
are not lost during conscious sedation; therefore, 1. Relief of anxiety and apprehension preopera-
it is safer. However, by itself, conscious sedation tively and to facilitate smooth induction.
is not able to suppress pain of dental procedure; 2. Amnesia for pre- and postoperative events.
local anaesthetic must be injected in addition. 3. Supplement analgesic action of anaesthetics
Drugs used for conscious sedation are: and potentiate them so that less anaesthetic
1. Diazepam It is injected i.v. in small (1–2 mg) is needed.
repeated doses or by slow infusion until the 4. Decrease secretions and vagal stimulation
desired level of sedation is produced indicated caused by the anaesthetic.
126 General Anaesthetics and Skeletal Muscle Relaxants

5. Antiemetic effect extending to the postope- risk of gastric regurgitation and aspiration
rative period. pneumonia. Ranitidine or famotidine benefit by
6. Decrease acidity and volume of gastric juice raising pH of gastric juice; may also reduce its
so that it is less damaging if aspirated. volume and thus chances of regurgitation.
Prevention of stress ulcers is another advantage.
Different drugs achieve different purposes. One
The proton pump inhibitor omeprazole/
or more drugs may be used in a patient depen-
pantoprazole is an alternative.
ding on the needs.
6. Antiemetics Metoclopramide injected pre-
1. Sedative-antianxiety drugs Benzodiaze-
operatively is effective in reducing postoperative
pines like diazepam or lorazepam have become
vomiting. By enhancing gastric emptying and
popular drugs for preanaesthetic medication
tone of LES, it reduces the chances of reflux and
because they produce tranquility and smoothen
its aspiration.
induction with little respiratory depression. They
counteract CNS toxicity of local anaesthetics. Domperidone and Ondansetron (5-HT3 antagonist)
can be used as alternatives.
Promethazine is an antihistaminic with sedative,
antiemetic and anticholinergic properties. It SKELETAL MUSCLE RELAXANTS
causes little respiratory depression and has been
used particularly in children. Skeletal muscle relaxants are drugs that act
peripherally at neuromuscular junction/ muscle
II

2. Opioids Morphine or pethidine, i.m. allay anxiety


and apprehension of the operation, produce pre- and fibre itself or centrally in the cerebrospinal axis
postoperative analgesia, smoothen induction, and to reduce muscle tone and/or cause paralysis.
SECTION

supplement poor analgesic (thiopentone, halothane) or The neuromuscular blocking agents are used
weak (N2O) anaesthetics but have disadvantages like in conjunction with general anaesthetics to
respiratory depression, greater fall in BP due to the
anaesthetic, interference with pupillary signs, lack of provide muscle relaxation for surgery, while
amnesic action, delayed recovery, more postoperative centrally acting muscle relaxants are used
constipation and urinary retention, etc. primarily for painful muscle spasms and spastic
Use of opioids is now mostly restricted to those neurological diseases.
having preoperative pain.
3. Anticholinergics Atropine or hyoscine (0.6 mg PERIPHERALLY ACTING MUSCLE
i.m./i.v.) have been used, primarily to reduce salivary
and bronchial secretions. They are infrequently needed
RELAXANTS
now, because only non-irritant anaesthetics are used. I. Neuromuscular Blocking Agents
However, they must be given before hand when ether is
used. The main aim of their use now is to prevent vagal A. Nondepolarizing (Competitive) blockers
bradycardia, hypotension and prophylaxis of laryngo-
spasm. 1. Long acting: d-Tubocurarine, Pancuronium,
Doxacurium, Pipecuronium.
Glycopyrrolate This quaternary atropine substitute is
a potent antisecretory and antibradycardiac drug; acts 2. Intermediate acting: Vecuronium, Atracurium,
rapidly and is less likely to produce central effects (see Cisatracurium, Rocuronium, Rapacuronium.
Ch. 5). 3. Short acting: Mivacurium.
4. Neuroleptics Chlorpromazine, triflupromazine or B. Depolarizing blockers
haloperidol i.m. are infrequently used in premedication.
They allay anxiety and have antiemetic action. However, Succinylcholine (SCh., Suxamethonium),
they potentiate respiratory depression and hypotension Decamethonium (C-10)
caused by the anaesthetics and delay recovery.

5. H2 blockers Patients undergoing prolonged II. Directly Acting Agents


operations and obese patients are at increased Dantrolene sodium, Quinine
Neuromuscular Blocking Agents 127

NEUROMUSCULAR BLOCKING AGENTS


Curare It is the generic name for certain plant extracts
used by south American tribals as arrow poison for game
hunting. The animals got paralysed even if not killed by
the arrow. Natural sources of curare are Strychnos
toxifera, Chondrodendron tomentosum and related plants.
Muscle paralysing active principles of these are tubocura-
rine, toxiferins, etc.

MECHANISM OF ACTION
The site of action of both competitive and
depolarizing blockers is the endplate of skeletal
muscle fibres.
Competitive block (Nondepolarizing block)
This is produced by curare and related drugs.
The competitive blockers have affinity for the
nicotinic (NM) cholinergic receptors at the muscle
endplate but have no intrinsic activity. The NM
receptor has been isolated and studied in detail.
It is a protein with 5 subunits (α2 β ε or γ and

CHAPTER
δ) which are arranged like a rosette surrounding
the Na+ channel (see Fig. 3.3). The two α subunits Fig. 8.1: Illustration of characteristics of competitive (A)
carry 2 ACh binding sites; these have negatively and depolarizing (B) neuromuscular blockade in sciatic
nerve-gastrocnemius muscle of cat
charged groups which combine with the cationic A. Tubocurarine (d-TC) produces progressive decrease
head of ACh → opening of the Na+ channel. in twitch tension; tetanic stimulation (TET) produces poorly
Most of the competitive blockers have two or sustained contracture, which is followed by post-tetanic

8
more quaternary N+ atoms which provide the potentiation (PTP); Neostigmine (Neo) restores the twitch
contractions.
necessary attraction to the same site, but the bulk B. Succinylcholine (SCh) produces initial augmentation of
of the antagonist molecule does not allow twitches followed by progressive block; tetanus is well
conformational changes in the subunits needed sustained, but there is no PTP; block is not reversed (rather
worsened) by neostigmine.
for opening the channel. The ACh released from
motor nerve endings is not able to combine with
its receptors to generate endplate potential (EPP) (just as ACh does) and initially produce twitch-
and muscle fails to contract in response to nerve ing and fasciculations. These drugs do not
impulse. The antagonism is surmountable by dissociate rapidly from the receptor → induce
increasing the concentration of ACh in vitro and prolonged partial depolarization of the region
by anticholinesterases in vivo. around muscle endplate → Na+ channels get
inactivated (because transmembrane potential
The competitive blockers also block the
drops to about –50 mV) → ACh released from
prejunctional nicotinic receptors located on
motor nerve endings is unable to generate
motor nerve endings and supplement the post
propagated muscle action potential (MAP) →
junctional block.
flaccid paralysis in mammals. In other words, a
Depolarizing block Decamethonium and SCh zone of inexcitability is created around the end-
have affinity as well as submaximal intrinsic plate preventing activation of muscle fibre. In
activity at the NM cholinoceptors. They depola- birds, the area of depolarization is more
rize muscle endplates by opening Na+ channels extensive and spastic paralysis occurs.
128 General Anaesthetics and Skeletal Muscle Relaxants

Table 8.2: Features of competitive and typical depolarizing block

Competitive block Depolarizing block


(d-TC) (C-10)
1. Paralysis in man Flaccid Fasciculations → flaccid
2. Paralysis in chick Flaccid Spastic
3. Effect on isolated No contraction, Contraction
frog’s rectus muscle Antagonism of ACh
4. Species sensitivity Rat > Rabbit > Cat Cat > Rabbit > Rat
5. Human neonates More sensitive Relatively resistant
6. Tetanic stimulation Poorly sustained contraction Well-sustained contraction
during partial block
7. Neostigmine Antagonises block No effect
8. Ether anaesthesia Synergistic No effect
9. Order of paralysis Fingers, eyes → limbs → neck, Neck, limbs → face, jaw, eyes,
face → trunk → respiratory pharynx → trunk → respiratory
10. Effect of lowering Reduces block Intensifies block
temperature
11. Effect of cathodal Lessens block Enhances block
current to endplate
II

Depolarizing blockers also have 2 quaternary flaccid paralysis, but fasciculations are not promi-
N+ atoms but the molecule is long, slender and nent in well-anaesthetized patients. Though the
SECTION

flexible. The features of classical depolarizing sequence in which muscles are involved is
block differ markedly from that of nondepo- somewhat different from the competitive blockers
larizing block (see Fig. 8.1 and Table 8.2). (Table 8.2), the action of SCh develops with such
rapidity that this is not appreciated. Apnoea
In many species, e.g. dog, rabbit, rat, monkey, in slow
contracting soleus muscle of cat, and under certain generally occurs within 45–90 sec, but lasts only
conditions in man the classical depolarizing block 2–5 min; recovery is rapid.
described above (phase I block) is followed by phase II
2. Autonomic ganglia Because the cholinergic
block, which is due to desensitization of the NM receptor
to ACh, and superficially resembles nondepolarizing receptors in autonomic ganglia are nicotinic
block in features. SCh readily produces phase II block (though of a different subclass NN), competitive
in patients with atypical or deficient pseudocho- neuromuscular blockers produce some degree of
linesterase. ganglionic blockade. SCh may cause ganglionic
stimulation.
ACTIONS 3. Histamine release d-TC releases histamine
1. Skeletal muscles Intravenous injection of from mast cells resulting in hypotension, flush-
nondepolarizing blockers rapidly produces ing, bronchospasm and increased respiratory
muscle weakness followed by flaccid paralysis. secretions. Histamine releasing potential of other
Small fast response muscles (fingers, extraocular) neuromuscular blockers is graded in Table 8.3.
are affected first; paralysis spreads to hands, 4. C.V.S.
feet—arm, leg, neck, face—trunk—finally inter- d-Tubocurarine produces a significant fall in BP.
costal muscles—diaphragm: respiration stops. This is due to—
Recovery occurs in the reverse sequence; (a) ganglionic blockade,
diaphragmatic contractions resume first. (b) histamine release, and
Depolarizing blockers typically produce fas- (c) reduced venous return—a result of paralysis
ciculations lasting a few seconds before inducing of limb and respiratory muscles.
Neuromuscular Blocking Agents 129

Table 8.3: Comparative properties of neuromuscular blocking drugs

Drug Dose £ Onset* Duration@ Hist. Gang. Vagal


(mg/kg) (min) (min) release block block
LONG ACTING
1. d-Tubocurarine 0.2–0.4 4–6 30–60 +++ ++ ±
2. Pancuronium 0.04–0.1 4–6 60–120 ± ± +
3. Doxacurium 0.03–0.08 4–8 60–120 + – –
4. Pipecuronium 0.05–0.08 2–4 50–100 ± – –

INTERMEDIATE ACTING
5. Vecuronium 0.08–0.1 2–4 30–60 ± – ±
6. Atracurium 0.3–0.6 2–4 20–35 + – –
7. Rocuronium 0.6–0.9 1–2 25–40 – – ±

SHORT ACTING
8. Mivacurium 0.07–0.15 2–4 12–20 + – –
9. Succinylcholine 0.5–0.8 1–1.5 3–6 ++ St. St.
£
Initial paralysing dose for opioid/nitrous oxide/oxygen anaesthesia. In patients anaesthetised with

CHAPTER
ether/halothane/isoflurane, the dose may be 1/3–1/2 of the figure given.
*Time to maximal block after i.v. injection.
@
Duration of surgical grade relaxation after usual clinical doses; time to 95% recovery of muscle twitch
is nearly double of the figure given (especially for long-acting drugs). Duration is also dose dependent.
St. — Stimulation

Heart rate may increase due to vagal ganglionic single dose. They do not cross placenta or pene-
blockade. Pancuronium and vecuronium also trate brain. d-TC, pancuronium, doxacurium and

8
tend to cause tachycardia. All newer nondepolar- pipecuronium are partly metabolized while
izing drugs have negligible effects on BP and HR. vecuronium, atracurium, rocuronium and
Cardiovascular effects of SCh are variable. mivacurium are largely metabolized in the body.
BP occasionally falls on account of its muscarinic Atracurium is inactivated in plasma by spon-
action causing vasodilatation. taneous nonenzymatic degradation (Hofmann
5. G.I.T. The ganglion blocking activity of elimination) in addition to that by cholinesterases.
competitive blockers may enhance postoperative The unchanged drug is excreted in urine as well
paralytic ileus after abdominal operations. as in bile.
SCh is rapidly hydrolysed by plasma
6. C.N.S. All neuromuscular blockers are qua-
pseudocholinesterase—action lasts for 3 to 5 min.
ternary compounds—do not cross blood-brain
Some patients have genetically determined
barrier—no CNS effects.
abnormality (low affinity for SCh) or deficiency
of pseudocholinesterase. In them, SCh causes
PHARMACOKINETICS dominant phase II blockade resulting in muscle
All neuromuscular blockers are quaternary paralysis and apnoea lasting for hours.
compounds—not absorbed orally. They are practi-
cally always given i.v. Muscles with higher blood INTERACTIONS
flow receive more drug and are affected earlier. 1. Thiopentone sod and SCh solutions should
Redistribution to non-muscular tissues plays a not be mixed in the same syringe—react chemi-
significant role in the termination of action of a cally.
130 General Anaesthetics and Skeletal Muscle Relaxants

2. General anaesthetics potentiate competitive they may be needed for setting of mandibular frac-
blockers. tures.
3. Anticholinesterases reverse the action of com- Succinylcholine is employed for brief proce-
petitive blockers. Neostigmine 0.5–2 mg i.v. is dures, e.g. endotracheal intubation, laryngo-
almost routinely used after pancuronium and scopy, bronchoscopy, esophagoscopy, reduction
other long acting blockers to hasten recovery at of fractures and to treat laryngospasm, etc.
the end of operation. 2. Assisted ventilation of critically ill patients
4. Antibiotics Aminoglycoside antibiotics re- in intensive care units can be facilitated by
duce ACh release from prejunctional nerve continuous infusion of a competitive neuro-
endings and have a weak stabilizing action on muscular blocker which reduces chest wall
the postjunctional membrane. In clinically used resistance to inflation.
doses they do not by themselves produce muscle 3. Convulsions and trauma from electrocon-
relaxation but potentiate competitive blockers. vulsive therapy can be avoided by the use of
Tetracyclines (by chelating Ca2+) polypeptide muscle relaxants.
antibiotics, clindamycin and lincomycin also 4. Severe cases of tetanus and status epilep-
synergise with competitive blockers. ticus, may be paralysed by a neuromuscular
5. Calcium channel blockers Verapamil and blocker (repeated doses of a competitive blocker)
others potentiate both competitive and depola- and maintained on intermittent positive pressure
rizing neuromuscular blockers. respiration.
II

6. Diuretics produce hypokalaemia which


enhances competitive block. DIRECTLY ACTING MUSCLE RELAXANTS
SECTION

7. Diazepam, propranolol and quinidine intensify Dantrolene This muscle relaxant is chemically and
competitive block, while high dose of cortico- pharmacologically entirely different from neuromuscular
steroids reduce it. blockers. It does not affect neuromuscular transmission
or MAP, but uncouples contraction from depolarization
of the muscle membrane; depolarization triggered release
TOXICITY of Ca2+ from sarcoplasmic reticulum is reduced.
Used orally dantrolene reduces spasticity in upper
1. Respiratory paralysis and prolonged apnoea motor neurone disorders, hemiplegia, paraplegia, cerebral
is the most important problem. palsy and multiple sclerosis.
2. Flushing can occasionally occur with atra- Used i.v. it is the drug of choice for malignant
hyperthermia which is due to persistent release of Ca2+
curium and mivacurium.
from sarcoplasmic reticulum (induced by fluorinated
3. Fall in BP and cardiovascular collapse can anaesthetics and SCh in genetically susceptible
occur, especially in hypovolemic patients. individuals).
4. Cardiac arrhythmias and even arrest have Muscular weakness is the dose limiting side effect.
occurred, especially with SCh. Troublesome diarrhoea is another problem. Long-term use
5. Precipitation of asthma with histamine can cause serious liver toxicity.
releasing neuromuscular blockers. Quinine This antimalarial drug increases refractory
6. Postoperative muscle soreness after SCh. period and decreases excitability of motor endplates.
Muscle tone in myotonia congenita is reduced. Taken at
bed time it may abolish nocturnal leg cramps in some
USES patients.
1. The most important use of neuromuscular
blockers is as adjuvants to general anaesthesia; CENTRALLY ACTING MUSCLE RELAXANTS
adequate muscle relaxation can be achieved These are drugs which reduce skeletal muscle tone
at lighter planes. They are specially valuable by a selective action in the cerebrospinal axis,
in abdominal and thoracic surgery. In dentistry without altering consciousness. They selectively
Centrally Acting Muscle Relaxants 131

depress spinal and supraspinal polysynaptic clinical efficacy of none of the above drugs as
reflexes involved in the regulation of muscle tone muscle relaxant is well established. Gastric
without significantly affecting monosynaptically irritation and sedation are the most important side
mediated stretch reflex. Polysynaptic pathways effects.
in the ascending reticular formation which are Diazepam (see Ch. 9) is the prototype of
involved in the maintenance of wakefullness are benzodiazepines (BZDs) which act in the brain
also depressed, though to a lesser extent. All on specific receptors enhancing GABAergic
centrally acting muscle relaxants do have some transmission. It reduces muscle tone by supra-
sedative property and they overlap with anti- spinal rather than spinal action. Sedation limits
anxiety drugs. They have no effect on neuro- the dose which can be used for reducing muscle
muscular transmission and on muscle fibres, but tone but gastric tolerance is very good. It is
reduce decerebrate rigidity, upper motor neurone particularly valuable in spinal injuries and
spasticity and hyperreflexia. Prominent diffe- tetanus. Combined with analgesics, it is popular
rences between centrally and peripherally acting for rheumatic disorders associated with muscle
muscle relaxants are listed in Table 8.4. spasm.

CLASSIFICATION Baclofen It is an analogue of the inhibitory


transmitter GABA; acts as selective GABAB
(i) Mephenesin Mephenesin, receptor agonist.
Carisoprodol,

CHAPTER
congeners The GABA receptors have been divided into:
Chlorzoxazone,
GABAA receptor Intrinsic ion channel receptor—increases
Chlormezanone, Cl¯ conductance; blocked by bicuculline; facilitated by
Methocarbamol. BZDs.
(ii) Benzodiazepines Diazepam and others.
GABAB receptor G-protein coupled receptor; hyper-
(iii) GABA derivative Baclofen. polarizes neurones by increasing K+ conductance and
(iv) Central α2 agonist Tizanidine. altering Ca2+ flux; bicuculline insensitive.

8
Mephenesin was the first drug found to reduce Baclofen does not affect Cl¯ transport and its
muscle tone by depressing spinal internuncial actions are not antagonized by bicuculline.
neurones, which modulate polysynaptic reflexes The primary site of action of baclofen is in
that maintain muscle tone. It is not used clinically the spinal cord where it depresses both poly-
because of toxicity. Its congeners like carisoprodol, synaptic and monosynaptic reflexes. As such, it
chlorzoxazone, chlormezanone and methocarbamol does produce muscle weakness. It reduces
have low toxicity and are used for musculoskeletal spasticity in many neurological disorders like
disorders associated with muscle spasm. They multiple sclerosis, amyotropic lateral sclerosis,
are often combined with NSAIDs. However, spinal injuries and flexor spasms but is relatively
Table 8.4: Comparative features of centrally acting and peripherally acting muscle relaxants

Centrally acting Peripherally acting


1. Decrease muscle tone without reducing Cause muscle paralysis, voluntary movements
voluntary power lost
2. Selectively inhibit polysynaptic reflexes in CNS Block neuromuscular transmission
3. Cause some CNS depression No effect on CNS
4. Given orally, sometimes parenterally Practically always given i.v.
5. Used in chronic spastic conditions, Used for short-term purposes
acute muscle spasms, tetanus (surgical operations)
132 General Anaesthetics and Skeletal Muscle Relaxants

ineffective in stroke, cerebral palsy, rheumatic analgesics. They may help to relieve trismus occurring
and traumatic muscle spasms and parkinso- after a dental procedure. However, efficacy of these
nism. drugs is not impressive.
Tizanidine This recently introduced clonidine 2. Torticollis, lumbago, backache, neuralgias
congener is a central α2 adrenergic agonist— respond in the same way as acute muscle
inhibits release of excitatory amino acids in spasms.
spinal interneurones. Facilitation of inhibitory
transmitter glycine has also been demonstrated. 3. Anxiety and tension associated with increa-
It inhibits polysynaptic reflexes; reduces muscle sed tone of muscles and bruxism (involuntary
tone and frequency of muscle spasms without grinding of teeth during sleep; often stress related)
reducing muscle strength. may be benefited.
It is indicated in spasticity due to neuro- 4. Spastic neurological diseases like hemiple-
logical disorders and in painful muscle spasms gia, paraplegia, spinal injuries, multiple
of spinal origin. Side effects are dry-mouth, sclerosis, and cerebral palsy are somewhat
drowsiness, night-time insomnia and hallucina- benefited by baclofen, diazepam, tizanidine and
tions. Dose-dependent elevation of liver test dantrolene.
values has been noted. 5. Tetanus Most commonly diazepam is infu-
sed i.v. and the dose is titrated by the response.
Uses of centrally acting muscle relaxants Methocarbamol is an alternative.
II

1. Acute muscle spasms Overstretching of a 6. Electroconvulsive therapy Diazepam may


SECTION

muscle, sprain, tearing of ligaments and tendons, be used to suppress convulsions.


dislocation, fibrositis, bursitis, etc. cause painful 7. Orthopaedic manipulations may be per-
spasm of muscles. The mephenesin like and BZD formed under the influence of diazepam or
muscle relaxants are often combined with methocarbamol given i.v.
9
Drugs Acting on Central Nervous System
Sedative-Hypnotics, Alcohols, Antiepileptics and
Antiparkinsonian Drugs

