Variation in Drug Responsiveness

Factors affecting Drug Response

Prepared by Phamacology Department Faculty of Medicine Sriwijaya University Dr. dr. Mgs. Irsan Saleh, M.Biomed

Variation in Drug Responsiveness Individuals may vary considerably in their responsiveness to a drug.

A single individual may respond differently to the same drug at different times during the course of treatment.
Quantitative variations in drug response are in general more common and more clinically important. An individual patient is hyporeactive or hyperreactive to a drug in that the intensity of effect of a given dose of drug is diminished or increased in comparison to the effect seen in most individuals.

The general mechanisms of variations in drug response

1. Alteration in concentration of drug that reaches the receptor Because of pharmacokinetic reasons age, weight, sex, disease state, liver and kidney function. Genetic differences in metabolism.
2.

Variation in concentration of an endogenous receptor ligand E.g. 1. 1. Propranolol & pheochromocytoma, Astheletes 2. Saralasin & Angiotensin II

Mechanisms

Contd.

3. Alterations in number or function of receptors

E.g. Thyrotoxicosis B-receptors in heart Down regulation from agonists stimulation Up-regulation due to antagonist. Propranolol What is the effect of sudden withdrwal of the antagonist?
4. Changes

in components of response distal to the receptor:

Changes of the post-receptors mechanisms. Change in second messenger or ion flux E.g. Morphine

Factors modifying drug response

1. Age
A. Infants and Children -Different from adults
Drug Absorption -Altered Transdermal AbsorptionFaster- Thin Skin Distribution-BBB> permeable- conc. In CNS (kernicterus)

Metabolism-system not fully developed Grey baby syndromeChloramphenicol Excretion- t of drugs of renally secreted excreted
Dose of a Child= Dillings Method Youngs Method % Method
1Mo= 10% of the adult dose 1yr=25% 3yr=33% 7yr=50% 12 yr= 75%

Factors modifying drug response

B. Elderly: Renal Function -- Dose to be Hepatic metabolism-Oral bioavailability ADRs and DDI incidence sensitivity to drugs---NSAIDS, CNS and Depressants, antiHTN, Diuretics, Digoxin. Elderly ageing 60-70 years need dose of adults Above 70 years need of adult dose

Factors modifying drug response

2. Body mass:
Affects the conc. of the drug at the site of action. 1. Weight alone in drugs with wide TI e.g. Penicillin
individual dose (adult or child) = BW (kg) X average adult dose 70 70

2. Body surface area: In drugs with Low TI e.g. A. cancer

BSA Dose = BSA (m2) X Adult dose/1.73,

BSA= (Height (cm) X weight (Kg) / 3600 For obese people a consideration of lipid soluble drugs be made (Propranolol- Vd is )

Factors modifying drug response

3. Gender (Sex): more sensitive to drugs in general, & specifically to CNS drugs. Why? Certain Drugs act specifically in , eg progesterone, ergot alkaloids, estrogens, oxytocin. respond differently to certain drugs eg Nitrous oxidevivid dreams, Halothane---Hepatitis.
During menstruation avoid salicylates. Why? During pregnancy Avoid teratogenic drugs. Like? During labor avoid morphine. Why? During lactation Avoid harmful drugs. Give examples?

Factors modifying drug response

4. Ethnicity & Race: Different response to drugs among different species, eg Blacks require & Mongols doses atropine & to dilate pupil. -blockers less effective as antiHTN in BLACKS.

5. Route of administration: Dose required--- I/V & SL, Inhalation<I/M<S.C<Oral

MgSO4 Purgative orally (after food, empty stomach) 4gm, 15 gm Rectally dehydrating IV Anticonvulsant Streptomycin. Comment on oral & IM?

Factors modifying drug response

6. Environmental: Exposure to insecticides, carcinogens; Tobacco smoke induces drug metabolism. Alcohol consumption, Hypnotic doses differ in day and night

7. Psychological: Nervous and anxious patients require more General Anesthetics. Placebo effects of drugs: Reactions which are not related to the pharmacological effects of the drug

Factors modifying drug response

8. Genetics (Pharmacogenetics): = idiosyncrasy
Abnormal pharmacological response due to genetic abnormality. Occurs on first exposure

Succinyl-choline apnea due to absent atypical pseudocholinesterase. Rapid hemolysis due to sulphonamides, NSAIDS, anti -malarials in Glucose 6 Phosphate dehydrogenase (G6PD) deficiency. Halothane, suxamethonium Malignant hyperthermia Drug Acetylating enzymes: Slow & Fast acetylators.INH

Factors modifying drug response

9. Pathological

states (Influence of diseases):

A. Some drugs act only when there is disease

Aspirin as antipyretic Digitalis as a diuretic in HF

Pathology may cause supersensitivity

Adrenaline in thyrotoxicosis B.blockers in bronchial asthma

Pathology may affect drug kinetics

Achlorhydria intrinsic facor absorption of Vit. B12 pernicious anemia

Liver disease: What effect? Renal Disease; What effect? Iron deficiency anemia--- absorption of Fe . Others: AspirinAsthmatic Attack . How?

