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Chapter 1

General principles of Pharmacology

Pharmacology is an experimental science dealing with the properties of drugs


& their effects on living systems. It includes;

 Pharmacodynamics; response to drug action.


 Pharmacokinetics; the mathematical description of temporal changes
in concentration of drug & their metabolites within the body.
 Therapeutics; the treatment of disease in general using drugs , surgery,
radiation, behavioral modification & other modalities.
 Pharmacotherapy; use of drugs in the treatment of disease.
 Chemotherapy; a branch of pharmacology dealing with drugs that
selectively inhibit or destroy specific agents of disease such as bacteria ,
viruses, fungi, &other parasites. Term has been extended to the use of
drugs in treatment of neoplastic diseases. Selective toxicity ia a notion
central to chemotherapy. Drugs that are useful as chemotherapeutics
affect the pathogen or abnormal cell more adversely than normal cells.
 Toxicology; concerned with the adverse effects of xenobiotics. Its scope
includes drugs, chemicals responsible for household, industrial waste,
food additives, radioactive substances. & pesticides. Toxicology is the
science that defines the limits of safety of chemical agents.

Pharmacodynamics

Pharmacodynamic terms;

(1) Receptor is the macromolecule component of the body tissue with


which the drug interacts to initiate its pharmacologic effects.
(2) Agonist is a drug that possesses affinity for a particular receptor
& causes a change in the receptor that results in an observable
effect. A full agonist produces a maximum response when it
occupies all or a fraction of the receptors, a partial agonist
produces a sub-maximal response even if it occupies all the
receptors.
(3) Affinity describes the tendency of a drug to combine with a
particular kind of receptors.

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(4) Efficacy (intrinsic activity) refers to the maximal effect a drug can
produce.
(5) Potency refers to the dose that must be administered to produce a
particular effect of given intensity & is influenced by; i- affinity; ii-
pharmacokinetic processes that determine the drug concentration
in the vicinity of its site of action. Potency varies inversely with
dose, the lower the dose required to produce a stated response,
the more potent the drug.
(6) Antagonist is a drug that blocks the response produced by an
agonist by interaction with the receptor or other component of
the effector mechanism, competitive antagonism is reversible &
surmountable eg. atropine or propranolol. A non-competitive
antagonist conceptually removes the receptor, or response
mechanism, from the system eg. the platelet inhibiting action of
aspirin.
(7) Selectivity of a drug depends on its capacity to preferentially
produce a particular effect. The characteristic action of a drug is
produced at lower doses than those required to produce other
actions. A truly selective drug produces only one single effect,
e.g. heparin.
(8) Specificity when all the effects produced by a drug are due to a
single mechanism of action the drug is said to be specific. A
specific drug acts at only one type of receptors but may produce
multiple pharmacologic effects because of location of receptors
in various organs, e.g. acepromazine, with actions that include
sedation (increased dopamine turnover rate in the brain) ;
antiemetic (depress CTZ); hypotension (alpha-adrenergic
blockade) ;antispasmodic (anticholinergic action in the smooth
muscles of the GIT) ; & hypothermia (interference with the
hypothalamic control of temperature regulation). In the other
hand atropine is a specific drug wherein all its varied effects can
be attributed to its antimuscarinic action.
(9) Desensitization, tachyphylaxis, tolerance & resistance are synonymous
terms used to describe the gradual diminishing of drug effects
when it is given continuously or repeatedly. Mechanisms that
give rise to the phenomena include ;
1- Change in receptors.
2- Loss of receptors.

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3-Exhaustion of mediators.
4-Increased metabolic degradation.
5-Physiological adaptation.
6-Active extrusion of the drug from cells (mainly
chemotherapeutics).
Tolerance ensues when the condition gets aggravated while resistance is a
term conserved for microorganisms.

Drugs

The word is derived from the Old French drogue which meant herb.

Drugs have been defined as articles intended to be used in the diagnosis, mitigation,
treatment or diagnosis of diseases in humans or other animals; & articles other than
food intended to affect the structure or function of the body.

Nutraceuticals
Are nutritional products which allegedly have some therapeutic value in
addition to their scientifically recognized nutritional contents.

Sources of drugs;

1- Plants; most of the old remedies were derived from plants


& included all plant structures; roots; park; seeds; leaves
etc. Active principals included alkaloids, glycosides, oils,
saponines, tanines & resins.
2- Animals; many useful old medicines were prepared from
animals. Modern drugs of animal origin can be
exemplified by i) hormones:
insulin, gonadotrophins & the anabolic steroids.
ii) vitamins: cod liver oil contains vitamins A & D. iii) sera
& antisera.
3- Micro-organisms; i) the
penicillins. ii) bacteria
are now being genetically modified to produce certain
substances.
4- Mineral origin; including many simple compounds of
medicinal value ; Epson salt; MgSO4 & NaCl.

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5- Synthetic compounds.
The classification of drugs

1- Anatomic site of action; atropine classified as a gastrointestinal


drug.
2- Therapeutic effect; atropine classified as an anti-spasmodic.
3- Mechanism of action; atropine classified as an anti-cholinergic.
4- Source or pharmaceutical properties; atropine classified as a
saponaceous alkaloid.
The nomenclature of drugs

1- Approved or official name; is given by an approved body such as


The British Pharmacopoeial commission. The advantages of using
official names are that i) They are informative e.g.
Diazepam & Nitrozepam have the commercial names Valium &
Mogaden respectively.
ii) The patient is given better choice regarding availability and price
of the drug. An approved name indicating the establishment of a
drug is usually entered into an official publication commonly
known as a Pharmacopoeia e.g. The British Pharmacopoeia (BP) or The
United States Pharmacopoeia (USP). Additional information about
monographs on actions & uses of drugs plus their toxicities &
antidotal measures are given in the so cold Pharmaceutical Codex e.g.
The British Codex.
2- Commercial or propriety names; are coined by pharmaceutical
manufacturers on their drugs & get registered as trade marks. The
advantages of using a commercial drug name in prescribing are;
i) The confidence of the prescription writer. ii) The
psychological preference of the patient or iii) The actual
superiority of the trade mark.
3- Chemical names; which correspond to the formula of the drug &
are usually not practical in prescribing being very long, detailed &
complex.
The posology of drugs

1- Posology is the study of medicine dosage, the effect of the drug &
individual tolerance or susceptibility. Metrology is the study of
weights & measures as applied to preparation & administration of
drugs.

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2- A dose is the quantity of medication to be administered at one time.
Dosage refers to determination & regulation of multiple doses. An
effective dose is that amount of a drug necessary to elicit the desired
therapeutic response in the patient.
Targets for drug action

Protein targets for drug action on mammalian cells can be divided into
4 categories;

1- Receptors.
2- Ion channels.
3- Enzymes.
4- Carrier-molecules.
Other types of protein targets for specific classes of drugs are also
known & include;

I- Certain structural proteins such as tubulin, the target for


colchicine.
II- Intracellular immunophillins which are targeted by
cyclosporine & other immunosuppressive agents.
III- DNA, RNA, cell wall constituents & other proteins , of
microorganisms & cancer cells are targeted by
chemotherapeutic agents.
1- Receptors ;
Form the sensory elements in the system of chemical
communication that coordinates the function of all the different cells in
the body, the chemical messengers being hormones, transmitter substances
or other mediators such as cytokines & growth factors.

Many therapeutically-useful synthetic drugs act, either as agonists


or antagonists, on receptors for known endogenous mediators;

 Receptor, activated by binding with agonist , acts directly


eg. by opening or closing ion-channels , or indirectly thro a
transduction mechanism in enzyme activation or
inhibition , ion-channel modulation or DNA
transcription.

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 Receptor, inactivated by binding with antagonist, becomes
unavailable to endogenous mediators & their characteristic
effects are inhibited.

Receptor Agonist Antagonist

nACh Ach D- tubocurarine


Nicotine α-bungarotoxin

β-adrenoceptors Noradrenaline Propranolol


Isoprenaline
H1 Histamine Mepyramine

-Dimenhydranate
-Diphenhydramine
- Chlorpheniramine
maleate

H2 Impromidine Ranitidine
Cimetidine
Famotidine

Opiate Morphine Naloxone

D2 Dopamine Chlorpromazine

Insulin Insulin ?

5HT2 5HT Ketanserin

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2- Ion-channels;

Some ion channels, known as ligand-gated ion channels, are directly linked
to a receptor & opens only when the receptor is occupied by an agonist. Many
other types of ion channels also serve as targets for drug action.

I- Physical blocking is the simplest type of interaction


where the drug molecule physically blocks the ion
channel, e.g. the blocking action of local anaesthetics
on the voltage- gated Na-channel, also the blocking of
Na entry into renal tubular cells by amiloride.
II- Binding to accessory sites of channel protein eg. the
action of the dihydropyridine vasodilators on Ca
channels which usually open in response to
depolarization of the membrane & may be inhibited or
facilitated according to the structure of the
dihydropyridine. The binding of the drug molecule
thus influences the gating the channel.
Benzodiazepines bind to a region of the GABA receptor/Cl-channel
complex – physical block - , this region being distinct from the GABA binding
site. Most benzodiazepines are agonists that act to facilitate the opening of the
channel by GABA, but some inverse agonists are known that have the
opposite effect causing anxiety rather than tranquility.

K-channels in the membrane of the pancreatic B-cells open when the


intracellular ATP level drops & are blocked by drugs of the sulphonylurea
class used in the treatment of diabetes. Blocking these channels causes B-cells
to depolarize thus stimulating insulin secretion. Sulphonylureas do not
physically block the channel, but modulate its gating by binding to an
associated protein, the sulphonylurea receptor.

The same type of K-channels occurs in smooth muscle cells, & is targeted
by the new vasodilator cromokalim that selectively opens such channels &
hyperpolarizes the cells.

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Ion channel modulation by drugs is one of the most important
mechanisms by which pharmacologic effects are produced at the cellular level.

Ion channel Blocker Modulator

Voltage-gated Na- - Local Veratridine


channel anaesthetics
- Tetradotoxin
Renal tubule Na- Amiloride Aldosterone
channel

GABA-gated Cl-channel Picrotoxin Benzodiazepines


ATP-sensitive K-channel ATP Cromokalim
Voltage-gated Ca- Divalent cations (eg. dihydropyridines
channel Cd2+)

3- Enzymes;

Many drugs are targeted on enzymes;

I- The drug molecule is a substrate that acts as a competitive inhibitor of


the enzyme, either

A-Reversibly e.g. neostigmine acting on AChE or

B-Irreversibly, e.g. aspirin action on cyclooxygenase.

II- The interaction involves a drug as a false-substrate, wherein the drug


molecule undergoes chemical transformation to form an abnormal product
which subverts the normal metabolic pathway e.g. the anticancer fluro-uracil
which replaces uracil as an intermediate in purine synthesis but cannot be
converted into thymidylate, thus blocking DNA synthesis & preventing cell
division.

III- Pro-drugs; Drugs may require enzymatic degradation to convert them the
inactive pro-drug form to the active drug.

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Inactive Active

Cortisone Hydrocortisone

Predinsone Predinsolone

Chloral hydrate Trichloroethanol

Active Active

- Heroin Morphine

- Codeine

Propranolol 4 hydroxypropranolol

Diazepam Nordiazepam  Oxazepam

Active Toxic

Paracetamol N-acetyl-p-benzo-quinone-imine

Halothane Tri-fluoroacetate

Sulphonamides Acetylated derivatives

Methoxyflurane Fluoride

4- Carrier-molecules;

 The transport of ions & small organic molecules across cell membrane
generally requires a carrier protein since the permeating molecules are
often too polar (ie. Insufficiently lipid-soluble) to penetrate lipid
membranes on their own.

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 E.g.s include glucose & amino acids transport into cells, ions & organic
molecules by the renal tubules, Na & Ca ions out of cells & the uptake
of neurotransmitter precursors (eg. choline) or the NTs themselves (e.g.
noradrenaline, 5HT, glutamate & peptides) by nerve terminals.
Receptor families;

1- Channel-linked – ionotropic – receptors; are membrane-receptors on


which fast neurotransmitters act e.g. nACh, GABAA & glutamate receptors.

 The receptor consists of 4 different subunits inserted into the


membrane.
 The long extracellular N-terminal of the alpha-subunits has 2 ACh-
binding sites, both must bind ACh in order to activate the receptor &
open the channel.
 Other receptors for fast-NTs such as GABAA, 5HT3 & glutamate are
built into the same pattern.
 Sequence variations between Rs in different spp. & Rs
subtypes in the same spp exist in different organs e.g.
nACh Rs in different regions of the brain vary among
themselves & from the muscle receptors for example in
sensitivity to blocking agents.
 The mean channel life-time is the average duration for which
the channel stays open.
 The channel conductance produced by different ACh
agonists is equal, but the channel life-time varies.
 Agonist of high efficacy activates a large proportion of
receptors.
 Some transmitters like glutamate cause individual
channels to open to any one of several distinct
conductance levels.
2- G-protein coupled – metabotropic - receptors; (7-
transmembrane receptors)

 Membrane receptors coupled to intracellular effector system


via a G-protein.
 mAch. R , adrenoceptors, dopamine R, 5HT R, opiate R,
purine R & olfactory chemoceptors.

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 A single polypeptide chain of 400-500 residues & 7 trans-
membrane α-helices, extra-cellular amino terminus, intra-
cellular carboxy terminus & a 3rd cytoplasmic loop that couples
to the G-protein.
 Usually a particular R subtype couples selectively to a particular
G-protein.
 G-proteins has enzymatic activity catalyzing the conversion of
GTP to GDP, the so activated G-protein by the activation of R
then dissociates releasing its active forms (α-GTP & βγ-
subunits) which diffuse in the membrane & can associate with
different enzymes & ion channels causing activation or
inactivation.
 A single agonist-R complex can activate several G-protein
molecules.
 These associate with effector enzymes & produce many
molecules of 2nd messenger.
 Further amplification occurs before the final cellular response
is produced.
 2nd messenger targets for G-proteins include;
1- Adenylate cyclase / cAMP system which regulates protein
kinases & enzymes of metabolism, cell division &
differentiation. Many drugs function
by increasing or decreasing the catalytic activity of
adenylate cyclase thereby lowering or raising cAMP within
the cell. M2 receptors of myocardium, α2-
adrenoceptors in smooth muscles & opioid receptors
inhibit ACase.
Forskolin & floride ions directly activate the enzyme.
Phosphodiesterases hydrolyse cAMP within the cells, the
hydrolysis is inhibited by drugs such as methylxanthines
(e.g. theophylline & caffeine). Selective inhibitors of
phosphodiesterases has use in cardiovascular, respiratory
& other conditions e.g. Sildenafil (Viagra).
2- The phospholipase C/ inositol phosphate system; lithium
an agent used in psychiatry blocks the recycling pathway of
PI. Inositol tri-phosphate acts on
specific R coupled to Ca-selective channel in the ER
membrane by releasing a flood of intra-cellular Ca. This

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occur in response to a variety of agonists e.g. in smooth m.
contraction, increased myocardial contraction, secretion
from exocrine glands & NT from neurons.
3- DAG is produced whenever R-induced PI hydorolyses
occurs activating the membrane bound protein kinase C
(13 types) which phosphorelates serine & threonine
residues of various intra-cellular proteins.
4- Regulation of ion channels directly without 2nd messenger
e.g. mAch. R in cardiac muscles enhances K permeability
causing hyper polarization inhibiting electric activity,
opioid analgesics reduce excitability by opening K
channels.
3- Tyrosine kinase & guanylate cyclase linked Rs; membrane Rs that
have intracellular protein kinase domain. Are Rs for hormones e.g.
insulin, when Rs are activated cytosolic kinases are activated
allowing control of many cellular functions e.g. cell growth &
differentiation, gene transcription, & release of inflammatory
mediators. Few hormone Rs e.g. ANF are linked to guanylate
cyclase.
4- Rs that regulate gene transcription; are intracellular proteins.
Ligands include thyroid hrn., vit. D & retinoic acid.
Rs have a conserved DNA-binding site attached to variable ligand-
binding & transcription control domains. DNA-binding domain
recognizes specific base sequences thus promotes or represses
particular genes. Depending on cell type & ligand nature effects are
diverse & are produced by altered protein synthesis i.e. slow.
Receptor malfunction associated with disease

1) Auto-antibodies directed against receptor proteins

 Myasthenia gravis (Neuro-muscular junction disease): the auto-


antibodies inactivate nACh. R.
 Auto-antibodies mimic the effect of agonist: e.g. thyroid hyper-
secretion caused by activation of thyrotropin receptors: e.g.
severe hypertension (α-adrenoceptors), cardiomyopathy (β-
adrenoceptors) & epilepsy (glutamate receptors).
2) Mutations in gene encoding receptors & proteins involved in signal
transduction

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 Inherited mutations of genes encoding G-protein coupled
receptors: e.g. mutated vasopressin & ACTH receptors leading
to resistance to these hormones; mutations in genes encoding
growth factors can result in malignant transformations.

Quantitative responces in the patient

The purpose of administering a drug to a patient is to generate a particular


response of desired intensity.

This response will usually be produced by establishing & maintaining for a


certain time an effective concentration of the drug in the immediate vicinity
of its site of action.

A fundamental principle of pharmacology is that the intensity of response


elicited by a drug is a function of the dose administered.

The reponse of the patient to different doses of a drug (the dose-response


relationship) conforms to the principles for drug-receptor interactions which
can be represented graphically in at least 2 ways; as the dose of a drug is
increased the intensity of response is increased (the graded dose-response curve),
or as the dose is increased the number or proportion of patients responding is
increased (the quantal dose-response curve);

1- (A) The relationship is depicted between the drug dose & the response.

(B) More commonly the concentration of the drug is expressed on a


logarithmic scale.

The slope of the log dose-response indicates the range of doses over which the
drug acts, from minimally detectable to maximally effective. The variability in
response can be related to physiologic, pathologic or drug-indused variations
in a patient or to individual variations in a population of patients.

2- An end point to a response or effect is defined, and the dose of drug


required, to achieve that end point, is determined in a group of individuals
from the population. A frequency distribution curve is obtained with the
most sensitive members of the population responding & reaching the end

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point at the lowest dose of the drug & with the most-resistant members of the
population requiring the highest doses. At any given dose concentration an
individual patient has either responded to treatment or not. The sensitivity of
a drug is distributed normally with respect to the logarithm of the dose. In
this population, the dose required to produce the end point effect in 50% of
the individuals is known as the median effective dose (ED50). The quantal dose
response relationship can be depicted in on of 2 ways; a cumulative normal
distribution relationship, sigmoid, or a normal probability density function
relationship, bell-shaped.

The slope indicates the range over which the population is affected, the
steeper the slope the narrower the dose range which encompasses the majority
of the population.

Under the ideal & unlikely case that a drug has no undesirable toxic effects
the ED100 (the dose adequate to be effective in all individuals of the
population) can be used effectively in all patients, but for most drugs as the
dose is increased undesirable or toxic effects become increasingly common &
at hi dose may cause death, therefore the greater the gap between the dose
that effective dose & the toxic or lethal dose the safer the drug. The ratio
between the drug dose that produces toxic or lethal effect & that dose which
generates the desired therapeutic response is the therapeutic index & indicates
the selectivity of the drug & its usability.

The variation in the dose response curve (DRC)

Considering the low of mass action & assuming that a drug is reversibly binding
its receptors, & that the maximum response is produced when all the
receptors are occupied, then

Drug (c) + free receptors (100-Y) ← k1/k2 →Drug receptor complex (Y) ↔
response.

Where c is the free drug concentration in the bio-phase, Y is fraction of


receptors occupied & is proportional to the dose administered & k1/k2 = k is
the affinity equilibrium constant.

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At any given drug concentration

The response = Y. The maximum response.

k1 + C (100-Y) = k 2 + Y.

Rearranging;

Y/ {C (100-Y)} = k1/ k 2.

The dose that will occupy half of the receptors in the drug-receptor complex
gives a 50% response. This corresponds to a situation wherein Y/ (100-Y) = 1.
& 1/ED50= k. so that the median effective dose is the reciprocal of the affinity
constant of the tissue receptor for the particular drug.

1) DRC & occupancy curve.

2) DRC modified by the presence of a competitive antagonist (Isoprenaline


on heart in the presence of propranolol).

3) DRC in the presence of a non competitive antagonist.

4) Drug-receptor interaction working model.

Pharmacokinetics

Are defined as the mathematical description of drug conc. changes in the


body.

Biologic membranes may be viewed as fluid mosaics of functional units


composed of lipoprotein complexes, with a bi-layer of amphipathic lipids,
their hydrocarbon chains oriented inwards to form a continuous hydrophobic
phase & their hydrophilic heads oriented outwards, individual lipid
molecules move laterally endowing the membrane with fluidity, flexibility,
high electric resistance & relative impermeability to high-polar molecules.
Membrane proteins embedded in the bi-layer serve as receptors signaling
electrical or chemical pathways.

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Transfer of drugs across membranes;

A- Passive processes; Diffusion;

1- Along a conc. gradient by virtue of lipid solubility (water-lipid


partition coefficient of the drug) until steady-state equilibrium is
reached.
2- For ionic compounds equilibrium is dependant on; pH-
differences across the membrane, & on electro-chemical gradient for
ions.
3- Most membranes are relatively-permeable to water & small water
soluble molecules by; diffusion, hydrostatic pressure or osmotic
differences.
4- The conc. gradient for many ions is determined by active-
transport e.g. Na & K,, the trans-membrane potential
determines the distribution of other ions e.g. chloride.
5- Channels with selectivity for individual ions exist.
6- In terms of drug distribution, penetration of drugs into extra-
cellular fluid of the brain & CSF is similar to diffusion into
intracellular fluid elsewhere in the body. Passage of a drug from
cerebral circulation into brain extra-cellular fluid can take place
only by diffusion thro capillary endothelial cells (blood-brain
barrier).
7- A drug enters CSF from systemic circulation only by diffusion
thro the choroidal epithelial cells (blood-CSF barrier).
8- The penetration of drugs into aqueous-humor of the eye
involves diffusion thro the blood-aqueous barrier.
9- Blood-sertoli cells & blood-tunica albogenia barriers are the
most efficient barriers.
10- Fever & certain inflammatory conditions increase the capacity
of drugs to cross these barriers.
The influence of pH

Most drugs are weak acids or bases present in solution as both ionized
& non-ionized species. The non-ionized species are usually lipid-soluble &
readily diffuse across the membrane to achieve equilibrium on both sides. The
ionized moiety is often virtually excluded from trans-membrane diffusion
because of its low lipid solubility.