SEDATIVE-HYPNOTICS Sleep
The duration and pattern of sleep varies considerably
Sedative A drug that subdues excitement and among individuals. Age has an important effect on
calms the subject without inducing sleep, though quantity and depth of sleep. It has been recognized that
drowsiness may be produced. Sedation refers to sleep is an architectured cyclic process in which the subject
passes from stage 0 (awake) to stage 4 (cerebral sleep)
decreased responsiveness to any level of stimula- through stage 1 (dozing), stage 2 (unequivocal sleep) and
tion; is associated with some decrease in motor stage 3 (deep sleep transition) of non-rapid eye movement
activity and ideation. (N-REM) sleep interspersed with REM (paradoxical) sleep
(Fig. 9.1). About 20–30% of sleep time is spent in REM,
Hypnotic A drug that induces and/or main- while stage 2 occupies the major part of NREM sleep.
tains sleep, similar to normal arousable sleep. This Dreams and nightmares occur during REM sleep. The
cyclic pattern of sleep stages, particularly REM, is consi-
is not to be confused with ‘hypnosis’ meaning a dered to be essential for sleep to be refreshing.
trans like state in which the subject becomes
passive and highly suggestible. CLASSIFICATION
The sedatives and hypnotics are more or less
global CNS depressants with somewhat differing 1. Barbiturates For practical reasons divided
time-action and dose-action relationships. Those into—
with quicker onset, shorter duration and steeper Long acting Phenobarbitone
Short acting Pentobarbitone
dose-response relationships are prefered as
Ultrashort acting Thiopentone sod.
hypnotics, while more slowly acting drugs with
flatter dose-response curves are employed as 2. Benzodiazepines May be divided according
sedatives. However, there is considerable overlap; to primary use—
a hypnotic at lower dose may act as sedative.
Hypnotic Antianxiety
Thus, sedation—hypnosis—general anaesthesia
Diazepam Diazepam
may be regarded as increasing grades of CNS Flurazepam Chlordiazepoxide
depression. Hypnotics given in high doses can Nitrazepam Oxazepam
produce general anaesthesia. However, benzo- Alprazolam Lorazepam
diazepines (BZDs) cannot be considered non- Temazepam Alprazolam
selective or global CNS depressants like barbitu- Triazolam Anticonvulsant
rates. Diazepam
Treatment of insomnia is the most important Clonazepam
use of this class of drugs. Clobazam
134 Drugs Acting on CNS

Fig. 9.1: A normal sleep cycle

3. Newer nonbenzodiazepine hypnotics 1. CNS Barbiturates produce dose-dependent


Zopiclone, Zolpidem, Zaleplon effects:
II

Chloral hydrate, Triclophos, Paraldehyde, Methaqualone sedation → sleep → anaesthesia → coma.


and Meprobamate are historical sedative-hypnotics no
Hypnotic dose shortens the time taken to fall
SECTION

longer used.
In addition, some antihistaminics (promethazine, diphen- asleep and increases sleep duration. The sleep is
hydramine), some neuroleptic/antidepressants (chlorpro- arousable, but the subject may feel confused and
mazine, amitriptyline), some anticholinergic (hyoscine) and unsteady if waken early. REM and stage 3, 4 sleep
opioids (morphine, pethidine) have significant sedative
action, but are not reliable for treatment of insomnia. are decreased; REM-NREM sleep cycle is dis-
rupted. The effects on sleep become progressively
less marked if the drug state given every night
BARBITURATES consecutively. A rebound increase in REM sleep
Barbiturates have been popular hypnotics and and nightmares is often noted when the drug is
sedatives of the last century up to 1960s but are discontinued after a few nights of use. Hangover
not used now. However, they are described first (dizziness, distortions of mood, irritability and
as they are the prototype of CNS depressants. lethargy) may occur in the morning after a nightly
Barbiturates are substituted derivatives of dose.
barbituric acid (malonyl urea). They have variable Sedative dose (smaller dose of a longer acting
lipid solubility, the more lipid soluble ones are barbiturate) given at daytime can produce
more potent and shorter acting. They are insoluble drowsiness, reduction in anxiety and excitability.
in water but their sodium salts dissolve yielding However, barbiturates do not have selective anti-
highly alkaline solution. anxiety action. They can impair learning, short-
term memory and judgement, and have no anal-
gesic action; small doses may even cause hyper-
Pharmacological actions algesia. Euphoria may be experienced by addicts.
Barbiturates are general depressants for all Barbiturates have anticonvulsant property.
excitable cells, the CNS is most sensitive where The 5-phenyl substituted agents (phenobarbitone)
the effect is almost global, but certain areas are have higher anticonvulsant : sedative ratio, i.e.
more susceptible. they have specific anticonvulsant action.
Sedative-Hypnotics 135
Barbiturates depress all areas of the CNS, but bitone enters very slowly. Plasma protein binding varies
with the compound, e.g. thiopentone 75%, phenobarbitone
reticular activating system is the most sensitive;
20%.
its depression is primarily responsible for Three processes are involved in termination of action
inability to maintain wakefulness. of barbiturates: the relative importance of each varies with
the compound.
Mechanism of action Barbiturates appear to act
(a) Redistribution It is important in the case of highly
primarily at the GABA : BZD receptor–Cl¯ lipid soluble thiopentone and other ultrashort acting
channel complex (see Fig. 9.2) and potentiate barbiturates. After their i.v. injection, consciousness is
GABAergic inhibition by increasing the lifetime regained in 6–10 min due to redistribution (see Ch. 2),
of Cl¯ channel opening induced by GABA. They while the ultimate disposal occurs by metabolism (t½ of
elimination phase is 9 hours).
do not bind to the BZD receptor, but bind to
another site on the same macromolecular complex (b) Metabolism Drugs with intermediate lipid solubility
(short acting barbiturates) are primarily metabolized in
to exert the GABA-facilitatory action. At high liver by oxidation, dealkylation and conjugation. Their
concentrations, barbiturates directly increase Cl¯ plasma t½ ranges from 12–40 hours.
conductance (GABA-mimetic action; contrast (c) Excretion Barbiturates with low lipid solubility (long
BZDs which have only GABA-facilitatory action) acting agents) are significantly excreted unchanged in urine.
and inhibit Ca2+ dependent release of neurotrans- The t½ of phenobarbitone is 80–120 hours. Alkalinization
of urine increases ionization and excretion. This is most
mitters. In addition, they depress glutamate-
significant in the case of long acting agents.
induced neuronal depolarization through AMPA Barbiturates induce hepatic microsomal enzymes and
receptors (a type of excitatory amino acid increase the rate of their own metabolism as well as that of

CHAPTER
receptors). At very high concentrations, barbitu- many other drugs.
rates depress Na+ and K+ channels directly.
Uses
2. Other systems
Respiration is depressed by relatively higher doses. Except for phenobarbitone in epilepsy and thio-
Barbiturates do not have selective antitussive pentone in anaesthesia, barbiturates are seldom
action. used now. They are occasionally employed as

9
Hypnotic doses of barbiturates produce a adjuvants in psychosomatic disorders.
slight decrease in BP and heart rate: magnitude Adverse effects
of change not differing from that during normal
Side effects Hangover, mental confusion, impaired
sleep. Toxic doses produce marked fall in BP due performance and traffic accidents.
to ganglionic blockade, vasomotor centre depres- Idiosyncrasy In an occasional patient barbiturates
sion and direct decrease in cardiac contractility. produce excitement.
However, the dose producing cardiac arrest is Hypersensitivity Rashes, swelling of eyelids, lips, etc.
about 3 times larger than that causing respiratory Tolerance and dependence Both cellular and pharmaco-
failure. kinetic tolerance develops on repeated use.
Tone and motility of bowel is decreased Psychological as well as physical dependence occurs
and barbiturates have considerable abuse liability—one
slightly by hypnotic doses; more profoundly of their major disadvantages. Withdrawal symptoms
during intoxication. are—excitement, hallucinations, delirium, convulsions;
Barbiturates tend to reduce urine flow by deaths have occurred.
decreasing BP and increasing ADH release. Acute barbiturate poisoning
Manifestations are due to excessive CNS depression—
Pharmacokinetics patient is flabby and comatose with shallow and failing
Barbiturates are well absorbed from the g.i. tract. They are respiration, fall in BP and cardiovascular collapse, renal
widely distributed in the body. The rate of entry into CNS shut down, pulmonary complications, bullous eruptions.
is dependent on lipid solubility: highly lipid soluble Lethal dose depends on lipid solubility. It is 2–3 g for
thiopentone has practically instantaneous entry while less the more lipid soluble agents (short acting barbiturates)
lipid soluble ones (pentobarbitone) take longer; phenobar- and 5–10 g for less lipid soluble phenobarbitone.
136 Drugs Acting on CNS
Treatment 7. A specific BZD antagonist flumazenil has been
Gastric lavage; supportive measures such as patent developed which can be used in case of poisoning.
airway, assisted respiration, oxygen, maintenance of blood
volume by fluid infusion and use of vasopressors. CNS actions The overall action of all BZDs is
Alkaline diuresis: with mannitol and sodium bicarbonate
qualitatively similar, but there are prominent
in the case of long acting barbiturates only. Haemodialysis
and haemoperfusion is highly effective in removing long differences in selectivity and time course of action:
acting as well as short acting barbiturates. different members are used for different purposes.
There is no specific antidote for barbiturates. The In contrast to barbiturates, they are not general
approach is to keep the patient alive till the poison has depressants, but exert relatively selective anxio-
been eliminated.
lytic, hypnotic, muscle relaxant and anticon-
Interactions vulsant effects. Even when apparently anaesthetic
dose of diazepam is administered i.v., some degree
1. Barbiturates induce the metabolism of many of awareness is maintained.
drugs and reduce their effectiveness—warfarin, They hasten onset of sleep, reduce intermittent
steroids (including contraceptives), tolbutamide, awakening and increase total sleep time. Time
griseofulvin, chloramphenicol, theophylline. spent in stage 2 is increased while that in stage
2. Additive action with other CNS depressants 3 and 4 is decreased. They tend to shorten
—alcohol, antihistamines, opioids, etc. REM phase, but effect is less marked than with
3. Sodium valproate increases plasma concen- barbiturates. Most subjects wake up with a feeling
tration of phenobarbitone. of refreshing sleep. Some degree of tolerance
4. Phenobarbitone competitively inhibits as well
II

develops to the sleep promoting action of BZDs


as induces phenytoin and imipramine meta- after repeated nightly use.
bolism: complex interaction.
SECTION

Given i.v., diazepam causes analgesia. In


5. Phenobarbitone decreases absorption of contrast to barbiturates, BZDs do not produce
griseofulvin from the g.i.t. hyperalgesia. They also produce centrally
mediated skeletal muscle relaxation and exert
BENZODIAZEPINES (BZDs) anticonvulsant activity (see p. 131 and 147).
Chlordiazepoxide and diazepam were intro- Other actions Diazepam decreases nocturnal
duced around 1960 as antianxiety drugs. Since gastric secretion and prevents stress ulcers. BZDs
then, this class has proliferated and has gained do not significantly affect bowel movement.
popularity over barbiturates as hypnotic and
sedative as well, because— Site and mechanism of action
1. BZDs have a high therapeutic index. Inges- Benzodiazepines act preferentially on midbrain
tion of even 20 hypnotic doses does not usually ascending reticular formation (which maintains
endanger life. wakefulness) and on limbic system (thought and
2. Hypnotic doses do not affect respiration or mental functions). Muscle relaxation is produced
cardiovascular functions. by a primary medullary site of action and ataxia
3. BZDs have practically no action on other body is due to action on cerebellum.
systems. Only on i.v. injection the BP falls and BZDs act by enhancing presynaptic/post-
cardiac contractility decreases. synaptic inhibition through a specific BZD
4. BZDs cause less distortion of sleep architec- receptor which is an integral part of the GABAA
ture. receptor–Cl¯ channel complex. The subunits of
5. BZDs do not alter disposition of other drugs this complex form a pentameric transmembrane
by microsomal enzyme induction. anion channel (Fig. 9.2) gated by the primary
6. They have lower abuse liability: tolerance is ligand (GABA), and modulated by secondary
mild, psychological and physical dependence ligands which include BZDs. The modulatory
and withdrawal syndrome are less marked. BZD receptor increases the frequency of Cl¯
Sedative-Hypnotics 137

CHAPTER
Fig. 9.2: Schematic depiction of GABAA-benzodiazepine receptor-chloride channel complex
The chloride channel is gated by the primary ligand GABA. The benzodiazepine (BZD) receptor modulates GABAA
receptor in either direction : agonists like diazepam facilitate, while inverse agonists like DMCM hinder GABA mediated Cl¯
channel opening, and BZD antagonist flumazenil blocks the action of both. The barbiturate receptor, located elsewhere,
also facilitates GABA and is capable of opening Cl¯ channel directly as well. Bicuculline blocks GABAA receptor, while

9
picrotoxine blocks the Cl¯ channel directly

channel opening induced by submaximal Pharmacokinetics


concentrations of GABA. The GABAA antagonist There are marked pharmacokinetic differences
bicuculline antagonizes BZD action in a non- among BZDs because they differ in lipid solubility
competitive manner. It is noteworthy that the by > 50-fold. Oral absorption of some is rapid
BZDs do not themselves increase Cl¯ conduc-
while that of others is slow. Absorption from i.m.
tance; have only GABA facilitatory but no GABA
sites is irregular except for lorazepam. Plasma
mimetic action. This probably explains the lower
protein binding also varies markedly (flurazepam
ceiling CNS depressant effect of BZDs.
10% to diazepam 99%). BZDs are widely
The BZD receptor exhibits a considerable degree of
constitutive activation. As such, it is capable of fine tuning distributed in the body. The more lipid soluble
GABA action in either direction. While the BZD-agonists members enter brain rapidly and have a two
enhance GABA induced hyperpolarization (due to influx phase plasma concentration decay curve; first due
of Cl¯ ions), and decrease firing rate of neurones, other
to distribution and later due to elimination. A
compounds called BZD-inverse agonists like dimethoxy-
ethyl-carbomethoxy-β-carboline (DMCM) inhibit GABA relatively short duration of action is obtained with
action and are convulsants. The competitive BZD- single dose of a drug that is rapidly redistributed,
antagonist flumazenil blocks the sedative action of BZDs even though it may have a long elimination t½.
as well as the convulsant action of DMCM.
Using the elimination t½ alone to predict duration
Recently, several subtypes of the BZD receptor have been
described which may explain the differing pharmacological
of action may be misleading. However, elimi-
profile of individual BZD compounds. nation t½ determines duration of action in case of
138 Drugs Acting on CNS

Table 9.1: Some pharmacokinetic and clinical features of benzodiazepines used as hypnotics

Drug t½ (hr)* Redistribution $ Hypnotic Clinical indications


dose (mg)
I. LONG ACTING
Flurazepam 50–100 – 15–30 Chronic insomnia, short-term insomnia
Diazepam 30–60 + 5–10 with anxiety; Frequent nocturnal awakening;
Nitrazepam 30 ± 5–10 Night before operation or dental procedure

II. SHORT ACTING


Alprazolam 12 + 0.25-0.5 Individuals who react unfavourably to
Temazepam 8–12 + 10–20 unfamiliar surroundings or unusual timings
Triazolam 2–3 - 0.125–0.25 of sleep. Sleep onset difficulties.
* t½ of elimination phase, including that of active metabolite
$
+ indicates that redistribution contributes to termination of action of single dose

drugs whose elimination is by far the dominant The dependence producing liability of BZDs
feature or when the drug is given repeatedly. is low. They are seldom abused alone. Drug
Benzodiazepines are metabolized in liver by abusers find them rather bland and prefer other
dealkylation and hydroxylation to many meta- CNS depressants. Withdrawal syndrome is
bolites, some of which may be active. The generally mild. Drug seeking behaviour is not
biological effect half-life of these drugs may be prominent. Anxiety, insomnia, restlessness,
II

longer than the plasma t½ of the administered malaise, loss of appetite, bad dreams is all that
occurs in most cases. Agitation, panic reaction,
SECTION

compound. Some BZDs (e.g. diazepam) undergo


enterohepatic circulation. BZDs and their phase tremors and delirium are occasional; convulsions
I metabolites are excreted in urine as glucuronide are rare.
conjugates. BZDs cross placenta and are secreted
in milk. Interactions
Drugs with a long t½ or those which generate BZDs synergise with alcohol and other CNS
active metabolites cumulate on nightly use; their depressants leading to excessive impairment.
action may then extend into the next day. Some Concurrent use with sod. valproate has provoked
features of BZDs used as hypnotic are given in psychotic symptoms.
Table 9.1. Drug interactions due to microsomal enzyme
induction are not significant.
Adverse effects Action of BZDs can be prolonged by CYP 3A4
Benzodiazepines are relatively safe drugs. Side inhibitors like ketoconazole, erythromycin and
effects of hypnotic doses are dizziness, ataxia, others. Cimetidine, isoniazid and oral contra-
disorientation, amnesia, prolongation of reaction ceptives also retard BZD metabolism.
time—impairment of psychomotor skills (should
NON-BENZODIAZEPINE HYPNOTICS
not drive). Hangover is less common. Weakness,
blurring of vision, dry mouth and urinary Zopiclone This newer cyclopyrrolone hypno-
incontinence are sometimes complained. Like any tic is an agonist at a subtype of BZD receptor
hypnotic, BZDs can aggravate sleep apnoea. involved in the hypnotic action. The effect on sleep
Tolerance to the sedative effects develops resemble those of BZDs, but it does not alter REM
gradually, but there is little tendency to increase sleep and tends to prolong stages 3 and 4. It is
the dose. Cross tolerance to alcohol and other reported not to disturb sleep architecture; but
CNS depressants occurs. some degree of next morning impairment can
Sedative-Hypnotics 139

occur. Zopiclone has been used to weanoff short term (weeks) or transient (a day or two,
insomniacs taking regular BZD medication. Its mostly situational) problem.
t½ is 5-6 hours. Dentists are likely to need to prescribe a
Zopiclone is indicated for short-term treatment hypnotic either to ensure sleep night before the
of insomnia. dental procedure in an apprehensive patient, or
to supplement analgesics before and after dental
Zolpidem An imidazopyridine which pre-
surgery. A longer acting BZD, like diazepam, is
ferentially acts on a subtype of BZD receptors that
mostly preferred. Because of rapid onset of action
are important in mediating hypnotic effect . Only
oral zolpidem can be given to anxious patients in
some BZD like actions but not others are
the dentist’s office before carrying out the dental
prominent. Hypnotic effect is pronounced, but
procedure.
anticonvulsant, muscle relaxant and antianxiety
effects are not evident. Its advantages are: relative 2. Other uses
lack of effect on sleep stages; minimal residual • As anxiolytic and for daytime sedation.
daytime sedation and fading of hypnotic action • As anticonvulsant, especially emergency con-
on repeated nightly use; no/little rebound trol of status epilepticus, febrile convulsions,
insomnia on discontinuation; near absence of tetanus, etc.
tolerance or physical dependence and low abuse • As centrally acting muscle relaxant for
potential combined with safety in overdose like muscular spasms.
BZDs. The t½ is short (2 hr). • For preanaesthetic medication, i.v. anaes-

CHAPTER
thesia or conscious sedation.
Zaleplon This is the shortest acting of the newer
• Alcohol withdrawal in dependent subjects.
non-BZD hypnotics that selectively act on a subset
• Along with analgesics, NSAIDs, spasmolytics,
of BZD receptors which appear to mediate the
antiulcer and many other drugs.
hypnotic action. It is rapidly absorbed and rapidly
cleared by hepatic metabolism with a t½ of 1 hour.
As such, it is effective only in sleep-onset BENZODIAZEPINE ANTAGONIST

9
insomnia; does not prolong total sleep time or Flumazenil It is a BZD analogue which has
reduce the number of awakenings. Because of little intrinsic activity (practically no effect on
brevity of action, it can be taken late at night normal subjects), but competes with BZD agonists
without causing morning sedation. No tolerance as well as inverse agonists for the BZD receptor
or dependence has been reported and hypnotic and reverses their depressant or stimulant effects
effect does not fade on nightly use. However, its respectively.
use should be limited to 1-2 weeks. Flumazenil abolishes the hypnogenic, psycho-
motor, cognitive and EEG effects of BZDs. On i.v.
USES
injection action of flumazenil starts in seconds
Currently, BZDs are one of the most frequently and lasts for 1–2 hr; elimination t½ is 1 hr. It has
prescribed drugs. They have also been combined been used to reverse the effect of BZD employed
with many other categories of drugs with a view for i.v. anaesthesia or conscious sedation, and as
to improve efficacy by relieving attendant anxiety. an antidote for BZD overdose/poisoning.
1. As hypnotic When indicated, BZDs are the
hypnotic of choice and the newer non-BZD ETHYL ALCOHOL (Ethanol)
compounds zopiclone, zolpidem or zaleplon are Alcohols are hydroxy derivatives of aliphatic
also being used. hydrocarbons. When unqualified, ‘alcohol’ refers
Insomnia arises under a variety of circum- to ethyl alcohol or ethanol. Pharmacology of alcohol
stances. It could be a long term (months-years), is important for its presence in beverages (which
140 Drugs Acting on CNS

have been used since recorded history) and for Alcohol can induce sleep but is not a
alcohol intoxication, rather than as a drug. dependable hypnotic. Some individuals report
poor quality of sleep and early morning awaken-
PHARMACOLOGICAL ACTIONS ing. Sleep architecture may be disorganized and
Local actions Ethanol is a mild rubefacient and sleep apnoea aggravated. It raises pain threshold
counterirritant when rubbed on skin. By eva- and also alters reaction to it, but is not a depen-
poration it produces cooling. Applied to delicate dable analgesic—severe pain can precipitate
skin (scrotum) or mucous membranes (oral confusion and convulsions. During the time
mucosa) it produces irritation and burning alcohol is acting on brain, it exerts anticonvulsant
sensation: should not be applied in the mouth. action, but this is followed by lowering of seizure
Injected s.c. it causes intense pain, inflammation threshold: seizures may be precipitated in
and necrosis followed by fibrosis. Injected around epileptics. Chronic alcohol abuse damages brain
a nerve it produces permanent damage. neurones.
Alcohol is an astringent—precipitates surface Other actions Alcohol affects many body
proteins and hardens skin. By precipitating functions in a dose-dependent manner.
bacterial proteins it acts as an antiseptic. The 1. Vasodilatation, flushing, tachycardia, mild
antiseptic action increases with concentration rise in BP at low doses (due to sympathetic
from 20 to 70%, remains constant from 70 to 90% stimulation), but fall in BP at high levels (due to
and decreases above that. vasodilatation, cardiac and vasomotor centre
II

CNS Alcohol is a neuronal depressant. Since depression).


the highest areas are most easily deranged and 2. Respiratory centre is depressed at high
SECTION

these are primarily inhibitory—apparent exci- concentrations.


tation and euphoria are experienced at lower 3. Though alcohol is reputed to combat cold
plasma concentrations (30–100 mg/dl). Hesita- because it produces a sense of warmth due to
tion, caution, self-criticism and restraint are lost cutaneous vasodilatation, heat loss is actually
first. Mood and feelings are altered; anxiety greater in cold surroundings.
may be allayed. With increasing concentration 4. Dilute alcohol (10%) stimulates gastric
(100–150 mg/dl) mental clouding, disorganiza- secretion, but high concentrations inhibit it and
tion of thought, impairment of memory and other cause mucosal congestion progressing to gastritis.
faculties, alteration of perception and drowsiness Gastroesophageal reflux is worsened due to
supervene. At 150–200 mg/dl the person is decrease in the tone of lower esophageal
sloppy, ataxic and drunk; 200–300 mg/dl result sphincter. Bowel movement may be altered.
in stupor and above this unconsciousness 5. Moderate amounts of alcohol do not cause
prevails, medullary centres are paralysed and liver damage in well nourished individuals, but
death may occur. Though alcohol can produce chronic alcoholism along with nutritional defi-
anaesthesia, margin of safety is narrow. ciencies may cause alcoholic cirrhosis of liver.
Any measurable concentration of alcohol pro- 6. Regular intake of small to moderate amounts
duces a measurable slowing of reflexes: driving of alcohol raises HDL-cholesterol level: risk of
is dangerous. Performance is impaired, fine dis- coronary artery disease is reduced by 15–35%.
crimination and precise movements are oblitera- 7. Urine flow may increase due to inhibition of
ted; errors increase. ADH secretion.