Factors modifying drug response

10. Drug interactions:= Combined effects of drugs
A). Addition =1+1=2 . Value? e.g. Ephedrine + Aminphylline as bronchodilators Nitrous oxide + Ether (Gen Anesthesia) B. Synergism: 1+1=>2 Thiazides diuretic + Atenolol for hypertension. Value? Time synergism: Procaine + Adrenaline (Prolongation of time of drug action Prolonged Local anesthesia) C. Potentiation: 1+0=2. Value? ACh + Physostigmine Aspirin + Hypnotics (analgesic)

Factors modifying drug response

B). Antagonism
I. Pharmacological Antagonism: I. Pharmacodynamic:
A. Competitive-reversible antagonism: Define E.g. Atropine + Ach on M receptors

B. Non-Competitive-irreversible antagonism: Define E.g. pheoxybezamine & NA on -receptors Organophsophorus & CE C. Partial agonists: define Pentazocine for Mu receptors Pindolol for -1 receptors

D. Reversal antagonism:

Adrenaline + phentolamine

Factors modifying drug response Antagonism

II. Pharmaokinetic antagonism: One drug alters the phamacokinetic of another drug E.g. Phenobarbitone & warfaine. Cholestyramine & absorption NaHCO3 excretion of Aspirin II. Physiologic, or functional, antagonism: Two drugs on two different receptors with two opposite effects a. May be two agonists like adrenaline & Histamine b. Or two different antagonists as atropine & propranolol III. Chemical antagonism: When two drugs combine with each other chemically Dimercaprol chelates lead. HCl + Al(OH)3 V. Physical: One drug antagonises the effect of the other by physical methods e.g. Charcoal adsorbs many drugs

Factors modifying drug response

11. Accumulation:
Rate of Administration > Rate of elimination (Longer t1/2 drugs, Zero order Kinetic model drugs) E.g. Digoxin (no loading dose is given) Slow excretion-- Toxicity Prolonged use of chloroquin Retinal damage Passive accumulation of lead in bones We have to decrease the dose or frequency of administration

Factors modifying drug response

12. Hyper susceptibility, super sensitivity, Drug intolerance:
Exaggerated normal pharmacological response to usual normal dose. Is due to clearance or up-regulation of receptors AspirinInfants Hypothermia Thyrotoxicosis and adrenaline arrhythmia

13. Hypersensitivity, Drug allergy:

Definition: Abnormal pharmacological response to the usual
dose of a drug due to Ag-Ab reaction Skin reactions, fever, asthma, anaphylactic reactions, blood reactions. Histamines, prostaglandin, kinnins These are not dose dependent (not all drugs, not all persons, not dose-dependent, not first exposure Do not reuse the same drug) E.g Penicillin anaphylaxis

Types of Hypersensitivity reactions

1. Humoral
A. Anaphylactic reactions (Type I) (IgE) on mast cell Penicillin anaphylaxis B. Cytotoxic Reactions (Type II) IgG & IgM + Compl. On cell Thrombocytopenia/ hemolysis, Anemia C. Retarded/Arthus reaction (Type III) IgG + compliment on endothelial cellvasculitis Inflammatory response

2. Cell Mediated (Type IV) Delayed

Hypersensitivity reactions Antigen + Sensitized T-lymphocytes inflammation e.g. Contact dermatitis, rashes, fever, photosensitization) 12 hours to develop

14. Tolerance
Failure of response to the usual dose of the drug: Definition: Decrease in the response of the drug on repeated administration of the same drug dose. You have to increase the dose to obtain the original effect Types of tolerance: 1. Congenital tolerance (Racial, species, individual) 2. Acquired (opium, tea, nitrates, hypnotics). Reversible. No all action
Cross tolerance: (Morphine-Pethidine) Ethyl alcohol & GA Tachyphylaxis: Acute acquired (Amphetamine, Ephedrine Explain its mechanism? Bacterial resistance to antibiotics
(Staph. To Penicillin)

Drug dependence:
Habituation (Psychic, Less use, Withdrawal-Craving for drug, eg. Smoking, Tea, Coffee) Addiction (Psychic and Physical- Compulsive drug use, Fatal withdrawal syndrome. E.g. Cocaine, Morphine, CNS stimulants (Amphetamine)

Characters of acquired tolerance

1. It is a temporary process. Reversible. Explain? 2. Varies from one drug to another: a. Rapid with ephedrine & very slow with adrenaline b. No tolerance to digitalis, or diuretic effect of alcohol 3. Does not affect all actions of the drug E.g. morphine Rapid tolerance to analgesia, RD, euphoria But no tolerance to miosis or constipation 4. It may afect therapeutic doses rather than the toxic dosestherapeutic index 5. Drug dependence (Habituation & addiction) may follow tolerance

Mechanisms of tolerance:
1. Pharmacodynamic causes : tissue responsiveness down regulation of receptors- e.g. (opiates, nicotine, tea, nitrates), antibody production to protein like drugs e.g. PTH 2. Pharmacokinetic causes: Decreased GIT drug absorption (ethanol), or enzyme induction (Antepileptics) or increased rate of drug disposition (metabolism or excretion). 3. Depletion or exhaustion of endogenous neurotransmitter.

Dosage of drugs (psology)

Loading dose: It is the dose given at the onset of therapy to achieve rapid increase in drug plasma concentration to reach Css (Steady state concentration) within therapeutic range Maintenance dose: It is the dose needed to keep plasma drug concentration constant at the steady state i.e. to compensate for drug loss in between doses Lethal dose:= fatal dose Dose that produces death in all exposed animals LD50 (median lethal dose: Minimum dose that produces death in 50% of experimental animals

Dosage of drugs (psology)

TD50 (median toxic dose) dose that would produce particular toxic effect in 50% of animals ED50 (Median effective dose) Dose that produces a certain pharmacological effect in 50% of experimental animals

Therapeutic index: LD50/ED50 It is a measure for safety of the drugs. The higher the index the safer the drug Therapeutic dose: The average adult dose required to produce a therapeutic effect (adult male 20-60 y & 70 kg) Maximum tolerated dose: The largest safe dose that can be taken