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The degree of ionization of an organic electrolyte is dependant on;

1- Its pKa value (-ve logarithm of the acidic-ionization, or


dissociation, constant).
2- pH of the medium.
E.g. 1) weak organic acids such as aspirin (pKa 3.5), phenylbutazone
(pKa 4.4), sulphadiazine (pKa 6.4) & phenobarbitone (pKa 7.4) are
well-absorbed from the stomach (pH 1.4) into plasma (pH 7.4).

E.g. 2) the acidic reaction of urine promotes passive re-absorption of


acidic drugs (pKa between 3- 7.2) from the distal portion of the
nephron. Urinary alkalinization will promote their excretion, a
technique that may has clinical application in management of
overdose (provided that the drug is excreted unchanged).

E.g. 3) basic drugs (narcotic analgesics, phenothiazines,

ketamine, diazepam & antiarrhythmic agents) tend to concentrate


in fluids that are acidic relative to plasma e.g. intracellular fluid (pH
7).

B- Carrier-mediated transport;

 Sites; neuronal membranes, choroid plexus, renal tubules &


hepatocytes.
 Characteristics; selectivity, competitive inhibition, saturability,
requirement for energy & movement against electrochemical gradient.
 Types ;
1- Active transport; requires a direct expenditure of energy e.g. transfer
into bile & urine of strongly acidic or basic drugs & drug-
metabolites, also the removal of drugs e.g. penicillin from CNS.
2- Facilitated diffusion; not energy-dependant nor does it move
substances against gradient e.g. uptake of glucose into cell facilitated
by insulin.
Absorption;

 Bioavailability; is a term used to indicate the extent to which


a drug reaches its site of action.

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 1st pass effect; defines the effect of passage of drugs thro the
liver before reaching the systemic circulation.
Factors that modify absorption;

1. Solubility; aqueous more rapidly absorbed than oily.


2. Rate of dissolution.
3. Local conditions at site of absorption; deltoid better
than gluteus.
4. Drug conc. in the dosage form (GIT in particular).
5. Circulation to the site of administration; (+) massage
& heat, (-) vasoconstrictors & shock.
6. Area of the absorbing surface to which the drug is
exposed.
Routes of drug administration;

Drugs are administered in prepared dosage form, the product contains


a certain amount of pharmacologically-active drug substances. The dosage
form & route of administration can influence the selectivity of a drug product
& thereafter its clinical indication.

A- Enteral administration;

1. Oral; weak acidic drugs absorption is optimal in the acidic


environment of the stomach, wherein weak basic drug absorption is
optimal in the relatively-alkaline small intestine.
Factors that accelerate gastric emptying into intestine are likely to
increase the rate of absorption.

Drugs destroyed by gastric juice or cause gastric irritation are coated,


with the possibility of failure of dissolution.

Advantages are; convenience, safety & economy.

Disadvantages; requires cooperative patients, affects bioavailability,


slow & unpredictable.

2. Sublingual; specific non-ionic high lipid-soluble drugs e.g. nitroglycerine


are readily-absorbed. Mouth is drained to superior vena cava, so the

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drug is protected from 1st pass metabolism by the liver (completely
destroyed).
3. Rectal; useful in patients that are unconscious or vomiting. 50% of the
medication is approximately bio-available. Absorption is incomplete,
irregular & irritation to rectal mucosa is not uncommon.
B- Parenteral injection; is either vascular including i/v & intera-arteriorly, or
extra-vascular including I/m & S/c . Absorption is determined by the area of
the capillary membrane in I/m & S/c thro large aqueous channels in the
endothelial membrane by indiscriminate diffusion of molecules regardless of
lipid-solubility. Larger molecules e.g. proteins, slowly gain access to circulation
by way of lymphatics, parenterally-given drugs are subjected to 1st pass in the
lungs.

1- I/v;

Advantages;

1. Drug attains immediate predictable systemic conc. useful in


emergency.
2. The entire dose is almost bio-available.
3. By controlling the rate of infusion the effects can be titrated
e.g. surgical anaesthesia with pentobarbitone.
4. Certain irritating hypertonic solutions can only be given I/v.
5. Continuous-infusion maintaining steady-state conc.
Disadvantages;

1. Potentially the most dangerous route, rapid high conc.


enhances the likelihood of toxicity particularly in CNS.
2. Drugs in oily vehicles or suspensions are contra-indicated.
3. Drugs that precipitate blood components or hemolyse RBCs
are also contra-indicated.
4. Anti-septic measures should be taken carefully & the
administration performed slowly, except in the case of i/v
bolus in the induction of rapid anaesthesia with thiopentone.
2- Subcutaneous administration;

 Rate of absorption is often adequately constant & slow


to provide sustained effects that may be varied

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intentionally e.g. the soluble & insoluble forms of
insulin.
 Solid pellets (e.g. hormones) are implanted under the
skin to produce effects over weeks & months.
 Disadvantages in certain irritating drugs that may cause
severe pain & necrosis.
3- I/m administration;

 Rapid absorption depending on the blood flow to the area.


 Aqueous solutions absorbed more rapidly.
 Deltoid more than gluteus particularly in females.
 Very obese & very emaciated subjects show unusual patterns of s/c &
i/m absorption.
 Penecillin is often administered I/M, irritant drugs can be
administered i/m.
4- Intra-arterial administration;

 Localizes the response to the particular organ or tissue.


 1st pass is not evident.
 Diagnostic agents are sometimes administered I/arteriorly.
5- Intrathecal;
Used once rapid local effects are needed on the meninges & cerebrospinal
axis e.g. spinal anaesthesia & CNS infections.

6- Intra-peritonial;

 Large surface.
 Drug absorbed via portal circulation, 1st pass thro the liver.
 Lab. procedure.
 Infections & adhesions.
C- Pulmonary absorption;

Advantages;

 Gases & volatile drugs may be inhaled.


 Rapid (large surface).
 1st pass thro liver avoided.
 Useful in pulmonary disease e.g. bronchial asthma.
Disadvantages;

20
 Poor ability to regulate dose.
 Cumbersomeness of methods of administration.
 Many drugs & gases irritate pulmonary epithelium.
D- Topical application;

I- Mucus membranes; conjunctiva, nasopharynx,


oropharynx, vagina, colon, & urethra. Aim is local
effects, however, sometimes generalized effects are
achieved e.g. ADH is applied to the nasal mucosa.
II- Skin ; few drug penetrate intact skin, surface area &
lipid-solubility being the determinant factors, as well as
oily vehicles & rubbing (innunction). Occlusive
dressings of polyethylene enhance absorption.
Dimethylsulfoxide, skin irritant & sorption promoter
vehicle, enhances penetration of the stratum cornium.
Controlled-release topical patches e.g. scopolamine
(behind the ear) for motion sickness, & trans-dermal
oestrogen replacement therapy.
III- Eye; local effects, requires absorption thro the cornea.
Disadvantages include corneal infection or trauma.
Bio-equivalence;

Two pharmaceutically-equivalent drug products are considered bio-equivalent


when the rate & extent of bio-availability of the active ingredients is not
significantly different.

T1/2A;

The time it takes for half of the administered drug to reach the systemic
circulation.

The Distribution of Drugs

Drugs are conveyed thro-out the body in the circulating blood & reach the
tissues of every organ in an amount determined by blood flow & conc. to the
organ. The conc. attained in the tissues depends on the capacity of the drug
to;

21
1. Penetrate capillary endothelium (influenced mainly by plasma-protein
binding).
2. Diffuse across cell membrane.
CNS & CSF;

A- Entry of drugs into CSF is restricted by;

1. Absence of intercellular pores & pinocytic vesicles & predomination of


tight-junctions.
2. The unique arrangement of glial cells contributes to the slow diffusion
of organic acids & bases into the CNS.
B- Strongly-ionized agents such as quaternary amines are normally unable to
enter CNS.

C- Organic ions are extruded from CSF into blood at choroids plexus by
transport processes similar to those of renal tubules.

D- The barrier is neither absolute nor invariable;

1. Large doses of penicillin may produce seizures.


2. Meningeal or encephalic inflammation increases permeability.
3. Maneuvers to increase permeability of the barrier are important to
enhance efficiency of chemotherapeutics in treatment of local
infections & tumors.
Drug Reservoirs;

Are body compartments in which a drug accumulates, if a reservoir has a


large capacity & fills rapidly, then larger quantities are initially required to
provide a therapeutically-effective conc. in the target organ.

I- Plasma proteins binding;

Sulfadimethoxine 81 % Thiopentone 75 %

Sulfisoxazole 68 % Sulfadiazine 17 %

Clorpromazine 94 % Chloramphinicol 39 %

Propranolol 97 % Amphetamine 27 %

22
Morphine 12 %

1. Acidic drugs extensively bind albumin, basic drugs bind alpha1-


glycoprotein & beta-globulin, binding is reversible.
2. Binding to plasma proteins limits drug conc. in tissues & at
locus of action since only the free drug equiliberates across
membranes.
3. Although binding limits glomerular filteration it does not
generally limit tubular secretion or hepatic metabolism, so it is
a transport mechanism that fosters the delivery of drugs to sites
of elimination.
4. Binding is rather non-selective. Many drugs with physico-
chemical similarities compete for binding sites e.g.
displacement of bilirubin from albumin by sulfonamides
increasing the risk of encephalopathy in the newborn, this
could be of concern in drugs with narrow therapeutic indices
e.g. warfarin displacement by phenylbutazone.
5. Alteration of molecular structure can influence the % of drug
binding e.g. digoxin (27 %) & digitoxin (89 %) wherein these
complex molecules differ only in a hydroxyl group.
6. Certain diseases such as hypoalbuminaemia (nephrotic
syndrome) or chronic renal failure cause an increase in the %
of free drug in plasma & site of action.
II- Cellular Reservoirs;

Quinacrine (anti-malarial) after long term therapy, attains a conc.


in the liver several thousands times that of plasma.

1- Tissue binding of drugs occurs to proteins, phospholipids &


nucleoproteins, it is generally reversible.
2- Neutral fat (10 ~ 50 % of body wt.) accumulates many lipid
soluble drugs e.g. thiopentone. It is a stable reservoir (low blood
flow).
3- Bone is a reservoir for tetracyclines & other metal ion chelating
agents, it can become a reservoir for release of toxic agents such
as lead or radium long after exposure has ceased.

23
4- The GIT is the major trans-cellular reservoir in the case of
slowly-absorbed oral drugs & particularly those agents
undergoing entero-hepatic circulation.
III- Re-distribution;

Terminates drug effects primarily when a highly lipid soluble drug


acting on the brain or the cardiovascular system is rapidly administered I/v or
inhaled e.g. thiopentone.

IV- Placental transfer of drugs;

 Drugs may cause congenital anomalies or adverse effects in the


newborn.
 Drugs cross the placenta primarily by simple diffusion in rates
variable from early to late pregnancy.
 It would be inaccurate to view the placenta as a barrier, the fetus is,
at least to some extent, exposed to essentially all the drugs taken by
the mother.
Special drug delivery systems;

1. Biologically-errodable micro-spheres of polymers; engineered to adhere


to mucosal epithelium of gut, such micro-spheres can be loaded with
drugs as a means of improving absorption e.g. insulin & polymers of
fumaric acid.
2. Pro-drugs ; Zidovudine is phosphorelated to its active tri-phosphate
metabolite only in cells containing appropriate reverse transcriptase
hence conferring selective toxicity towards cells infected with HIV. The
cytotoxic drug Cyclophosphamide becomes active only after
metabolism in the liver therefore causing no GIT damage when taken
orally.
3. Antibody-drug conjugates; e.g. attachment of a cytotoxic drug to an
antibody directed towards a tumor-specific antigen.
4. Packaging in liposomes; liposomes are vehicles produced from certain
aqueous phospholipids & can be filled with non lipid soluble drugs
released after disruption in the reticulo-endothelial cells particularly in
the liver. Liposomes are also concentrated in malignant tumors
achieving selective delivery of cytotoxic agents e.g. Amphotericin (an
antifungal used in the treatment of systemic mycosis) is available in a
liposomal formulation that is less nephrotoxic than the regular one.

24
Volume of Distribution;

It is defined as the volume of fluid required to contain the total


amount, Q, of a drug in the body at the same conc. as that present in plasma,
Cp.

Vd = Q / Cp

Vd serves as a proportionality constant relating plasma conc. of a drug to its


total amount in the body at any given time after pseudo-distribution
equilibrium has been attained.

Rate of Distribution (T ½ D);

Can be described as the time it takes 50% of the drug in the plasma to
distribute outside the bloodstream.

Drugs confined to plasma compartment;

 Heparin (molecule too large).


 Evans blue (strong albumin binding). Vd is used to measure plasma
volume.
2 Compartmental Distribution Models;

 1st order kinetics i.e. the rate at which the drug is removed from the
compartment is proportional to its conc. in that compartment ,
wherein in zero-order kinetic a constant amount of the drug is
cleared from the compartment regardless of its conc. i.e. saturation
kinetics.
 Partitioning depends on blood flow, lipid solubility & protein
binding.
 Elimination takes place exclusively from the central compartment.
 Absorption takes place exclusively to the central compartment.
3 Compartmental open models;

 Drugs that has high affinity for certain tissues by selective binding e.g.
digoxin, pentazocin & diazepam.
 Drugs that undergo re-distribution e.g. thiopentone.

25
Drug Elimination

Mechanisms of drug elimination are bio-transformation (metabolism) &


excretion. Although it is usual for one process to predominate, both hepatic-
metabolism & renal-excretion are involved in the elimination of most drugs.

1. Lipid solubility is prerequisite for bio-transformation by hepatic


microsomal enzyme system.
2. Polar drugs & drug metabolites are excreted by the kidneys.
3. Wide extra-vascular distribution & selective tissue-binding e.g. the
localization of thiopental in body fat reduces the rate of elimination of
a drug by limiting its accessibility to eliminating-organs.
4. It is common for a drug to be metabolized along 2, or more, pathways
simultaneously.
Drug Bio-transformation

Drugs undergo metabolic changes in the body that are directed primarily
towards formation of metabolites that have physico-chemical properties
favorable to their excretion, metabolites are generally less lipid soluble &
more polar in nature rendering them suitable for carrier-mediated excretion
processes & more likely to be partitioned into fluids of the body such as the
blood stream.

PhaseI reactions;

Usually unmask or expose or introduce to the drug molecule polar groups


such as –OH, -SH, -COOH & -NH. These functional groups enable the
compound to undergo conjugation.

A- Oxidation; liver microsomal enzymes are mixed-function oxidases of the


ER that have specific requirement for reduced NADPH & molecular oxygen.

1. NADPH reduces cytochrome P-450(which is the oxidizing enzyme of


the microsome) as follows; NADPH + A + H+  AH2
+ NADP+.
2. Reduced cytochrome P-450 reacts with molecular oxygen to form an
active oxygen intermediate; AH2 + O2  “active
oxygen complex”.

26
3. The interaction between this complex & a lipid soluble drug or steroid
substrate yields a hydroxylated substrate, oxidized P-450 & an
equivalent molar fraction of water;
“active oxygen complex” + Drug Oxidized Drug + A + H2O.

Oxidative reaction Drug Metabolite

Aromatic hydroxylation - Phenobarbital - p-hydroxyphenobarbital


- Penylbutazone
- Oxyphenbutazone*

Aliphatic oxidation Pentobarbital Pentobarbital alcohol

N-dealkylation Diazepam N-desmethyl diazepam*

O-dealkylation Phenacetin Acetaminophen*

Oxidative de-amination Amphetamine Phenylacetone

B- Reduction ; hepatic microsomes reduce azo & nitro compounds to


corresponding amines in anaerobic conditions & the requirement for
NADPH mediated by enzymes that contain flavine adenine dinucleotide FAD
e.g. prontosil (azo dye) is reduced to sulfanilamide (antibacterial), e.g.
inactivation of chloramphinicol, & the reductive dehalogenation of
halothane & methoxyflurane.
C- Hydrolysis; is an important pathway for compounds with an ester linkage (-
coo-) or an amide bond (-coNH-) e.g. suxamethonium, atropine, pethedine &
hydrocortisone. Most amines are hydrolyzed more slowly than the
corresponding esters. Use of procainamide as an anti-arrhythmic is based on
its slow rate of hydrolysis, compared with that of procaine, with the ultimate
formation of the active metabolite N-acetyl procainamide*.

Phase II reactions (conjugation);

27
A drug or, phase I metabolite, containing a suitable functional group is
combined to endogenous substances that include glucouronic acid, glutathione,
glycine, cysteine, methionine, sulfate & acetate.

1. These processes utilize energy.


2. Catalysis by an enzyme is required.
3. The activated form of the endogenous substance undergoes
conjugation e.g. acetyl-coA for acetate & uridine diphosphate glucouronic
acid (UDPGA) for glucouronic acid.
4. The total pool of sulfate in the body can be exhausted so that
glucourinidation predominates.
5. Acetylation decreases water solubility as-well-as lipid solubility of
sulfonamides increasing the risk of crystalluria.
Metabolic- transformations mediated by GI microflora;

1. GI microflora mediate metabolic transformations especially hydrolytic


& reductive reactions.
2. Enteric sulfonamides e.g. phthalylsulfathiazole & succinylsulfathiazole
depend on microfloral release of sulfathiazole for their antibacterial
activity.
3. Microfloral hydrolysis is also responsible for activation of
anthraquinone glycosides.
4. The hydrolytic enzyme responsible, beta-glucourinidase, is principally
found in E. coli.
5. The release of bile acids from their conjugates leads to the entero-
hepatic circulation of drugs & the function of bile acids in fat
absorption.

Drug Phase II reaction

- Morphine Glucourinidation
- Salicylates
- Acetaminophen
- Chloramphinicol
- Steroid hormones*
- Thyroxin
- Bilirubin

28
- Phenol Sulfate conjugation
- Acetaminophen
- Morphine
- Isoproterenol (CA)
- Ascorbic acid
Sulfonamides Acetylation

Factors affecting drug metabolism;

I- Genetic; wide inter-individual differences in drug bio-transformation is due


to inherited autosomally-recessive traits, polymorphism, this may include the
rapidity & the metabolic pathway & thereafter the metabolic end-products.

II- Physiologic;

1. Age & gender E.g. i-


Cytochrome P450, CYP3A7 is expressed exclusively in the fetus
(although drug metabolism is generally active at low levels in feti).
E.g. ii- newborns are able to catalyze most phase I reactions (at slow
rates) & there is impairment of bilirubin glucourinidation during the
1st 2 weeks. E.g. iii- the age-related decrease in
hepatic mass, enzymes (particularly CP450) & blood flow 
decreased metabolic capacity.
E.g. iv- clinical reports of decreased oestrogen & benzodiazepines
oxidation in females suggest gender-related metabolic variations.
2. Disease: hepatitis, alcoholic liver disease, fatty liver disease, biliary
cirrhosis, hepatic carcinoma & cardiac insufficiency.
E.g. diazepam & morphine in hepatic disease & lidocaine &
propranolol in decreased hepatic blood flow.
3. State.
III- Metabolic drug interactions;

1. Induction; an increased synthesis of de novo cytochrome P450 associated


with exposure to certain drugs & environmental agents e.g. rifampin
liver & gut induction on; corticosteroids, cyclosporine, diazepam,
quinidine, digoxin & oral contraceptives. Auto-induction occurs with
the anticonvulsant carbamazepine.

29
2. Inhibition ; competition between 2 or more drugs for the active site of
the same enzyme e.g. cimetidine & the antifungal ketoconazole inhibit
oxidative drug metabolism by forming tight complexes with CP450 , a
metabolite of erythromycin has the same effect.
Drug excretion

Renal excretion is the principal process of drug elimination. Drugs


eliminated unchanged include;

1. Many antibiotics (most penicillins, cephalosporins such as


cephradin & cephalexin, aminoglycosides such as gentamycin
/ neomycin / apramycin, & oxytetracycline).
2. Most diuretics (excluding ethacrynic acid).
3. Neuromuscular blockers (d-tubocurarine & gallamine).
Metabolites are usually cleared more rapidly than the parent
compounds. 3 renal processes are involved;

I- Glomerular filteration;

 Glomerular capillaries allow drugs of molecular wt < 20 000 to pass


into the filterate.
 Plasma protein-bound drugs are completely held back.
II- Tubular secretion & re-absorption;

 80 % of the renal blood flow is delivered at the tubules.


 2 independent & rather non-selective carrier systems deliver drugs to
tubular lumen; one for acidic drugs e.g. acetyl salicylic acid,
furosemide, acetazolamide, thiazides, penicillins & probenecid, & the
other for organic bases e.g. narcotic analgesics such as morphine &
pethidine, amines such as 5HT, histamine & dopamine, & quinine.
 Carriers can transport drugs against electro-chemical gradient reducing
plasma levels to zero.
 Secretion is not influenced by P.P.B. e.g. penicillin ( 80% protein-
bound ) is completely removed via proximal-tubular secretion ,
cloxacillin ( 80% ppb ) & ampicillin ( 20% ppb ) have the same
plasma t1/2e . This indicates the dissociation of the drug-albumin
complex after the removal of the free spp.