Alcohol : conscious anaesthesia death.

Ether : conscious anaesthesia death.


Ethyl Alcohol 141
8. Though reputed as an aphrodisiac, alcohol 2. Individuals taking sulfonylureas (especially
actually impairs performance of sexual act. chlorpropamide), certain cephalosporins
9. Uterine contractions are dampened at (cefoperazone) or metronidazole have expe-
moderate blood levels. rienced bizarre, somewhat disulfiram like
10. Hyperglycaemia (due to Adr release) occurs reactions when they consume alcohol.
initially, but high levels deplete hepatic glycogen 3. Acute alcohol ingestion inhibits, while chro-
and cause hypoglycaemia. nic intake induces tolbutamide, phenytoin
(and many other drugs) metabolism.
PHARMACOKINETICS 4. Insulin and sulfonylureas: alcohol enhances
hypoglycaemia acutely.
Though some alcohol is absorbed from stomach,
5. Aspirin and other NSAIDs cause more gastric
very rapid absorption occurs when it reaches
bleeding when taken with alcohol.
duodenum and small intestine. Limited first pass
6. Alcoholics are more prone to paracetamol
metabolism takes place in stomach wall and in
toxicity due to enhanced generation of its toxic
liver. Alcohol gets distributed widely in the body
metabolite.
(vol of distribution 0.7 L/kg), crosses blood-brain
barrier efficiently: concentration in brain is very FOOD VALUE
near blood concentration. It also crosses placenta
freely. It is oxidized in liver to the extent of 98%. Alcohol requires no digestion and is metabolized rapidly.
It is an energy yielding substrate: 7 Cal/g, but these cannot
Even with high doses, not more than 10% escapes

CHAPTER
be stored. It also does not supply body building and other
metabolism. essential constituents of food. Those who consume
substantial part of their caloric intake as alcohol, often
Alcohol Aldehyde
suffer from nutritional deficiencies. Thus, alcohol is an
Ethyl Acetaldehyde Acetate CO2+
alcohol dehydro- dehydro- H 2O
imperfect and expensive food.
genase genase
TOXICITY
Metabolism of alcohol follows zero order kinetics,

9
i.e. a constant amount (8–12 ml of absolute A. Side effects of moderate drinking Nausea,
alcohol/hour) is degraded in unit time, vomiting, flushing, hangover, traffic accidents.
irrespective of blood concentration. Thus, rate of B. Acute alcoholic intoxication Hypotension,
consuming drinks governs whether a person will gastritis, hypoglycaemia, collapse, respiratory
get drunk. depression, coma and death.
Excretion occurs though kidney and lungs, Treatment: Institute gastric lavage, maintain
but neither is quantitatively significant. Concen- patent airway and take steps to prevent aspiration
tration in exhaled air is about 0.05% of blood of vomitus. Positive pressure respiration may be
concentration: this is utilized for medicolegal needed if it is markedly depressed. Most patients
determination of drunken state. The subject blows will recover with supportive treatment, mainte-
in a balloon and alcohol is measured by a portable nance of fluid and electrolyte balance and
breath analyser. correction of hypoglycaemia by glucose infusion
till alcohol is metabolized.
INTERACTIONS
C. Chronic alcoholism On chronic intake,
1. Alcohol synergises with tranquilizers, anti- tolerance develops to subjective and behavioral
depressants, antihistaminics, hypnotics, effects of alcohol, but is generally of a low degree.
opioids → marked CNS depression with It is both pharmacokinetic (reduced rate of
motor impairment can occur: Chances of absorption due to gastritis and faster metabolism
accidents increase. due to enzyme induction) and cellular tolerance.
142 Drugs Acting on CNS

Psychic dependence often occurs even with drinking. However, because of risk of severe reaction, it is
rarely employed.
moderate drinking; depends a lot on individual’s
likings and attitudes.
CLINICAL USES
Physical dependence occurs only on heavy
and round-the-clock drinking (if alcohol is Medicinal uses of ethanol are primarily restricted
present in the body continuously). Heavy to external application and as a vehicle for liquid
drinking is often associated with nutritional preparations used internally.
deficiencies, because food is neglected and 1. As antiseptic and disinfectant: because of good
malabsorption may occur. In addition to impaired cleansing property and that it evaporates
mental and physical performance, neurological without leaving any residue, alcohol is used to
afflictions are common—polyneuritis, pellagra, disinfect working surfaces in dentistry. Being
tremors, seizures, loss of brain mass, Wernicke’s irritant, it is not suitable for application to oral
encephalopathy, Korsakoff’s psychosis and mucosa.
megaloblastic anaemia. Alcoholic cirrhosis of 2. Rubefacient and counterirritant for sprains,
liver, hypertension, cardiomyopathy, CHF, joint pains, etc.
arrhythmias, stroke, acute pancreatitis, impo- 3. Rubbed into the skin to prevent (but not to
tence, gynaecomastia, infertility and skeletal treat) bedsores. Astringent action of alcohol
myopathy are other complications. Incidence of is utilized in antiperspirant and aftershave
oropharyngeal, esophageal and hepatic malig- lotions.
4. Alcoholic sponges to reduce body tempera-
II

nancy and respiratory infections is high; immune


function is depressed. ture in fever.
SECTION

5. Intractable neuralgias (trigeminal and others),


Dental implications Alcoholics have higher severe cancer pain—injection of alcohol
incidence of heavy dental plaque, calculus around the nerve causes permanent loss of
deposits, chronic periodontitis and tooth loss due transmission.
to poor oral hygiene. Dentists, while prescribing 6. To ward off cold—may benefit by causing
metronidazole or certain cephalosporins for perio- vasodilatation of blanched mucosae.
dontal infections should warn patients not to drink. 7. As appetite stimulant and carminative.
Concurrent ingestion of NSAIDs and alcohol should 8. To treat methanol poisoning.
be prohibited.
METHYL ALCOHOL (Methanol, Wood alcohol)
Treatment: Psychological and medical suppor-
tive measures are needed during withdrawal. Methyl alcohol is added to rectified spirit to render it unfit
Substitution therapy with BZDs like diazepam for drinking. It is only of toxicological importance.
Unscrupulous mixing of methylated spirit with alcoholic
or chlordiazepoxide is given to suppress beverages or its inadvertent ingestion results in methanol
withdrawal syndrome, followed by their gradual poisoning.
discontinuation. The long acting opioid anta- Methanol is metabolized to formaldehyde and formic
gonist naltrexone helps to prevent relapse of acid by alcohol and aldehyde dehydrogenases respectively,
but the rate is 1/7th that of ethanol. Like ethanol, it follows
alcoholism. zero order kinetics and t½ of 20–60 hours has been
Disulfiram It is an aldehyde dehydrogenase inhibitor measured.
which prevents further oxidation of acetaldehyde generated Methanol also is a CNS depressant, but less potent
from ingested alcohol. As a result, when the subject drinks than ethanol. Toxic effects of methanol are largely due to
a small quantity of alcohol after taking disulfiram, he formic acid, since its further metabolism is slow and folate
experiences distressing symptoms like flushing, burning dependent.
sensation, throbbing headache, sweating, uneasiness, Manifestations of methanol poisoning are vomiting,
tightness in chest, vomiting, etc. (aldehyde syndrome). headache, epigastric pain, uneasiness, dyspnoea, brady-
This has been used as an aversion technique in chronic cardia and hypotension. Delirium may occur and the
alcoholics who have been motivated and have stopped patient may suddenly pass into coma. Acidosis is
Antiepileptic Drugs 143
prominent and entirely due to production of formic acid. or little bilateral jerking. EEG shows characteristic 3 cycles
The specific toxicity of formic acid is retinal damage. per second spike and wave pattern.
Blurring of vision, congestion of optic disc followed by 3. Atonic seizures (Akinetic epilepsy): Unconsciousness
blindness always precede death which is due to respiratory with relaxation of all muscles due to excessive inhibitory
failure. discharges. Patient may fall.
4. Myoclonic seizures Shock-like momentary contrac-
Treatment tion of muscles of a limb or the whole body.
1. Keep the patient in a quiet, dark room; protect the
eyes from light. II. Partial seizures
2. Gastric lavage with Sod. bicarbonate, supportive
1. Simple partial seizures (SPS, cortical focal epilepsy):
measures to maintain ventilation and BP.
lasts 1/2–1 min. Often secondary. Convulsions are
3. Combat acidosis by i.v. Sod. bicarbonate infusion—the
confined to a group of muscles or localized sensory
most important measure; prevents retinal damage
disturbance depending on the area of cortex involved in
and other symptoms.
the seizure, without loss of consciousness.
4. Pot. chloride infusion is needed only when hypo-
kalaemia occurs due to alkali therapy. 2. Complex partial seizures (CPS, temporal lobe epilepsy,
5. Ethanol retards methanol metabolism. This helps by psychomotor): attacks of bizarre and confused behaviour
reducing the rate of generation of toxic metabolites. and purposeless movements, emotional changes lasting 1–
6. Haemodialysis: clears methanol as well as its toxic 2 min along with impairment of consciousness. An aura often
metabolite formate and hastens recovery. precedes. The seizure focus is located in the temporal lobe.
7. Fomepizole (4-methylpyrazole) is a specific inhibitor 3. Simple partial or complex partial seizures secondarily
of alcohol dehydrogenase—retards methanol meta- generalized The partial seizure occurs first and evolves
bolism. It has several advantages over ethanol, but is into generalized tonic-clonic seizures with loss of

CHAPTER
not available commercially. consciousness.
8. Folate therapy: Calcium leucovorin injected repeatedly
has been shown to reduce blood formate levels by Most of the cases are primary (idiopathic), some
enhancing its metabolism. may be secondary to trauma/surgery on head,
intracranial tumour, tuberculoma, cysticercosis,
ANTIEPILEPTIC DRUGS cerebral ischaemia, etc. Treatment is symptomatic
Epilepsies These are a group of disorders of and the same whether epilepsy is primary or

9
the CNS characterized by paroxysmal cerebral secondary.
dysrhythmia, manifesting as brief episodes
(seizures) of loss or disturbance of consciousness, CLASSIFICATION
with or without characteristic body movements 1. Barbiturate Phenobarbitone
(convulsions), sensory or psychiatric phenomena. 2. Deoxybarbiturate Primidone
Epilepsy has a focal origin in the brain, 3. Hydantoin Phenytoin
manifestations depend on the site of the focus, 4. Iminostilbene Carbamazepine
regions into which the discharges spread and Oxcarbazepine
postictal depression of these regions. Epilepsies 5. Succinimide Ethosuximide
have been classified variously; major types are: 6. Aliphatic carboxylic Valproic acid
1. Generalised seizures acid (sodium valproate)
Divalproex
1. Generalised tonic-clonic seizures (GTCS, major epi-
7. Benzodiazepines Clonazepam,
lepsy, grand mal): commonest, lasts 1–2 min.
The usual sequence is aura—cry—unconsciousness—tonic Diazepam,
spasm of all body muscles—clonic jerking followed by Lorazepam
prolonged sleep and depression of all CNS functions. Clobazam
2. Absence seizures (minor epilepsy, petit mal): 8. Phenyltriazine Lamotrigine
prevalent in children, lasts about 1/2 min. 9. Cyclic GABA analogue Gabapentin
Momentary loss of consciousness, patient apparently
freezes and stares in one direction, no muscular component Pregabalin
144 Drugs Acting on CNS
10. Newer drugs Vigabatrin, therapeutic doses, that does not increase further
Topiramate with dose; rather toxic doses produce excitement.
Zonisamide Tonic-clonic epilepsy is suppressed but paroxys-
Levetiracetam mal focal EEG discharge and ‘aura’ persist.
Phenobarbitone Mechanism of action: Phenytoin has a stabili-
Phenobarbitone is the first efficacious anti- zing influence on neuronal membrane—prevents
epileptic introduced in 1912. Enhancement of repetitive detonation of normal brain cells during
GABAA receptor mediated synaptic inhibition ‘depolarization shift’. This is achieved by pro-
appears to be its most important mechanism of
longing the inactivated state of voltage sensitive
sedative as well as anticonvulsant action.
neuronal Na+ channel (Fig. 9.3) that governs the
Phenobarbitone has specific anticonvulsant
refractory period of the neurone. As a result, high
activity which is not entirely dependent on general
CNS depression. This may be due to its less frequency discharges are inhibited with little effect
marked effect on Ca2+ channels and glutamate on normal low frequency discharges. Intracel-
release compared to hypnotic barbiturates. With lular accumulation of Na+ that occurs during
continued use of phenobarbitone sedation wanes repetitive firing is prevented.
off but not the anticonvulsant action. Its ability to selectively inhibit high frequency
The major drawback of phenobarbitone as an firing confers efficacy in trigeminal neuralgia as
antiepileptic is its sedative action. Long-term well.
II

administration (as needed in epilepsy) may


Pharmacokinetics Absorption of phenytoin by
produce additional side effects like—behavioral
oral route is slow, and it is 80–90% bound to
SECTION

abnormalities, diminution of intelligence, impair-


ment of learning and memory, hyperactivity in plasma proteins.
children, mental confusion in older people. Phenytoin is metabolized in liver by hydroxy-
lation and glucuronide conjugation. The kinetics
Uses Phenobarbitone is one of the cheapest and of metabolism is capacity limited; changes from
least toxic antiepileptics. It has broad-spectrum first order to zero order over the therapeutic
efficacy in generalized tonic-clonic (GTC), simple range—small increments in dose produce dispro-
partial (SP) and complex partial (CP) seizures:
portionately high plasma concentrations. The t½
but is less popular than carbamazepine, pheny-
(normally 12–24 hr) progressively increases (up
toin or valproate.
to 60 hr) when plasma concentration rises.
Status epilepticus: Phenobarbitone may be injected
i.m. or i.v. but response is slow to develop. Adverse effects These are numerous; some
It is not effective in absence seizures. occur at therapeutic plasma concentration after
prolonged use, while others are a manifestation
Primidone A deoxybarbiturate, converted by
of toxicity due to overdose.
liver to phenobarbitone and phenylethyl malona-
mide (PEMA). Activity is mainly due to these active At therapeutic levels
metabolites. Antiepileptic efficacy and side effects (a) Gum hypertrophy: Commonest (20% inci-
are similar to phenobarbitone. However, it may dence), more in younger patients and is due
control seizures in some patients refractory to to overgrowth of gingival collagen fibres. It
other drugs.
can be minimized by maintaining good oral
hygiene. In some patients it may be so massive
Phenytoin (Diphenylhydantoin)
as to require surgery.
Phenytoin is a major antiepileptic drug, but is not (b) Hirsutism, coarsening of facial features
a CNS depressant; some sedation occurs at (troublesome in young girls), acne.
Antiepileptic Drugs 145

CHAPTER
Fig. 9.3: Major mechanisms of anticonvulsant action
m: Activation gate; h: Inactivation gate; GAT-1: GABA transporter;
GABA-T: GABA transaminase; SSA: Succinic semialdehyde

9
(c) Hypersensitivity reactions are—rashes, DLE, induction both enhance each other’s degra-
lymphadenopathy; neutropenia is rare but dation—unpredictable overall interaction.
requires discontinuation of therapy. • Carbamazepine and phenytoin increase each
(d) Megaloblastic anaemia: phenytoin decreases other’s metabolism.
folate absorption and increases its excretion. • Valproate displaces protein bound phenytoin
(e) Osteomalacia
and decreases its metabolism: plasma level of
(f) Used during pregnancy—can produce foetal
unbound phenytoin increases.
hydantoin syndrome (hypoplastic phalanges,
• Chloramphenicol, isoniazid, cimetidine, dicu-
cleft palate, hare lip, microcephaly).
marol, and warfarin inhibit phenytoin meta-
At high plasma levels (dose-related toxicity) bolism—can precipitate its toxicity.
(a) Cerebellar and vestibular manifestations: • Phenytoin induces microsomal enzymes and
ataxia, vertigo, diplopia, nystagmus are the increases degradation of steroids (failure of oral
most characteristic features. contraceptives), doxycycline, theophylline.
(b) Drowsiness, behavioral alterations, mental
Uses Phenytoin is one of the most widely used
confusion and hallucinations.
antiepileptic drugs for—
(c) Epigastric pain, nausea and vomiting.
1. Generalized tonic-clonic, simple and comp-
Interactions Phenobarbitone competitively lex partial seizures. It is ineffective in absence
inhibits phenytoin metabolism, while by enzyme seizures.
146 Drugs Acting on CNS

2. Status epilepticus: occasionally used by slow is induced by phenobarbitone, phenytoin,


i.v. injection. valproate and vice versa.
3. Trigeminal neuralgia: second choice drug to Erythromycin, fluoxetine, isoniazid inhibit
carbamazepine. metabolism of carbamazepine.
Fosphenytoin This water soluble prodrug of Uses It is the most effective drug for CPS and
phenytoin has replaced phenytoin for i.v. use, shares first choice drug status with phenytoin for
because it is less damaging to the intima of the GTCS and SPS.
vein. Trigeminal and related neuralgias: carbamazepine
is the drug of choice. These neuralgias are
Carbamazepine characterized by attacks of high intensity electric
Chemically related to imipramine, it was intro- shock-like or stabbing pain set off by even trivial
duced in the 1960s for trigeminal neuralgia; is stimulation of certain trigger zones in the mouth
now a first line antiepileptic drug. Its pharmacolo- or on the face. Drugs benefit by interrupting
gical actions resemble phenytoin but many temporal summation of afferent impulses (by a
differences have been noted. Though its action selective action on high frequency nerve impulses).
on Na+ channels (prolongation of inactivated Carbamazepine is not an analgesic but has a spe-
state) is similar to phenytoin, the profile of action cific action (almost diagnostic) in these neuralgias.
on neuronal systems in brain is different. About 60% patients respond well. Phenytoin and
Carbamazepine has a therapeutic effect in baclofen are less efficacious alternatives.
II

mood disorders and an antidiuretic action, Manic depressive illness and acute mania: as an
probably by enhancing ADH action on renal alternative to lithium.
SECTION

tubules. Oxcarbazepine This newer congener of carba-


Oral absorption of carbamazepine is slow and mazepine does not generate the epoxide meta-
variable. It is 75% bound to plasma proteins and bolite, so that toxic effects and drug interactions
metabolized in liver by oxidation to an active due to this metabolite are avoided. Indications
metabolite (10-11 epoxy carbamazepine) as well are similar to carbamazepine, but doses required
as by hydroxylation and conjugation to inactive are 1½ times larger.
ones. Initially, its plasma t½ is 20–40 hours but
decreases to 10–20 hr on chronic medication due Ethosuximide
to autoinduction of metabolism. It has an entirely different profile of anticonvulsant action
than phenytoin and is clinically effective only in absence
Adverse effects Carbamazepine produces seizures. The primary action appears to be exerted on
dose-related neurotoxicity—sedation, dizziness, thalamocortical system which is involved in the generation
vertigo, diplopia and ataxia. Vomiting, diarrhoea, of absence seizures. Thalamic neurones exhibit prominent
‘T’ (transient) current which is low threshold Ca2+ current
worsening of seizures are also seen with higher that amplifies repetitive spikes. Ethosuximide selectively
doses. suppresses T current without affecting other types of Ca2+
Hypersensitivity reactions are rashes, photosen- or Na+ currents. It also does not potentiate GABA. This
sitivity, hepatitis, lupus like syndrome and rarely correlates well with its selective action in absence seizures,
which is its only indication.
agranulocytosis, aplastic anaemia.
Increased incidence of minor foetal malforma- Valproic acid (Sodium valproate)
tions has been reported. Its combination with
It is a broad-spectrum anticonvulsant effective in
valproate doubles teratogenic frequency.
several experimental models of epilepsy.
Interactions Carbamazepine is an enzyme Remarkably, valproate produces little sedation
inducer: can reduce efficacy of haloperidol and or other central effects. It is effective in partial
oral contraceptives. Metabolism of carbamazepine seizures, GTCS as well as absence seizures.
Antiepileptic Drugs 147

Valproate appears to act by multiple mechanisms: Divalproex This coordination compound of


(i) A phenytoin-like frequency dependent valproic acid with sodium valproate has better
prolongation of Na+ channel inactivation. gastric tolerance, but is absorbed more slowly.
(ii) Attenuation of Ca2+ mediated ‘T’ current
(ethosuximide like). Clonazepam
(iii) Augmentation of release of inhibitory trans-
mitter GABA by inhibiting its degradation (by It is a benzodiazepine with prominent anticon-
GABA-transaminase). vulsant properties, but is singularly ineffective in
GTCS.
Adverse effects Toxicity of valproate is low. Benzodiazepines potentiate GABA induced
Anorexia, vomiting, drowsiness, ataxia and Cl– influx to produce sedation and the same
tremor are dose-related side effects. However, mechanism has been held responsible for the
cognitive and behavioral effects are not pro- anticonvulsant property. At large doses, high
minent. frequency discharges are inhibited akin to
Alopecia, curling of hair, and increased bleeding phenytoin.
tendency have been observed. The dentist may face The most important side effect of clonazepam
excess bleeding while executing a dental procedure. is sedation and dullness. Motor disturbances and
A rare but serious adverse effect is fulminant ataxia are dose-related adverse effects.
hepatitis; occurs only in children (especially below Clonazepam has been primarily employed in

CHAPTER
3 yr age). absence seizures. It is also useful as an adjuvant
Used during pregnancy, it has produced neural in myoclonic and akinetic epilepsy. However, its
tube defects (spina bifida) in the offspring. value is limited by development of tolerance.

Uses Valproic acid is the drug of choice for Clobazam This BZD analogue is generally used
absence seizures. as adjuvant to other antiepileptic drugs in
It is an alternative/adjuvant drug for GTCS, SPS refractory epilepsy.

9
and CPS.
Myoclonic and atonic seizures—control is often Diazepam
incomplete, but valproate is the drug of choice. It has anticonvulsant activity in a variety of
Mania and bipolar illness: as alternative to models but is not used for long-term therapy of
lithium. epilepsy because of prominent sedative action
and rapid development of tolerance to the anti-
Interactions epileptic effect. However, administered i.v., it is
• Valproate increases plasma levels of phenob- the drug of choice for emergency control of
arbitone by inhibiting its metabolism. convulsions, e.g. status epilepticus, tetanus,
• It displaces phenytoin from protein binding eclampsia, convulsant drug poisoning, etc.
site and decreases its metabolism → pheny- Rectal instillation of diazepam is the prefer-
toin toxicity. red therapy for febrile convulsions in children.
• Valproate and carbamazepine induce each
Lorazepam Injected i.v., it is an alternative to
other’s metabolism.
diazepam for emergency control of seizures with
• Concurrent administration of clonazepam and
the advantage of more sustained effect.
valproate is contraindicated because absence
status may be precipitated. Lamotrigine A new anticonvulsant having
• Foetal abnormalities are more common if carbamazepine-like action profile. Prolongation
valproate and carbamazepine are given con- of Na+ channel inactivation and suppression of
currently. high frequency firing has been demonstrated. In
148 Drugs Acting on CNS

addition, it may directly block voltage sensitive but has similar antiseizure property as well. It
Na+ channels, thus stabilizing the presynaptic appears to cause less sedation than gabapentin.
membrane and preventing release of excitatory Vigabatrin (γ vinyl GABA) It is an inhibitor of GABA-
neurotransmitters, mainly glutamate and transaminase, the enzyme which degrades GABA. Its
aspartate. anticonvulsant action may be due to increase in synaptic
Lamotrigine is a broad-spectrum antiepileptic. GABA concentration. It is effective in many patients with
refractory epilepsy, especially partial seizures with or
Initially found useful as add-on therapy in without generalization. It is used only as adjuvant
refractory cases of partial seizures and GTCS, it medication.
has now been shown effective as monotherapy
Topiramate This weak carbonic anhydrase
as well. Absence and myoclonic or akinetic
inhibitor has broad-spectrum anticonvulsant
epilepsy cases have also been successfully treated.
activity and appears to act by multiple
Side effects are sleepiness, dizziness, diplopia,
mechanisms, viz phenytoin-like prolongation of
ataxia and vomiting. Na+ channel inactivation, GABA potentiation
Gabapentin This lipophilic GABA derivative and antagonism of certain glutamate receptors.
crosses to the brain and enhances GABA release, Topiramate is indicated for supplementing
but does not act as agonist at GABAA receptor. primary antiepileptic drug in refractory SPS, CPS
Added to a first line drug, it reduces seizure and GTCS. Promising results have been obtained
frequency in refractory partial seizures with or in myoclonic epilepsy also.
without generalization. Beneficial effects in manic
II

Zonisamide Another newer weak carbonic anhydrase


depressive illness and migraine have also been inhibitor with multiple anticonvulsant actions. It is
indicated as ‘add on’ therapy for refractory partial seizures.
SECTION

reported. Gabapentin is now considered to be the


first line drug for pain due to diabetic neuropathy, Levetiracetam This new anticonvulsant drug has a
postherpetic and other neuralgias. unique profile of action in experimental seizures and
lacks all the major anticonvulsant mechanisms of action.
Pregabalin This newer congener of gabapentin It is used as adjuvant medication for refractory partial
has been particularly used for neuropathic pain, seizures.

Table 9.2: Choice of antiseizure drugs

Type of seizure First choice drugs Second choice drugs Alternative/Add-on drugs
1. Generalised tonic-clonic/ Carbamazepine, Valproate, Lamotrigine, Gabapentin,
simple partial with or Phenytoin Phenobarbitone Topiramate
without generalization
2. Complex partial with or Carbamazepine, Gabapentin, Clobazam, Zonisamide
without generalization Valproate, Lamotrigine Topiramate
Phenytoin
3. Absence Valproate Lamotrigine Clobazam
Clonazepam
4. Myoclonic Valproate Lamotrigine Primidone, Clobazam,
Topiramate Clonazepam
5. Atonic Valproate Clonazepam, Lamotrigine
Clobazam
6. Febrile seizures Diazepam (rectal) — —
7. Status epilepticus Diazepam (i.v.) Fosphenytoin (i.v.) Gen. anaesthetics
Lorazepam (i.v.) Phenobarbitone
(i.v., i.m.)
Antiparkinsonian Drugs 149

TREATMENT OF EPILEPSIES The head should be turned to the side to prevent the
Antiepileptic drugs suppress seizures but do not tongue from falling back and obstructing the airway.
cure the disorder; the disease may fade out though The seizure usually passes off in a few
after years of successful control. The aim of drugs minutes. Continuation or postponement of the
is to control and totally prevent all seizure activity procedure after the fit is over depends on the
at an acceptable level of side effects. The cause of circumstances. The patient must be sent back
epilepsy should be searched in the patient; if home with an escort. In case the seizures do not stop,
found and treatable, an attempt to remove it management is as for status epilepticus.
should be made. Some general principles of sym- Status epilepticus When seizure activity occurs
ptomatic treatment with antiepileptic drugs are: for >30 min, or two or more seizures occur without
(i) Choice of drug (Table 9.2) and dose is recovery, it is labelled status epilepticus. Recurrent
according to the seizure type(s) and need of the tonic-clonic convulsions without recovery of
individual patient. consciousness is an emergency; fits have to be
(ii) Initiate treatment early, because each seizure controlled as quickly as possible to prevent death
episode increases the propensity to further and permanent brain damage.
attacks. Start with a single drug, gradually (a) Diazepam 10 mg i.v. bolus injection (2 mg/
increase dose till full control of seizures or side min) followed by fractional doses every 10 min,
effects appear. Use combinations when all reason- or slow infusion titrated to control the fits has
able monotherapy fails. been the standard treatment. However, it

CHAPTER
redistributes rapidly so that anticonvulsant effect
(iii) Therapy should be as simple as possible. A
starts fading after 20 min. Lorazepam is less lipid
seizure diary should be maintained.
soluble with slow redistribution: anticonvulsant
(iv) All drug withdrawals should be gradual effect of i.v. dose lasts for 6-12 hours. It is therefore
(except in case of toxicity). Prolonged therapy preferred; 0.1 mg/kg (injected at 2 mg/min) is
(may be life long, or at least 3 years after the last effective in 75-90% cases.

9
seizure) is needed. Withdrawal may be attempted (b) Phenobarbitone (100-200 mg i.m./i.v.) or
in selected cases. fosphenytoin (maximum 1000 mg phenytoin
(v) Dose regulation may be facilitated by monito- equivalent) act more slowly; may be used
ring of steady-state plasma drug levels. alternatively to diazepam/lorazepam or substi-
tuted for them after the convulsions have been
(vi) When women on antiepileptic therapy con- controlled.
ceive, antiepileptic drugs should not be stopped. (c) Refractory cases may be treated with i.v.
Though most antiseizure drugs have been shown midazolam/propofol/thiopentone anaesthesia,
to increase the incidence of birth defects, disconti- with or without curarization.
nuation of therapy carries a high risk of status (d) General measures, including maintenance of
epilepticus. It may be advisable to substitute airway (intubation if required), oxygenation, fluid
valproate and give folic acid supplementation. and electrolyte balance, BP, normal cardiac
(vii) In an epileptic patient dental procedure should be rhythm, euglycaemia and care of the unconscious
carried out only after ensuring that the patient is under must be taken.
adequate anticonvulsant drug cover.
ANTIPARKINSONIAN DRUGS
(viii) In the event of a patient developing an attack of
These are drugs that have a therapeutic effect in
tonic-clonic seizures during dental procedure, the first
parkinsonism.
priority is to prevent injuries due to biting or fall. Any
denture or instrument should be immediately removed Parkinsonism It is an extrapyramidal motor
from the mouth and a gag placed between the teeth. disorder characterized by rigidity, tremor and
150 Drugs Acting on CNS

hypokinesia with secondary manifestations like acts on heart, blood vessels, other peripheral
defective posture and gait, mask-like face and organs and on CTZ (though located in the brain,
sialorrhoea; dementia may accompany. If untrea- i.e. floor of IV ventricle, it is not bound by blood-
ted, the symptoms progress over several years to brain barrier). About 1–2% of administered
endstage disease in which the patient is rigid, levodopa crosses to the brain, is taken up by the
unable to move, unable to breathe properly; surviving dopaminergic neurones, converted to
succumbs mostly to chest infections/embolism. DA which is stored and released as a transmitter.
Parkinson’s disease (PD) is a progressive degenerative
disorder, mostly affecting older people, first described by Actions
James Parkinson in 1817.
The most consistent lesion in PD is degeneration of 1. CNS Levodopa hardly produces any effect
neurones in substantia nigra pars compacta and the in normal individuals. Marked symptomatic
nigrostriatal (dopaminergic) tract. This results in deficiency improvement occurs in parkinsonian patients.
of dopamine (DA) in the striatum which controls muscle
Hypokinesia and rigidity resolve first, later tremor
tone and coordinates movements. An imbalance between
dopaminergic (inhibitory) and cholinergic (excitatory) as well. Secondary symptoms of posture, gait,
system in the striatum (Fig. 9.4) occurs giving rise to the handwriting, speech, facial expression, mood,
motor defect. Though the cholinergic system is not self-care and interest in life are gradually
primarily affected, its suppression (by anticholinergics)
normalized.
tends to restore balance.
Drug-induced temporary parkinsonism due to neuro- The effect of levodopa on behaviour has been
leptics, metoclopramide (dopaminergic blockers) is now described as a ‘general alerting response’. In some
II

fairly common. patients this progresses to excitement—frank


psychosis may occur. Embarrassingly dispropor-
SECTION

CLASSIFICATION tionate increase in sexual activity has also been


I. Drugs affecting brain dopaminergic system noted.
(a) Dopamine precursor : Levodopa (l-dopa) 2. CVS The peripherally formed DA can cause
(b) Peripheral decarboxylase inhibitors : tachycardia by acting on β adrenergic receptors.
Carbidopa, Benserazide. Postural hypotension due to central and
(c) Dopaminergic agonists: Bromocriptine, ganglionic action is quite common.
Ropinirole, Pramipexole
(d) MAO-B inhibitor: Selegiline 3. CTZ The peripherally formed DA gains access
(e) COMT inhibitors: Entacapone, Tolcapone to the CTZ without hindrance—elicits nausea and
(f) Dopamine facilitator: Amantadine. vomiting by stimulating dopaminergic D2
receptors. Tolerance occurs gradually to this action.
II. Drugs affecting brain cholinergic system
(a) Central anticholinergics : Trihexyphenidyl 4. Endocrine DA acts on pituitary mammotro-
(Benzhexol), Procyclidine, Biperiden. pes to inhibit prolactin release → blood prolactin
(b) Antihistaminics : Orphenadrine, level falls.
Promethazine.
Pharmacokinetics
LEVODOPA
Levodopa is rapidly absorbed from the small
Levodopa has a specific salutary effect in PD: intestines by utilizing the active transport process
efficacy exceeding that of any other drug used meant for aromatic amino acids.
alone. It is inactive by itself, but is the immediate It undergoes high first pass metabolism in g.i.
precursor of the transmitter DA. More than 95% mucosa and liver. The peripheral and central
of an oral dose is decarboxylated in the peripheral pathway of metabolism of levodopa is depicted
tissues (mainly gut and liver). DA thus formed in Fig. 9.5.
Antiparkinsonian Drugs 151

CHAPTER
9
Fig. 9.4: Simplified scheme of side loop circuits in the basal ganglia that provide modulatory input to the motor cortex.
The striatal GABAergic neurones receive side-loop excitatory glutamatergic (Glu) input from the motor cortex and
modulatory dopaminergic (DA) projections from the substantia nigra pars compacta (SN-PC). There are also balancing
cholinergic (ACh) interneurones. The striatal neurones express both excitatory D1 and inhibitory D2 receptors. The output
from the striatum to substantia nigra pars reticulata (SN-PR) and internal globus pallidus (GP-I) follows a direct and an
indirect pathway. The direct pathway modulated by DI receptors releases inhibitory transmitter GABA, while the dominant
indirect pathway modulated by D2 receptors has two inhibitory (GABAergic) relays and an excitatory (glutamatergic)
terminal. Due to this arrangement, dopaminergic action in the striatum exerts inhibitory influence on SN-PR and GP-I via
both the pathways. The output neurones from SN-PR and GP-I feedback on the motor cortex through the thalamus using
an inhibitory GABAergic link and an excitatory glutametergic terminal. The basal ganglia modulatory loop serves to
smoothen output to the spinal motor neurone and reduce basal tone.
The degenerative lesion (in SN-PC) of Parkinson’s disease (PD) decreases dopaminergic input to the striatum,
producing an imbalance between DA and ACh, resulting in hypokinesia, rigidity and tremor.

About 1% of administered dose that enters Adverse effects


brain, aided by amino acid carrier mediated active Side effects of levodopa therapy are frequent and
transport across brain capillaries, also undergoes often troublesome. Some are prominent in the
the same transformation. The plasma t½ of beginning of therapy while others appear late.
levodopa is 1–2 hours. Pyridoxal is a cofactor for 1. Nausea and vomiting: Tolerance gradually
the enzyme dopa-decarboxylase. The metabolites develops and then the dose can be progressively
are excreted in urine mostly after conjugation. increased.
152 Drugs Acting on CNS

Fig. 9.5: Metabolic pathways of levodopa in the periphery and the brain
3-OMD—3-O-methyldopa; COMT—catechol-O-methyl transferase; MAO—monoamine
oxidase; 3-MT—3-methoxytyramine; DOPAC—3,4 dihydroxy phenylacetic acid; HVA—
homovanillic acid (3-methoxy-4-hydroxy phenylacetic acid), DDC—dopa decarboxylase
II

fluctuation. ‘End of dose’ deterioration, develops


SECTION

2. Postural hypotension: It occurs in about 1/3rd


of patients, but is mostly asymptomatic; some into rapid ‘switches’ or ‘on-off’ effect. With time
patients experience dizziness, few have fainting ‘all or none’ response develops, i.e. the patient is
attacks. Tolerance develops with continued treat- alternately well and disabled. This is probably a
ment. Care should be taken by the dentist that patients reflection of progression of the disorder: with
on levodopa therapy do not sit up and leave the dental progressive degeneration of DA neurones the
chair abruptly from a reclining position. ability to regulate storage and release of DA may
3. Cardiac arrhythmias be largely lost.
4. Exacerbation of angina
5. Alteration in taste sensation Interactions
6. Abnormal movements: Facial tics, grimacing, 1. Pyridoxine: Abolishes therapeutic effect by
tongue thrusting, choreoathetoid movements of enhancing peripheral decarboxylation of levo-
limbs, etc. start appearing after a few months of dopa.
use of levodopa. They may become as disabling 2. Phenothiazines, butyrophenones, metoclopra-
as the original disease itself—are the most mide reverse the therapeutic effect of levodopa by
important dose limiting side effects. Orofacial blocking DA receptors.
dyskinesias may make brushing difficult—damage 3. Antihypertensives: postural hypotension is
teeth and pose difficulty in wearing dentures. accentuated.
7. Behavioral effects: Range from mild anxiety,
nightmares, etc. to severe depression, mania,
PERIPHERAL DECARBOXYLASE INHIBITORS
hallucinations, mental confusion or frank psy-
chosis. Carbidopa and benserazide are extracerebral dopa
3. Fluctuation in motor performance: After 2–5 decarboxylase inhibitors; they do not penetrate
years of therapy, the level of control of blood-brain barrier and do not inhibit conversion
parkinsonian symptomatology starts showing of levodopa to DA in brain. Administered along
Antiparkinsonian Drugs 153

with levodopa, they increase its t½ in the It serves to improve control and smoothen ‘end of
periphery and make more of it available to cross dose’ and ‘on-off’ fluctuations. Dyskinesias are
blood-brain barrier to reach its site of action. less prominent with bromocriptine compared to
levodopa.
Benefits obtained on combining with levodopa are—
1. The plasma t½ of levodopa is prolonged and Ropinirole and Pramipexole These are two
its dose is reduced to approximately 1/4th. nonergoline, selective D2/D3 receptor agonists
2. Systemic concentration of DA is reduced, with negligible affinity for D1 and nondopami-
nausea and vomiting are not prominent. nergic receptors. The therapeutic effect as supple-
3. Cardiac complications are minimized. mentary drugs to levodopa in advanced cases of
4. Pyridoxine reversal of levodopa effect does not PD, as well as side effect profile is similar to
occur. bromocriptine; but they are better tolerated with
5. ‘On-off’ effect is minimized. fewer g.i. symptoms.
6. Degree of improvement may be higher. Ropinirole and pramipexole are being
increasingly used as monotherapy for early PD
Problems not resolved or accentuated are— as well with the possible advantage of lower
1. Involuntary movements ⎫ may even be more incidence of dyskinesias and motor fluctuations.
2. Behavioral abnormalities ⎬ pronounced and MAO-B INHIBITOR
⎭ appear earlier.
3. Postural hypotension. Selegiline (Deprenyl) It is a selective and

CHAPTER
Currently, levodopa is practically always used irreversible MAO-B inhibitor. Two isoenzyme
along with a decarboxylase inhibitor forms of MAO, termed MAO-A and MAO-B are
recognized; both are present in peripheral
adrenergic structures and intestinal mucosa,
DOPAMINERGIC AGONISTS while the latter predominates in brain and blood
The DA agonists can act on striatal DA receptors platelets. Unlike nonselective MAO inhibitors,

9
even in advanced patients who have largely lost selegiline in low doses (10 mg/day) does not
the capacity to synthesize, store and release DA interfere with peripheral metabolism of dietary
from levodopa. Moreover, they can be longer amines; CA accumulation and hypertensive
acting, exert subtype selective activation of DA reaction does not develop, while intracerebral
receptors involved in parkinsonism and not share degradation of DA is retarded. This is responsible
the concern expressed about levodopa of for the therapeutic effect in parkinsonism. Higher
contributing to dopaminergic neuronal damage doses can produce hypertensive interactions.
by oxidative metabolism. Selegiline alone has mild antiparkinsonian
action in early cases. Administered with levodopa
Bromocriptine It is an ergot derivative which it prolongs levodopa action, attenuates motor
acts as potent agonist on D2, but as partial agonist fluctuations and decreases ‘wearing off’ effect.
or antagonist on D1 receptors. Improvement in However, advanced cases with ‘on-off’ effect are
parkinsonian symptoms occurs within ½–1 hr of not improved and the peak dose levodopa side
an oral dose and lasts 6–10 hours. If used alone, effects such as dyskinesias, mental confusion or
doses needed in parkinsonism are high, expen- hallucinations may be worsened.
sive and often produce intolerable side effects— Selegiline interacts with pethidine causing
vomiting, hallucinations, hypotension, nasal excitement, rigidity, hyperthermia, respiratory
stuffiness, conjunctival injection. depression. It may interact with tricyclic anti-
In parkinsonism, bromocriptine is used only depressants and selective serotonin reuptake
in advanced cases as a supplement to levodopa. inhibitors as well.
154 Drugs Acting on CNS
COMT INHIBITORS which striatal dopaminergic system exerts its
Two selective, potent and reversible COMT inhibitors influence, is now considered to be more important.
Entacapone and Tolcapone have been introduced as Amantadine can be used in milder cases, or
adjuvants to levodopa-carbidopa for advanced PD. When in short courses to supplement submaximal doses
peripheral decarboxylation of levodopa is blocked by
carbidopa/benserazide, it is mainly metabolized by COMT
of levodopa.
to 3-O-methyldopa (see Fig. 9.5). Blockade of this pathway
by entacapone/tolcapone prolongs the t½ of levodopa CENTRAL ANTICHOLINERGICS
and allows a larger fraction of administered dose to cross
to brain. Since COMT plays a role in the degradation of These are drugs having a higher central : peri-
DA in the brain as well, COMT inhibitors could preserve
pheral anticholinergic action ratio than atropine,
DA formed in the striatum and supplement the peripheral
effect. However, entacapone acts only in the periphery but the pharmacological profile is similar to it. In
(probably because of short duration of action ~2 hr). For addition, certain H1 antihistaminics have
tolcapone also the central action is less important. significant central anticholinergic property. There
Entacapone may be used to smoothen ‘wearing off’ is little to choose clinically among these drugs,
effect or increase ‘on’ time with levodopa-carbidopa.
though individual preferences vary.
Because of reports of acute fatal hepatitis and
rhabdomyolysis, use of tolcapone is highly restricted. They act by reducing the unbalanced choli-
nergic activity in striatum of parkinsonian
patients. Generally, tremor is benefited more than
DOPAMINE FACILITATOR
rigidity; hypokinesia is affected the least.
Amantadine Developed as an antiviral drug for Sialorrhoea is controlled by their peripheral
II

prophylaxis of influenza A2, it was found action. The overall efficacy is much lower than
serendipitiously to benefit parkinsonism. It acts levodopa. However, they are cheap and produce
SECTION

rapidly but has lower efficacy than levodopa, less side effects than levodopa. They may be used
though higher than anticholinergics. About alone in mild cases. In others, they can be
2/3rd patients derive some benefit. However, combined with levodopa.
tolerance develops over few months and the Anticholinergics are the only drugs effective
efficacy is lost. While amantadine is believed to in drug (phenothiazine) induced parkinsonism.
act by promoting presynaptic synthesis and The side effect profile is similar to atropine.
release of DA in brain its antagonistic action on Xerostomia caused by them may aggravate dental
NMDA type of glutamate receptors, through caries.
10
Drugs Acting on Central Nervous System
Psychopharmacological Agents