30
 Competition occurs between drugs sharing the transporter e.g.
penicillin & probenecid (ceftiofur)R
III- Diffusion across the renal tubule

 pH & pKa dependant.


 Drug in the filterate & plasma equiliberates.
 Highly lipid-soluble drugs are passively re-absorbed & slowly cleared.
 Highly polar drugs e.g. digoxin & aminoglycosides achieve urine levels
100 folds times that of plasma.
 Alkalinization of urine can overcome overdose of acidic drugs.
Biliary excretion

 Hepatocytes transfer substances, including drugs, from plasma to bile.


 Enterohepatic circulation creates a reservoir wherein 20% of the total
drug recycles e.g. morphine & ethinylestradiol. De-acetylated
rifampicin & intact vecuronium are excreted in feces.
Excretion by other routes

 pH- determined simple- diffusion of non- ionized spp. into saliva, sweat
& tears, attaining levels parallel to plasma.
 The better part of alkaline drugs is partitioned to milk being more
acidic relative to plasma. Non-electrolytes such as ethanol & urea
equiliberate.
 Sensitive methods for detection of toxic metals in hair & skin have
forensic significance.
Iatrogenesis

Adverse drug reaction (ADR)

It is unintended harm by drug used, at normal dose, in prevention or


therapy of disease. It may;

1. Require discontinuation of therapy.


2. Require treatment change, dose modification or supportive therapy.
3. Necessitate or prolong hospitalization.
4. Negatively affect prognosis.
5. Induce temporary or permanent disability or death.
6. Withdrawal, abuse, accidental poisoning & overdose complications
are excluded from ADR.

31
Side effect

Are defined as known, expected reactions resulting in little or no change


in patient management e.g. nausea due to neoplastic medication or sedation
due to antihistamines. The frequency is predictable, intensity is related dose
size.

Classification of ADR

1. Lack of efficacy; provided that the drug is given at the proper dose,
route, interval & duration to treat a condition for which efficacy had,
previously, been instituted.
2. Allergy ;
 Cannot be anticipated.
 Are not dose dependant.
 Clinical presentation ranges from mild rash to anaphylaxis.
 Mechanism, usually, involves a drug or its metabolite(s)
forming covalent bonds with an endogenous substance
resulting in an antigen.
 Cross-reactivity may develop i.e. a subject allergic to a drug
develops similar reactions to drugs belonging to the same
formulation. 100% of humans allergic to penicillin are equally
allergic to other penicillins, 20% react to cephalosporins.
3. Semi-allergy ;
 Similar clinical presentation.
 Underlying mechanism is not immunologic.
 Haematologic reactions similar to autoimmune haemolytic
anaemia e.g. following I/v dimethyl sulfoxide (conc.> 20%).
 Cardio-pulmonary reactions e.g. following I/v drugs dissolved
in polyethylene glycol vehicle.
 Hyperpyrexia (drug fever) e.g. aspirin (due to uncoupling of
oxidative -phosphorylation).
4. Organ damage ;
 Complex mechanisms.
 Not related to drug pharmacodynamics.
 Aminoglycoside & tetracycline nephro-toxicity is not
explained by the binding of these antibiotics to bacterial
ribosomal subunits & inhibition of protein synthesis.

32
 Acetaminophen reactive metabolites causing hepatotoxicity
not related to the analgesic antipyretic actions of the drug.
5. Idiosyncratic (individual);

 Not described by 1— 4.
 Not dose dependant.
 Often genetically determined.
Characteristics of ADR;

 Diagnosis of certain ADR s is challenging especially when resembling


conditions they are supposed to treat e.g. drug fever associated with
aspirin, however, there often is a temporal definable relationship
between administration & the offset of manifestation.
 Manifestations improve with discontinuing therapy.
 ADR initially present as a mild rash may, on subsequent use, result in a
severe fatal reaction.

Drug- drug Interactions

Is the change in magnitude of pharmacological effect of a drug by


some other factor including drugs, drug vehicles, food, nutrients,
plastic components of syringes or I/v infusion sets & environmental
chemicals.

Invetro; due to mixing in the same syringe or vial of incompatible


drugs or their solvents resulting in hydrolysis, oxidation, reduction,
complexation, acid- base reactions ( pH ) & precipitation exemplified
by the following pairs ;

 Adrenaline + Na-bicarbonate.
 Gentamycin + Carpenecillin.
 Ketamine + Barbiturates.
 Methylpredinsolone Na-succinate + Ca-gluconate.
In-vivo; I- Pharmacodynamic interactions;

 Enhanced or reduced effects.


 Expression of new or different effects.

33
II- Pharmacokinetic interactions;

Of more common occurrence, clinical presentations may not be


apparent.

1- Cimetidine & other H2 receptor blockers alter gastric pH


affecting absorption of co-administered medications thro gastric
mucosa.
2- Metclopramide (+) , anticholinergic agents (-) &
sympathomimetic agents alter gastric emptying & delivery of
drugs to intestine for absorption.
3- Competition between drugs for plasma protein binding alters
distribution & transiently increase free drug concentration.
4- Induction (takes time to subside).
5- Inhibition (subsides immediately after withdrawal).
6- Alteration of cardiac output or hepatic blood flow e.g.
propranolol.
7- Alteration of renal haemodynamics & blood flow (GFR).
8- Competition at tubular level between drugs sharing the same
transporter.
9- Re-absorption of a drug can be modified by a drug that changes
urine pH or blood flow.
10- Synergism occurs when the effect of interaction exceeds the
additive effects that might likely be predicted from the
concurrent administration e.g. penicillin + aminoglycosides such
as gentamycin, neomycin or apramycin or therapy with a
potentiated sulfonamide.
11- A documented or a potential interaction is rarely a contra-
indication for the concurrent co-administration of medications.
It is yet another component of risk assessment in therapeutic
decision.
Drug- food interactions

Definitions

An interaction resulting from a physical, chemical, physiologic or


pathophysiologic relationship between a drug and a nutrient, multiple
nutrients, food in general or a nutritional status, and is considered clinically

34
significant if alters therapeutic response or compromises nutritional status
thereby influences health outcomes particularly in vulnerable populations.

Factors affecting drug- food interactions

1. Multiple medications.
2. Extremes of age.
3. Genetic variants in drug transporters, enzymes or receptors.
4. Impaired organ function.
5. Poor nutritional status defined as altered body composition or function
due to any imbalance between an individual`s nutrient requirements
and intake, where due to poor dietary intake or altered nutrient
disposition.

Historic perspectives

Effect of On
Vitamin C deficiency Barbiturates action
Iron Tetracycline absorption
Isonaizid Vitamin B6 metabolism
Malnutrition Drug disposition
Drugs Nutrient disposition

Classification of drug- food interactions

Precipitation factor Object of interaction Potential consequence


Nutritional status Drug Treatment failure or
Food or food Drug drug toxicity
component
Specific nutrient or a Drug
dietary supplement
ingredient
Drug Nutritional status Altered nutritional
Drug Specific nutrient status

Location and mechanisms of drug- food interactions

35
Site of interaction Consequence Mechanism
Delivery device or GI- Reduced bioavailability Physicochemical
lumen reaction and
inactivation
GI- mucosa Altered bioavailability Altered transporter
and/ or enzyme
function
Systemic circulation or Altered distribution/ Altered transporter,
tissues effect enzyme function or
other physiologic
function
Organs of excretion Altered clearance Antagonism,
impairment or
modulation of
elemination

Nutritional status effects on drug disposition

1. Impact of PCM on medication

Drug disposition is negatively impacted function to the altered composition


and function of the body. In severe PCM drug absorption may be reduced,
protein carriers limited, and metabolism slowed resulting in high free drug
concentrations and potential toxicity.

 Absorption is particularly affected in children with severe PCM,


alcoholic adults, and if there is deficiency of Zn or vit D and
secondarily generalized malabsorption.
 Distribution of drugs is especially altered in kwashiorkor wherein
extracellular fluid accumulation and low serum albumin are
exacerbated by the liver`s inflammatory response to infection, fluid
shifts and edema also impact drug levels in tissues.
 Metabolism is consistently reduced.
 Renal drug clearance may be affected only in comorbidities or in
elderly stressed critical care patients.

36
2. Drug effects in PCM

Therapeutic effectiveness of a drug may be reduced or risk of toxicity


increased. Drugs with narrow therapeutic index can produce toxicity at
normal dose if bioavailability is increased due to impaired hepatic function, if
a given drug toxicity is due to its metabolites it will actually be reduced.

Salicylate Ototoxicity and nephrotoxicity enhanced by Mg and Zn


deficiency
Ketamine Prolonged duration
Phenytoin ↓metabolism and clearance
Gentamicin Ototoxicity and nephrotoxicity enhanced by Mg and Zn
deficiency
Chloramphinicol Limited carriers, greater renal than hepatic clearance
Clarithromycin Higher circulating level, normalized by administration
of cysteine
Itraconazole Higher circulating level, normalized by administration
of cysteine
Isoniazid Transaminitis and proliferation of RER in liver tissue
Cancer chemoth. Poor toleration and prognosis
Immunosupressants A larger loading dose is needed

3. Influence of overweight and obesity on medication

Definitions

Obesity is a chronic disorder with a complex pathophysiology involving


genetic and environmental factors, which impact the balance between energy
intake and expenditure and manifest as excess body fat. It is associated with
significant risk of morbidity and mortality, increased costs of health-care and
reduced quality of life.

The body mass index BMI is an expression of an individual`s weight relative


to their height in kilograms per meter squared (kg/ m2).

Term BMI ≥
2
Overweight 25 kg/ m

37
Obesity 30 kg/ m2
Morbid obesity 40 kg/ m2
 BMI in combination with waist circumference are closely linked to
health risks of overweight.
 BMI- for- age growth curves in children 5- 19 yr defines overweight
between the 85th - 95th percentiles, and obesity as ≥ the 95th percentile.
 Non- obese middle aged adults have a fat mass of about 20 kg
corresponding to about 25% of TBW in men and 33% in women.
 Obese individuals have a larger lean body mass accounting for 20-
40% of the excess weight, the rest 60- 80% is adipose tissue.
 Obese individuals have higher absolute body water.

Assessing body weight for drug dosing

The term dosing weight refers an actual TBW or an alternative body weight
considered for dosing in volume- overloaded, or obese patient, it is affected by
the following factors:

1. Substance being evaluated for dosing and how it is differently handled


in obesity.
2. Age, gender and ethnicity.
3. Weight and height.

Body Equation for men Equation for women


weight
term
Ideal 52 kg + 1.9 kg/ in › 5 ft 49 kg + 1.7 kg/ in › 5 ft

Optimum 48.2 kg + 2.7 kg/ in › 5 ft 45.5 kg + 2.3 kg/ in › 5 ft

Lean 50 kg + 2.3 kg/ in › 5 ft 45.5 kg + 2.3 kg/ in › 5 ft

Predicted (1.57)(kg) –(0.0183)(BMI)(kg) (1.75)(kg) –(0.0242)(BMI)(kg)


normal
Cell mass (kg) {79.5 –(0.24)(kg) – (kg) {69.8 –(0.26)(kg) –
(0.15)(yr)} 73.2 (0.12)(yr)} 73.2
Lean mass (1.1013)(kg) – (1.07)(kg) –(0.0148)(BMI)(kg)

38
(0.01281)(BMI)(kg)

 The Optimum body weight equation was described for use in


determining approximate caloric requirements in diabetic patients.
 The Lean body weight equation was described for use in determining
critical creatinine clearance and drug dosing.
 The Predicted normal weight depends on the BMI which is more
practical as an external measure of obesity.
 The Body Cell mass is more a measure of body composition which is
more accurate for the purpose of drug dosing, age and gender
influence metabolic rate, lean tissue and thereafter body composition.
 The Lean body mass is used as the reference standard best predictor of
dosage.

Effects on drug disposition kinetics

 Oral absorption is not affected in obesity (e.g. cyclosporine,


dexfenfluramine, midazolam, penicillin, propranolol). Transdermal or
subcutaneous absorption is not well characterized. Depending on
needle length and local fat depot intramuscular injection in most
cases may be characterized as intralipomatous, which also is not well
characterized.
 There are increases in blood volume, cardiac output, and organ mass
which affect drug distribution.
 Albumin level is not altered (phenytoin, thiopentone) while α1- acid
glycoprotein is increased (↓propranolol, ↕triazolam and verapamil).
There may be increased binding of fatty acids to albumin potentially
altering drug binding sites.
 Excretion is affected by increased heart output, fatty liver infiltration,
portal inflammation and fibrosis, and increased renal clearance.
Metabolism associated genes may be differentially expressed in obese
individuals, CYP2E1 activity increases in liver and adipose tissue.
Adipose tissue itself is metabolically active, activity varies between

39
adipose tissue compartments (i.e. omental, S/c) thereby affected by
obesity phenotype.
 Hepatic 1st pass extraction is not affected, drugs that undergo
oxidation and conjugation (glucuronide and sulfate) may have
increased clearance in obesity (e.g. lorazepam, oxazepam).
 Renal clearance can be increased due to increased GFR (e.g.
aminoglycosides, cefamandole, cefotaxime, ciprofloxacin, lithium,
procainamide), or tubular secretion (e.g. cimitidine, ciprofloxacin,
procainamide), or decreased reabsorption (e.g. lithium).
 Taking pharmacokinetic alterations into account, even if a drug is
delivered to loci of action in appropriate concentration the
therapeutic response is other than expected. This occurs due to
alterations in tissue sensitivity at target organ or downstream.
 There is increased sensitivity to e.g. (glipizide, glyburide,(atracurium,
verapamil). Receptor expression or affinity may be altered, the drug
effect may be more pronounced including toxicity.

Drug administration with food

 Most drugs are oral.


 Timing of administration with food is convenient to patients and
nursing staff.
 Some drugs are irritating to GIT, serving with food diminish this
effect.
 For some drugs administration with food can alter absorption, or
therapeutic effects i.e. pharmacokinetic or pharmacokinetic
interaction.

Factors affecting interaction due to co- administration

1. Drug properties: especially for drugs whose absorption is solubility-


limited.
2. Dosage form properties e.g. modified release dosage forms.
3. Meal volume.

40
4. Caloric load of the meal: as they increase feed-back signals from
intestine delay stomach emptying rate.
5. Meal type.
6. Meal viscosity.
7. Meal effect on GI pH.
8. Meal calcium content as the stomach regulates the rate of Ca delivery
to intestine, and the intestine regulates the stomach delivery of Ca-
chelators through feed-back mechanisms.
9. Drug binding to meal and biliary components.
10. Meal effects on first-pass elimination.
11. Permeability limitations due to intestinal efflux
12. Meal effects on region-dependant absorption.
13. Meal effects on splanchnic blood flow.

Drugs NOT to be taken with food (on an empty stomach)

Azithromycin ↓absorption
Bisphosphonates ↓absorption specially dairy product
Dextroamphetamine ↓absorption specially acidic food
Digoxin Delayed absorption and peak levels
Diltiazem absorption↑ with fasting
Furosemide absorption↑ with fasting
Glipizide ↑ effect 30 minutes before meal
Levothyroxine absorption↑ with fasting
Metroindazole Food ↓ peak
Phenytoin ↓absorption
Proton pump inhibitors Before meals↑ effect
Quinolones Cations (Ca, Fe, Zn), antacids and
dairy products ↓absorption
Tetracyclines ↓absorption Fe/milk/food
Theophylline ↓absorption
Warfarin ↓absorption
Zafirlukast Food ↓absorption by 40%
Zolpidem Food delay onset of action

41
Drugs to be taken with food

Amoxicilin/clavulanate absorption↑, GI upset↓


(Augmentin)
Carbamazepine absorption↑
Carvedilol ↓ risk of orthostatic hypotention
Divalproex GI upset↓
Fenofibrate ↑bioavailability
Prednisolone GI upset↓
Metformin GI upset↓
Labetalol absorption↑
Metoprolol absorption↑
Niacin GI upset↓
Nitrofurantoin ↓tolerance ↑bioavailability
NSAIDs GI upset↓
KCl GI upset↓
Tamsulosin Bioavailability, 30 mints bef. Meals
Trazodone absorption↑ by 20 %
Venlafaxine GI upset↓

Drug induced changes to nutritional status

1. Drugs associated with weight gain


Psychotropics, antidiabetics, corticosteroids, oestrogen, OCP, alcohol,
β- blockers, and cyproheptadine.
2. Drugs associated with weight loss
 Are predominantly CNS stimulants including amphetamine,
armodafinil, caffeine, dextramphetamine, doxapram,
ergotamine, lisdexamphetamine, methamphetamine,
methylphenidate, modafinil, and theophylline.
 Others include SSRI, fenfluramine and dexfenfluramine has
been manufactured for the sole purpose of weight loss.
Anticonvulsants as lamotrigine and topiramate reduce body
weight.

42
 Anorexic drugs include antihistamines, bethionol, dacarbazine,
epirubicin, etoposide, fluvoxamine, perhhixiline, pimozide,
sibutramine, temozolamide, trazodone, and zonisamide.
 Caffeine causes greater thermogensis, lipolysis, fat oxidation and
insulin secretion in obese individuals.
 Alcohol and nicotine intake are associated with weight loss.
3. Drug- associated alteration of GI function
 Altered taste perception.
 Drug- induced emesis.
 Drug- induced motility changes↕
4. Drug- induced metabolic effects
 Hyo- or hyperglycaemia.
 Lipid changes.
 Protein changes.
5. Drug- induced nutrient depletion
 Mineral/ electrolyte disturbances.
 Vitamin deficiencies.

Therapeutic drug monitoring


Drug therapy in special patient populations

(A) During pregnancy;

Relatively few drugs have specifically demonstrated safety during


pregnancy.

Physiologic changes Pharmacokinetic process affected

1- Increased gastric pH Absorption

2- Decreased GI motility Dissolution & absorption

3- Decreased ppb Risk of toxicity

4- Increased cardiac output Elimination

43
5- Progesterone-mediated liver Elimination
induction

Factors affecting placental transfer of drugs;

1. Dose.
2. Frequency of dosing.
3. Vd.
4. PPb.
5. Clearance.
6. Placental blood flow.
7. Rate of diffusion across the plancenta ; determined by
the following ;
 Conc. differences between maternal & foetal
circulation.
 Surface area for diffusion.
 Lipid solubility.
 pH ; maternal fluids are relatively slightly more
alkaline than foetal fluids , basic drugs e.g.
atropine, adrenaline, propranolol, quinidine,
erythromycin & trimethoprim tend to
concentrate in fetal plasma & acidic drugs e.g.
penicillin, aspirin, furosemide & phenobarbitone
diffuse slowly across the placenta.
Potential effects due to foetal exposure to drugs

1. Teratogenic effects.
2. Failure of implantation & early termination of pregnancy.
3. Mutagenesis & growth retardation.
4. Later in pregnancy the foetus may show manifestations of the
pharmacodynamics of the drug.

(B) Neonatal & pediatric patients

Physiologic difference from adult Effect

44
1- Immature percutaneous barrier ↑ Percutaneous absorption

2- Variable gastric emptying rates Irregular oral drug absorption

-irregular peristalsis

- increased mucosal permeability

3- Greater body water particularly Larger Vd


extracellular fluid

4- Lower plasma albumin Decreased plasma p. binding

5- Incomplete bbb immediately Greater CNS distribution


postpartum

6-Lower adipose tissue ↓ Vd for lipid soluble drugs

7- Immature liver metabolism ↓ metabolism

8- limited GFR for a few days ↓ renal excretion


p.partum

9- Tubular secretion develops 3~ 4 ↓ tubular secretion


wks p.p.

 Applying dosage regimens designed for adults leads to accumulation


toxicity due to difference in disposition kinetics.
 Following drugs are unsafe & contra-indicated in neonates
tetracyclines, sulfonamides & floroquinolones e.g. di, orbi, marbo,
enro & ciprofloxacin.

(C) Geriatric patients

Aging results in physiologic changes that potentially alter drug disposition


& may lead to enhanced or toxic effects.

Physiologic change Result

45
1) Increased gastric pH Alteration of ionization

2) Prolonged gastric emptying Delay of absorption

3) Weakened peristalsis Delay of dissolution

4) Atrophy of macro- & micro-villi Decreased rate, not extent ,of


absorption

5) More adipose tissue Larger Vd of lipid soluble drugs

6) Less body water Smaller Vd of water soluble drugs

7) Less plasma albumin Less plasma protein binding

8) Reduced hepatic blood flow Reduced biotransformation

9) Reduced renal functional mass & Reduced rate of elimination


flow

(D) Patients with liver failure

1. Although the content & activity of both phase I & II enzymes is


decreased, hepatic metabolism of drugs is not overwhelmed until
extreme loss of > 80 % of hepatic function has occurred.
2. Many drugs of common use are well-tolerated in patients with liver
failure. β-lactam antibiotics such as penicillin & cephalosporins are
safe.
3. Lincosamides (clindamycin & lincomycin), macrolides (azithromycin,
clarithromycin & tylosin), sulfonamides & chloramphinicol should be
avoided.
4. Prednisone & cortisone are better avoided, they require the hepatic
reduction of a keto group. Prednisolone & hydrocortisone are suitable
alternatives.
5. Glucocorticoids are generally avoided.