The psychopharmacological agents or psycho- Neuroses These are less serious; ability to comprehend
tropic drugs are those having primary effects on reality is not lost, though the patient may undergo extreme
suffering. Depending on the predominant feature, it may
psyche (mental processes) and are used for be labelled as:
treatment of psychiatric disorders. (a) Anxiety An unpleasant emotional state associated
with uneasiness and concern for the future.
Psychiatric diagnostic categories are often imprecise. The (b) Phobic states Fear of the unknown or of some specific
criteria adopted overlap in individual patients. Nevertheless, objects, person or situations.
broad divisions have to be made, primarily on the basis of
(c) Obsessive compulsive Limited abnormality of
predominant manifestations, to guide the use of drugs.
thought or behaviour (ritual like) which the patient is not
Psychoses These are severe psychiatric illness with serious able to overcome even on voluntary effort.
distortion of thought, behaviour, capacity to recognise reality (d) Reactive depression due to physical illness, loss,
and of perception (delusions and hallucinations). There is blow to self-esteem or bereavement, but is excessive or
inexplicable misperception and misevaluation; the patient disproportionate.
is unable to meet the ordinary demands of life. (e) Post-traumatic stress disorder Varied symptoms
(a) Acute and chronic organic brain syndromes (cognitive following distressing experiences like war, riots, earth-
disorders) Such as delirium and dementia; some toxic or quakes, etc.
pathological basis can often be defined; prominent features (f) Hysterical Dramatic symptoms resembling serious
are confusion, disorientation, defective memory and physical illness, but situational, and always in the presence
disorganized behaviour. of others; the patient does not feign but actually undergoes
(b) Functional disorders No underlying cause can be the symptoms, though the basis is only psychic and not
defined; memory and orientation are mostly retained but physical.
emotion, thought and behaviour are seriously altered.
(i) Schizophrenia (split mind), i.e. splitting of perception Pathophysiology of mental illness is not clear,
and interpretation from reality—hallucinations, inability though some ideas have been formed, e.g. dopa-
to think coherently. minergic overactivity in the limbic system may be
(ii) Paranoid states with marked persecutory or other kinds involved in schizophrenia and mania; mono-
of fixed delusions (false beliefs) and loss of insight into
the abnormality. aminergic (NA, 5-HT) deficit may underlie
depression. Treatment is empirical, symptom
Affective disorders The primary symptom is change in
mood state; may manifest as: oriented and not disease specific. However, it is
Mania—elation, hyperactivity, uncontrollable thought highly effective in many situations. Depending
and speech, may be associated with violent behaviour, or on the primary use, the psychotropic drugs may
Depression—sadness, loss of interest and pleasure,
be grouped into:
worthlessness, guilt, physical and mental slowing, melan-
cholia, self destructive ideation. 1. Antipsychotic (neuroleptic, ataractic, major
It may be bipolar (manic-depressive) with cyclically
alternating manic and depressive phases or unipolar tranquillizer) useful in all types of functional
(mania or depression) with waxing and waning course. psychosis, especially schizophrenia.
156 Drugs Acting on CNS
2. Antianxiety (anxiolytic-sedative, minor tran- Pharmacology of chlorpromazine (CPZ) is
quillizer) used for anxiety and phobic states. described as prototype. Comparative features of
3. Antidepressants used for minor as well as other drugs are presented in Table 10.1.
major depressive illness, phobic states, obsessive-
compulsive behaviour, and certain anxiety PHARMACOLOGICAL ACTIONS
disorders.
1. CNS Effects differ in normal and psychotic
4. Antimanic (mood stabiliser) used to control individuals.
mania and to break into cyclic affective disorders.
5. Psychotomimetic (psychedelic, psychodys- In normal individuals CPZ produces indifference
leptic, hallucinogen). These are seldom used to surroundings, paucity of thought, psychomotor
therapeutically but produce psychosis like states, slowing, emotional quietening, reduction in
majority are drugs of abuse like LSD, cannabis. initiative and tendency to go off to sleep from
which the subject is easily arousable. Sponta-
Tranquillizer It is an old term meaning “a drug which
reduces mental tension and produces calmness without
neous movements are minimized, but slurring of
inducing sleep or depressing mental faculties.” It has been speech, ataxia or motor incoordination does not
interpreted differently by different people; some extend it occur.
to cover both chlorpromazine like and antianxiety drugs,
others feel that it should be restricted to the antianxiety In a psychotic CPZ reduces irrational beha-
drugs only. The term ‘tranquillizer’ is therefore best avoided. viour, agitation and aggressiveness and controls
psychotic symptomatology. Disturbed thought
II

ANTIPSYCHOTIC DRUGS and behaviour are gradually normalised, anxiety


is relieved. Hyperactivity, hallucinations and
SECTION

(Neuroleptics)
These are drugs having a salutary therapeutic delusions are suppressed.
effect in psychoses. All phenothiazines, thioxanthenes and buty-
rophenones have the same antipsychotic efficacy,
but potency differs in terms of equieffective doses.
CLASSIFICATION The aliphatic and piperidine side chain pheno-
1. Phenothiazines thiazines (CPZ, triflupromazine, thioridazine)
Aliphatic side chain: Chlorpromazine have low potency, produce more sedation and
Triflupromazine cause greater potentiation of hypnotics, opioids,
Piperidine side chain: Thioridazine etc. The sedative effect is produced immediately
Piperazine side chain: Trifluoperazine while antipsychotic effect takes weeks to develop.
Fluphenazine Moreover, tolerance develops to the sedative but
2. Butyrophenones Haloperidol not to the antipsychotic effect. Thus, the two
Trifluperidol appear to be independent actions.
Penfluridol Performance and intelligence are relatively
3. Thioxanthenes Flupenthixol unaffected but vigilance is impaired. Extrapyra-
4. Other heterocyclics Pimozide midal motor disturbances (see adverse effects) are
Loxapine intimately linked to the antipsychotic effect but
5. Atypical antipsychotics Clozapine are more prominent in the high potency com-
Risperidone pounds and least in thioridazine, clozapine and
Olanzapine other atypical antipsychotics. No consistent effect
Quetiapine on sleep architecture has been noted.
Aripiprazole Chlorpromazine lowers seizure threshold
Ziprasidone and can precipitate fits in untreated epileptics.
Antipsychotic Drugs 157

Table 10.1: Comparative properties of antipsychotic drugs


Drug Antipsychotic Relative activity Trade name
dose (mg/day)
Extrapyramidal Sedative Hypotensive Antiemetic
1. Chlorpromazine 100–800 ++ +++ ++ ++ LARGACTIL

2. Triflupromazine 50–200 ++± +++ ++ +++ SIQUIL

3. Thioridazine 100–400 + +++ +++ ± MELLERIL, THIORIL

4. Trifluoperazine 2–20 +++ + + +++ TRINICALM

5. Fluphenazine 1–10 +++ + + +++ ANATENSOL

6. Haloperidol 2–20 +++ + + +++ SERENACE, HALOPIDOL

7. Trifluperidol 1–8 +++ + + +++ TRIPERIDOL

8. Flupenthixol 3–15 +++ + + + FLUANXOL

9. Pimozide 2–6 +++ + + + ORAP, NEURAP

10. Loxapine 20–100 ++ + ++ + LOXAPAC

11. Clozapine 50–300 – +++ +++ – LOZAPIN, SIZOPIN

CHAPTER
12. Risperidone 2–12 ++ ++ +++ – RESPIDON, SIZODON

13. Olanzapine 2.5–10 + + ++ – OLACE, OLZAP

14. Quetiapine 50-400 ± +++ ++ – QUEL, SOCALM

15. Aripiprazole 5-30 ± ± ± – ARIPRA, BILIEF

10
16. Ziprasidone 40-160 + + + – AZONA, ZIPSYDON

The piperazine side chain compounds have a dopaminergic projections to the temporal and
lower propensity for this action. Temperature prefrontal areas constituting the ‘limbic system’
control is knocked off at relatively higher doses and in mesocortical areas is probably responsible
rendering the individual poikilothermic—body for the antipsychotic action.
temperature falls if surroundings are cold. The The atypical antipsychotics like clozapine
medullary respiratory and other vital centres are have weak D2 blocking action. However,
not affected, except at very high doses. It is very clozapine has additional 5-HT2 and α1 adrenergic
difficult to produce coma with these drugs. blocking action, and is relatively selective for D4
Neuroleptics, except thioridazine, have potent receptors. Thus, antipsychotic property may
antiemetic action exerted through the CTZ. depend on a specific profile of action of the drugs
However, they are ineffective in motion sick- on several neurotransmitter receptors.
ness. Dopaminergic blockade in the basal ganglia
appears to cause the extrapyramidal symptoms,
Mechanism of action All antipsychotics (except while that in CTZ is responsible for antiemetic
clozapine like) have potent dopamine D2 receptor action.
blocking action; antipsychotic potency has shown
good correlation with their capacity to bind to 2. ANS Neuroleptics have varying degrees of
D2 receptor. Phenothiazines and thioxanthenes α adrenergic blocking activity which may be
also block D1, D3 and D4 receptors. Blockade of graded as:
158 Drugs Acting on CNS
CPZ = triflupromazine > thioridazine > fluphe- Neuroleptics are hedonically (pertaining to
nazine > haloperidol > trifluoperazine > cloza- pleasure) bland drugs. Physical dependence is
pine > pimozide, i.e. more potent compounds probably absent. No drug seeking behaviour is
have lesser α blocking activity. imparted.
Anticholinergic property of neuroleptics is
weak and may be graded as: PHARMACOKINETICS
thioridazine > chlorpromazine > trifluproma-
Oral absorption of CPZ is somewhat unpredic-
zine > trifluoperazine = haloperidol.
table and bioavailability is low. More consistent
The phenothiazines have weak H1-antihista-
effects are produced after i.m. or i.v. administra-
minic and anti-5-HT actions as well.
tion. It is highly bound to plasma as well as tissue
3. Local anaesthetic Chlorpromazine is as proteins. Volume of distribution is large (20 L/
potent a local anaesthetic as procaine. Others kg). It is metabolized by liver into a number of
have weaker membrane stabilizing action. metabolites. The acute effects of a single dose
generally last for 6–8 hours. The elimination t½ is
4. CVS Neuroleptics produce hypotension (pri-
variable, but mostly is in the range of 18–30 hours.
marily postural) by a central as well as periphe-
ral action on sympathetic tone. The hypotensive Atypical (second generation) neuroleptics
action is more marked after parenteral adminis- Lately some antipsychotic drugs like clozapine,
tration and roughly parallels the α adrenergic risperidone, olanzapine, quetiapine, aripiprazole and
blocking potency. Partial tolerance develops after ziprasidone have been developed which have a
II

chronic use. Reflex tachycardia accompanies pharmacological profile distinct from CPZ,
hypotension. produce few extrapyramidal symptoms, no/mild
SECTION

High doses of CPZ directly depress the heart hyperprolactinaemia; tardive dyskinesia is
and produce ECG changes (Q-T prolongation and rare. They tend to suppress both positive and
suppression of T wave). CPZ exerts some negative symptoms of schizophrenia (the older
antiarrhythmic action, probably due to membrane drugs have little effect on negative symptoms).
stabilization. Arrhythmia may occur in overdose, Many patients refractory to the typical anti-
especially with thioridazine. psychotics respond to these drugs. The atypical
antipsychotics have only weak D2, but potent
5. Endocrine Neuroleptics consistently inc-
5-HT2 antagonistic activity alongwith variable
rease prolactin release by blocking the inhibitory
α adrenergic, muscarinic and H1 histaminergic
action of DA on pituitary lactotropes. This may
blocking property. These features may account
result in galactorrhoea and gynaecomastia.
for the above differences.
They reduce gonadotropin secretion, but
The major limitation of clozapine is higher
amenorrhoea and infertility occur only occa-
incidence of agranulocytosis and other blood
sionally. ACTH release in response to stress is
dyscrasias. This is not the case with olanzapine ,
diminished—corticosteroid levels fail to increase
risperidone and others. Currently, they are being
under such circumstances. Release of GH is also
increasingly prescribed. Though, there is no
reduced, but this is not sufficient to cause growth
convincing evidence of higher efficacy, they
retardation in children or to be beneficial in acro-
produce fewer side effects and neurological
megaly.
complications. Some atypical antipsychotics are
Tolerance and dependence Tolerance to the also effective in mania and bipolar disorder.
sedative and hypotensive actions develops within
days or weeks, but the antipsychotic, extra- ADVERSE EFFECTS
pyramidal and other actions based on DA Neuroleptics are very safe drugs in single or infre-
antagonism do not display tolerance. quent doses, but side effects are common.
Antipsychotic Drugs 159
I. Based on pharmacological actions roxyzine injected i.m. clears the reaction within
(dose related) 10–15 minutes.
1. CNS Drowsiness, lethargy, mental con- (c) Akathisia Restlessness, feeling of discomfort,
fusion: more with low potency agents; increased apparent agitation manifested as a compelling
appetite and weight gain; aggravation of seizures desire to move about but without anxiety is seen
in epileptics. in some patients. A central anticholinergic may
2. α Adrenergic blockade Postural hypotension, reduce the intensity in some cases; propranolol is
palpitation, inhibition of ejaculation (especially more effective, but most cases require reduction
with thioridazine) are more common with of dose.
low potency phenothiazenes. Dentists should
(d) Malignant neuroleptic syndrome It occurs
instruct patients to get up slowly from a reclining dental
rarely with high doses of potent agents; the patient
chair.
develops marked rigidity, immobility, tremor, fever,
3. Anticholinergic Dry mouth (may promote semiconsciousness, fluctuating BP and heart rate;
caries tooth), blurring of vision, constipation, lasts for 5–10 days after drug withdrawal and may
urinary hesitancy in elderly males (thioridazine be fatal. Anticholinergics are of no help.
has the highest propensity); absent in high
Intravenous dantrolene may benefit. Bromocrip-
potency agents.
tine in large doses has been found to be useful.
4. Endocrine Amenorrhoea, infertility, gynae-

CHAPTER
comastia, galactorrhoea—due to hyperprolac- (e) Tardive dyskinesia It occurs late in therapy,
tinaemia. sometimes even after withdrawal of the neuro-
leptic: manifests as purposeless involuntary facial
5. Extrapyramidal disturbances These are the
and limb movements like constant chewing,
major dose limiting side effects; more prominent
with high potency drugs like fluphenazine, pouting, puffing of cheeks, lip licking, choreo-
haloperidol, pimozide, etc., least with thiori- athetoid movements. Dental problems may arise

10
dazine and atypical antipsychotics. These are of because of involvement of orofacial muscles. Attrition
following types. of teeth may result from grinding. It is probably a
manifestation of progressive neuronal degenera-
(a) Parkinsonism with typical manifestations— tion along with supersensitivity to DA. There is
rigidity, tremor, hypokinesia, mask like facies, no satisfactory solution of the problem.
shuffling gait. Anticholinergic antiparkinsonian
drugs may counteract these symptoms. 6. Miscellaneous Weight gain, blue pigmen-
A rare form of extrapyramidal side effect is tation of exposed skin, corneal and lenticular
perioral tremors ‘rabbit syndrome’ that generally opacities, retinal degeneration, cardiac arrhyth-
occurs after few years of therapy. mia are rare complications. Impairment of glucose
tolerance and worsening of diabetes has been
(b) Acute muscular dystonias Bizarre muscle reported with some drugs like clozapine and
spasms, mostly involving linguo-facial muscles olanzapine.
—grimacing, tongue thrusting, torticollis, locked
jaw; occurs within a few hours of a single dose or II. Hypersensitivity reactions These are not
at the most in the first week of therapy. It is more dose related.
common in children below 10 years and in girls, 1. Cholestatic jaundice.
particularly after parenteral administration; 2. Skin rashes, urticaria, contact dermatitis,
overall incidence is 2%. It lasts for one to few hours photosensitivity.
and then resolves spontaneously. One of the 3. Agranulocytosis is rare; more common with
central anticholinergics, promethazine or hyd- clozapine.
160 Drugs Acting on CNS
INTERACTIONS ineffective in motion sickness: probably because
1. Neuroleptics potentiate all CNS depressants — dopaminergic pathway through the CTZ is not
hypnotics, anxiolytics, alcohol, opioids and anti- involved in this condition.
histaminics. Dentists should be careful while
prescribing any of these drugs to patients receiving ANTIMANIC (MOOD STABILIZING) DRUGS
neuroleptics. LITHIUM CARBONATE
2. Neuroleptics block the actions of levodopa and
direct DA agonists in parkinsonism. Lithium is a small monovalent cation. In 1949, it
3. CPZ and few others abolish the antihyper- was found to exert beneficial effects in manic
tensive action of clonidine and methyldopa, patients.
probably due to central α2 adrenergic blockade. Later, the importance of maintaining a
4. Enzyme inducers (barbiturates, anticon- narrow range of serum lithium concentration was
vulsants) can reduce blood levels of neuroleptics. realized and unequivocal evidence of its efficacy
was obtained. At present, lithium is a drug of its
USES own kind to exert a prophylactic effect in bipolar
manic depressive illness (MDI). Over the past
1. Schizophrenia The neuroleptics are used
2 decades antiepileptics like carbamazepine,
primarily in functional psychoses: have
valproate, etc. and atypical antipsychotics have
indefinable but definite therapeutic effect: produce
emerged as alternatives to lithium.
a wide range of symptom relief. They control
II

positive symptoms (hallucinations, delusions,


disorganized thought, restlessness, insomnia, Actions and mechanism
SECTION

anxiety, fighting, aggression) better than negative 1. CNS Lithium has practically no acute effects
symptoms (apathy, loss of insight and volition, in normal individuals as well as in MDI patients.
affective flattening, poverty of speech, social with- It is neither sedative nor euphorient; but on
drawal). Some patients do not respond, and prolonged administration, it acts as a mood
virtually none responds completely. They are only stabiliser in bipolar disease. Given to patients in
symptomatic treatment, do not remove the cause of acute mania, it gradually suppresses the episode
illness. taking 1–2 weeks; continued treatment prevents
2. Mania Antipsychotics are required for rapid cyclic mood changes. The markedly reduced sleep
control, may be given i.m. Lithium or valproate time in manic patients is normalized.
may be started simultaneously or after the acute The mechanism of antimanic and mood
phase. stabilizing action of lithium is not known. It has
been proposed that:
3. Organic brain syndromes Neuroleptics are (a) Li+ partly replaces body Na+ and is nearly
not very effective. May be used on a short-term equally distributed inside and outside the cells
basis. (contrast Na+ and K+); this may affect ionic fluxes
4. Anxiety Neuroleptics should not be used for across brain cells or modify the property of cellular
simple anxiety. Patients not responding to BZDs, membranes.
or those having a psychotic basis for anxiety may (b) Li+ may correct imbalance in the turnover of
be treated with a neuroleptic. brain monoamines.
(c) The above hypothesis cannot explain why
5. As antiemetic Neuroleptics are potent Li+ has no effect on people not suffering from
antiemetics—control a wide range of drug and mania. An attractive hypothesis has been put
disease induced vomiting at doses much lower forward based on the finding that lithium inhibits
than those needed in psychosis. They are hydrolysis of inositol-1-phosphate. As a result,
Antimanic Drugs 161

Fig. 10.1: Proposed mechanism of antimanic action of lithium


PIP-Phosphatidyl inositol phosphate; PIP2-Phosphatidyl inositol bisphosphate; IP3-

CHAPTER
Inositol trisphosphate; IP-Inositol-1-phosphate; PLc-Phospholipase C; DAG-Diacyl
glycerol; PKc-Protein kinase C; Gq-Coupling Gq protein; R- Neurotransmitter receptor

the supply of free inositol for regeneration of in the extracellular water and then gradually
membrane phosphatidyl-inositides, which are enters cells and slowly penetrates into the CNS,
the source of IP3 and DAG, is reduced (Fig. 10.1). ultimately attaining a rather uniform distribution

10
The hyperactive neurones involved in the manic in total body water.
state may be preferentially affected, because Lithium is handled by the kidney in much the
supply of inositol from extracellular sources is same way as Na+. Most of the filtered Li+ is
meagre. Thus, lithium may ignore normally reabsorbed in the proximal convoluted tubule.
operating receptors, but ‘search out’ and After a single dose of Li+, urinary excretion is
selectively, though indirectly, dampen signal rapid for 10–12 hours followed by a much slower
transduction in the overactive ones. phase lasting several days. The t½ of the latter
phase is 16–30 hours.
2. Other actions Lithium inhibits the action of There is marked individual variation in the
ADH on distal tubules and causes a diabetes rate of lithium excretion. Since the margin of
insipidus like state. safety is narrow, monitoring of serum lithium
It has some insulin-like action on glucose meta- concentration is essential for optimal therapy.
bolism. Serum lithium level 0.5–0.8 mEq/L is considered
Leukocyte count is increased by lithium therapy. optimum for maintenance therapy in bipolar
Lithium reduces thyroxine synthesis by inter- disorder, while 0.8–1.1 mEq/L is required for
fering with iodination of tyrosine. episodes of mania. Toxicity symptoms occur
frequently when serum levels exceed 1.5 mEq/L.
Pharmacokinetics and control of therapy Adverse effects Side effects are common but are
Lithium is well absorbed orally and is neither mostly tolerable. Toxicity occurs at levels only
protein bound nor metabolized. It first distributes marginally higher than therapeutic levels.
162 Drugs Acting on CNS
1. Nausea, vomiting and mild diarrhoea. the interval between cycles of mood swings:
2. Thirst and polyuria are experienced by most. episodes of mania as well as depression are
3. Fine tremors and rarely seizures. attenuated, if not totally prevented.
4. CNS toxicity manifests as plasma concen- Recurrent unipolar depression also responds to
tration rises—coarse tremors, giddiness, ataxia, lithium therapy. Combination of antidepressant
motor incoordination, nystagmus, mental confu- + lithium is often used initially, and lithium alone
sion, slurred speech, hyper-reflexia. In acute is continued in the maintenance phase.
intoxication, these symptoms progress to muscle
3. Lithium is sporadically used in many other
twitchings, drowsiness, delirium, coma and con-
recurrent neuropsychiatric illness, cluster headache,
vulsions. Vomiting, severe diarrhoea, albumi-
etc. and as an adjuvant to tricyclic antidepres-
nuria, hypotension and cardiac arrhythmias are
sants in patients of major depression not fully
the other features.
relieved by the latter.
There is no specific antidote to lithium.
5. On long-term use, some patients develop renal
Alternatives to lithium
diabetes insipidus and goiter.
6. Lithium is contraindicated during pregnancy; Approximately 50% patients of mania and bipolar
foetal goiter and other congenital abnormalities disorder show incomplete or poor response to
can occur. lithium. Many do not tolerate it or are at special
risk of toxicity. Alternatives are:
II