(E) Patients of renal failure

46
1. Diminished clearance.
2. Diminished hepatic biotransformation & plasma protein binding due
to uremia.
3. Drugs requiring renal elimination & nephro-toxic drugs are contra-
indicated e.g. aminoglycosides.
Prescription order writing

 A desire to take medicine is, perhaps, a great feature which


distinguishes people from other animals.
 The Code of Hammurabi described penalties for malpractice by
practitioners.
 The oldest record of Egyptian drug codification is the Kahun papyrus
written about 2000 BC. It deals with veterinary medicine & uterine
disease of women.
 The Ebers papyrus (1550 BC) is a compilation of a No. of disease
conditions & 829 prescriptions for medicaments employed in Egyptian
medicine.
 The foremost Greek physician Hippocrates (460-375 BC) had little use
for drugs after recognizing that sick people usually tended to get well
regardless of treatment. This concept of the healing power of nature
became known as The Vis Medicatrix Naturae .
 A precept from the Hippocratic school which still provides an ethical
basis for the practice of therapeutics is “ Above all, do not harm”.
 Works of Galen (131-201) dealing with physiology & materia medica were
authoritative for the next 1400 years & consist of preparations of plants
by soaking or boiling & classification of medicinal plants.
 Muslims distilled wines & beers to obtain ethanol for preparing
tinctures. Geber Ibn Hajar (702-765) classified drugs & poisons of his
time & recognized that “The difference between a drug & a poison was a
matter of dosage. Any drug can be toxic if given in large enough amounts”.

Proficiency at writing a prescription order accurately & speedily requires


practice. The order should be written legibly. It is convenient & the accepted
form to have one`s name, address, telephone No., office hours & registration
No. printed on the order blank. Orders should be written in ink & a doctor

47
should keep a copy for the files, this protects the physician & serves to
complete the record of treatment.

Choice of drug name

 Use the official name.


 Use the official name followed by the manufacturer`s name between
parenthesis if the product has distinct advantages. Some pts exhibit
dramatic changes in response when switched from one product to
another on subsequent refills, this is of particular concern in drugs with
low therapeutic indices e.g. anti-epileptic drugs.
 Write “dispense as written” or verbally communicate the
pharmacist if need be.
Choice of a system of wts & measures

 Always write in the metric system.


 Designate the amount of drugs by numbers & indicate the desired
metric wt or volume.
Construction of the prescription order

1. Date.

2. Name, age, sex of patient.

Address of patient.

3. Rx

4. Ampicillin Oral suspension 250mg/5ml.

5. Dispense 200 ml (with oral syringe).

6. Label: Take 5ml orally at 8AM; 12noon, 4PM; &8PM


daily for 10days for infection. Ampicillin 250mg/5ml,
200ml.

7. Do not refill.

8. Signature.

48
 Rx is abbreviation for recipe the Latin for “Take thou”.
 (4) drug, strength & inert additives, (5) directions to the pharmacist, (6)
directions to the patient, (7) refill informations.
1. The physician, & or pharmacist, should demonstrate how the drug is
used.
2. Expressions such as “Take as desired” or “Take as
necessary” or “Take every 8hrs” should be avoided (i.e.
specify).
3. To avoid possible error, the 1st word of the directions to the pt. should
serve as a reminder of the correct route of administration; Take for
internal use; Apply for ointment or lotion; Insert for
suppositories; & Place for drops of the conjunctival sac, external
auditory canal or nostril.
4. The directions to the pt should also include a reminder of the
intended purpose of the prescription e.g. “for relief of pain”,
“for relief of headache” or “to relief itching”.
5. If it is desirable to administer a drug in a larger amount than is
customarily employed, underline the dose or write ”Correct
amount” or “Correct dose” with your initials at the side.
6. Indicate the No. of refills on each original prescription order,
irrespective of whether the substance is controlled or not.
7. Dosage should include the no. of days for which medication is
contemplated, no. of doses per day & size of each dose.
8. The max. limit is indicated for most prescriptions depending on
stability & cost of the drug & the possible necessity for alternation of
the ttt.
9. If the pt is depressed or potentially suicidal do not prescribe total
amounts of drug that would prove lethal if taken all at one time.
10. Storage of unused portions of a prescription & sharing of prescriptions
with others should be discussed with any pt who receives an important
medication.
11. Usual dose is intended to serve only as a guide to the physician who
very frequently must give more or less than what is usual in order to
optimize therapy.

49
Abbreviations commonly used in prescribing

Abbreviation Latin Meaning

ad. lib. ad libitum Freely as wanted

aa ana Of each

A ante Before

a.c. anti cibum Before meals

aq. aqua Water

b.i.d.(BID) bis in die Twice a day

Cap. capula Capsule

C cum With

dos. dosis A dose

eq.pts equalis partis Equal parts

gtt gutta A drop

H hora Hour

M. misce Mix

n.r. non repetatur Not to be repeated

o.d. omne die Everyday

p.c. post cibum After meals

p.r.n. pro re nata As occasion requires

50
q.i.d.(QID) quarter in die 4 times a day

s.i.d.(SID) semel in die Once a day

Sig.S. Signa Write on the label

S.O.S. Si opus sit If necessary

Sol. solutio Solution

Stat. statim Immediately

Tab. tabella a tablet

t.i.d. ter in die 3 times a day

Chapter 2

Tissue-hormones & naturally-occurring substances

I. Amines; histamine & serotonin.


II. Peptides; kinins, angiotensin, substance P, prostaglandins,
adenosine, SRSA & vasopressin.
III. Oxytocic drugs ; drugs that stimulate uterine motility; ergot
& ergot-alkaloids, & oxytocin.

Histamine (2- 4-imidazolyl ethylamine)

It is synthesized from histidine by histidine-decarboxylase. The


enzyme is present in mast cells. Histamine is complexed with heparin &
stored in granules in mast cells & basophils, it also is formed in GIT by
bacterial action.

Absorption is restricted by;

1) Presence in the GIT wall of an enzyme which oxidizes &


methylates histamine.

51
2) Inactivation in the liver & kidney by histaminase &
imidazole-N-methyl transferase.
3) Acetylation of histamine occurs in the GIT lumen & tissues
after absorption.
Release;

1) In the GIT immediately following synthesis.


2) In the skin following physical injury from disrupted mast
cells.
3) Following the complication of antigen-antibody on the cell
surface, this may involve activation of phospholipase-A & so
increases membrane permeability.
4) Exocytosis; an active process requiring Ca2+ that contribute
to release of histamine induced by certain drugs like
morphine, curare, 5HT & tetracyclines, & snake &
scorpion venoms .β-adrenoceptor agonists & Ca-chelating
agents inhibit mast cell secretion.
Actions & effects;

 Histamine acts on H1, H2 & H3.


 2-methylhistamine acts preferentially on H1.
 4-methylhistamine & impromidine act preferentially on H2.
 The activation of these receptors bring-about the following ;
1) Contraction of smooth muscles of bronchi , gut , large blood
vessels & adrenal medulla leading to secretion of
catecholamines.
2) Relaxation of small arterioles to the extent that peripheral
vascular resistance and blood pressure falls.
3) Increased capillary permeability.
4) Stimulation of gastric acid secretion & other exocrine glands.
5) Stimulate sensory nerve endings evoking the classic symptoms
of urticaria; itch & pain, & the triple -response; flush-flare
wheal.
6) Large doses; blood pressure falls accompanied by
haemoconcentration due to plasma extravasation (histaminic
shock)
7) H3 receptors are believed to be linked to inhibition of adenylyl
cyclase via an inhibitory G-protein.
Clinical manifestations;

52
1- Salivation.
2- Vomiting.
3- Colic.
4- Diarrhea.
5- Rapid weak pulse.
Clinical use;

1) Diagnosis of achlorhydria & pheochromocytoma.


2) Triple response evaluation of integrity of innervation &
circulation.
3) Desensitization of allergic patients by repeated injection.
The effects of histamine can be antagonized by;

A) Adrenalin ‘physiological antagonism’.


B) MAO ‘distructive non-competative antagonism’
C) Classical antihistamines ‘pharmacological antagonism’
 Diphenhydramine HCl (BenadrylR), anti-motion sickness, marked
sedation.
 Pyrilamine maleate (HistosolR), prominent sedation.
 Chlorpheniramine maleate (TeldrinR), moderate sedation.
 Dimenhydrinate (DramamineR), antimotion sickness, prominent
sedation.
 Promethazine (PhenerganR), long acting, anti-motion sickness, marked
sedation.
 Clemastine (TavistR), few side effects.
 Terfenadine (SeldaneR), non sedative.
 Astemizole (HistmanalR), non sedative.
 Amitriptyline (ElvaR), tricyclic.
H1-antihistamines also bock other receptors including muscarinic &
dopamine receptors.

Clinical use

1)Symptomatic relief of allergies, e.g. chlorpheniramine & clemastine.


2)Anti-emetic e.g. meclizine & dimenhydrinate.
3)Over the counter hypnotics e.g. diphenhydramine.
4)Promethazine represents the transition to the neuroleptic
phenothiazines.
 Burimamide, H2 antagonist, too poor oral absorption.

53
 Metiamide, H2 antagonist, agranulocytosis.
 Cimetidine, ranitidine, famotidine & nizatidine, H2 antagonists in
common use.
Clinical use

Inhibit gastric acid secretion, used in peptic ulcer.

Side effects

1- Sedation, drowsiness & ataxia.


2- Irritability, convulsions & hyperpyrexia.
3- Nausea, vomiting, constipation & diarrhea (orally).
4- Anticholinergic effect; dry mouth, pupil-dilation, blurred vision
& tachycardia.
5- Local anaesthetic & allergenic (topical antipruritic use).
6- Terratogenic effects.

5HT (serotonin; vasotonin; or enteramine)

Is the decarboxylation product of 5-hydroxytryptophan (5HTP) which is


synthetized from tryptophan by tryptophan 5-hydroxylase.

De-activation

1- Oxidative-deamination by MAO yielding 5-hydroxyindolacetic acid


(5HIAA) which is secreted in urine & feces.
2- N-acetylation & 5-methylation in the pineal gland to melatonin hrn
used in the female reproductive cycle.
Actions

1) Released from mast cells during anaphylaxis, contract vascular smooth


muscles particularly venous system.
2) Contraction of the uterus, intestine & bronchioles.
3) Reflex slowing of heart & regulation of gut motility.

Agonists at 5HT receptors

1) Sumatriptan & other triptans; ttt of migrane.


2) Cisapride; prokinetic.

54
3) Fluoxetine blocks reuptake of released serotinine; antidepressant,
anxiolytic, psychomotor stimulant & appetite depressant.
4) Buspirone; anxiolytic.
Antagonists

1) Morphine, atropine, & cocaine in GIT.


2) Dihydroergotamine & phenoxybenzamine in smooth muscles during
anaphylaxis.
3) Lysergic acid diethyl amide (LSD) which is a hallucinogen used in
psychotherapy.
4) Cyproheptadine blocks 5HT, histamine & prostaglandins.
5) Reserpine depleates 5HT in the brain.
6) Ondansetron hi effective against cytotoxic-drugs induced emesis.
7) Ketanserin; antihypertensive.
2) Peptides ;

Kinins

 Kallikreinogens of blood or urine are activated by Ag/Ab-reaction or


trypsin to kallikreins which are serine protease enzymes.
 Kallikreins catalyse the conversion of bradykininogens to
bradykinins.
 Inactivated by bradykinin kinase.
Actions

1) Active vasodilator; lower BP & increase capillary permeability.


2) Contraction of uterus, intestine & bronchi.
3) Release of adrenaline.
4) Kallidin lysyl bradykinin is an isomer of bradykinin released by
salivary, sweat glands & kidney & can be converted to bradykinin.
5) All are important algesic & inflammatory initiators.
Angiotensin

1. Renin is released in response to β-activation of renal sympathetic


nerves.
2. It converts angiotensinogen to angiotensin-I.
3. Angiotensin-I is converted by ACE in the lining of blood vessels to
angiotensin-II.
4. Angiotensinases inactivate this to angiotensin-III.

55
Actions

1) Angiotensin-II is a very active vasoconstrictor. Its release is followed by


a rise in BP, release of adrenaline, stimulation of ganglia & contraction
of smooth muscles.
2) Maintains adequate renal blood flow & stimulates aldesterone
secretion leading to Na-retention & increased plasma volume.
3) The rennin-angiotensin-aldosterone mechanism is involved in the
aetiology of chronic hypertension.
Antagonists

1) Saralasin is used in management of angiotensin hypertension.


2) Captopril & enalapril (ACE-inhibitors) are used to relief
vasoconstriction & lessen fluid retention in patients of CHF.
Substance-P

Its actions are similar to bradykinins but more rapid onset. It maintains
peristalsis. Has a neurotransmitter action in CNS.

Prostaglandins

 40 PGs belonging to 4 groups are synthetised in tissues from PUFA


such as arachidonic & linolenic acids by PG-synthases.
 Some cause contraction & others are relaxants.
 PGE & PGF are the most plentiful with very short T1/2e by rapid
conversion to the 15-keto half-amine derivatives by the
dehydrogenase particularly abundant in the lungs.
 Act at specific receptors permeating Ca into cell increasing cAMP
leading to stimulant response.
Actions

1- Affect all organs e.g. platelet aggregation, initiation of thrombosis,


endothelial cells contain PGI2 (prostacycline) a powerful aggregator &
vasodilator.
2- Inflammation PGE & PGA are more potent vasodilators than
histamine increasing permeability & clotting.
3- PGF2α, a powerful broncho-constrictor during allergy, constricts veins,
pulmonary vasculature & ovarian arteries. It also contracts uterus
which relaxes to PGE.

56
4- Inhibit gastric acid secretion due to histamine.
5- Reproduction; PGF2α stimulates sperm transport in female genital
tract; regulates cycle by producing leutolysin; diffuses from uterus to
uterine artery, vein, ovarian artery, ovary & corpus leutium causing
leutolysis; increases uterine contractility at term wherein relaxin causes
relaxations; contracts the amblical vein & causes vasoconstriction
postpartum.
Clinical use

1) The leutolytic action of PGs e.g. the synthetic PGF2α, cleprestenol, can
be used to induce abortion & institute a new cycle.
2) Treatment of pyometra.
Contra-indications

1) Pregnancy (even skin-contact).


2) I/v administration (cardiovascular effects).
Antagonists

1) Interference with synthesis by interfering with PG-synthetase; ASA,


phenylbutazone, meclofenamic acid, & indomethacin (given for pain
of the back).
2) Inhibition of action; cyproheptadine.

Adenosine

 Is released as AMP, ADP & ATP by adrenal medulla &


adrenergic nerves together with adrenaline.
 ATP has been proposed as a NT of the purinergic nervous
system in GIT. It induces relaxation of gut smooth muscles.
SRSA

Belong to the group of fatty acids produced in the lungs during anaphylaxis
associated with leukotrienes.

Vassopressin (ADH)

57
A hypothalamic polypeptide transported & stored in the posterior pituitary
bound to the neurophysins. It is released due to electrical discharge, Ach,
dehydration, haemorrhage, emotional or physical stress & alcohol.

Actions

1) Physiological increase of distal tubule permeability.


2) Control of tonicity.
3) Deficiency causes diabetes inspidus & rise of BP.
4) The signal for ADH release originates in osmoreceotors in the brain
in reaction to blood composition.
5) Involved in memory & learning together with dopamine.

Oxytocic drugs; uterotonic or abortifacient drugs;

Are drugs that stimulate uterine motility.

1) Ergot & ergot alkaloids (Claviceps purperea);

A series of optically-active isomers;

 The L-form designated by (-ine) is active & occurs naturally in alkaloids.


 The D-form designated by (-inine) is completely inactive & results from
chemical manipulation.
 The substance isolated from ergot is a mixture called ergotoxine
consisting of 2 pure substances; ergotamine & ergotaminine.
Class of compound Vasoconstriction Oxytocic Adrenergic
activity blockade

1) Natural A. Acids High activity, - Highly active. Active.


specially
(alkaloids) - Delayed onset.
ergotamine

2) Dehydrogenated Much-less than Active only on More active


the parent pregnant uterus than parent.
Alkaloids
alkaloid
(dehydroergotamine)

3) Amine alkaloids Slightly active - High activity. Inactive.

58
(methysergide) - Rapid onset.

(methylergomethrine) - Effective
orally.

2) Oxytocin

Like ADH a hypothalamic nanopeptide, complexed with neurophysins-I &


-II, migrates & stored in posterior pituitary, released by afferent nerve
impulses originating in the dilating uterine surface & vagina.

Actions;

 Powerful uterine contractions at term completing stage-II of labor.


 The responsiveness of myometrium to oxytocin is dependant on
the simultaneous level of the female sex steroids being high when
oestrogen dominates & low under progesterone.
 These steroids exert this effect by controlling the polarization of
smooth muscle cell membrane & oxytocin-receptors.
 Oxytocin also is released in milk led down by nursing & during
sexual intercourse.
 By affecting coronary circulation it may be the cause of sudden
death during parturition.
Clinical use

1) Aids the expulsion of foetus in a dilated cervix


(contraindicated against a closed cervix).
2) Aids the expulsion of placenta.
3) Aids uterine involution & controls uterine bleeding.
Mechanism of action

1) Releases Ca-ions which are very important for depolarization of uterine


muscles.
2) Releases PGF2α from myometrium with additive action on contraction.
3) Released from corpus leutium of ovary together with progesterone
between day 1 & 12 of the cycle.

59
Chapter 3
Drugs affecting the cardiovascular system

Treatment of hypertesnsion

 Decreases the risk of stroke, coronary events, heart failure and renal
impairment.
 Aetiology of hypertension, risk factors and the presence of
complications such as left ventricular hypertrophy should be
established.
 Advice on lifestyle changes should be given.

Drug strategy

Since

o BP = CO X TPR
o CO (cardiac output) = HR x SV
o R (resistance) α VL /r4. Wherein V is the blood viscosity, L is the
length and r is the radius of the vessel.

Then drug strategy in the treatment of hypertension aims to:

o ↓ TPR
o ↓ CO
o ↓ Body fluid volume

Lowering of BP may result in

o Reflex tachycardia (with the risk of precipitating angina or MI) not seen
with sympatholytic drugs which would rather cause orthostatic
hypotension.
o Oedema due to renin release.

Thresholds and targets for treatment

HYPER CLINIC AMBULATO ACTION


TENSIO BP ≥ RY BP ≥
N mmHg mmHg

60
STAGE 140/ 90 135/ 85 o Treat pt under 80 who have target
1 organ damage, cardiovascular
disease or 10 year risk > 20% of
CV disease, renal disease, or DM.
o In the absence of these conditions
advise lifestyle changes.
o In the absence of these conditions,
in pt under 40, specialist advice for
2ndary causes of HTN is needed.
STAGE 160/ 100 150/ 95 Treat all pts regardless of age.
2
SEVERE Systolic ≥ Treat promptly as HTN crises.
180 or
Diastolic ≥
110

TARGETS

TARGET BP TYPE PATIENTS


mmHg
≤ 140/ 90 Clinic Under 80
≤ 135/ 85 Ambulatory Under 80
≤ 130/ 80 Clinic Atherosclerotic CV disease, DM, eye, or
cerebrovascular disease.

SPECIAL PATIENTS

TARGET BP ≤ mmHg ACTION


ELDERLY o Clinic 150/ 90
over 80 o Ambulatory 145/
85
ISOLATED o Clinic 140/ 90 o Common in pt over 60
SYSTOLIC o Ambulatory 135/ associated with increased
HTN 85 CV risk.
≥ 160 / ≤ 90 o Treat as pt with raised
systolic and diastolic BP.
o Refer pt with postural

61
HTN.
DM o Clinic 140/ 80 o HTN more common with
o 130/ 80 in renal, type 2.
eye, or o In type 1 HTN indicates
cerebrovascular co- presence of DM
morbidity nephropathy
o Require combination
therapy
o ACE-inhibitors or
receptor blockers are
useful in diabetic
nephropathy and delay
micro –albuminuria in
type 2 DM .
RENAL o Clinic 140/ 90 o ACE-inhibitors or
DISEASE o 130/ 80 in chronic receptor blockers.
renal disease, DM, o ACE-inhibitors caution
or proteinuria ≥ 1 with renal impairment.
gm/ 24 hrs. o Thiazides are ineffective.
o High dose loop diuretics
is required.
PREGNANCY o Uncomplicated o Labetalol, methyldopa, or
chronic HTN 150/ modified- release
100. nifedipine are commonly
o Chronic with target used.
organ damage o Aspirin 75 mg OD is
multiparas 140/ 90. advised in risk of pre-
o Pre-eclampsia, or eclampsia.
BP ≥ 160/ 110, or o Hi risk of developing
who require special pre-eclampsia is
care 150/ 80~ 100. associated with chronic
kidney disease, DM,
autoimmune disease and
chronic HTN.
o MgSO4 is used in pre-
eclampsia and eclampsia.
o 2 days postpartum
previous therapy is re-

62
instituted.
HTN CRISES o Too rapid o A HYPERTENSIVE
reduction of BP EMERGENCY is severe
precipitates the risk HTN with damage to the
of reduced organ target organs with signs of
perfusion leading to papilloedma or retinal
cerebral infarction, haemorrhage, or acute
blindness, coronary syndrome, acute
deterioration of aortic dissection, acute
renal function, or pulmonary oedema,
myocardial encephalopathy, cerebral
ischaemia. infarction or
o Few minutes~ 2 hrs haemorrhage, eclampsia
BP should be or renal failure.
reduced 20~ 25%. o I/V therapy of Na
o In HTN urgency BP nitroprusside, labetalol,
is reduced gradually glyceryl trinitrate,
over 24~ 48 hrs. phentolamine,
hydralazine, or esmolol as
need be.
o HYPERTENSIVE
URGENCY is severe
HTN BP ≥ 180/ 110
without acute target
organ damage.
o Oral labetalol, Ca-
channel blockers,
amlodipine, felodipine,
or isradipine.
o Sublingual nefidipine is
not recommended.

Classification of anti- hypertensive drugs

VASODILATORS

1. Angiotensin-converting enzyme inhibitors [ ACE-inhibitors]


2. Angiotensin-receptor blockers

63
3. Drugs acting to open K channels
4. Calcium channel blockers
5. Nitrates

DIURETICS

1. Inhibitors of renal Na/Cl re-absorption [Thiazides]


2. Inhibitors of renal Na/K/2Cl re-absorption [ Loop ]
3. Mineralocoticoid receptor antagonists
4. Renal sodium channel blockers
5. Osmotic

SYMPATHOLYTICS

1. α- adrenoceptor antagonists
2. β- adrenoceptor antagonists
3. Combined α and β adrenoceptor antagonists
4. Ganglionic blockers
5. Adrenergic neuron blockers

α2 agonists: Clonidine and Methyldopa

o α2 are presynaptic Gi – coupled receptor that function to negative


feedback inhibition of NE release, stimulation of these α2 – R results in
indirect ↓ stimulation of α1 and β1 leading to ↓ sympathetic outflow,
↓ TPR but also ↓ HR.
o Both drugs are used in mild to moderate hypertension.
o Clonidine is used in Opiate withdrawal
o Methyldopa is used in control of hypertension during pregnancy, its hi-
PPB reduces its transfer across placenta but increases the potential of
forming haptens.
o Side effects include positive Coomb`s test for methyldopa, and
oedema formation and CNS depression for both.
o Drug interactions: TCA decreases their antihypertensive effects and
vice versa.

64
Drugs interfering with storage vesicles

Reserpine (Destroys vesicles)

o ↓ CO ↓ TPR (↓NE in the periphery).


o ↓ NE ↓ dopamine and ↓serotonin in CNS.
o Side effects include: severe depression that may lead to suicide,
oedema, and increased GI secretions due to an unopposed PANS
output.

Guanethidine

o Accumulated in nerve endings by reuptake process where it binds


vesicles interfering with NE release.
o Side effects include oedema and diarrhea.
o Drug interactions TCA inhibit the reuptake and actions of
guanethidine.

α1 blockers: Prazosin Doxazosin Terazosin

o ↓ arteriolar and venous resistance.


o Reflex tachycardia.
o Used in hypertension and in symptomatic ttt of BPH by decreasing the
sphincter tone of the bladder allowing better emptying against the
narrow urethra.
o Side effects include syncope with the first doses and urine
incontinence.
o Advantage good effect on lipid profile.

β blockers:

o 1ary antihypertensive mechanism by ↓ renin release by leaving α1


predominance on the juxtaglomerular cells of the kidney .
o 2ndry actions by ↓ HR and↓ muscle contractility.
o Side effects include:
 Cardiovascular depression with the potential of heart
block.

65
 Fatigue when they cross BBB.
 Sexual dysfunction and ↓ libido by eliminating the role of
catecholamines in arousal.
 Increased LDL and TG by inhibiting lipolysis, does not
cause overt clinical disease but in a patient with
dyslipidaemia α blockers is a better choice.
o Cautions include:
 Asthma
 Vasospastic disorders
 DM (mask hypoglycaemic events such as palpitations)

Direct acting vasodilators: Drugs acting through nitric oxide

Hydralazine

o ↓ TPR through arteriolar dilation.


o Used in mild to moderate hypertension
o Used in control of hypertension during pregnancy, its hi- PPB reduces
its transfer across placenta but increases the potential of forming
haptens.
o Side effects
 SLE like syndrome and slow acetylators
 Oedema
 Reflex tachycardia

Nitroprusside

o ↓ TPR through dilation of arterioles and venules.


o Used as an I.V. drug of choice in hypertensive emergencies.
o Side effect is cyanide poisoning limiting its use for 24 ~36 hrs and
decreased by the prior administration of nitrites and the co-
administration of thiosulfate.

Direct acting vasodilators: Drugs acting to open K channels

Minoxidil and Diazoxide

66
o Opening K channels they cause hyperpolarization of smooth muscles
resulting in arteriolar dilation.
o Diazoxide is used in hypertensive emergencies.
o Minoxidil is used in severe hypertension and as topical application in
baldness.
o Side effects:
 Minoxidil causes hypertrichosis.
 Diazoxide causes hyperglycaemia by interfering with insulin
release by hyperpolarizing the beta pancreatic cells, it has been
tried for ttt of insulinomas.
 Both drugs cause oedema and reflex tachycardia.

Direct acting vasodilators: Ca channels blockers

o Block L –type channels in the heart and blood vessels leading to


decreased intracellular Ca.
o Verapamil is cardioselective, Diltiazem is mixed, and Nefidipine and
other dihydropyridines are vasoselective.
o Use:
 Hypertension.
 Angina particularly vasospastic.
 Arrhythmia particularly the cardioselective Verapamil and
Diltiazem.
o Side effects
 Dihydropyridines cause reflex tachycardia and gingival
hyperplasia
 Verapamil causes constipation.

Renin inhibitors, Angiotensin-converting enzyme inhibitors and


Angiotensin-receptor blockers

[ACE-inhibitors]: Captopril

o Block the formation of angiotensin II thereby prevent the stimulation


of AT1 receptor.
o ↓ aldosterone, vasodilation

67
o Prevent degradation of bradykinin

[AR- blockers]: Losartan

o Block AT1 receptor generating the same effects of ACEI.


o Do not interfere with the degradation of bradykinin.

Renin inhibitors: Aliskiren

o Block the formation of angiotensin I.


o Generates the same effects of ACEI.
o Do not interfere with the degradation of bradykinin.

Uses of ACEIs, ARBs and Renin Is:

o All are used in mild to moderate HTN.


o Protective against diabetic nephropathy (ACEIs, ARBs).
o CHF (ACEIs, ARBs).

Side effects of ACEIs, ARBs and Renin Inhibitors:

o Dry cough (ACEIs) is due to increased bradykinin for which no


therapeutic antagonist is available it is mor common in females and is
alimiting factor for the use of the class, use ARBs.
o Hyperkalaemia via ↓ aldosterone.
o Acute renal failure in renal artery stenosis, bilateral renal artery stenosis
is an absolute contraindication for the class.
o Angiooedema.

Contraindication: pregnancy.

Treatment of Pulmonary Hypertension

The disease could be idiopathic, or secondary to left heart failure, right/left


shunting or lung fibrosis such as in pneumoconiosis. Agents used are more
selective to the pulmonary circulation than the systemic circulation.

Bosentan

68
o Endothelin ET-1 is a vasoconstrictor more potent than angiotensin- II,
it is targeted by bosentan which is an endothelin ETA receptor
antagonist.
o Administered orally.

Epoprostenol

o Is a prostacyclin [PGI2] analog.


o Administered via infusion pump.
o Contraindicated in pregnancy.

Sildenafil

o Inhibits type V PDE which is abundant in the pulmonary vasculature


in addition to the corpus cavernosum vascular bed.
o ↑ cGMP.
o Pulmonary artery relaxation leading to ↓ pulmonary hypertension.

Use of antihypertensive drugs in comorbid conditions

Indication Suitable drugs


Angina Beta Blockers, CCBs
Diabetes ACEIs/ ARBs
Heart failure ACEIs/ ARBs, Beta Blockers
Post MI Beta Blockers
BPH Alpha Blockers
Dyslipidaemia Alpha Blockers, CCBs, ACEIs/ARBs

Anti- arrhythmic drugs


Class I: Na Channel Blockers

o Block fast acting Na channels (↓ I Na).


o Preferentially in the open or activated state.
o ↑ APD and ERP
o Also blocks K channels (prolong repolarization).

Quinidine

69
o Muscarinic receptor blockade
o Alpha block ( possible reflex tachycardia)
o Wide clinical use in many arrhythmias; in atrial fibrillation, need initial
digitalization (to slow AV conduction)
o Side effects include Cinchonism (tinnitus, ocular dysfunction, CNS
excitation, GI), hypotension, prolongation of QRS and QT interval
(torsades)
o Drug interactions includes: hyperkalaemia inhances effects and vice
versa, displaces digoxin from tissue binding sites.

Procainamide

o Less muscarinic blockade


o Metabolized by N-acetyltransferase
o Side effects include SLE- like syndrome, haematotoxicity, and Cv
effects (torsades).

Disopyramide

Class I B: Na Channel Blockers

o Block fast acting Na channels (↓ I Na).


o Block inactivated channels (slow conduction in ischaemic and hypoxic
heart).
o ↓ APD due to the block of slow Na `window` currents

Lidocaine

o Post MI
o Open cardiac surgery
o Digitalis toxicity
o Side effects include seizures due to CNS excitation, but less cardiotoxic
effects relative to conventional anti-arrhythmics.
o I.V. use only (due to first pass metabolism).

Mexiletine and Tocainide

70
o Same as lidocaine
o Oral formulations.

Class I C: Na Channel Blockers

o Block any shape of Na channels


o Block fast acting Na channels especially His- Perkinji tissue.
o No effect on APD `either having APD or not`
o No ANS effect

Flecainide

o Limited use due to its proarrhythmogenic effect leading to sudden


cardiac death.
o A second choice drug used as a last struggle when other conventional
anti-arrhythmic are not functioning `Passport to heaven`.

Class II: Beta Blockers

o ↓ SA and AV nodal activity (↑PANS activity).


o ↓ slope in phase 4
o ↓ O2 demand due to their (-) inotropic effect
o Propranolol (non selective) and acebutalol and esmolol (selective) are
commonly used in prophylaxis post MI and supraventricular
tachyarrhythmias (SVTs).
o Esmolol I.V. is used in acute supraventricular tachyarrhythmias (SVTs).

Class III: K Channel Blockers

o ↓ I K slowing phase 3.
o ↑ APD and ERP

Amiodarone

o Mimics class I, II, III and IV.


o ↑ APD and ERP in all cardiac tissue.
o Use: any arrhythmia.
o T1/2E > 80 days due to selective tissue binding and a large Vd.

71
Side effects (are due to iodination of tissues)

o Pulmonary fibrosis.
o Blue pigmentation of the skin.
o Phototoxicity.
o Corneal deposits.
o Hepatic necrosis (rare).
o Thyroid dysfunction (5% of patients↑or ↓).

Sotalol

o ↓ I K slowing phase 3.
o β1 blockade leading to ↓ HR and AV conduction.
o Used in life- threatening ventricular arrhythmias.

Class IV: Ca Channel Blockers

o ↓ phase 0 and phase 4.


o ↓ SA and AV nodal activity (↑PANS activity).

Verapamil and Diltiazem

o Used in supraventricular tachyarrhythmias (SVTs).


o Side effects include constipation (Verapamil), AV block, dizziness,
flushing, and hypotension.
o Drug interactions include additive AV blockade with β- blockers and
digoxin, verapamil displaces digoxin from tissue binding sites.

Unclassified

Adonesine

o A neuromodulator neurotransmitter water soluble substance with a


short T1/2E < 10 second. Adenosine act through G1- coupled receptors
in the nodal tissues (similar to M2) and Gq- coupled receptors in the
bronchioles (similar to M3) decreasing intracellular cAMP and
hyperpolarizing these tissues.
o ↓ SA and AV nodal activity (↑PANS activity).

72
o The drug of choice in supraventricular tachycardias and AV nodal
arrhythmias.
o Side effects include flushing, sedation and profound dyspnea `elephant
sitting on chest`.
o Antagonized by methylxanthines theophylline and caffeine which are
used in COPD but cause ventricular tachycardia.

Magnesium

o Compete with Ca antagonizing its physiological actions.


o Used in life threatening supraventricular tachyarrhythmias (torsades),
also used in premature labor.
o Drugs causing torsades include K- channel blockers, neuroleptics,
TCAs, and the proarrhythmic class III anti arrhythmic drugs.

Heart Failure

It is the end stage of cardiovascular disease. It is defined as decreased cardiac


output [CO]. It leads to temporary compensation, followed by heart
remodeling generating a status of decompensation that ultimately results in
irreversible heart failure.

Pathophysiology:

o ↓ CO → ↓BP + ↓ renal blood flow → Stimulation of renin/


angiotensin/ aldosterone system → Na retention → ↑ BP + oedema →
↑ capillary filteration + ↑ venous pressure + ↑blood volume →
↑preload + pulmonary congestion → Dilated hypertrophy→ ↓↓ CO.
o ↓ CO → ↓BP → ↑ sympathetic stimulation → ↑ HR +
↑contractility + ↑BP → ↑ afterload → Dilated hypertrophy → ↓↓
CO.
o ↓ CO → ↑ endsystolic volume → ↑ enddystolic volume → Starling`s
compensation → dilated heart → Dilated hypertrophy → ↓↓ CO.

Pharmacotherapy aims at:

o ↓ Preload

73
o ↓ Afterload
o ↑ Contractility
o ↓ Heart remodeling
 ACEIs, ARBs, carvedilol, and spironolactone are used in CHF.
 Inotropes are more beneficial in acute CHF.

Mechanism of action of inotropes

Dobutamine

 Stimulates β1 receptors via a Gs protein which stimulates adenlyl cyclase


↑ intracellular conversion of to cAMP.
 cAMP via protein A kinase activation phosphorelates ligand dependant
Ca channels opening them → Ca flushes into the cell.
 The strength of contractility of muscle is directly proportional to the
level of I/C Ca which relieves actin/myosin filaments from their
troponin/ tropomysin interaction allowing them to slide against each
other during the depolarization of the muscle.
 β1 receptors rapidly desensitize, use of β1 agonists beyond acute
management of CHF is not indicated.

Inamrinone and milrinone

 I/ C phosphodiesterase inhibitors.
 Generate effects similar to dubtamine without using the β1 system
enabling their use beyond acute management of CHF.

Digoxin

1. Direct inotropic effect


 A 10 000 fold range exists between cardiac intracellular Ca ions level
[0.1umol] to the extracellular levels in mmols.
 Na/ Ca exchanger pump is a 2ndary active transport that bushes Ca
ions outside cells deriving its energy from a gradient of ↑ extracellular
Na ions level which is maintained by the Na/ K/ ATPase pump.

74
 Digoxin competes with K for the binding site and sits in the K influx
site blocking the ATPase pump and thereby the 2ndary active transport
pump.
 ↑ cellular Na → depolarization → muscle contraction.
 ↑ ↑ cellular Ca →↑ muscle contractility → + ve inotropy.
2. Indirect effect: Inhibition of neuronal ATPase → neuronal
depolarization + ↑ Ca level → the following
 PANS ↑ vagal tone → ↓ HR + ↑ dystolic filling time i.e. –ve
chronotropic + +ve inotropic effects.
 ↑ sympathetic activity → ↑ contractility i.e. +ve inotropic effect.

Pharmacokinetics:

 Long t1/2E necessitates a loading dose clinically referred to as patient


digitalisation.
 Renal clearance, this is particularly important considering that
CHF is associated with deteriorating glomerular function.
 Large VD with the possible tissue displacement by other drugs.

Uses:

 CHF.
 Supraventricular tachycardia.

Side effects:

 Anorexia, nausea and ECG abnormalities.


 Disorientation and visual abnormalities [halos].
 Arrhythmia.

Management of toxicity:

 Fab antibodies against digoxin.


 Supportive managements [electrolytes, lidocaine, phenytoin etc.].

Interactions:

 Diuretics [K level both ↑ or ↓]

75
 Quinidine and verapamil [displacement from tissues].
 Proarrhythmics such as sympathomimetics.

Other drugs:

Diuretics:

 Loop diuretics to ↓ preload.


 Spironolactone ↓ remodeling.

Metoprolol [β1 blocker] and carvedilol [mixed α and β blocker].

Nesiritide

 Recombinant human B- type ANF. ANF is released by an over-


stretching right atrium to ↑ renal Na secretion and ↑ dieresis.
 ↑ cGMP → vasodilation.
 Used in acute decompensated CHF.
 Expensive.

Anti- Anginal Drugs

Pharmacology

Nitrates

o Are prodrugs of nitric oxide [NO]. Via vasodilation they ↓ TPR, ↓


CO and ↓ O2 requirement. They also ↓ infarct size and post MI
mortality [I.V. nitroglycerine].
o NO is synthesized in the vascular endothelial cells by the breakdown of
L-arginine by NO synthase.
o The stimulus for the activation of the synthase arise by activation of
endothelial Gq receptors including M3, bradykinin, 5HT, H1, PGs,
leukotriens and other inflammatory mediators receptors.
o NO diffuses as a gas to vascular smooth muscles of large veins and
stimulate gunalyl cyclase in order to increase cGMP producing the
massive vasodilation of the inflammatory response.

76
o Nitroglycerine is broken down to NO with the requirement of cysteine
[a critical GSH amino acid] which limits the use of nitroglycerine on a
chronic basis. I.V., sublingual or transdermal patches.
o Nitroprusside is used as an I.V. drug of choice in hypertensive
emergencies, the potential of cyanide poisoning limits its use for 24
~36 hrs and decreased by the prior administration of nitrites and the
co-administration of thiosulfate.
o Isosorbide is prescribed for oral chronic use [extended release
formulations].

Side effects:

 Reflex tachycardia that can be detrimental in patients with angina.


 Fluid retention.
 Flushing, headache and orthostatic hypotension, patient using
nitrates for the first time should assume a sitting position for a while
lest they pass out or faint.

Contraindications:

 Tachyphylaxis: acute tolerance within 24 hrs due to the exhaustion


of GSH cysteine required for the catabolic activation of
nitroglycerine, it is indicated for acute use, and transdermal patches
should be dismounted at nighttime.
 Cardiovascular toxicity with sildenafil via additive ↑↑↑ in cGMP
→ massive ↓↓↓ in BP → reflex tachycardia and the potential
triggering of MI.

Ca Channel Blockers

 Verapamil and other cardioselective CCBs ↓ myocardial workload and


O2 demand.
 Nifedipine and other arterioselective CCBs are indicated in vasospastic
angina contributing to coronary dilation.
 Reflex tachycardia is a potential caution, these hypotensive reflexes are
commonly managed with use of β blockers.

77
Beta Blockers

 Indicated in angina of effort.


 Contraindicated in variant angina, lest they aggravate vasospastic
disease.

Carvedilol

 Is clinically equivalent to isosorbide in angina of effort.

1. Treatment of Stable Angina

Angina pectoris is the principal syndrome of ischaemic heart diseases IHD


that if not addressed adequately may develop into irreversible myocardial
infarction MI.

Stable/ classic angina [angina of effort or exercise]

o Is due to atherosclerotic coronary occlusion.


o Drug therapy aims to ↓ oxygen demand by ↓ TPR or ↓ CO or both
[nitrates, CCBs, and β blockers].

Vasospastic/ variant angina [prinzmetal angina]

o Is due to a reversible ↓ in coronary blood flow 2ndry to vasospasm.


o Drug strategy is to ↑ oxygen delivery by ↓ vasospasm [nitrates and
CCBs]

2. Acute coronary syndromes

Spectrum of conditions that can be diagnosed on the basis of clinical


presentation, ECG changes and cardiac markers, including:

o Unstable angina
o Non- ST- segment elevation myocardial infarction [NSTEMI].
o ST- segment elevation myocardial infarction [STEMI].

Unstable angina and NSTEMI

78
Rupture of atheromatous plaque characterized by:

 Stable angina that suddenly worsens.


 Recurring or prolonged angina at rest.
 New onset severe angina.
 There is evidence of myocardial necrosis in NSTSEMI but less
significant than in STEMI.
 There is risk of progression to STEMI or sudden death particularly in
patients experiencing pain at rest.

Initial Management:

1. Oxygen: if there is evidence of hypoxia, pulmonary oedema or


continuing myocardial ischaemia.
2. Nitrates: to relieve ischaemic pain.
3. Diamorphine or morphine if pain continues given by slow I.V.
infusion.
4. Metoclopramide as an antiemetic.
5. Aspirin 300 mg chewed or dispersed in water.
6. Clopidogril 300 mg, or 600 mg prior to percutaneous intervension.
7. Heparin: unfractionated, LMW or fondaparinux.
8. β blockers: should be continued forever if not otherwise
contraindicated.
9. Diltiazem or verapamil: in patients without left ventricular
dysfunction and in whom β blockers are inappropriate.
10. Eptifibatide and tirofiban: in hi risk of MI or death.

Long term Management: standard angina ttt.

Prevention of cardiovascular events:

1. Counseling pertaining to lifestyle changes.


2. Aspirin 75 mg OD.
3. Antihypertensive ttt if indicated.
4. Statin.
5. ACEIs.

79
6. Clopidogril for 12 months.

STEMI

Occasionally results from coronary spasm or embolism, arteritis, spontaneous


thrombosis or sudden severe elevation of BP, but more commonly results
from rupture of atheromatous plaque characterized by:

 Thrombosis and myocardial ischaemia.


 Irreversible necrosis of the heart muscle.
 Long term complications.

Initial Management: similar to the abovementioned.

Long term Management:

1. Aspirin 75 mg OD.
2. Clopidogril for 12 months.
3. Warfarin for those at low risk of beeding or intolerant to
Clopidogril.
4. β blockers: should be continued forever if not otherwise
contraindicated.
5. Diltiazem or verapamil if β blockers are inappropriate.
6. ACEIs.
7. Nitrates.
8. Eplerenone.
9. Statins.

Implantable pacemaker and cardioverter-defibrillator

o An implantable cardioverter-defibrillator (ICD) is a specialized device


designed to directly treat patients at risk for sudden cardiac death due
to ventricular tachyarrhythmias.
o A permanent pacemaker is an implanted device that provides electrical
stimuli, thereby causing cardiac contraction when intrinsic myocardial
electrical activity is inappropriately slow or absent.