Interactions
1. Carbamazepine Soon after its introduction
1. Diuretics (thiazide, furosemide) raise plasma as antiepileptic carbamazepine (CBZ) was found
SECTION

levels of lithium. to prolong remission in bipolar disorder. Its


2. NSAIDs also cause Li+ retention (along with efficacy in mania and bipolar disorder has now
Na+ retention). Dentists should refer patients for been confirmed and is rated almost equal to
monitoring and adjusting Li+ therapy when they lithium. Patients with rapid cycling of mood state
prescribe NSAIDs. Tetracyclines and ACE inhi- do better on combined Li + CBZ treatment.
bitors are other drugs capable of producing
Li+ retention. 2. Sodium valproate A reduction in manic
3. Lithium tends to enhance insulin/sulfonyl- relapses is noted when valproate is used in
urea induced hypoglycaemia. bipolar disorder. High dose valproate is a rapidly
acting alternative to oral antipsychotic ±
Use benzodiazepine for acute mania. For bipolar
1. Acute manic episode (inappropriate cheer- illness it can be useful in those not responding to
fullness, motor restlessness, nonstop talking, Li or CBZ or not tolerating these drugs. Valproate
flight of ideas and progressive loss of contact with has a favourable tolerability profile.
reality; sometimes violent behaviour): though The newer anticonvulsants like lamotrigine
lithium is effective, response is slow. Most and topiramate have also been found effective in
psychiatrists prefer to use a neuroleptic, generally bipolar disorder: can serve as alternative drugs.
by i.m. route, with or without diazepam, and start 3. Atypical antipsychotics Olanzapine, ris-
lithium after the episode is under control. peridone, aripiprazole and quetiapine ± a BZD
Maintenance lithium therapy is generally given are now among the first line drugs for mania not
to prevent recurrences. requiring parenteral medication. Olanzapine is
2. Prophylaxis in bipolar disorder Lithium has approved for maintenance therapy of bipolar
proven efficacy in bipolar disorder. It lengthens illness as well.
Antidepressant Drugs 163
ANTIDEPRESSANT DRUGS contain predominantly MAO-A, while MAO-B predo-
minates in certain areas of brain and in platelets. Liver
These are drugs which can elevate mood in contains both isoenzymes.
depressive illness. Practically all antidepressants Iproniazid, a congener of the antitubercular drug
affect monoaminergic transmission in the brain isoniazid, was found to cause mood elevation that was
ascribed to its ability to inhibit MAO. Iproniazid and
in one way or the other and many of them have related drugs that were nonselective and irreversible MAO
other associated properties. Particularly over the inhibitors were used briefly as antidepressants, but were
past two decades, a large number of antidepres- abandoned because of high toxicity and interaction with
sants with an assortment of effects on reuptake/ several foods and drugs. The most important interaction
metabolism of biogenic amines and on pre/post- known as cheese reaction occurs when the subject receiving
MAO inhibitor ingests tyramine rich foods including certain
junctional aminergic/cholinergic receptors have
cheese, beer, wines, etc. The indirectly acting sympatho-
become available so that a cogent classification is mimetic amine escapes degradation in the intestinal wall
difficult. The following working classification may and liver → reaches systemic circulation in high concentra-
be adopted. tion and displaces large amounts of NA from transmitter
loaded sympathetic nerve endings → hypertensive crisis,
CLASSIFICATION cerebrovascular accident and other complications. Similar
hypertensive reaction can occur with cold remedies,
I. Reversible inhibitors of MAO-A (RIMAs) levodopa, tricyclic antidepressants as well. Because these
Moclobemide, Clorgyline MAO inhibitors in addition inhibit drug metabolizing
enzymes, several drugs get potentiated. The opioid
II. Tricyclic antidepressants (TCAs) pethidine produces excitation, delirium, high fever,

CHAPTER
A. NA + 5-HT reuptake inhibitors convulsions, etc. because its metabolism is diverted to
Imipramine, Amitriptyline, generate excess of norpethidine.
Trimipramine, Doxepin, Dothiepin, Recently, some MAO-A selective and reversi-
Clomipramine ble inhibitors have been developed which have
B. Predominantly NA reuptake inhibitors useful antidepressant property coupled with low
Desipramine, Nortriptyline, Amoxapine, toxicity and freedom from dangerous interactions

10
Reboxetine in the recommended dose range.

III. Selective serotonin reuptake inhibitors Reversible inhibitors of MAO-A (RIMAs)


(SSRIs)
Fluoxetine, Fluvoxamine, Paroxetine, Moclobemide It is a reversible and selective
Sertraline, Citalopram, Escitalopram MAO-A inhibitor with short duration of action;
full MAO activity is restored within 1–2 days of
IV. Atypical antidepressants stopping the drug. Because of competitive enzyme
Trazodone, Mianserin, Mirtazapine, inhibition, tyramine is able to displace it from the
Venlafaxine, Duloxetine, Tianeptine, enzyme so that potentiation of pressor response
Amineptine, Bupropion. to ingested amines is weak and dietary restrictions
are not required. Clinical trials have shown moclo-
MAO INHIBITORS
bemide to be an efficacious antidepressant,
MAO is a mitochondrial enzyme involved in the oxidative comparable to TCAs, except in severe cases. It
deamination of biogenic amines (Adr, NA, DA, 5-HT). lacks the anticholinergic, sedative, cognitive,
Two isoenzyme forms of MAO have been identified.
MAO-A: Preferentially deaminates 5-HT and NA, and psychomotor and cardiovascular adverse effects
is inhibited by clorgyline, moclobemide. of typical TCAs and is safer in overdose. This
MAO-B: Preferentially deaminates phenylethylamine makes it a particularly good option in elderly
and is inhibited by selegiline. patients and in those with heart disease.
Dopamine is degraded equally by both isoenzymes.
Their distribution also differs. Peripheral adrenergic Adverse effects are nausea, dizziness,
nerve endings, intestinal mucosa and human placenta headache, insomnia, rarely excitement and liver
164 Drugs Acting on CNS
Table 10.2: Comparative properties and trade names of tricyclic and related antidepressants

Drug Sedation Antimuscarinic Hypotension Cardiac Seizure Daily Trade name


arrhythmia precipitation dose (mg)
Tricyclic antidepressants
1. Imipramine + ++ ++ +++ ++ 50–200 DEPSONIL,ANTIDEP
2. Amitriptyline +++ +++ +++ +++ ++ 50–200 AMLINE, TRYPTOMER
3. Trimipramine +++ +++ ++ +++ ++ 50–150 SURMONTIL
4. Doxepin +++ ++ ++ ++ ++ 50–150 SPECTRA, DOXIN
5. Clomipramine ++ +++ ++ +++ +++ 50–150 CLOFRANIL, CLONIL
6. Dothiepin ++ ++ ++ ++ ++ 50–150 PROTHIADEN
7. Nortriptyline + ++ + ++ + 50–150 SENSIVAL
8. Amoxapine + + ++ ++ ++ 100–300 DEMOLOX

Selective 5-HT reuptake inhibitors


1. Fluoxetine ± — — — ± 20–50 FLUDAC, FLUNIL
2. Fluvoxamine ± — — — — 50–200 FLUVOXIN
3. Paroxetine ± ± — — — 20–50 XET
II

4. Sertraline ± — — — — 50–200 SERENATA


5. Citalopram — — — — — 20–40 CELICA
SECTION

6. Escitalopram — — — — — 10-20 ESDEP, FELIZ-S

Atypical antidepressants
1. Trazodone +++ — ± ± — 50–200 TRAZODAC
2. Mianserin ++ + ++ + ++ 30–100 TETRADEP
3. Bupropion –, ↑ — — — +++ 150–300 SMOQUIT
4. Mirtazapine +++ — ± — — 15–45 MIRT, MIRTAZ
5. Venlafaxine — — — ± — 75–150 VENLOR
6. Duloxetine — — — — — 30-80 DELOK

damage. Chances of interaction with other drugs PHARMACOLOGICAL ACTIONS


and alcohol are remote, but caution is advised
The TCAs inhibit monoamine uptake and interact
while coprescribing pethidine, SSRIs and TCAs.
with a variety of receptors viz. muscarinic, α
adrenergic, histamine H1, 5-HT1, 5-HT2 and
TRICYCLIC ANTIDEPRESSANTS (TCAs)
occasionally dopamine D2. However, relative
Imipramine, an analogue of CPZ, was found potencies at these sites differ among different
during clinical trials (1958) to selectively benefit compounds. The newer selective serotonin reup-
depressed but not agitated psychotics. In contrast take inhibitors (SSRIs) and atypical antidepres-
to CPZ, it inhibited NA and 5-HT reuptake into sants interact with fewer receptors and have more
neurones. A large number of congeners were soon limited spectrum of action (produce fewer side
added and are collectively called tricyclic anti- effects). The actions of imipramine are described
depressants (TCAs). as prototype.
Antidepressant Drugs 165
1. CNS Effects differ in normal individuals and Uptake blockade appears to initiate a series of
the depressed. time-dependent changes in the number and
In normal individuals it induces a peculiar clumsy sensitivity of aminergic receptors that culminate
feeling, tiredness, light-headedness, sleepiness, in antidepressant effect after a few weeks.
difficulty in concentrating and thinking, unsteady None of these compounds, except amoxapine,
gait. These effects tend to provoke anxiety. There block DA receptors or possess antipsychotic
is no mood elevation or euphoria; effects are rather activity.
unpleasant and may become more so on repeated
administration. 2. ANS Most tricyclic antidepressants are potent
In depressed patients little acute effects are pro- anticholinergics—cause dry mouth, blurring of
duced, except sedation. After 2–3 weeks of vision, constipation and urinary hesitancy as side
continuous treatment, the mood is gradually effect. The anticholinergic potency is graded in
elevated, patients become more communicative Table 10.2. They potentiate exogenous and
and start taking interest in self and surroundings. endogenous NA by blocking uptake.
Thus, TCAs are not euphorients but only anti- 3. CVS Effects on cardiovascular function are
depressants. Sedative property varies among prominent, and may be dangerous in overdose.
different compounds (see Table 10.2). The more Tachycardia: due to anticholinergic and NA poten-
sedative ones are suitable for depressed patients tiating actions.
showing anxiety and agitation. The less sedative Postural hypotension: due to inhibition of cardio-

CHAPTER
or stimulant ones are better for withdrawn and vascular reflexes and α1 blockade.
retarded patients. ECG changes and cardiac arrhythmias: T wave sup-
The TCAs lower seizure threshold and pro- pression or inversion is the most consistent
duce convulsions in overdose. Clomipramine and change. Arrhythmias occur in overdose due to
bupropion have the highest seizure precipitating interference with intraventricular conduction,
potential. Amitriptyline and imipramine depress combination of NA potentiating + ACh blocking

10
respiration in overdose only. actions and direct myocardial depression. Older
patients are more susceptible. The SSRIs and
Mechanism of action The TCAs and related atypical antidepressants are safer in this regard.
drugs inhibit NET and SERT the transporters
which mediate active uptake of biogenic amines Tolerance and dependence
NA and 5-HT into their respective neurones and Tolerance to the anticholinergic and hypotensive
thus potentiate them. They, however, differ effects of imipramine like drugs develops gradually,
markedly in their selectivity and potency for though antidepressant action is sustained.
different amines (see classification above). Most of Psychological dependence on these drugs is
the compounds do not inhibit DA uptake, except rare because their acute effects are not pleasant.
bupropion. There is some evidence of physical depen-
Uptake inhibition results in increased concen- dence occurring when high doses are used for
tration of the amines in the synaptic cleft in the long periods, but they do not carry abuse potential.
CNS and periphery. Tentative conclusions drawn
are: PHARMACOKINETICS
• Inhibition of DA uptake correlates with stimu- The oral absorption of TCAs is good, though often
lant action; but is not primarily involved in slow. They are highly bound to plasma and tissue
antidepressant action. proteins—have large volumes of distribution
• Inhibition of NA and 5-HT uptake is associated (~20 L/kg). They are extensively metabolized
with antidepressant action. in liver; the major route for imipramine and
166 Drugs Acting on CNS
amitriptyline is demethylation whereby active sions and coma. Respiration is depressed, body
metabolites—desipramine and nortriptyline res- temperature may fall, BP is low, tachycardia is
pectively are formed. Metabolites are excreted in prominent. ECG changes and ventricular
urine over 1–2 weeks. The plasma t½ of amitrip- arrhythmias are common.
tyline, imipramine and doxepin range between Treatment is primarily supportive with gastric
16–24 hours. lavage, respiratory support, fluid infusion,
maintenance of BP and body temperature. Aci-
ADVERSE EFFECTS dosis must be corrected by bicarbonate infusion.
Diazepam may be injected i.v. to control
Side effects are common with tricyclic antidep-
convulsions and delirium. Most important is
ressants.
treatment of cardiac arrhythmias, for which
1. Anticholinergic: dry mouth, bad taste, consti-
pation, epigastric distress, urinary retention propranolol / lidocaine may be used.
(especially in males with enlarged prostate),
blurred vision, palpitation. Decreased sali- INTERACTIONS
vation increases risk of dental caries, oral thrush, 1. TCAs potentiate directly acting sympathomi-
etc. metic amines (in cold/asthma remedies).
2. Sedation, mental confusion and weakness, Adrenaline containing local anaesthetic should be
especially with amitriptyline and more seda- avoided for dental anaesthesia due to risk of
tive congeners. potentiation and precipitation of cardiac arrhy-
3. Increased appetite and weight gain is noted thmia.
II

with most TCAs and trazodone, but not with 2. TCAs abolish the antihypertensive action
SECTION

SSRIs and bupropion. of clonidine by preventing its transport into


4. Some patients may switch to hypomania or adrenergic neurones.
mania. Probably, this reflects a basic bipolar 3. Chances of Q-T prolongation and cardiac
illness, the other pole being unmasked by the arrhythmia increase when erythromycin is
antidepressant. given to patients on TCA therapy.
5. Sweating and fine tremors are relatively 4. TCAs potentiate CNS depressants, including
common. alcohol and antihistaminics.
6. Seizure threshold is lowered—fits may be pre- 5. Phenobarbitone induces as well as competi-
cipitated, especially in children. tively inhibits imipramine metabolism.
7. Postural hypotension, especially in older Carbamazepine and other enzyme inducers
patients; less severe with desipramine like enhance metabolism of TCAs.
drugs and insignificant with SSRIs. Patients 6. SSRIs inhibit metabolism of many drugs
should not abruptly sit up or stand from a reclining including TCAs—dangerous toxicity can
position on the dental chair. occur if the two are given concurrently.
8. Cardiac arrhythmias, especially in patients 7. When used together, the anticholinergic
with ischaemic heart disease—may be respon- action of neuroleptics and TCAs may add up.
sible for sudden death in these patients.
9. Rashes and jaundice due to hypersensitivity SELECTIVE SEROTONIN REUPTAKE
are rare. INHIBITORS (SSRIs)
Acute poisoning It is frequent; usually self- The major limitations of standard TCAs are:
attempted by the depressed patients, and may • Frequent anticholinergic, cardiovascular and
endanger life. Manifestations are: neurological side effects.
Excitement, delirium and other anticholinergic • Relatively low safety margin, hazardous in
symptoms followed by muscle spasms, convul- overdose; fatalities common.
Antidepressant Drugs 167
• Lag time of 2–4 weeks before antidepressant festing as agitation, muscle rigidity, twitchings,
action manifests. convulsions and hyperthermia.
• Significant number of patients respond The overall antidepressant efficacy of SSRIs
incompletely and some do not respond. is similar to that of TCAs, but in severe depression,
To overcome these shortcomings, a large TCAs appear to be more efficacious.
number of newer antidepressants have been
Other uses of SSRIs The SSRIs are now 1st
developed since 1980s. The most significant of
choice drugs for OCD, panic disorder, social
these are the SSRIs which selectively inhibit
phobia, eating disorders and post-traumatic stress
membrane associated 5-HT transporter SERT.
disorder. They are also being increasingly used
Though, none of the newer drugs has surpassed
for many anxiety disorders, body dysmorphic
older TCAs in overall efficacy, some patients not
disorder, compulsive buying and kleptomania.
responding to one type of drug may respond to
Elevation of mood and increased work capacity
the other. More importantly, the newer drugs have
has been reported in postmyocardial infarction
improved tolerability, both in therapeutic use as
and other chronic somatic illness patients. Thus,
well as in overdose.
SSRIs are being used to improve outlook on life
The relative safety and better acceptability of
and to feel good, even in apparently nondepressed
SSRIs has made them 1st line drugs in depression
patients. Wisdom of such use though is
and allowed their extensive use in anxiety,
questionable.
phobias, OCD and related disorders. The SSRIs,

CHAPTER
produce little or no sedation, do not interfere with
cognitive and psychomotor function or produce ATYPICAL ANTIDEPRESSANTS
anticholinergic side effects. They are devoid of α The distinctive features of some atypical
adrenergic blocking action—postural hypoten- antidepressants are outlined below.
sion does not occur—suitable for elderly patients. 1. Trazodone It is the first atypical anti-
They have practically no seizure precipitating depressant; selectively but less efficiently blocks

10
propensity and do not inhibit cardiac conduc- 5-HT uptake and has prominent α blocking as
tion—overdose arrhythmias are not a problem. well as weak 5-HT2 antagonistic action. It is
However, they frequently produce nausea. Weight sedative but not anticholinergic, causes brady-
gain is not a problem with SSRIs, but they more cardia rather than tachycardia, does not interfere
commonly interfere with ejaculation or orgasm. with intracardiac conduction—less prone to cause
A new constellation of mild side effects, viz. arrhythmia. Inappropriate, prolonged and pain-
nervousness, restlessness, insomnia, anorexia, ful penile erection (priapism) occurs in a few
dyskinesia, headache and diarrhoea is associated recipients as does postural hypotension.
with them, but patient acceptability is good.
Increased incidence of epistaxis and ecchymosis 2. Mianserin It is unique in not inhibiting
has been reported, probably due to impairment of either NA or 5-HT uptake; but blocks presynaptic
platelet function. Gastric blood loss due to NSAIDs α2 receptors—increases release and turnover of
may be increased by SSRIs. NA in brain which may be responsible for
The SSRIs inhibit drug metabolizing iso- antidepressant effect. Blood dyscrasias and liver
enzymes CYP2D6 and CYP3A4: elevate plasma dysfunction have restricted its use.
levels of TCAs, haloperidol, clozapine, terfena- 3. Tianeptine This antidepressant is reported
dine, astemizole, warfarin, β blockers, some BZDs to increase rather than inhibit 5-HT uptake, and
and carbamazepine. Use of tramadol to relieve has shown efficacy in anxiodepressive states
dental pain should be avoided in patients receiving particularly with psychosomatic symptoms as
SSRIs due to risk of ‘Serotonin syndrome’ mani- well as in endogenous depression.
168 Drugs Acting on CNS
4. Amineptine Like tianeptine, it enhances 5- take still longer. The SSRIs are currently used
HT uptake but has antidepressant property. It as first choice for their good tolerability and safety.
produces anticholinergic side effects, postural The newer atypical agents also offer some
hypotension, conduction disturbances and advantages. However, the TCAs are still the
arrhythmias. most effective in severely depressed patients. After
a depressive episode has been controlled, conti-
5. Venlafaxine A novel antidepressant nued treatment at maintenance doses for months
referred to as ‘serotonin and noradrenaline reuptake is recommended to prevent relapse. Therapy is
inhibitor’ (SNRI), because it inhibits uptake of both generally not continued beyond one year.
these amines; but, in contrast to older TCAs, does
not interact with cholinergic, adrenergic or 2. Obsessive-compulsive and phobic states: The
histaminergic receptors or have sedative property. SSRIs are the drugs of choice due to better patient
Venlafaxine does not produce the usual side acceptability. TCAs, especially clomipramine, are
effects of TCAs; tends to raise rather than depress highly effective in OCD and panic disorders.
BP and is safer in overdose. SSRIs and TCAs also reduce compulsive eating
in bulimia, and help patients with body dysmorphic
6. Duloxetine This is another SNRI similar in disorder, compulsive buying and kleptomania,
properties to venlafaxine. In addition to depres- though these habits may not completely die.
sion, duloxetine is useful in panic attacks,
neuropathic pain and stress urinary incontinence 3. Anxiety disorders: Antidepressants, especially
SSRIs, exert a delayed but sustained beneficial
in women.
II

effect in many patients of generalized anxiety


7. Mirtazapine It acts by a novel mechanism disorder; may be used along with a short course
SECTION

viz. blocks α2 auto- (on NA neurones) and hetero- of BZDs to cover exacerbations. SSRIs have also
(on 5-HT neurones) receptors enhancing both proven helpful in post-traumatic stress disorder.
NA and 5-HT release. Accordingly, it has been
4. Neuropathic pain: Imipramine/amitriptyline
labelled as “noradrenergic and specific serotonergic
afford considerable relief in post-herpetic
antidepressant” (NaSSA). It is a H1 blocker and neuralgia, diabetic and some other types of
quite sedative, but not anticholinergic or anti- chronic pain.
dopaminergic. Efficacy in depression is reported
to be comparable to TCAs and benefit may start 5. Attention deficit-hyperactivity disorder in
earlier. children: TCAs with less depressant properties
like imipramine and amoxapine are emerging as
8. Bupropion This inhibitor of DA and NA alternatives to amphetamine like drugs.
uptake has excitant rather than sedative property.
It is metabolized into an amphetamine like 6. Enuresis: Imipramine 25 mg at bedtime
reduces bedwetting in children above 5 years.
compound. It is marketed in a sustained release
formulation as an aid to smoking cessation. Side 7. Migraine: Amitriptyline has some prophylactic
effects are insomnia, agitation, dry mouth and value.
nausea. Seizures occur in overdose. 8. Pruritus: Some tricyclics have antipruritic
property.
USES
1. Endogenous (major) depression: The aim is ANTIANXIETY DRUGS
to relieve symptoms of depression and restore Anxiety Some degree of anxiety is a part of
normal social behaviour. The tricyclic and related normal life. Treatment is needed when it is
antidepressants are of proven value. Response disproportionate to the situation and excessive.
takes at least 2–3 weeks to appear, full benefits Some psychotics also exhibit pathological anxiety.
Antianxiety Drugs 169
Antianxiety drugs These are an ill-defined more selective for the limbic system and have
group of drugs, mostly mild CNS depressants proven clinically better in both quality and
which are aimed to control the symptoms of quantity of improvement in anxiety and stress-
anxiety, produce a restful state of mind without related symptoms. At antianxiety doses,
interfering with normal mental or physical cardiovascular and respiratory depression is
functions. In dentistry, the most important application minor.
of antianxiety drugs is for premedication of Because anxiety is a common complaint, is a
apprehensive patients and as adjuncts to local part of most physical and mental illness, and
anaesthesia. BZDs also counteract the CNS toxi- because BZDs:
city of local anaesthetics. The anxiolytic-sedative (i) have little effect on other body systems,
drugs differ markedly from antipsychotics, and (ii) have lower dependence producing liability,
more closely resemble sedative-hypnotics. They: (iii) are relatively safe even in gross overdosage,
1. Have no therapeutic effect to control thought
disorder of schizophrenia. they are presently one of the most widely used
2. Do not produce extrapyramidal side effects. class of drugs. Potent BZDs like lorazepam and
3. Have anticonvulsant property. clonazepam injected i.m. have adjuvant role in
4. Produce physical dependence and carry the management of acutely psychotic and manic
abuse liability. patients. Higher doses induce sleep and impair
performance.

CHAPTER
CLASSIFICATION Adverse effects of BZDs noted in their use as
hypnotics are described in Ch. 9. Side effects
1. Benzodiazepines Diazepam
that occur in their use to relieve anxiety are—
Chlordiazepoxide
sedation, light-headedness, psychomotor and
Oxazepam
cognitive impairment, vertigo, confusional state
Lorazepam
(especially in elderly), increased appetite and
Alprazolam

10
weight gain, alterations in sexual function. Some
2. Azapirones Buspirone
Ispapirone women fail to ovulate while on regular use of
Gepirone BZDs. The major constraint in their long-term use
3. Sedative Hydroxyzine for anxiety disorders is their potential to produce
antihistaminic dependence.
4. β blocker Propranolol Differences between individual BZDs recom-
mended for anxiety are primarily pharmaco-
In addition to the above drugs, antidepres- kinetic: choice of one over the other is largely
sants, especially the selective serotonin reuptake empirical.
inhibitors (SSRIs), are effective in obsessive-
compulsive disorder (OCD), phobias, panic and Buspirone
many types of severe generalized anxiety It is the first azapirone, a new class of antianxiety
disorders. drugs, distinctly different from BZDs. It:
• Does not produce significant sedation or
cognitive/functional impairment.
Benzodiazepines
• Does not interact with BZD receptor or modify
The pharmacology of benzodiazepines (BZDs) as GABAergic transmission.
a class is described in Ch. 9. Some members have • Does not produce tolerance or physical depen-
a slow and prolonged action, relieve anxiety at dence.
low doses without producing significant CNS • Does not suppress BZD or barbiturate with-
depression. In contrast to barbiturates, they are drawal syndrome.
170 Drugs Acting on CNS
• Has no muscle relaxant or anticonvulsant Hydroxyzine A H1 antihistaminic with sedative, anti-
activity. emetic, antimuscarinic and spasmolytic properties. It may
be used in reactive anxiety or that associated with marked
Buspirone relieves mild-to-moderate
autonomic symptoms.
generalized anxiety, but is ineffective in severe
cases, in those showing panic reaction and in
OCD. The therapeutic effect develops slowly: β Blockers (see Ch. 6)
maximum benefit may be delayed up to 2 weeks. Many symptoms of anxiety (palpitation, rise in
The mechanism of anxiolytic action is not clearly BP, shaking, tremor, gastrointestinal hurrying,
known, but may be dependent on its selective etc.) are due to sympathetic overactivity and these
partial agonistic action on 5-HT1A receptors. By symptoms reinforce anxiety. Propranolol and
stimulating presynaptic 5-HT1A autoreceptors, it other nonselective β blockers help anxious
reduces activity of dorsal raphe serotonergic patients troubled by these symptoms, by cutting
neurones. the vicious cycle and provide symptomatic relief.
Side effects of buspirone are minor: dizziness, They do not affect the psychological symptoms
nausea, headache, light-headedness, rarely such as worry, tension and fear, but are valuable
excitement. It does not potentiate CNS depres- in acutely stressful situations (examination fear,
sants. Though most patients on buspirone remain unaccustomed public appearance, etc.). They may
alert, those operating machinery/motor vehicles be used for performance/situational anxiety or
should be cautioned. as adjuvant to BZDs.
II
SECTION
11
Cardiovascular Drugs
Drugs Affecting Renin-Angiotensin System, Calcium Channel
Blockers, Drugs for Hypertension, Angina Pectoris and
Myocardial Infarction

Drugs having their major action on heart or blood cells. Thus, local renin-angiotensin systems
vessels, or those used primarily for cardiovascular appear to operate in several organs in addition to
disorders are designated ‘Cardiovascular drugs’. the circulating one.
They can act directly on the cardiovascular
structures or through the autonomic/central ACTIONS
nervous system, kidney, autacoids or hormones
1. The most prominent action of AII is vasocons-
which regulate cardiovascular function.
triction—produced directly as well as by enhan-
cing Adr/NA release from adrenal medulla/
ANGIOTENSIN
adrenergic nerve endings and by increasing central
Angiotensin II (AII) is an octapeptide generated sympathetic outflow. BP rises acutely. As a pressor
in the plasma from a precursor plasma α2 globulin, agent, AII is much more potent than NA.
and is involved in electrolyte, blood volume and 2. AII increases force of myocardial contraction
pressure homeostasis. Drugs that interfere with by promoting Ca2+ influx. Reflex bradycardia
the generation or action of AII have assumed great predominates in the intact animal. Cardiac output
importance in the treatment of cardiovascular is often reduced and cardiac work is increased
diseases. (due to rise in peripheral resistance).
Renin-angiotensin system (RAS) The gene- 3. Acting on a chronic basis AII induces hyper-
ration and metabolism of AII in circulation is trophy, hyperplasia and increased intercellular
depicted in Fig. 11.1. The enzyme renin secreted matrix production in the myocardium and
by kidney splits off a decapeptide Angiotensin I vascular smooth muscle by direct cellular effects.
(AI) from angiotensinogen. AI is largely inactive Indirectly, volume overload and increased t.p.r.
but is rapidly converted to AII by angiotensin- caused by AII contributes to the hypertrophy and
converting enzyme (ACE) which removes 2 amino remodeling (abnormal redistribution of muscle
acids from the carboxy terminus of the mass) in heart and blood vessels. Fibrosis and
decapeptide. The ACE is located primarily on the dilatation of infarcted area with hypertrophy of
luminal surface of vascular endothelial cells the noninfarcted ventricular wall is seen after
(especially in lungs). Circulating AII has a very myocardial infarction. Progressive cardiac myo-
short t½ (1 min); due to serial degradation by cyte death and fibrotic transformation occurs
peptidases termed angiotensinases. in CHF. These changes are important risk factors
Many tissues, especially heart, blood vessels, for cardiovascular morbidity and mortality.
brain, kidneys, adrenals generate AII inside their ACE inhibitor therapy retards/reverses many of
172 Cardiovascular Drugs

Fig. 11.1: Physiological regulation of electrolyte balance, plasma volume


and blood pressure by the renin-angiotensin system
II

these changes imparting a pivotal role to AII in causes NO-dependent vasodilatation, promotes
SECTION

vascular and ventricular hypertrophy, apoptosis apoptosis and myocardial fibrosis, the function
and remodeling. subserved by them is not clear.
4. AII contracts many visceral smooth muscles
in vitro, but in vivo effects are insignificant. PATHOPHYSIOLOGICAL ROLES
5. AII and AIII are trophic to zona glomerulosa 1. Mineralocorticoid secretion AII (also AIII)
of the adrenal cortex—enhance synthesis and is the physiological stimulus for aldosterone
release of aldosterone. This acts on distal tubule
secretion from adrenal cortex.
to promote Na+ reabsorption and K+/H+ excretion.
These effects are exerted at concentrations lower 2. Electrolyte, blood volume and pressure homeo-
than those required to cause vasoconstriction. stasis The RAS plays an important role in
6. In addition to exerting indirect effect on kidney maintaining electrolyte composition and volume
through aldosterone, AII promotes Na+/H+ of extracellular fluid (see Fig. 11.1). Changes that
exchange in proximal tubule → increased Na+, lower blood volume or pressure, or decrease Na+
Cl– and HCO3¯ reabsorption. content induce renin release by:
Angiotensin receptors Specific angiotensin (i) Decreasing tension in the afferent glomeru-
receptors are present on the surface of target cells. lar arterioles: the intrarenal baroreceptor path-
Two subtypes (AT1 and AT2) have been way.
differentiated pharmacologically: Losartan is a (ii) Low Na+ concentration in the tubular fluid
selective AT1 antagonist, while PD 123177 is a sensed by macula densa cells: the macula
selective AT2 antagonist. Both subtypes are G- densa pathway.
protein coupled receptors. However, all known (iii) Baroreceptor and other reflexes which
effects of AII appear to be mediated by AT1 increase sympathetic impulses to JG cells—
receptor. Though AT2 receptors have been activated through β1 receptors: the β adreno-
detected in several tissues and their activation ceptor pathway.
Angiotensin Converting Enzyme Inhibitors 173
Increased renin is translated into increased described as prototype since most of its effects are
plasma AII which produces acute rise in BP by class effects common to all ACE inhibitors.
vasoconstriction, and more longlasting effects by
directly as well as indirectly increasing Na+ and Captopril
water reabsorption in the kidney. Rise in BP in It is a sulfhydryl containing dipeptide surrogate
turn inhibits renin release. of proline which abolishes the pressor action
3. Development of hypertension The RAS is of AI but not that of AII: does not block AII
directly involved in renovascular hypertension: receptors.
plasma renin activity (PRA) is raised in most By inhibiting their degradation it can also
patients. In essential hypertension and increase plasma kinin levels and potentiate the
pregnancy-induced hypertension also it appears hypotensive action of exogenously administered
to have a permissive role. bradykinin. Elevated kinins (and PGs whose
4. Secondary hyperaldosteronism The RAS is synthesis is enhanced by kinins) may be respon-
instrumental in the development of secondary sible for the cough and angioedema induced by
hyperaldosteronism. ACE inhibitors in susceptible individuals, but
kinins do not appear to be important for their
5. CNS AII can be formed locally in the brain
and may function as transmitter or modulator. hypotensive action in the long term.
Regulation of thirst, hormone release and sym- Captopril lowers BP. This effect is more

CHAPTER
pathetic flow may be the responses mediated. marked in Na+ depleted subjects and in those
with overactive RAS. Captopril-induced
Inhibition of renin-angiotensin system It can hypotension is a result of decrease in total
be achieved by: peripheral resistance. Both systolic and diastolic
1. Sympathetic blockers (β blockers, adrenergic BP fall. It has no effect on cardiac output.
neurone blockers, central sympatholytics)— Cardiovascular reflexes are not interfered with
decrease renin release. and there is little dilatation of capacitance vessels.

11
2. Renin inhibitory peptides and renin specific Because of these features, postural hypotension
antibodies block renin action—interfere with is not a problem.
generation of AI from angiotensinogen (rate Reflex (postural) changes in plasma aldoste-
limiting step). rone are abolished and basal levels are decreased
3. Angiotensin converting enzyme inhibitors— as a consequence of loss of its regulation by AII.
prevent generation of the active principle AII. However, physiologically sufficient mineralo-
4. Angiotensin receptor (AT1) antagonists— corticoid is still secreted under the influence of
block the action of AII on target cells. ACTH and plasma K+.
5. Aldosterone antagonists—block mineralocor-
ticoid receptors. Pharmacokinetics About 70% of orally adminis-
tered captopril is absorbed. Presence of food in
ANGIOTENSIN CONVERTING stomach reduces its bioavailability. Penetration
ENZYME INHIBITORS in brain is poor. It is partly metabolized and partly
excreted unchanged in urine. The plasma t½ is
Captopril, an orally active dipeptide ACE inhi-
~2 hours, but actions last for 6–12 hours.
bitor, was introduced in 1977 and quickly gained
wide usage. A multitude of ACE inhibitors like Adverse effects The adverse effect profile of all
enalapril, lisinopril, benazepril, ramipril, perindopril, ACE inhibitors is similar. Captopril is well
trandolapril, imidapril, and fosinopril, etc. are now tolerated by most patients; adverse effects are:
available. The pharmacology of captopril is 1. Hypotension.
174 Cardiovascular Drugs
2. Hyperkalemia more likely in patients with superior to others. Their important features are
impaired renal function and in those taking given in Table 11.1. Enalapril is a prodrug: has to
K+ sparing diuretics, NSAIDs or β blockers. be converted in the body to the active form.
3. Cough: a persistent brassy cough occurs in Therefore, it acts slowly; is less likely to cause
4-16% patients within 1–8 weeks. This is not abrupt hypotension and is longer acting. Other
dose related and appears to be caused by ACE inhibitors are also slow acting, longer acting
inhibition of bradykinin/substance P break- and more potent than captopril. Ramipril is
down in the lungs of susceptible individuals. claimed to cause greater inhibition of tissue RAS
4. Rashes, urticaria. because of extensive tissue distribution.
5. Angioedema: resulting in swelling of lips,
mouth, nose, larynx may develop within USES
hours to a few days.
6. Dysguesia: reversible loss or alteration of taste 1. Hypertension ACE inhibitors are now first
sensation. line drugs in all grades of hypertension. About
7. Foetopathic: foetal growth retardation, hypo- 50% patients respond to monotherapy with ACE
plasia of organs and foetal death may occur if inhibitors, and majority of the rest to their
ACE inhibitors are given during later half of combination with diuretics or β blockers or both.
pregnancy. They offer many advantages:
8. Headache, dizziness, nausea and bowel upset. (i) Lack of postural hypotension, electrolyte
9. Granulocytopenia and proteinurea: are rare. disturbances, feeling of weakness and CNS
II

10. Acute renal failure: is precipitated by ACE effects.


inhibitors in patients with bilateral renal artery (ii) Safety in asthmatics, diabetics and peri-
SECTION

stenosis. pheral vascular disease patients.


(iii) Reverse left ventricular hypertrophy and
Interactions Indomethacin (and other NSAIDs) increased wall-to-lumen ratio of blood
attenuate the hypotensive action. Hyperkalemia vessels that occurs in hypertensive patients.
can occur if K+ supplements/K+ sparing diuretics (iv) No hyperuricaemia, no deleterious effect on
are given with captopril. Antacids reduce
plasma lipid profile.
bioavailability of captopril, while ACE inhibitors
(v) No rebound hypertension on withdrawal.
reduce Li+ clearance and predispose to its toxicity.
(vi) Minimum worsening of quality of life
Other ACE inhibitors Differences among ACE parameters like general wellbeing, work
inhibitors are primarily pharmacokinetic reflected performance, sleep, sexual performance,
in time course of their action; no single drug is etc.
Table 11.1: Comparative features of ACE inhibitors

Captopril Enalapril Lisinopril Perindopril Ramipril


1. Chemical nature Sulfhydryl Carboxyl Carboxyl Carboxyl Carboxyl
2. Activity status Active Prodrug Active Prodrug Prodrug
3. Bioavailability 70% 50% 25% 20% 60%
(as active form)
4. Time to peak action 1 hr 4–6 hr 6–8 hr 6 hr 3–6 hr
5. Elimination t½ 2 hr 11 hr 12 hr 25–30 hr 8–48 hr
6. Mode of excretion Renal Renal Renal Renal Renal
7. Duration of action 6–12 hr 24 hr > 24 hr > 24 hr >24 hr
8. Daily dose (mg) 25–150 2.5–40 5–40 2–8 1.25–10
Angiotensin Antagonists 175
2. CHF ACE inhibitors cause both arteriolar Losartan It is a competitive antagonist and
and venodilatation in CHF patients: reduce after- inverse agonist of AII and 10,000 times more
load as well as preload. Though they have no selective for AT1 than for AT2 receptor; does not
direct myocardial action, stroke volume and block any other receptor or ion channel. It blocks
cardiac output are increased while heart rate is all overt actions of AII viz. vasoconstriction,
reduced. Considerable symptomatic relief is central and peripheral sympathetic stimulation,
obtained in nearly all grades of CHF. release of aldosterone and Adr from adrenals,
ACE inhibitors also retard the progression of renal actions promoting salt and water
left ventricular systolic dysfunction and prolong reabsorption, central actions like thirst, vaso-
survival of CHF patients. Long-term benefits of pressin release and growth-promoting actions on
ACE inhibitors may also accrue from withdrawal heart and blood vessels. No inhibition of ACE
of AII mediated ventricular hypertrophy, remodel- has been noted.
ing, accelerated myocyte apoptosis and fibrosis.
Pharmacologically, AT1 antagonists differ
Thus, ACE inhibitors are the first line drugs
from ACE inhibitors in that they do not interfere
in CHF.
with degradation of bradykinin and other ACE
3. Myocardial infarction (MI) ACE inhibitors substrates: no rise in level or potentiation of
administered while MI is evolving (within 24 hr bradykinin occurs. Consequently, many patients
of an attack) and continued for 6 weeks to several who develop cough with ACE inhibitors, tolerate
years reduce early as well as long-term mortality. it well.

CHAPTER
Losartan causes fall in BP in hypertensive
4. Prophylaxis in high cardiovascular risk
patients which lasts for 24 hours, while HR
subjects ACE inhibitors are protective in high
remains unchanged and cardiovascular reflexes
cardiovascular risk subjects even when there is
are not interfered. No significant effect on plasma
no associated hypertension or left ventricular
lipid profile, carbohydrate tolerance, insulin
dysfunction. Protective effect is exerted both on
sensitivity has been noted. It is also a mild
myocardium as well as vasculature and is

11
uricosuric. Data so far suggests that losartan has
independent of hypotensive action.
the same potential for regressing hypertensive left
5. Diabetic nephropathy Prolonged ACE inhibi- ventricular hypertrophy as ACE inhibitors.
tor therapy has been found to prevent or delay
Pharmacokinetics Oral bioavailability of losartan
end-stage renal disease in type I as well as type II
is only 33% due to first pass metabolism. It is
diabetics.
partially carboxylated in liver to an active
Chronic renal failure due to nondiabetic
metabolite (E3174) which is a 10-30 times more
causes may also be improved by ACE inhibitors.
potent noncompetitive AT1 antagonist. Both
6. Scleroderma crisis ACE inhibitors produce compounds are 98% plasma protein bound, do
dramatic improvement and are life saving. not enter brain and are excreted by the kidney.
The plasma t½ of losartan is 2 hours, but that of
ANGIOTENSIN ANTAGONISTS E3174 is 6–9 hours.
Over the past 2 decades, several nonpeptide orally Adverse effects Losartan is well tolerated; has
active AT1 receptor antagonists have been side effect profile similar to placebo. Like ACE
developed as alternatives to ACE inhibitors. These inhibitors, it can cause hypotension and
include losartan, candesartan, irbesartan, valsartan, hyperkalemia, but first dose hypotension is
telmisartan and few others. Selective antagonists uncommon and losartan is largely free of cough
of AT2 receptors as well as combined AT1 + AT2 and dysguesia inducing potential. Headache,
antagonists have also been produced but none is dizziness, weakness and upper g.i. side effects
in clinical use. are mild and occasional.
176 Cardiovascular Drugs
Candesartan is dose to dose more potent, val- Smooth muscle Smooth muscles depolarise
sartan and telmisartan nearly equipotent, while primarily by inward Ca2+ movement through
Irbesartan is less potent than losartan, but their voltage sensitive channel. These Ca2+ ions trigger
pharmacological profile and uses are similar. release of more Ca2+ from intracellular stores and
together bring about excitation-contraction
Uses of AT1 antagonists Losartan and other
coupling (see Fig. 11.4). The CCBs cause relaxation
AT1 antagonists are now first line antihyper-
by decreasing intracellular availability of Ca2+.
tensive drugs as alternative to ACE inhibitors,
They markedly relax arterioles but have mild
comparable in efficacy and other desirable
effect on veins. Extravascular smooth muscle
features, with the advantage of not inducing
(bronchial, biliary, intestinal, vesical, uterine) is
cough and a low incidence of angioedema, rash
also relaxed.
and dysguesia. AT1 antagonists are as effective
as ACE inhibitors in CHF, MI and diabetic Heart In the working atrial and ventricular
nephropathy as well. fibres, Ca2+ moves in during the plateau phase of
AP and elicits contraction through binding to
CALCIUM CHANNEL BLOCKERS troponin. The CCBs would thus have negative
These are an important class of cardiovascular inotropic action.
drugs which act by inhibiting L-type of voltage The 0 phase depolarization in SA and A-V
sensitive calcium channels in smooth muscles nodes is largely Ca2+ mediated. Automaticity and
and heart. There are 3 pharmacologically distinct conductivity of these cells appear to be dependent
II

subclasses of calcium channel blockers (CCBs): on the rate of recovery of the Ca2+ channel.
(a) Phenylalkylamines: Verapamil
SECTION

Recovery
(b) Benzothiazepines: Diltiazem
Resting channel Activated channel Inactivated channel
(c) Dihydropyridines: Nifedipine, Felodipine, (Non-conducting) (Conducts Ca2+) (Non-conducting)
Amlodipine, Nitrendipine, Lacidipine, Nimo-
dipine, Lercanidipine, Benidipine. The L-type Ca2+ channels activate as well as
The two most important actions of CCBs are: inactivate at a slow rate. Consequently, Ca2+ depo-
(i) Smooth muscle (especially vascular) relaxa- larized cells (SA and A-V nodal) have a
tion. considerably less steep 0 phase and longer
(ii) Negative chronotropic, inotropic and dromo- refractory period. The recovery process which
tropic action on heart. restores the channel to the state from which it can

Table 11.2: Comparative properties of representative calcium channel blockers

Verapamil Nifedipine Diltiazem


1. Channel blocking potency ++ +++ +
2. Frequency dependence of ++ – +
channel blockade
3. Channel recovery rate Much delayed No effect Delayed
4. Cardiac effects (In vivo
at usual clinical doses)
Heart rate ↓ ↑ ↓, –
A-V Conduction velocity ↓↓ – ↓
Contractility –, ↓ ↑ ↓,↑
Output –, ↓ ↑ –, ↑
5. Vascular smooth muscle ++ +++ +
relaxation
Calcium Channel Blockers 177
again be activated is delayed by verapamil and to vasodilator side effects like flushing, palpitation,
a lesser extent by diltiazem (resulting in headache, postural dizziness are largely avoided.
depression of pacemaker activity and conduction) A single daily dose is sufficient.
but not by DHPs (they have no negative Felodipine, nitrendipine, lercanidipine, benidi-
chronotropic/dromotropic action). Moreover, pine and lacidipine are the other highly
channel blockade by verapamil is enhanced at vasoselective long-acting DHPs.
higher rates of stimulation, that by nifedipine is Nimodipine is a short-acting DHP which
independent of frequency, while diltiazem is selectively relaxes cerebral vasculature; has
intermediate. Thus, verapamil slows sinus rate been specifically indicated for prevention of neuro-
and A-V conduction, but nifedipine does not. logical deficit following subarachnoid haemor-
Effect of diltiazem on sinus node automaticity and rhage.
A-V conduction is similar to that of verapamil. An occasional adverse effect of prolonged CCB
The relative potencies to block slow channels therapy having implications in dentistry is gum
in smooth muscle do not parallel those in heart. hyperplasia.
The DHPs are more selective for smooth muscle
L channels: at concentrations which cause vaso- USES
dilatation they have negligible negative inotropic
1. Angina pectoris All CCBs are effective in
action. Diltiazem causes less depression of
reducing frequency and severity of classical as
contractility than verapamil. Important differen-
well as variant angina. Benefit in classical angina

CHAPTER
ces between the three representative CCBs are
appears to be primarily due to reduction in cardiac
summarized in Table 11.2.
work: mainly as a result of reduced afterload.
Verapamil causes vasodilatation as well as
Though they can increase coronary flow in normal
cardiac depression. Along with lowering of BP, it
individuals, this is unlikely to be significant in
produces bradycardia, depresses A-V conduction
patients with fixed arterial obstruction. Exercise
and may worsen heart failure. It should not be
tolerance is increased.