80
Indications for ICD placement

Secondary prophylaxis

i. Survivors of cardiac arrest due to VF or hemodynamically unstable VT.


ii. Excluding cases in which there are “completely reversible causes,”

Primary prophylaxis

Class I indications (ie, the benefit greatly outweighs the risk):

 Structural heart disease, sustained VT


 Syncope of undetermined origin, inducible VT or VF at
electrophysiologic study (EPS)
 Left ventricular ejection fraction (LVEF) < 35% due to prior MI, at
least 40 days post-MI, NYHA class II or III
 LVEF ≤35%, NYHA class II or III
 LVEF ≤30% due to prior MI, at least 40 days post-MI
 LVEF < 40% due to prior MI, inducible VT or VF at EPS

Class IIa indications (ie, the benefit outweighs the risk):

 Unexplained syncope, significant LV dysfunction, nonischemic


cardiomyopathy
 Sustained VT, normal or near-normal ventricular function
 Hypertrophic cardiomyopathy with 1 or more major risk factors
 Arrhythmogenic right ventricular dysplasia/cardiomyopathy
(ARVD/C) with 1 or more risk factors for sudden cardiac death (SCD)
 Long QT syndrome, syncope or VT while receiving beta-blockers
 Non- hospitalized patients awaiting heart transplant
 Brugada syndrome, syncope or VT
 Catecholaminergic polymorphic VT, syncope or VT while receiving
beta-blockers
 Cardiac sarcoidosis, giant cell myocarditis, or Chagas disease

Pacemaker indications

1. Absolute indications for pacemaker placement:

 Sick sinus syndrome

81
 Symptomatic sinus bradycardia
 Tachycardia-bradycardia syndrome
 Atrial fibrillation with sinus node dysfunction
 Complete atrioventricular block (third-degree block)
 Chronotropic incompetence (inability to increase the heart rate
to match a level of exercise)
 Prolonged QT syndrome
 Cardiac resynchronization therapy with biventricular pacing

2. Relative indications:

 Cardiomyopathy (hypertrophic or dilated)


 Severe refractory neurocardiogenic syncope

Temporary emergency pacing is indicated for therapy of significant and


hemodynamically unstable bradydysrhythmias and for prevention of
bradycardia-dependent malignant dysrhythmias.

Magnet Inhibition

 In most devices, placing a magnet over a permanent pacemaker


temporarily "reprograms" the pacer into asynchronous mode; it does
not turn the pacemaker off
 If the device company parameters are known, application of a magnet
can determine whether the pacer's battery needs to be replaced
 Although many different branded pacemaker/ ICD magnets are
available, in general, any pacemaker/ICD magnet can be used to
inhibit the device
 Magnet use inhibits further ICD discharge; it does not, however,
inhibit pacing

Indications for ICD deactivation:

 End-of-life care (after a discussion with the patient and family)


 Inappropriate shocks
 During resuscitation
 With transcutaneous pacing (external pacing can cause an ICD to fire)
 During procedures such as central lines or surgery with electrocautery

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ICD complications and malfunctions

1. Acute surgical complications:

 Pain
 Bleeding
 Pneumothorax
 Hemothorax
 Cardiac perforation with or without pericardial effusion
and tamponade.
 Pulseless electrical activity following intraoperative
defibrillation threshold testing

2. Subacute ICD complications:

 Pain
 Infection
 Pocket hematoma
 Wound dehiscence
 Lead dislodgment
 Deep venous thrombosis
 Upper extremity edema
 Degradation of lead function

3. Chronic complications include the following:

 Device-related pain
 Lead fracture
 Inappropriate shocks
 Erosion of device through skin
 Immunologic rejection – Rare

Pacemaker complications and malfunction:

 Pneumothorax
 Pericarditis
 Infection
 Skin erosion
 Hematoma

83
 Lead dislodgment
 Venous thrombosis

Major pacemaker malfunctions:

 Failure to output
 Failure to capture
 Failure to sense
 Pacemaker-mediated tachycardia
 Runaway pacemaker
 Pacemaker syndrome
 Twiddler's syndrome
 Cardiac monitor pseudomalfunction
 Pacemaker pseudomalfunction

Inpatient Care

Reasons for admission:

 Device investigation: To determine an eminent battery failure


 Addition of antiarrhythmic medications
 Treatment of MI
 Treatment of patient discomfort
 Provision of psychological support: Up to 35% of people develop
anxiety disorder following ICD placement.

84
Chapter 4

URO- GENITAL PHARMACOLOGY

Erectile disorders

Priapism

1. Occurs due to penile deformities such as angulation, cavernosal fibrosis


and Peyronie`s disease (a superficial fibrosing disorder of the penis
resulting in plaque formation and penile deformity affects up to 13%
of men). Alprostadil and similar drugs may also induce priapism.
2. Treatment should not be delayed for more than 6 hrs.
3. Initial treatment by aspiration of 20- 50 ml of blood through penile
corpus cavernosum using a 20 gauge butterfly needle under aseptic
conditions. This may be repeated on the opposite corpus if need be.
4. If aspiration fails, lavage of corpus cavernosum is done by introducing
sterile physiological saline solution thro the first needle and drainage
thro the opposite one.
5. If aspiration and lavage are unsuccessful intracavernosal injection of a
sympathomimetic with alpha action, with continuous monitoring of
blood pressure and pulse, as follows:
o Phenylephrine 100- 200 micrograms every 5- 10 mints,
maximum total dose of 1 mg.
o Adrenaline 10- 20 micrograms every 5- 10 mints, maximum
total dose of 100 micrograms.
o Metaraminol 1 mg diluted into 50 ml of normal saline and
given in 5 ml corpora injections every 15 mints.
6. Caution with intracavernosal sympathomimetic injection includes
coronary heart disease, hypertension, cerebral eschaemia, and anti-
depressant therapy. Metaraminol has been associated with fatal
hypertensive crisis.
7. If sympathomimetics are unsuccessful urgent surgical referral for
management is needed possibly including shunt procedure.

Erectile dysfunction

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Is failure to produce satisfactory erection possibly due to psychogenic,
vascular, neurogenic or endocrine abnormality. Drug induced impotence is
not uncommon.

Alprostadil (PGE1)

Indication: erectile dysfunction.

1. Intracavernosal injection.
2. Urethral application wherein a barrier contraceptive should be used if
the partner is pregnant.

Contraindications

1. Predisposition to prolonged erection (sicklers, m. myeloma or


leukaemia).
2. Use with other drugs for erectile dysfunction.
3. In patients with penile implants.
4. When sexual activity is medically inadvisable.
5. Urethral application is contraindicated in urethral strictures,
hypospadia, curvature, balanitis, and urethritis.

Side effects

1. Priapism, balanitis, phimosis, or ejaculation abnormalities.


2. Hypotension, hypertension, dizziness, and headache.
3. Penile pain and pain localized to buttocks, leg, testis, or abdomen.
Penile fibrosis, oedema, rash or haematoma.
4. Urethral burning or bleeding.

Phosphodiesterase type-5 inhibitors

Sildenafil, Tadalafil, and Vardenafil

Indications

1. Erectile dysfunction.
2. Sildenafil and Tadalafil are also indicated in pulmonary hypertension.

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Cautions

1. Cardiovascular disease, left ventricular outflow obstruction.


2. Penile deformity.
3. Predisposition to priapism.

Contraindications

1. Patient on nitrates, or patients in whom vasodilation or sexual activity


is inadvisable.
2. Hx of non-arteritic anterior optic neuropathy.
3. Hypotension with systolic pressure below 90mmHg, recent stroke,
unstable angina and MI.

Side effects

1. Dyspepsia, nausea and vomiting.


2. Headache, dizziness, myalgia, back pain, visual disturbance and nasal
congestion.
3. Hypotension, hypertension, palpitation, and epistaxis.
4. Priapism, arrhythmia, MI, seizures and sudden hearing loss.

Drug interaction: with alpha blockers increase the risk of postural


hypotension.

Papaverine and phentolamine

1. Papaverine is indicated as smooth muscle relaxant.


2. Erectile dysfunction in patients with neurologic or psychogenic
impotence.
3. Phentolamine is added if the response to papaverine is inadequate.
4. Persistence of the erection for more than 4 hrs is an emergency.

Drugs affecting renal function: diuretics


1. The current therapeutic goal of diuretic use is increased excretion of
Na followed by water.
2. The degree of Na loss in urine (natriuresis),or in combination with Cl
(saluresis) varies with the mechanism of action of the drug ,all(except

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osmotic diuretics) inhibit specific enzymes ,transporter proteins
,hormone receptors or ion channels that function (directly or
indirectly) in renal Na re- absorption.
3. Diuretics also alter elimination of other ions to varying degrees
eg.K,H,Ca,Mg,Cl,HCo3 and phosphates.
4. The most common indication for diuretic use is mobilization of tissue
oedema.

1-Inhibitors of carbonic-anhydrase

The prototype drug in the class is acetazolamide. Others are oral


dichlorophenamide, methazolamide, and topical ophthalmic dorozolamide.

Mechanism of action

 Activity in the CA-rich proximal tubule is non competitive


reversible inhibition of CA, decreased formation of carbonic acid
results in fewer H ions which are usually exchanged with Na from
the lumen. More Na is available for combining with urinary
HCO3.
 Other actions are due to the wide distribution of CA in tissues
including the CNS and eye leading to anticonvulsant action and
reduced intraocular pressure due to decreased formation of
aqueous humor which is CA -dependant .

Toxicity, ADR, contraindications, and drug interactions

1) Side effects associated with sulfonamides; CNS drowsiness and


disorientation, and hepatic encephalopathy especially in pre-existing
hepatic conditions.
2) Electrolyte disturbances due to Na and K wasting, respiratory or
metabolic acidosis or compromised respiratory function.
3) Calculi-formation is enhanced (CaPo4).
Therapeutic use

1) Reduction of intraocular pressure by inhibition of formation of aqueous


humor;
2) Methazolamide is prefered for long-term glaucoma therapy over
acetazolamide .

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3) 2% ophthalmic solution of dorozolamide is used in the treatment of
glaucoma-associated increased intraocular pressure without
cardiovascular or pulmonary side effects (bitter metal-like taste).
4) Adjunctive therapy for epilepsy and mountain sickness.
5) Limited diuretic use due to rapid development of tolerance.

2- Osmotic diuretics

I. Solutions containing solutes that are freely filtered by glomeruli (low


m.wt.)
II. Undergo limited tubular re-absorption.
III. Of more osmolarity relative to plasma.
IV. Are pharmacologically inert, e.g. Mannitol, glyserine, isosorbide, urea,
and hypertonic saline solutions.
Mechanism of action

a) Hyperosmolar solutions establish an osmotic gradient between


plasma and tissue water compartment.
b) Effects thro-out the tubule particularly the loop of Henle. Na re-
absorption is markedly reduced, the nephron fails to recapture
the increased loads of salt and water.
c) Increased cortical and medullary blood flow due to increased
renal vascular flow and GFR.
d) Increased excretion of other electrolytes.
e) Extra-renal mechanisms include; transient effects on the vascular
tone; increased cardiac output by release of ANF, vasodilatory
PGs and inhibition of rennin release.
Absorption and elimination

a) Mannitol is not metabolized.


b) Elimination halflife is dose-dependent (1.5 hrs).
c) Mannitol and urea are administered I/v (slowly), glycerine and
isosorbide orally.
d) Only glycerine is eliminated by biotransformation.
Adverse effects and drug interactions

1) Acute hypertension and hyponatremia.


2) Nausea and vomiting.

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3) Rapid expansion of plasma volume that may precipitate CHF or
pulmonary oedema.
4) Dehydration and electrolyte disturbances (hypertonic dehydration
developing although plasma volume is restored, body wt and
urinary output are monitored).
Contraindications

1) Ongoing intracranial haemorrage.


2) Anuric renal failure.
3) Severe dehydration.
4) Pulmonary congestion or oedema.

Therapeutic use

1) Prophylaxsis and treatment of renal failure.


2) Intracranial pressure.
3) Mobilization of oedema (with other diuretics)

3- Loop-diuretics; inhibitors of Na-K-2Cl symport


Drugs in this class include furosemide (lasix), ethacrynic acid,
bumetanide, and torsemide (all are sulfonamide derivatives except
ethacrynic acid).

Mechanism of action

1) Inhibit Na-K-2Cl symporter in the TAL by binding to Cl-binding


site in the transporter protein.
2) Interfere with establishment of hypertonic medullary interstitium
and disrupt countercurrent mechanism hence block kidney ability
to concentrate or dilute urine appropriately (cells of macula densa
generate part of their membrane voltage via Cl channels , the new
Cl equilibrium depolarizes these cells and enhance renin release).
3) Inhibit Ca and Mg re-absorption.
4) Weak CA-inhibiting activity.
5) Extra-renal activity includes production of PGs and prevention of
broncho-constriction by inhibiting the release of inflammatory
mediators from the lungs.
Toxicity and adverse effects

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1) Hyponatremia, reduced blood pressure and organ perfusion (risk
to patients with renal, cardiac or hepatic disease).
2) Hypokalaemia.
3) Mg and Ca deficiency.
4) Ototoxicity (1arely ethacrynic acid).
5) Bone marrow depression.
6) Hyperglycaemia related to impairment of conversion of pro-
insulin to insulin due to decreased K level.
7) Sulfonamide toxicity (1arely hypersensitivity).
Contra-indications:

Patients with fluid & electrolyte disturbances & anuria.

Drug interactions

1) Theophylline; enhanced effects.


2) Aminoglycosides; enhanced ototoxicity.
3) Digitalis; increased risk of arrhythmia due to hypokalaemia.
4) Aspirin; enhanced anticoagulant activity.
5) Corticosteroids; enhanced K wasting.
6) Insulin; alteration of insulin requirements.
Therapeutic use

Treatment of oedema of cardiac, hepatic or renal origin.

4- Thiazide and thiazide-like diuretics ; inhibitors of Na-Cl-symport

 Are derivatives of CA-inhibiting sulfonamides, promote renal


excretion of Cl (rather than HCo3) with Na, producing a true saluritic
effect.
 E.g. chlorothiazide, hydrochlorothiazide, and the quinazolinone
derivatives metolazone & chlorzalidone.

Mechanism of action;

1) 1ary action in the distal convoluted tubule and 2ndary CA-related


action in the proximal tubule.
2) NaCl co-transporter is reversibly inhibited.
3) Ca re-absorption is enhanced by increasing distal tubule Ca-
binding proteins.

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4) Peak diuresis is moderate compared to loop-diuretics, however,
they likewise enhance K excretion by increasing Na delivery to the
distal tubule.
Pharmacokinetics

1) Slow and incomplete GIT absorption.


2) High plasma protein binding.
3) Renal and renal-and-biliary excretion.
4) Effectiveness decreased with diminished renal blood flow.
Adverse effects

1) K-wasting.
2) Fluid and electrolyte disturbances.
3) Hyperglycaemia.
4) Hypercalcaemia.
5) Hyponatraemia and hypochloraemia.
6) Sulfonamide hypersensitivity.
7) Patients with severe renal disease, hypovolaemia and impaired
hepatic function are at risk.
8) Diabetic patients are at risk (derangements of glucose).
Drug interactions;

 Decreased anticoagulant and insulin effects.


 Increased anaesthetic and digitalis effects.
Therapeutic use

1) Oedma of cardiac, hepatic or renal origin.


2) Low-dose thiazides with front-line antihypertensives (e.g. ACE
inhibitors) is currently considered an alternative strategy for
management of hypertension.
3) Beneficial in the treatment of Ca nephrolithiasis.

5- Inhibitors of renal epithelial Na channels; K-sparing diuretics

 Amiloride and triamterene are organic bases secreted into the


proximal tubule by an organic base transport system.
 No parenteral form available.
Mechanism of action

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1) A mild increase of NaCl excretion and K retention, slightly augment
diuresis.
2) Used with loop or thiazide diuretics to decrease K excretion.
3) Triamterene exert effects that prolong cardiac action potential
duration.
Adverse effects

1) Hyperkalaemia.
2) Renal dysfunction and stones.
3) Rash and photosensitivity.
4) Use in patients with hepatic or renal disease is contra-indicated.
Therapeutic use

Clinically important for their K sparing properties in combination with


loop or thiazide diuretics.

6- Antagonists of mineralocorticoid receptors; K-sparing aldosterone


antagonists

Spironolactone, its active-metabolite canrenone and potassium canrenone


share a 4- ring steroid structure similar to aldosterone.

Mechanism of action

1) Aldosterone (steroid hormone) binds to mineralocorticoid receptors


(MRs) in the cytoplasm of target cells.
2) Aldosterone-induced protein (AIP) causes re-absorption of Na and
increases excretion of K and H in the late distal tubule and
collecting duct.
3) AIP has multiple effects in the activation, redistribution and de
novo synthesis of Na channels.
4) Aldosterone antagonists act by binding to MRs; blocking the
physiologic effects of aldosterone.
Pharmacokinetics

1) Well GIT absorption.


2) 60 ~ 90% plasma protein bound.
3) Extensive hepatic biotransformation (1st pass effect).
4) The metabolite canrenone has longer half-life (16 hrs).

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5) Peak diuresis 2~ 3 days after initiation of therapy.
Adverse effects

1)
Hyperkalaemia.
2)
Hyponatraemia and dehydration.
3)
Hyperchloraemic acidosis.
4)
Sexual impotence related to binding to progesterone and
dihydrotestosterone receptors.
Therapeutic indications

1) Hyperaldosteronism.
2) Oedema.
3) K wasting.

Chapter 5

Drugs used to treat diseases of the blood

Antianaemic drugs

Anaemia is defined as inadequate erythrocytic mass.

1- Iron

Is abundantly available in most foods.

1) Meat iron is absorbed intact as Hb and myoglobin.


2) Vegetable iron is less available as it is usually bound to
phytates.
3) Iron in salts must be reduced to ferrous before it can be
absorbed.
4) Iron cross the intestinal mucosal cell by active transport
regulated by mucosal cell iron stores and is available for
immediate transport to plasma via the beta-globulin
transferrin, or stored as ferritin.
5) There is no mechanism for iron excretion, it is usually lost
by exfoliation of intestinal mucosal cells into stools.
6) Bile, urine & sweat excretion is not uncommon.
Use

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 Treatment, or prevention, of iron deficiency anaemia in premature
infants, children, pregnant & lactating women, gastrectomy, severe
small bowl disease (mal-absorption), adults with blood loss,
menstruating women & GIT bleeding.
 Although oral administration predominates, parenteral iron therapy is
used in patients unable to tolerate or absorb, or cannot be maintained
on oral iron.
Adverse effects;

A) Overdose toxicity; causes necrotizing gastroenteritis, vomiting,


abdominal pain, bloody diarrohea superceeding shock,
lethargy & dyspnea.
B) Chronic toxicity; iron overload is known as
haemochromatosis or haemosiderosis characterized by
deposition of iron in tissues & is corrected by phlebotomy &
the use of deferoxamine.

2- Vitamin B12; cyanocobalamine; hydroxocobalamine

Pharmacokinetics

1) Is dietary available, readily absorbed & transported bound to


plasma glycoprotein transcobalamine.
2) Deficiency most often results from mal-absorption due to lack
of intrinsic factor, or loss or mal-function of the specific
absorptive mechanism in distal ileum.
3) Seldom nutritional deficiency is seen in strict vegetarians.
Pharmacodynamics

1) Methylcobalamine is an intermediate in the transfer of a


methyl group from N5-methyltetrahydrofolate to methionine,
tetrahydrofolate is essentially required for the synthesis of
purines required for DNA synthesis in rapidly dividing cells.
2) B12 is required in the enzymatic isomerization of
methylmalonyl-CoA to succinyl-CoA.
3) Accumulation of this substrate & disruption of methionine
pathway cause neurologic problems.

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Use

 Treatment, or prevention, of Vit B12deficiency, clinically manifested by


megaloplastic anaemia & neurologic syndrome that ensues with
weakness in peripheral nerves & progresses to spasticity, ataxia &
other CNS disorders.
 Correction of Vit B12arrests the neurologic deterioration but may not
reverse the condition fully.
 Although both forms are available for parenteral injection,
hydroxocobalamine is preferred for higher protein binding & longer
plasma half-life.
 Haematologic response to treatment is rapid, BM returns to normal
within 48 hrs.
3-Folic acid; pteroylglutamic acid

Pharmacokinetics

1) Absorption depends on metabolic requirements.


2) Undergoes urinary & faecal excretion & hepatic catabolism.
Pharmacodynamics

 Tetrahydrofolate co-factors are essential in the production of dTMP for


DNA synthesis.
 Folate deficiency (dietary) leads to megaloplastic anaemia without the
clinical neurologic syndrome characteristic of vit B 12 deficiency.
Use

1) Pregnancy.
2) Haemolytic anaemia.
3) Mal-absorption syndrome.
4) Renal dialysis.
5) Use of certain drugs that interfere with folate absorption e.g.
phenytoin, oral contraceptives & trimethoprim.

4-Erythropoietin

This haematopoietic growth factor is a glycosylated peptide of 165 AAs


& a plasma half-life of 4-13 hrs in patients of chronic renal -failure.
Pharmacodynamics;

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1) Is produced in the kidney in response to tissue hypoxia.
2) Stimulates erythroid proliferation & differentiation by interaction
with specific erythropoietin receptors on red cell progenitors.
3) Induce the release of reticulocytes from BM.
Use

1) Eliminates the need for blood transfusion in patients with chronic


renal-failure by improving the haematocrit & Hb level.
2) Failure to respond to erythropoietin is usually due to concurrent iron
-deficiency.
3) Treatment of 1ary (BM), & 2ndary anaemias; BM failures,
myeloproliferative & myelodysplastic disorders, multiple myeloma,
AIDS, cancer & chronic inflammation.
4) Treatment of anaemia offset by zidovudine treatment in patients with
HIV infection.
Adverse effects

Hypertension, thrombotic complications & mild allergic


reactions.
Blood-coagulation factors

 I Fibrinogen
 II Prothrombin
 III Thromboplastin
 IV Ca
 V Proaccelerin
 VI ------------------
 VII Proconvertin
 IIX Antihaemophelic factor
 IX Thromboplastin (Christmas )
 X Stuart Prower
 XI antecedent
 XII Hageman factor
 XIII Fibrin-stabilizing factor.
Anti-coagulent agents

1-Heparin

Is a heterogenous mixture of mucopolysacharides.

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Pharmacodynamics

1. Antithrombin precipitates the clotting factors (proteases) by forming


sable-complexes with them.
2. Active heparin binds tightly to antithrombin causing conformational
changes exposing its active-site for more-rapid interaction with
proteases.
3. Heparin is released intact from the process, bind to endothelial cell
surface ready for new processes.