11
used concurrently with β blockers or other cardiac
However, myocardial ischaemia may be
depressants.
aggravated by short-acting DHPs. This may be
Diltiazem has less marked cardiodepressant
due to decreased coronary flow secondary to fall
activity: fall in BP is attended by little change or
in mean arterial pressure, reflex tachycardia and
decrease in the HR. Though it produces milder
coronary steal. Trials using high dose regular
side effects, drug interactions and contraindi-
short-acting nifedipine formulation have reported
cations remain the same as for verapamil.
increased mortality among MI patients. The
Nifedipine is a rapidly acting dihydropyridine
sudden rush of sympathetic activity evoked by
(DHP) with short duration of action. It frequently
each dose of these preparations has been held
produces flushing, palpitation, headache and
responsible for the deleterious effect. The direct
ankle edema. Direct depression of heart is minimal
cardiac effect of verapamil and diltiazem to reduce
and overshadowed by reflex sympathetic stimu-
O2 requirement as well as less marked reflex
lation. Nifedipine has paradoxically worsened
sympathetic stimulation makes these drugs less
angina pectoris in some patients and has been
likely to aggravate ischaemia.
associated with higher mortality among
The capacity of CCBs to prevent arterial spasm
postmyocardial infarct subjects. The slow and
is undoubtedly responsible for the beneficial effect
long-acting DHPs have replaced nifedipine.
in variant angina.
Amlodipine is pharmacokinetically the most
distinct DHP. It is absorbed very slowly (peak 2. Hypertension CCBs are one of the first line
after 6–9 hours) and acts for > 24 hours. The early antihypertensive drugs. Though all 3 subgroups
178 Cardiovascular Drugs
of CCBs are equally efficacious, the long-acting Majority of cases are of essential (primary)
DHPs (e.g. amlodipine) are most commonly used hypertension, i.e. the cause is not known. Sympa-
followed by diltiazem. The CCBs lower BP by thetic and renin-angiotensin systems may or may
reducing peripheral resistance without compro- not be overactive, but they do contribute to tone of
mising cardiac output. Their advantages are: blood vessels and c.o. in hypertensives, as they
1. Do not compromise haemodynamics: no do in normotensives. Many antihypertensive
impairment of physical and mental work drugs interfere with these regulatory systems at
capacity, no sedation. one level or the other.
2. Can be used in asthma, angina and peripheral
vascular disease patients. CLASSIFICATION
3. Do not affect male sexual function.
4. No deleterious effect on plasma lipid profile, 1. Diuretics
uric acid level or electrolyte balance. Thiazides: Hydrochlorothiazide,
5. Do not impair renal perfusion. Chlorthalidone, Indapamide
6. No impairment of quality of life. High ceiling: Furosemide, etc.
7. No adverse foetal effects when given during K+ Sparing: Spironolactone,
pregnancy. Triamterene, Amiloride
Verapamil and diltiazem are not suitable for 2. ACE Inhibitors
patients with CHF or cardiac conduction defects Captopril, Enalapril, Lisinopril,
because of their negative inotropic and dromo- Perindopril, Ramipril, Fosinopril, etc.
II

tropic actions. On the other hand, DHPs may 3. Angiotensin (AT1) Antagonists
accentuate bladder voiding difficulty in elderly Losartan, Candesartan, Irbesartan, etc.
SECTION

males and gastroesophageal reflux. 4. Calcium Channel Blockers


3. Arrhythmias Verapamil and diltiazem are Verapamil, Diltiazem, Nifedipine, Felodipine,
highly effective in PSVT and for control of Amlodipine, Nitrendipine, Lacidipine, etc.
ventricular rate in supraventricular arrhythmias. 5. β Adrenergic Blockers
Propranolol, Metoprolol, Atenolol, etc.
4. Hypertrophic cardiomyopathy The negative
inotropic action of verapamil can be salutary in 6. β + α Adrenergic Blockers
this condition. Labetalol, Carvedilol
7. α Adrenergic Blockers
ANTIHYPERTENSIVE DRUGS Prazosin, Terazosin, Doxazosin,
These are drugs used to lower BP in hypertension. Phentolamine, Phenoxybenzamine
Hypertension is a very common disorder, 8. Central Sympatholytics
particularly past middle age. As such, many Clonidine, Methyldopa
patients presenting for dental treatment are likely 9. Vasodilators
to be on long-term antihypertensive drug therapy. Hydralazine, Sodium nitroprusside
Hypertension is not a disease in itself but is The ACE inhibitors, angiotensin antagonists
an important risk factor for cardiovascular and CCBs have already been described.
morbidity and mortality. Though the risk appears
to increase progressively with BP values over 120
DIURETICS
(systolic)/80 (diastolic) mm Hg, hypertension has
been defined by WHO-ISH* guidelines to be values Diuretics have been the standard antihyperten-
above 140/90 mm Hg. sive drugs over the past 4 decades, but they do
*WHO-ISH—World Health Organization and International not lower BP in normotensives. Their pharma-
Society of Hypertension. cology is described in Ch. 13.
Antihypertensive Drugs 179
Thiazides and related drugs (chlorthalidone, action lasting only for 4–6 hours after the
etc.) are the diuretic of choice in uncomplicated conventional morning dose may not maintain
hypertension. The proposed mechanism of anti- Na+ deficient state in vascular smooth muscle
hypertensive action is: round the clock. They are indicated in hyper-
1. Initially, the diuresis reduces plasma and e.c.f. tension only when it is complicated by:
volume by about 10% → decreased c.o. (a) Chronic renal failure: thiazides are ineffective.
2. Subsequently, compensatory mechanisms (b) Coexisting refractory CHF.
operate to almost regain Na+ balance and plasma (c) Resistance to combination regimens contain-
volume; c.o. is restored, but the fall in BP is ing a thiazide, or marked fluid retention due
maintained by a slowly developing reduction in to use of potent vasodilators.
t.p.r.
Potassium sparing diuretics Spironolactone
3. The reduction in t.p.r. is most probably an
or amiloride themselves lower BP slightly, but
indirect consequence of a small (~5%) persisting
they are used only in conjunction with a thiazide
Na+ and volume deficit. Decrease in intracellular
diuretic to prevent K+ loss and to augment the
Na+ concentration in the vascular smooth muscle
antihypertensive action.
may decrease stiffness of vessel wall, increase
their compliance and dampen responsiveness to Indapamide It is a mild diuretic, chemically
constrictor stimuli (NA, AII). Similar effects are related to chlorthalidone; reduces BP at doses
produced by salt restriction. which cause little diuresis or K+ loss.

CHAPTER
The fall in BP develops gradually over 2–4
weeks. During long-term treatment with thia- β-ADRENERGIC BLOCKERS
zides, the heart rate and c.o. remain unaffected, The pharmacology and mechanism of antihyper-
while t.p.r. is reduced despite compensatory tensive action of β blockers is described in Ch. 6.
increase in plasma renin activity which confirms They are mild antihypertensives; do not signifi-
persisting Na+ deficit. Thiazides have no effect cantly lower BP in normotensives. Used alone they

11
on capacitance vessels, sympathetic reflexes are suffice in 30–40% patients—mostly mild-to-
not impaired: postural hypotension is rare. moderate cases. In the large majority of the rest,
Thiazides are mild antihypertensives, average fall
they can be usefully combined with other drugs.
in mean arterial pressure is ~10 mm Hg. They
Their hypotensive response develops over 1–
potentiate all other antihypertensives (except
3 weeks and is well sustained. Despite short and
DHPs) and prevent development of tolerance to
differing plasma half-lives, the antihypertensive
these drugs by not allowing expansion of plasma
action of most β blockers is maintained over 24
volume. Maximal antihypertensive efficacy is
hours with single daily dose.
reached at doses equivalent to 25 mg of
All β blockers, irrespective of associated pro-
hydrochlorothiazide which has minimal diuretic
perties, exert similar antihypertensive effect.
effect. At 12.5–25 mg/day doses, complications
There are several contraindications to β
of diuretic therapy like hypokalaemia, fatigue, loss
blockers, including cardiac, pulmonary and
of energy, impotence, carbohydrate intolerance,
peripheral vascular disease and diabetes. The
dyslipidemia, hyperuricaemia are absent or mild.
nonselective β blockers have an unfavourable
As such, thiazides are a first choice antihyper-
effect on lipid profile (raise triglyceride level and
tensive, alone or in combination.
LDL/HDL ratio). They have also fared less well
High ceiling diuretics Furosemide is a strong on quality of life parameters like decreased work
diuretic, but a weaker antihypertensive than capacity, fatigue, loss of libido and subtle cogni-
thiazides. The explanation of this paradox may tive effects (forgetfulness, low drive). However,
lie in its brief duration of action. The natriuretic most of these drawbacks are minimized in the β1
180 Cardiovascular Drugs
selective agents and in those which penetrate fainting may occur in the beginning—called ‘first
brain poorly. Thus, there are several reasons to dose effect’
prefer a β1 selective hydrophilic drug like atenolol
Other advantages of prazosin are:
over propranolol.
Because of absence of postural hypotension, 1. Improves carbohydrate metabolism.
bowel alteration, salt and water retention; a low 2. Has favourable effect on lipid profile.
incidence of side effects, low cost; once a day 3. No impairment of cardiac contractility. Does
regimen and cardioprotective potential, β blockers not alter exercise capacity and uric acid levels.
continue to be one of the first line antihypertensive 4. Affords symptomatic improvement in coexis-
drugs. ting PVD or benign prostatic hypertrophy.
Prazosin is a moderately potent antihypertensive
β + α ADRENERGIC BLOCKERS with many desirable features, but is not used as a
first choice drug because fluid retention and tole-
Labetalol It is a combined α and β blocker; rance gradually develops; risk of CHF is increased.
reduces t.p.r. and acts faster than pure β blockers.
It has been used i.v. for rapid BP reduction in Terazosin, Doxazosin These are long-acting
cheese reaction, clonidine withdrawal, etc. Oral congeners of prazosin with similar properties and
labetalol therapy is restricted to moderately severe are suitable for once daily dosing.
hypertension not responding to pure β blocker.
Nonselective α blockers (Phentolamine,
Side effects of both α blocker and β blocker occur
Phenoxybenzamine)
II

with it.
The conventional α blockers have been disappointing for
Carvedilol This nonselective β + selective α1
SECTION

routine treatment of hypertension and are reserved for


blocker produces vasodilatation and has special situations like pheochromocytoma, clonidine
withdrawal, cheese reaction, etc., where circulating CAs
additional antioxidant/free radical scavenging
are responsible for the rise in BP.
properties.
CENTRAL SYMPATHOLYTICS
α-ADRENERGIC BLOCKERS
Clonidine It is an imidazoline derivative having complex
Prazosin (See Ch. 6) actions. Clonidine is a partial agonist with high affinity
This prototype of selective α1 antagonists dilates and high intrinsic activity at α2 receptors, especially α2A
subtype in brainstem. The major haemodynamic effects
both resistance and capacitance vessels; effect on result from stimulation of α2A receptors present mainly
the former predominating. The haemodynamic postjunctionally in medulla (vasomotor centre) → decrease
effects—reduction in t.p.r. and mean BP sympathetic outflow → fall in BP and bradycardia (also
accompanied by only slight decrease in venous due to enhanced vagal tone). In addition, clonidine
activates specific imidazoline receptors in the brain that also
return and c.o. are similar to that produced by a mediate reduction in central sympathetic tone.
direct acting vasodilator. However, there is little Clonidine is a moderately potent antihypertensive.
reflex cardiac stimulation and renin release Clonidine is active orally; metabolized as well as
during long-term therapy. Tachycardia does not excreted unchanged in urine with a t½ of 8-12 hours. Effect
of a single dose lasts for 6–24 hours.
compensate for the fall in BP because release
inhibitory α2 (presynap-tic) receptors are not Adverse effects Side effects with clonidine are relatively
common and disturbing.
blocked: autoregulation of NA release remains • Sedation, mental depression, disturbed sleep; dryness
intact. of mouth, nose and eyes, constipation.
Renal blood flow and g.f.r. are maintained but • Impotence, salt and water retention, bradycardia.
fluid retention may attend fall in BP. Cardio- • Postural hypotension occurs, but is mild.
• Rebound hypertension with tachycardia, restlessness,
vascular reflexes are not appreciably impaired headache, sweating occurs on sudden stoppage of
by chronic therapy, but postural hypotension and clonidine therapy due to:
Antihypertensive Drugs 181
(a) Sudden removal of central sympathetic inhibition myocardial contractility as well. Angina may be precipi-
resulting in release of large quantities of stored tated due to increased cardiac work as well as steal
CAs. phenomenon. Tolerance to the hypotensive action develops
(b) Supersensitivity of peripheral adrenergic struc- unless diuretics or β blockers or both are given together to
tures to CAs. block the compensatory mechanisms. The mechanism of
vascular smooth muscle relaxant action is not clearly
Regular schedule of drug administration must be known.
maintained to prevent rebound phenomena. Hydralazine is well absorbed orally. The chief
Interactions Tricyclic antidepressants and chlorpromazine metabolic pathway is acetylation, and there are slow or
abolish the antihypertensive action of clonidine, probably fast acetylators.
by blocking α receptors on which clonidine acts. The hypotensive effect lasts for 12 hours.

Use Moderate hypertension: relatively higher incidence Adverse effects are frequent and mainly due to
of side effects, impairment of quality of life and risk of vasodilatation.
withdrawal hypertension limit use of clonidine. 1. Facial flushing, conjunctival injection, throbbing
Other possible uses of clonidine are opioid withdrawal headache, dizziness, palpitation, nasal stuffiness, fluid
syndrome, postoperative epidural analgesia and meno- retention, edema, CHF.
pausal syndrome. 2. Angina and MI may be precipitated in patients with
coronary artery disease.
Methyldopa It is the α-methyl analogue of dopa, the
3. Paresthesias, tremor, muscle cramps, edema, rarely
precursor of dopamine (DA) and NA. The α methyl-NA
peripheral neuritis.
(a selective α2 agonist) formed in the brain from
4. Lupus erythematosus or rheumatoid arthritis like
methyldopa acts on central α2 receptors to decrease efferent
symptoms develop on prolonged use of doses above 100
sympathetic activity. Because methyldopa decreases t.p.r.
mg/day.

CHAPTER
more than HR or c.o., it may be acting on a different
population of neurones in the vasomotor centre than Use Hydralazine is occasionally used in moderate-to-
clonidine. In large doses it inhibits the enzyme dopa severe hypertension not controlled by the first line drugs.
decarboxylase in brain and periphery → reduces NA Usually, low doses are added to diuretics and
synthesis and forms the false transmitter methyl-NA in β blockers.
periphery as well. It is one of the preferred antihypertensives during
Methyldopa is a moderate efficacy antihypertensive. pregnancy.
Circulating levels of NA and renin tend to fall due to

11
reduction in sympathetic tone. Sodium nitroprusside It is a rapidly (within
seconds) and consistently acting vasodilator: has
Adverse effects Sedation, lethargy and reduced mental
capacity are common side effects. Cognitive impairment
brief duration of action (2–5 min)—vascular tone
may develop. Dryness of mouth, nasal stuffiness, can be titrated with the rate of i.v. infusion. It
headache, fluid retention, weight gain, impotence and relaxes both resistance and capacitance vessels:
postural hypotension are the other side effects. reduces t.p.r. as well as c.o. (by decreasing venous
Hypersensitivity phenomena are positive Coombs’
test, haemolytic anaemia, fever, rash, hepatitis, ‘flu’ like return). Myocardial work is reduced—ischaemia
illness, thrombocytopenia and rarely lupus syndrome. is not accentuated, as occurs with selective arte-
Use Methyldopa was widely used for mild-to-moderate riolar dilators (hydralazine). Little reflex tachy-
hypertension, but use has declined now because of the cardia is produced in supine posture.
availability of better tolerated agents. It is safe during Endothelial cells, RBCs (and may be other
pregnancy.
cells) split nitroprusside to generate NO which
VASODILATORS
relaxes vascular smooth muscle. The enzymes
involved are different from those that produce NO
Hydralazine/Dihydralazine It is a directly acting arte-
from glyceryl trinitrate. Moreover, nitroprusside
riolar vasodilator with little action on venous capacitance
vessels; reduces t.p.r. and causes greater reduction of is spontaneously converted to NO (and CN) by
diastolic than systolic BP. Reflex compensatory mecha- glutathione. This may be responsible for the
nisms are evoked which cause tachycardia, increase in c.o. different pattern of vasodilator action compared
and renin release → increased aldosterone → Na+ and
water retention. The disproportionate cardiac stimulation
to nitrates, as well as for the fact that no nitrate
appears to involve direct augmentation of NA release and like tolerance develops to nitroprusside action.
182 Cardiovascular Drugs
Nitroprusside has gained popularity in the principle of this approach is to match the
management of hypertensive emergencies: 50 mg requirements of individual patients with the
is added to a 500 ml bottle of saline. The infusion pharmacological and clinical properties of an
is started at 0.02 mg/min and titrated upward appropriate antihypertensive agent. For each class
with the response. of antihypertensive drugs, certain patients can
Side effects due to the vasodilator action of be identified who are best suited to be treated with
nitroprusside are—palpitation, nervousness, that drug as first choice therapy, and those in
vomiting, perspiration, pain in abdomen, weak- whom it should be avoided.
ness, disorientation, and lactic acidosis.
Combination therapy Though ~50% hyperten-
Nitroprusside has also been used to produce
sives can be successfully treated, at least initially,
controlled hypotension and in refractory CHF,
with a single drug, the addition of a second (and
pump failure accompanying MI, acute mitral
third) drug when monotherapy fails or is not
regurgitation. The ventricular performance is
tolerated, is often required. In practice a large
improved by reducing both pre- and afterload.
majority of hypertensives ultimately require 2 or
more drugs.
TREATMENT OF HYPERTENSION It is rational in such cases to combine drugs
The aim of antihypertensive therapy is to prevent with different mechanisms of action or different
morbidity and mortality associated with persis- patterns of haemodynamic effects:
tently raised BP by lowering it to an acceptable (a) Drugs which increase plasma renin activity—
II

level, with minimum inconvenience to the patient. diuretics, vasodilators, CCBs, ACE inhibitors
may be combined with drugs which lower
SECTION

Both systolic and diastolic BP predict the likeli-


hood of target organ damage and complications plasma renin activity—β blockers, clonidine,
such as: methyldopa.
(a) Cerebrovascular disease, transient ischaemic (b) All sympathetic inhibitors (except β blockers)
attacks, stroke. and vasodilators cause fluid retention: used
(b) Hypertensive heart disease—left ventricular alone tolerance develops. Addition of a diure-
hypertrophy, CHF. tic checks fluid retention and development of
(c) Coronary artery disease, angina, myocardial tolerance.
infarction, sudden cardiac death. (c) Hydralazine and DHPs cause tachycardia
(d) Arteriosclerotic peripheral vascular disease, which is counteracted by β blockers, while
retinopathy. the initial increase in t.p.r. caused by non-
(e) Dissecting aneurysm. selective β blockers is counteracted by the
(f) Glomerulopathy, renal failure. vasodilator.
Nonpharmacological measures (life style modi- (d) ACE inhibitors/AT1 antagonists are particu-
fication—diet, exercise, weight reduction, mental larly synergistic with diuretics; this combi-
relaxation, etc.) should be tried first and con- nation is very good for patients with asso-
currently with drugs. ciated CHF and left ventricular hypertrophy.
With the establishment of at least five groups (e) Other useful combinations are:
(ACE inhibitors, AT1 antagonists, CCBs, β ACE inhibitor + CCB or β blocker or clonidine
blockers, diuretics) of fi