Use

1) High-molecular weight (HMW) fraction of heparin has high-affinity


for antithrombin and markedly inhibits blood coagulation.
2) Low-molecular weight (LMW) heparins (eg. Enoxaparin &
Dalteparin) are effective in preventing the development of deep
venous thrombosis in the post-operative period.
3) Treatment of acute venous thrombo-embolic disease & acute coronary
syndrome.
Adverse effects

1) Bleeding; elderly women & patients with renal-failure are more-prone.


2) Allergic reactions; as heparin is collected from animals (porcine
intestinal mucosa & bovine lungs).
3) Osteoporosis & spontaneous fracture, & mineralocorticoid deficiency
with long-term therapy.
4) Release of lipoprotein-lipase lowers postprandial lipaemia.
5) Transient thrombocytopenia (5 days; induced aggregation).
Contra-indications

1- Hypersensitivity.
2- Active bleeding.
3- Haemophilia.
4- Thrombocytopenia.
5- Purpura haemorragica.
6- Severe hypertension.
7- Brain haemorrage & surgery.

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8- Endocarditis.
9- Active TB.
10- Ulcers.
11- Potential abortion.
12- Visceral carcinoma.
13- Advanced hepatic or renal disease.
Antidotal therapy

 Protamine sulphate, a basic peptide anticoagulant, that actively


precipitate heparin by forming stable-complexes.
 Overdose antidotal therapy may worsen the situation.

2-Warfarin & coumarin; (the oral anticoagulants)

Pharmacodynamics

 Act by blocking the carboxylation of glutamate residues of prothrombin


& factors VII, XI, X & the endogenous anticoagulant proteins C & S,
inactivating coagulation & preventing the reductive re-activation of vit
K-epoxide back to the active hydroquinone form.
 Delay in the action (12 hrs) is due to the long half-life (6-24 hrs) of
factors VII, IX, X & II.
Adverse effects

1- Foetal haemorragic-disorders & bone-deformities.


2- Cutaneous necrosis.
Drug Interactions

1- Enzyme-induction; eg barbiturates & rifampin.


2- Enzyme-inhibition.
3- Synergism; e.g. phenylbutazone & sulfinpyrazone which also
inhibit platelet function.
4- Competative antagonism; e.g. vit. K (synthesis of factors).
Antidotal therapy

Large doses of vit. K.

99
Anti-platelets agents

Decrease platelet aggregation and may inhibit thrombus formation in the


arterial circulation where anticoagulants have little effect.

ASA (AspirinR)

Alters the balance between prostanoids which promote and those inhibit
platelets aggregation. It irreversibly inhibits COX by acetylating its active
enzymic site → ↓ platelets thromboxane A2 synthesis and ↓ endothelial
prostacyclin synthesis. Endothelium can synthesize new enzyme, platelets
cannot. Replacement of affected cohort of platelets takes 7~ 10 days.
Inhibition of endothelial COX requires higher doses of aspirin. Low dose
aspirin ↓ thromboxane A2 without drastically ↓ prostacyclin synthesis.
Aspirin ↓incidence of postoperative venous thrombosis in men and ↓fatal
pulmonary embolism in both sexes.

 300 mg single dose aspirin is given ASAP after an ischaemic event.


 75 mg OD long term use in established CV disease, 10 year risk of CV
disease, diabetics over 50 0r for more than 10 years.

Clopidogrel

 Prevention of atherosclerotic events in peripheral arterial disease,


within 35 days of MI, 6 month ischaemic stroke and in acute MI and
acute coronary syndrome.
 Contraindicated in active bleeding and breast feeding.
 Side effects GI dyspepsia, pain and diarrhea and less commonly
vomiting, constipation, flatulence and ulceration. Bleeding [GI and
cranial]. Hallucinations or blood disorders are not uncommon.

Dipyridamole

 Used orally in combination with oral anticoagulants for the prophylaxis


of thromboembolism associated with prosthetic heart valves, and with
LD aspirin in ischaemic attacks including ischaemic stroke.

100
 Side effects include GI effects, headache, myalgia, hypotension and
worsening symptoms of coronary disease.

Abciximab

 A monoclonal AB for single use only in hi-risk patients undergoing


percutaneous transdermal coronary intervention.
 Glycoprotein IIb/ IIIa inhibitor preventing platelets aggregation by
blocking their fibrinogen binding receptors.
 Others include Eptifibatide and Tirofiban used with heparin and aspirin
to prevent early MI in patients of unstable angina.
 Contraindicated in active and potential bleeding [major surgery,
trauma within last 2 month, stroke in last 2 years, HTN and vascular
malformations].
 Side effects include bleeding, cardiac tamponade, ARDS and
hypersensitivity reactions.

Epoprostenol (prostacyclin)

 Used in combination with heparin to inhibit platelets aggregation


during renal dialysis.
 Used in combination with oral anticoagulants for the ttt of primary
pulmonary hypertension.
 T1/2E only 3 minutes so given as continuous I/V infusion.
 Potent vasodilator so side effects include flushing, headache and
hypotension. Bradycardia, tachycardia, anxiety, agitation, and jaw and
chest pain are not uncommon.

FIBRINOLYTIC DRUGS

Act as thrombolytics by activating plasminogen to plasmin, which degrades


fibrin and so breaks up thrombi.

Streptokinase

 Extracted from cultures of group C β- haemolytic streptococci.

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 Acts indirectly by forming stable complex with plasminogen which
gains enzymic activity due to a conformation change.
 Antigenic, actions may be reduced by anti-streptococcal Abs if already
present.

Urokinase

 Prepared from human urine or embryonic kidney cells.


 Acts directly as a plasminogen activator.
 Not antigenic.

Alteplase

 Is a t-PA, tissue- type plasminogen activator.

Reteplase and Tenecteplase

Indications

1. Acute myocardial infarction; alteplase, reteplase or streptokinase need be


given within 12 hrs of symptom onset, tenecteplase within 6 hrs.
Therapy is initiated by a large I.V. injection to overcome plasmin
inhibitors then followed by continuous infusion, T1/2E about 15 mints.
2. Pulmonary embolism; alteplase, streptokinase or urokinase by I.V. infusion
in normal saline or by injection into the pulmonary artery.
3. Thromboembolic occlusive vascular disease including deep –vein
thrombosis, peripheral vascular occlusion and I.V. catheters and
cannulas blocked by fibrin.
4. Streptokinase local use is indicated whenever removal of fibrin and
drainage of viscous exudates is desired, it has been tried successfully for
wounds not responding to antibacterial therapy including burns, ulcers,
chronic eczema, ear haematoma, otitis externa, cysts, fractures with
fistulous tracts and osteomyelitis. Parenteral use included ulcers,
eczema, dermatitis, edema, cellulitis, haematoma, trauma, and
pneumonia.

Side effects

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 Nausea, vomiting and bleeding usually limited to the site of injection
but cerebral or other site bleeding is not uncommon.
 In MI reperfusion arrhythmia and recurrent ischaemia and angina may
occur. Reperfusion may cause cerebral and pulmonary oedema.
 Hypotension.
 Convulsions.
 Further embolism due to detached micro-emboli.

Contra-indications

 Potential Haemorrhage.
 Hx of CVI.
 Use of streptokinase within 4 days of streptokinase or alteplase due to
prolonged persistence of Abs.

Cinical aspects

Overactivity or underactivity of the fibrinolytic mechanism may result


in haemorrhage or vascular thrombi respectively.
Hyperactive fibrinolysis has been recognized in a variety of pathologic
conditions including shock, blood disorders, cirrhosis, snake bite and
following lung surgery.
Hyperactive fibrinolysis may be associated with rapid digestion of
prothrombin by plasmin or inhibition of other factors including V,
VII, and VIII.
Underactive fibrinolysis plays a role in vascular occlusive disease
including MI, pulmonary thromboembolic disease, massive postsurgical
adhesions, and unrelated processes such as inflammation and
malignancy.

Therapeutic use of combined anti-coagulants & anti-platelets & fibrinolytic


drugs

Venous thrombo-embolism

o Underlying process is predominantly blood coagulation & fibrin


formation with a small component of platelet aggregation.

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o Heparin is used for short- term effect followed by oral anticoagulants for
prolonged therapy.
o S/C 6- hourly heparin is effective in the prevention of DVT. Larger
doses for a week are required if the DVT has already occurred, followed
by oral therapy for 3 months in a localized thrombus, extended to 6
months if there has been embolism to the lungs.
o Fibrinolytic therapy sometimes may be used followed by
anticoagulation to prevent recurrence.

Arterial thrombo-embolism

o A large component of platelet aggregation plus a fibrin- based blood


clot associated with underlying pathological changes in the vessels.
o Poor coronary response to oral anticoagulation, equivocal results with
anti-platelets both in prevention and treatment. Fibrinolysis has given
better results in expert hands.
o Acute peripheral arterial thrombo-embolism responds to fibrinolysis,
chronic disease does not.
o Oral anticoagulation combined with anti-platelets has been used in
cerebral vascular disease .

DIC

o Benefits from heparin therapy.

ANTIFIBRINOLYTIC DRUGS

Aminocaproic acid (AmicarR, Caprocid R)

 Analogue of lysine.
 Inhibits streptokinase & urokinase and also prevents the formation of
plasmin by plasminogen activator.
 Well absorbed orally and by injection.
 Use for bleeding not associated with fibrinolytic therapy is not
uncommon.

Aprotinin (TransylolR)

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 A biologic kallikrein or protease enzyme inhibitor.

Tranexamic acid

 Used to prevent or treat bleeding associated with excessive fibrinolysis


e.g. prostatectomy, bladder surgery, dental surgery in patient with
haemophilia, menorrhagia, conisation of the cervix and traumatic
hyphaema (recurrent IO bleeding leading to secondary glaucoma,
corneal staining and lens opacities). Also in hereditary angioedema,
epistaxis and in thrombolytic overdose.

Desmopressin

 Managementof mild haemophilia and von Willebrande`s disease.

Etamsylate

 Acts by correcting adhesion abnormalities not stabilization of fibrin.


 Reduces capillary bleeding in the presence of normal platelets number.
 Is currently used in blood loss in menorrhagia 500 mg TID during
menstruation.
 May cause nausea headache or rashes.

Agents used in hyperlipidaemia

1-Niacin; nicotinic acid; vit. B3

Pharmacokinetics

 Is well-absorbed, converted to nicotinamide & incorporated into


NAD.
 Undergoes urinary excretion unchanged.
Pharmacodynamics

o 1ary inhibition of VLDL secretion, in turn decreasing


LDL production.
o Increased clearance of VLDL via lipoprotein-lipase
pathway.

105
o Neutral sterols are lost in faeces as cholesterol is
removed from tissues.
Uses

1- Hypercholesterolaemia (LDL).
2- Nephrosis.
3- Lipaemia (triglycerides).
4- Hyperlipoprotienaemia.
Adverse effects;

1- Cutaneous vasodilatation.
2- Warmth.
3- A mild allergic reaction.

2-Fibric acid derivatives

Gemfibrozil, fenofibrate & clofibrate

Pharmacokinetics

o undergo intestinal absorption.


o tight plasma-protein binding.
o entero-hepatic circulation.
o readily cross the placenta.
o plasma half-life 90 minutes,(fenofibrate 20 hrs).
o hepatic metabolism & urinary excretion.
Pharmacodynamics

o Potentiate lipoprotein-lipase;
o Lipolysis of lipoproteins & triglycerides;
o Decrease intracellular lipolysis of lipoproteins;
o Decrease plasma VLDL;
o Moderately increase HDL-cholesterol 2ndary to
decreasing plasma triglycerides.
Use

Hypertriglyceridaemia wherein VLDL predominates.


Adverse effects

o Skin reactions.

106
o GIT symptoms & myopathy.
o Hypokalaemia & high level of GOT, GPT, & ALP.

3- Resins

Colestipol & cholestyramine

Are water-insoluble resins that precipitate bile acids in the


intestinal lumen by preventing their re- absorption.
Pharmacodynamics

o Bile acids are the metabolites of cholesterol;


o By enhancing their excretion, de novo-synthesis of bile
acids from cholesterol is activated in the liver (-ve feed-
back control);
o Increased uptake of LDL from plasma.
Use

1- Treatment of hypercholesterolaemia.
2- Relief of pruritis in cholestasis & bile salt accumulation (ecterus).
3- Removal of digitalis from GIT by binding the glycoside in overdose
toxicities.
Adverse effects

o Bloat & constipation (avoid in diverticularis).


o Diarrohea is not uncommon.
4- Competative HMG-CoA reductase inhibitors

Lovastatin, atorvastatin, simvastatin, cerivastatin, pravastatin & fluvastatin

Are analogs of 3-hydroxy-3-methylglutaryl-Coenzyme A.

Pharmacokinetics

o Moderately absorbed from GIT (fluv. is completely


absorbed).
o High-extraction by 1stpass in the liver.
o Biliary excretion & 20% renal excretion.
o Half-life 1-3 hrs (atorv. 14 hrs.).
Pharmacodynamics

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o Induce LDL receptors & increase hepatic catabolism of
LDL & VLDL.
o Decrease de novo cholesterologenesis.

Use Treatment of elevated plasma LDL.

Adverse effects

Elevate plasma aminotransferases activity, potential of myopathy.

Antimalarial Drugs

1. Falciparum malaria

o P. falciparum causes malignant malaria resistant to chloroquine.


o If the infective agent is not known or is a mixed infection the treatment
of falciparum is indicated.
o Due to rapid progress in unprotected individuals ttt is indicated in
those with features of severe malaria and possible exposure, even if the
initial blood tests for the organism were negative.

Quinine

o Oral administration is indicated if the patient can swallow and retain


tablets and there are no serious manifestations (e.g. impaired
consciousness).
o Adult dose is 600mg TID of quinine HCL, dihydrochloride or sulfate
for 5- 7 days.
o I.V. infusion of quinine is indicated in patients unable to swallow or
retain tablets, in seriously ill patients or if more than 2% of RBCs are
parasitized.
o A loading dose of 20mg/kg infused over 4hrs, then 8hrs after the start
of the loading dose maintenance dose of 10mg/kg is infused over 4hr
and repeated every 8hr until the patient can take orally to complete
the 7 day course of ttt.

108
o Children tolerate quinine ttt well. Oral dose is 10mg/kg TID for 7
days, I.V. infusion dose is calculated as for adults.
o Falciparum malaria is particularly dangerous during pregnancy
especially in the 3rd trimester. Quinine adult doses including the
loading dose can be given safely during pregnancy.

Doxycycline, clindamycin or pyrimethamine/sulfadoxine

o Are given as adjunctive therapy together or after quinine ttt.


o Doxycycline 200mg OD for 7days.
o Clindamycin 450 mg TID for 7days.
o Pyrimethamine 75mg /sulfadoxine 1.5g as a single dose.

Mefloquine is not indicated for concerns about resistance.

Malarone

o Is Proguanil with atovaquone.


o May be given instead of quinine in 4 `standard` tablets OD for 3days.
o Adjunctive therapy not indicated.

Riamet

o Is Artemether with lumefantrine.


o 4 tablets doses given at 0, 8, 24, 36, 48, and 60 hr (total of 24 tablets
over 60 hrs).
o May be given instead of quinine in 4 `standard` tablets OD for 3days.
o Adjunctive therapy not indicated.

Artesunate

o Is retained for difficult cases such as hyper-parasitaemia, deterioration


on optimal doses of quinine or infection acquired in quinine resistant
areas of south-east Asia.
o Artesunate I.V. is given with specialist advice on the basis of `named-
patient` use.

109
2. Benign malarias are caused by P. vivax and less commonly P. ovale and P.
malariae.

Chloroquine

o DOC.
o Primaquine is given after chloroquine course in P.vivax and P. ovale to
destroy parasites in liver and prevent relapse. This radical cure should
be postponed in pregnant ladies until pregnancy is over.

Contra-indications

o Caution in hepatic and renal impairments.

o It is contraindicated during pregnancy, but breast- feeding should be


avoided during chloroquine therapy.

o Epilepsy, severe GIT disorders and G6PD deficiency.

Side effects

o Retinopathy and visual disturbances.

o Convulsions and other CNS disturbances.

Chapter 6

ENDOCRINE PHARMACOLOGY

Drugs used in diabetes mellitus

Diabetes mellitus occurs due to lack of insulin or resistance to its actions.

 Type 1 diabetes (IDDM) occurs due to deficiency of insulin following


autoimmune destruction of pancreatic beta cells, patients require
adminsteration of insulin.
 Type 2 diabetes (NIDDM) occurs due to decreased insulin secretion or
peripheral resistance to its actions (or both), patients require
adminstration of oral antidiabetic drugs or insulin (or both).

110
Insulin

Therapeutic indications

1. Diabetic ketoacidosis (DKA).


2. Rapid onset of symptoms.
3. Substantial loss of weight.
4. Weakness.
5. Ketonuria.
6. A 1st degree relative who have type 1 diabetes.
7. All children with diabetes.
8. For type 2 diabetes when other methods have failed to achieve control.
9. For type 2 diabetes temporarily in the presence of intercurrent illness
or peri-operatively.
10. For type- 2 diabetes during pregnancy.

Therapeutic goals

1. To alleviate symptoms.
2. To avoid complications of therapy mainly hypoglycemia.
3. To maintain a normoglycemic status of 4- 9 mmol/l for most of the
time (4- 7 mmol/l before meals and less than 9 mmol/l postprandially)
or glycosylated hemoglobin (HbA1C) concentration of 6.5- 7.5%
(reference range 4- 6%).
4. To prevent complications of the disease.

Pharmacokinetics

1. Insulin is inactivated by gastro-intestinal enzymes and must therefore be


given by injection.
2. It is commonly administered S/C using the conventional syringe,
injection device `pen`, or by continuous S/C infusion using a portable
infusion pump which delivers a contiuous basal short acting insulin
infusion and and a patient- activated pollus at meal time.
3. It is commonly administered S/C in the upper arms, thighs, buttocks
or abdomen.

111
4. Although S/C absorption is slow and fairly regular, absorption from a
limb site may be increased if the limb is used in strenuous exercise after
the injection.
5. I/V infusion peri-operational, and during diabetic emergencies via a
syringe pump. If a syringe pump is not available soluble insulin 16
units/l is added to the I/V infusion of glucose 5 or 10% containing K.
The infusion is run at a rate appropriate to the patient fluid
requirements, depending on the volume of depletion, cardiac function,
age and other factors.
6. The duration of action of I/V insulin is only a few minutes. The
infusion should be stopped for 30 minutes is the patient becomes
overtly hypoglycemic (≤ 3mmol/l).
7. K levels should be regularly monitored with other plasma electrolytes.
8. NaCl 9% should replace 5% glucose if high blood glucose level persists
(≥ 15mmol/l).

Side effects

1. Hypoglycemia.
2. All insulin preparations including porcine, bovine and recombinant
insulin are immunogenic, immunological resistance to insulin actions
is not uncommon. Preparations of human sequence insulin, by
enzymatic modification of porcine insulin, should theoretically be less
immunogenic, but no evidence supports this in the clinical trials.
3. Fat hypertrophy at recurrent site of injection. Can be minimized by
using different injection sites in rotation.
4. Local allergic reactions (rare).
5. Weight gain.
6. Large babies that might develop postpartum hypoglycemia.

Insulin preparations

1. Short- acting insulins

Insulin Preparation Use Duration Notes


Soluble(Neutral) Highly- DM Rapid onset All routes of

112
e.g. Hypurin® purified DKA (30- 60min). adminstration.
porcine or Surgery Peak 2-
bovine 4hrs.
Duration
8hrs.
Soluble(Neutral) Human- DM Rapid onset Not indicated
e.g. Humulin® sequence DKA (30- 60min). for use in S/C
®
Insuman modified Surgery Peak 2- infusion.
porcine 4hrs.
Duration
8hrs
Aspart Recombinant DM Faster onset. Less
human Shorter hypoglycemic
insulin duration. events.
analogue
Glulisine Recombinant DM Faster onset. Less
human Shorter hypoglycemic
insulin duration events.
analogue
Lispro Recombinant DM Faster onset. Less
human Shorter hypoglycemic
insulin duration events.
analogue

2. Intermediate- and long- acting insulins

Insulin Preparation Use Duration Notes


Detemir Recombinant DM Long- acting. Should not
®
e.g. Levemir human Delayed be mixed
insulin onset 1- 2 with soluble
analogue hrs. insulin in
Peak 4- the same
12hrs. syringe.
Duration 16- OD or BID
35hrs. with soluble
insulin.
Glargine Recombinant DM Long- acting. Should not

113
e.g. Lantus® human Delayed be mixed
insulin onset 1- 2 with soluble
analogue hrs. insulin in
Peak 4- the same
12hrs. syringe.
Duration 16- OD or BID
35hrs. with soluble
insulin.
Insulin zinc Human- DM Long- acting.
suspension sequence or Delayed
(Mixed) porcine onset 1- 2
e.g. and/or hrs.
Hypurin® bovine Peak 4-
Bovine Lente insulin 12hrs.
complexed Duration 16-
with a 35hrs.
suitable zinc
salt
Isophane Porcine or DM Intermediate-
insulin bovine acting
(Isophane insulin or
protamine Human-
insulin sequence
injection) suspension
complexed
with a
suitable
protamine
Protamine Soluble DM Long- acting. Blunts the
Zinc Insulin insulin initial effect
complexed of soluble
with insulins.
protamine
and zinc
chloride

3. Biphasic insulins

114
Insulin Preparation Use Duration
Biphasic 25% insulin DM Intermediate-
insulin Lispro Lispro , 75% acting
e.g. insulin
Humalog®Mix Lispro
protamine
Biphasic 30% Insulin DM Intermediate-
insulin Aspart Aspart, 70% acting
e.g. Novomix® Insulin
Aspart
protamine
Biphasic Porcine or DM Intermediate-
Isophane human acting
insulin insulin
®
e.g. Mixtard complexed
with
protamine
sulphate in a
solution of
insulin of the
same species.

Oral antidiabetic drugs

Sulphonylureas

Drugs in the class include the long- acting Glibenclamide and


Chlorpropamide associated with a greater risk of hypoglycemia particularly in
the elderly, and the short- acting Gliclazide, Glipizide, Glimepiride and
Tolbutamide.

Mechanism of action

Act by augmenting insulin secretion by increasing depolarization of pancreatic


β- cells through K- channels. They are effective only when some residual β-
cells activity is present.

Therapeutic indications

115
1. Type 2 DM after the patient fails to respond to a 3 month restriction of
carbohydrate and energy intake and increased exercise.
2. Type 2 DM in patients who are not overweight and did not respond to
or tolerate Metformin.

Contra- indications

1. Severe hepatic impairment.


2. Pregnancy and breast- feeding.
3. DKA.
4. Caution with obesity, renal impairment, and elderly.

Side effects

1. Hypoglycemia.
2. GIT disturbances.
3. Chlorpropamide due to prolonged duration causes hypoglycemia more
frequently and face flushing so no longer recommended.
4. Occasional alteration of liver function and cholestatic jaundice.
5. Initial allergic reactions which may proceed to erythema multiform and
exfoliative dermatitis or photosensitivity.
6. Blood disorders including pancytopenia.

Biguanides

Metformin (GlucophageR)

Mechanism of action

Act by decreasing gluconeogenesis and by increasing peripheral glucose


utilization. Its actions depend on the presence of endogenous insulin so it is
effective only when some residual β- cells activity is present.

Therapeutic indications

1. Type 2 DM, the drug of choice in obese patients not controlled by diet
restriction alone.

116
2. Combined with sulphonylureas in patients not controlled by
sulphonylureas alone.
3. Increased insulin sensitivity aids in weight reduction.
4. Symptomatic management in polycystic ovary syndrome.
5. Normalization of menstrual cycle by increasing the rate of spontaneous
ovulation.
6. Improves hirsutism.

Contra- indications

1. DKA, lactic acidosis and renal impairment.


2. General anaesthesia.
3. Pregnancy and breast- feeding.

Side effects

1. GIT disturbances and taste disturbances.


2. Rare lactic acidosis.
3. Decreased B12 absorption.
4. Allergy.

Other antidiabetic drugs

Acarbose (GlucobayR)

Mechanism of action

Act by inhibiting intestinal α- glucosidases, it delays the digestion and


absorption of starch and sucrose thereby significantly lowering blood glucose.

Therapeutic indications

1. Type 2 DM, reserved for use in patients when other oral hypoglycemic
drugs are contraindicated or are not tolerated.
2. Postprandial hyperglycemia in type 1 DM.

Contra- indications

117
1. IBD, predisposition to partial intestinal obstruction, hernia, previous
abdominal surgery.
2. Hepatic or renal impairment.
3. Pregnancy and breast- feeding.

Side effects

1. GIT disturbances associated with flatulence and diarrhoea.


2. Allergy.

Nateglinide and Repaglinide

Mechanism of action

1. Stimulate insulin secretion.


2. Rapid onset and short duration of action.

Therapeutic indications

1. Type 2 DM, administered shortly after each main meal.


2. Repaglinide is indicated as monotherapy in patients who are not
overweight or in whom Metformin is not indicated, or it may be given
combined with Metformin.
3. Nateglinide is licensed only for use with Metformin.

Contra- indications

1. DKA.
2. Hepatic impairment.
3. Pregnancy and breast- feeding.

Side effects

1. Hypoglycemia.
2. GIT disturbances associated with flatulence and diarrhoea.
3. Allergy.

Thiazolidinediones

118
Pioglitazone and Rosiglitazone

Mechanism of action

Act by reducing peripheral insulin resistance. Their actions depend on the


presence of endogenous insulin so they are effective only when some residual
β- cells activity is present.

Therapeutic indications

Type 2 DM alone or with:

1. Sulphonylureas if Metformin is not indicated.


2. Metformin in risk of hypoglycemia.
3. Sulphonylureas and Metformin if Insulin is not indicated or if the
patient is obese or has a metabolic syndrome.

Contra- indications

1. Cardiovascular disease.
2. Hepatic impairment.
3. Pregnancy and breast- feeding.

Side effects

1. GIT disturbances.
2. Weight gain and oedema.
3. Headache dizziness, vertigo and visual disturbances.
4. Arthralgia and hypoaesthesia.
5. Insomnia and sweating.

Thyroid hormones

THYRO LEVOTHYROXINE-Na LIOTHYROXINE- Na


XINE
(Thyroxine Na) (L- Tri- iodothyronine Na)
Indication 1. Hypothyroidism o Severe hypothyroid
s (myxoedem). states where rapid
2. Diffuse non- toxic response is required.

119
goiter. o IV injection is the TFC
3. Hashimoto`s in hypothyroid coma.
thyroiditis. o Adjunct. T. include
4. Thyroid carcinoma. fluids, hydrocortisone,
5. Neonatal congenital anti- infection and
hypothyroidism. assisted ventilation.
6. Juvenile myxoedema.
Potency 1 4
(25 microgms are equivalent
to 100 microgms of
levothyroxine).
Onset of Slow but sustained suitable Rapid in a few hrs and
action & for maintenance therapy. disappear within 24- 48 hrs.
T1/2E
Pregnanc o Crosses placenta. o Does not cross
y& o Hi- doses detrimental placenta.
lactation to foetus. o Too small amounts to
o Too small amounts to affect tests for neonatal
affect tests for neonatal hypothyroidism.
hypothyroidism.
Side Mimic symptoms of Mimic symptoms of
effects hyperthyroidism hyperthyroidism

Antithyroid drugs

Carbimazole

Mechanism of action

Acts primarily by interfering with the synthesis of thyroid hormones.

Indications

1. Hyperthyroidism.
2. Preparation of thyroidectomy patients for surgery.

Contra- indications

1. Severe hepatic impairment.

120
2. Pregnancy, risk of afflicting neonatal goiter and hypothyroidism and
congenital defects including aplasia cutis.
3. Breast- feeding, may affect neonatal thyroid function.

Side effects

1. Hypothyroidism with over- treatment.


2. BM- suppression leading to neutropenia and agranulocytosis, patients
should be counseled to report immediately sore throat, mouth ulcers,
bruising, fever, malaise or non specific illness.
3. Rash and pruritus commonly treated with antihistamines without
discontinuing therapy.

Blocking- replacement therapy

Is the use of carbimazole with levothyroxine OD usually for 18 months, this


regimen is not suitable during pregnancy.

Propylthiouracil

Mechanism of action

Acts primarily by interfering with the synthesis of thyroid hormones.

Indications

1. Hyperthyroidism.
2. Reserved for patients who are intolerant of carbimazole or who
experience sensitivity reaction and other treatments are not
appropriate.

Contra- indications and side effects are similar to carbimazole.

Iodine

Indications

1. Adjunct to antithyroid drugs.

121
2. Radioactive Na- iodide (131I) is indicated for thyrotoxicosis in all ages, in
patients with heart disease and in those who relapse after
thyroidectomy.

Contra- indication

1. Long- term treatment due to development of tolerance.


2. Pregnancy.

Propranolol and nadolol

Indications

1. Thyrotoxic symptoms.
2. Adjunct to antithyroid drugs and iodine.
3. Neonatal thyrotoxicosis.
4. Supraventricular arrhythmias due to hyperthyroidism.

Treatment of thyrotoxic crisis (thyroid storm)

1. Emergency IV fluids.
2. Propranolol.
3. Hydrocortisone Na- succinate.
4. Oral iodine solution with carbimazole or propylthiouracil by NG- tube.

Corticosteroids

ž A steroid is a type of organic compound that contains a characteristic


arrangement of four cycloalkane rings that are joined to each other.
Examples of steroids include the dietary fat cholesterol, the sex hormones
estradiol and testosterone and the anti-inflammatory drug dexamethasone.

ž The core of steroids is composed of twenty carbon atoms bonded together


that take the form of four fused rings: three cyclohexane rings (designated
as rings A, B and C in the figure to the right) and one cyclopentane ring
(the D ring). The steroids vary by the functional groups attached to this
four-ring core and by the oxidation state of the rings. Sterols are special

122
forms of steroids, with a hydroxylgroup at position-3 and a skeleton
derived from cholestane

Common steriod drugs:

ž Beclomethasone

ž Betamethasone

ž Cortisone

ž Hydrocortisone

ž Prednisone

ž Prednisolone

123
ž Methylprednisolone

ž Dexamethasone

Betamethasone and dexamethazone:

 Have very high glucocorticoid activity

 With insignificant mineralocorticoid activity

 Have long duration of action

Cortisone and hydrocortisone:

 Have high mineralocorticoid activity

 Hydrocotisone is prefered because cortisone requires conversion in the


liver to hydro cortisone

 Hydrocotisone is used on short term basis by i.v injection for the


emergency mangement of some condtions

Prednisolone:

 Has predominantly glucocorticiod activity


 Is most commonly used orally for long term disease suppression

CLINICAL USE OF STEROIDS:

1- In patients of proven adrenocortical insfficincy.


2- Immunsuppresive: Used in treatment of autoimmune diseases e.g.
SLE or in organ transplantation
3- Blood pressure control: Increase blood pressure by mechanisms
involving action on the kidney and vascular system. Increase
sensetivity to pressor agents such as catecholamines , and angiotensin
II while decrease Nitric oxide -mediated endothelial dilatation .
4- Anti– inflammatory effect: Cortisol in large doses has anti-
inflammatory effects. It stablizes lysozyme membrane, decreases the

124
release of inflammatory lysozyme and decreases capillary permeability
which prevents loss of plasma proteins to tissues, it also interferes with
complement pathway activation and formation of chemical mediators
derived from arachidonic acid such as leukotrienes.
5- Steroids in hyper reactive airway: their anti-inflammatory action leads
to decreased mucosal edema and prevents release of broncho-
constricter substances. They have permissive role for bronchodilator
medication, that is, they enhance the efficacy of bronchodilators so
used in asthma.
6- In post- operative nausea and vomiting )PONV): The antiemetic
mechanism of corticosteroids is unknown. Dexamethasone a
corticosteroid with strong anti-inflammatory effects provides
postoperative analgesia & prevents nausea and vomiting in patients
undergoing chemotherapy and reduces postoperative nausea and
vomiting.
7- Post intubation laryngeal oedema: Prevent post-operative laryngeal
oedema by their anti-inflammatory action e.g. dexamethasone.
8- Sepsis: Patients having severe sepsis or in septic shock were found to
have unrecognised adrenal insufficiency.
9- Anaphylaxis: Corticosteroids can decrease the swelling & prevent the
recurrence of symptoms. Hydrocortisone is the preferred steroid
because of its fast onset of action.
10- In cerebral oedema: Steroids are of value in reduction or prevention of
cerebral oedema associated with parasitic infection or neoplasms.
11- In ampulatory surgery: Post- operative and post- discharge nausea and
vomiting are the most common complication of ampulatory surgery,
steroids decrease the incidence of post operative nausea and vomiting,
post-operative pain & stimulate appetite and induce a sense of well-
being (due to the release of endorphins) e.g. dexamethasone.
12- Epidural steroid injection (ESI) has been used to treat back pain (due
to nerve root irritation) in patients with a wide variety of spine
pathologies including spinal stenosis, disk-space narrowing, and
vertebral fractures. The purpose of an ESI is to deliver medication

125
directly to the affected nerve root limiting the effects of systemically
administered steroids.
13- Analgesic effect: Analgesic effect of steroids is suspected to be mediated
by anti-inflammatory and immunsuppressive mechanisms. The anti-
inflammatory action results in decreased production of various
inflammatory mediators that play a major role in amplifying and
maintaining of pain perception e.g. methylpredinsolone.
14- Pre-operative replacement therapy: Corticostroid supplementation
should be provided for patients being treated with steroid either for
hypocortisolism or for other diseases. Increase in plasma level of
cortisol due to severe surgical stress is one of the important
components of stress response. In the preoperative period due to
adrenal suppression, there can be increased vascular permeability,
inadequate vasomotor response, decreased cardiac output, decreased
systemic vascular resistance and left ventricular stroke volume index
which can lead to severe hypotension and cardiovascular collapse,
respiratory depression, hyponatremia, hypoglycaemia, hypercalcemia
and hemoconcentration.

Side effects

Long term side effects of steroids

Inhaled corticosteroids

 If inhaled corticosteroids are taken for a short period, most people


tolerate them well and have few or no side effects.
 Long-term use to treat a condition such as asthma can cause oral
thrush. Also it can affect the throat causing hoarseness.
 Rinsing the mouth out with water after using inhaled
corticosteroids can help prevent oral thrush.

Injected corticosteroids

 Corticosteroids that are injected into muscles and joints may cause
some pain and swelling at the site of the injection. However, this

126
should pass within a few days. Over time, repeated steroid injections
into a muscle can weaken it.
 Corticosteroids are usually only injected directly into the blood
when there is an urgent need for treatment. Corticosteroids injected
into the blood can cause side effects including:
 stomach irritation, such as indigestion, tachycardia, nausea,
insomnia, a metallic taste in the mouth, mood changes, from feeling
very happy one minute to being irritable, depressed or restless the
next.

Side effects of topical corticosteroids

 Topical corticosteroids can lead to thin skin, red skin lesions and
acne.

Oral corticosteroids

Side effects of oral corticosteroids that are used for short periods
include:

 Increased appetite that often leads to weight gain.

 Acne – affects most people at some point due to stimulation of the


sebaceous glands by increased testosterone levels.

 Mood changes.

Side effects of oral corticosteroids used for longer than three months
include:

 Further weight gain.


 Thinning skin which can bruise easily.
 Muscle weakness.
 A combination of fatty deposits that develop in the face (moon face),
stretch marks across the body and acne Cushing’s syndrome.

127
 Most side effects improve to reduced dosage. Osteoporosis can be a
persistent problem, particularly at over 65. With more vulnerablity to
breaking a bone.

 Regular checks and tests for conditions such as diabetes, high blood
pressure and glaucoma are needed.

128
 The onset of diabetes, or worsening of existing diabetes

 High blood pressure

 Glaucoma

 Cataracts

 Delayed wound healing

 Reduced growth in children

 Increased risk of infection

 Development of breast tissue in males gynecomastia (caused by high


levels of circulating estradiol),

 Suppressed adrenal gland hormone production

Mental heath

ž About 5%who takes the oral corticosteroid prednisolone experiences


changes in their mental state. These changes may include:

129
 Depressed and suicidal intentions.

 Feeling manic (very happy and full of energy and ideas)

 Feeling very anxious

 Feeling very confused

 Hallucinations (seeing or hearing things that are not really there)

 Having strange and frightening thoughts

Vulnerability to infection

 Chickenpox and shingles (the varicella-zoster virus)

 Measles (caused by the paramyxovirus) becoming very ill, even if has


been previously infected.

Reduce the risk of corticosteroid side effects:

 Lower doses or intermittent dosing.


 Switch to non- oral forms of corticosteroids.
 Dose- tapering when discontinuing therapy.

CHRONOBIOLOGY

Is the study of temporal variability in biological functions, is contributing


important new information to clinical medicine. To most the concept of
chronobiology is foreign and incompatible with that of homeostasis.

130
 Chronbiological mechanisms regulate sleep time, feeling hungry,
change in the level of hormones and in the body temperature.

 The biological rhythms affect the time in which disease may occur
when or intensify e.g. onset of asthma crises at the time of sleep, and
most epileptic seizures occuring in the morning or evening.

 Biological rhythms likewise in affect drugs and their dynamics and


kinetics. Thus, knowledge of biological rhythms may enables
medication at a time that increases the likelihood of therapeutic
benefit.

CHRONOPHARMACOLOGY

 The study of rhythmic, predictable-in-time differences in the effects


and/or pharmacokinetics of drugs.

131
 The once daily administration of medications at specified time selected
so as to minimize inhibition of the endogenous cortical secretion of &
to preserve the temporal organization of biological functioning.
Prednisone & methylprednisolone satisfy these requirements when
given in the morning on alternate days to patients adhering to diurnal
activity & nocturnal rest.
 Adrenal inhibition it is well documented with the administration of
corticosteroids at a time coinciding with the circadian crest of
endogenous adrenocortical secretion.
 Pluricorticoid therapy is the combined therapy of 2 or more
corticosteroids administered twice daily at specific times.

132
Chapter 7

Drugs affecting the GIT

(1) Salivary Stimulants

 Watery saliva is governed by parasympathetic NS.


 Viscous saliva is governed by sympathetic NS.
Indication

To improve appetite & digestibility.

1- Locally-acting agents are known as bitters e.g. nux vomica &


strychnine, act by stimulation of taste buds on the tongue.
2- Centrally-acting agents e.g. cabachol act by general stimulation of the
parasympathetic NS.

(2) Salivary Inhibitors (antisialagogues)

Indication

Surgery of the mouth.

Agent used is atropine.

Action

Mainly inhibition of bronchial secretions.

(3) Appetite Stimulants

Mechanisms & receptors

A- Appetite is primarily (not exclusively) controlled by ventral & lateral


nuclei of the hypothalamus.
B- Stimulatory mediators include noradrenaline (α2-receptors), dopamine
(D1 –receptors) & GABA. The inhibitory mediator is 5HT.
C- Neuropeptides control appetite by controlling the neurotransmitter
release; opiates & pancreatic polypeptides increase appetite, calcitonin,
cholecytokinin & corticotrophin-RF inhibit appetite.
Indications

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Cachexia, anorexia & weight-loss associated with cancer.

Agents

1- Drugs that inhibit gluconeogenesis e.g. hydrazine sulphate.


2- Drugs that promote gastric emptying e.g. metclopramide.
3- Steroids e.g. megestrol (less adverse effects than anabolic steroids).
4- Benzodiazepines e.g. I/v or oral diazepam or oral oxazepam through
GABA-induced effects & inhibition of satiety centre of hypothalamus.
5- Cyproheptadine the antihistaminic with antiserotonin properties.
6- Others include serotonin agonists, glucocorticoids, B-vitamins & the
anti-depressants; TCA & lithium.

Emesis

A complex protective reflex controlled by the emetic centre located in the


lateral reticular formation protected by the BBB.

Afferent pathways

1- Higher centres (cerebrum), mediators ACh & histamine, psychogenic


stimuli.
2- Elevated CSF, CNS disorders & head injury, mediators ACh &
histamine H1.
3- Vestibular apparatus, H1 & ACh e.g. in motion sickness.
4- Peripheral receptor via 9th cranial nerve to emetic centre, abdominal&
thoracic organs irritation, distention, hyperosmolarity & inflammation,
ACh.
The CTZ in area postrema outside BBB is stimulated by blood-bourn
chemical substances e.g. drugs, toxins, uremia, pyometra, liver disease,
endotoxemia, radiation sickness disease, digitalis, apomorphine, narcotic
analgesics & oestrogen. Initiators are dopamine receptors, 5HT & H1.

(4) Emetics

Indications

Intoxication, accidental ingestion of drugs by children & emergency


operations.

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1- Central emetics S/c apomorphine stimulates CTZ.
2- Peripheral emetics act by local irritation of gastric mucosa
 Rapidly acting as salts of heavy metals, hypertonic solutions or
mustard in warm water.
 Slowly acting which are used as nauseating expectorants e.g.
tincture ipecacuanha, tincture senega & ammonium chloride
& carbonate.

(5) Anti-emetic drugs

1- Antihistaminics (H1-blockers) diphenylhydramine, dimenhydinate,


chlorpheniramine maleate, meclizine, cyclizine & promethazine.
They act by inhibiting the vomiting centre, used in motion sickness.
2- Phenothazines chlorpromazine, trifluoperazine & thioethylperazine.
Act by blocking dopaminergic receptors in CTZ, effective against all
types of vomiting except motion sickness.
3- Butyrophenones droperidol & haloperidol, block D2-receptor in CTZ.
4- Thioxanthenes flupenthioxol, block D2-receptor in CTZ.
5- Metclopramide (primperan)R,
Actions

I. Antiemetic action by blocking D2 in CTZ.


II. Prokinetic action stimulating motility especially in proximal gut
but unlike cholinergic agonists does not stimulate gastric or
pancreatic secretions.
III. It releases ACh from cholinergic neurons in myenteric plexus of
enteric NS & may sensitize the intestinal smooth muscles to its
action.
IV. Its action is mediated by blocking dopamineric receptor D2, &
modulating serotonin receptor.
Uses;

1. Antiemetic especially in cancer chemotherapy, radiation


sickness, post-operative vomiting & hiccough.
2. Facilitates small bowel intubation, increases gastric emptying
after vagotomy or in diabetic gastroparesis, in reflux oesophagitis
& in emergency operation or labor to prevent aspiration of
gastric contents.

135
Adverse effects;

Parkinsonism, hyperprolactinaemia, galactorrhea & menstrual


disturbances.
6- Domperidone ( Motilium)R dopamineric antagonist which crosses BBB
to a limited extent so has less side effects.
7- Ondasteron, gransteron are 5HT antagonists used in vomiting indused
by cancer chemotherapy.
8- Hyoscine act by inhibiting the vomiting centre.
9- Pyridoxine (B6) in vomiting of pregnancy.
10- Glucocorticoids as dexamethasone can be combined with pyridoxine.

(5) Prokinetic drugs

1- Metclopramide, domperidone & cisapride. Both metclopramide &


cisapride are serotonine-R modulators.
2- Parasympathomimetics, as bethanechol, increase motility & secretions.
3- Motilin-like agents e.g. erythromycin ( motilin is a peptide hormone
which has prokinetic effect in upper gut by acting in specific motilin-R).
Eyrthromycin acts on these R so can be used in diabetic gastroparesis.

(6) Laxatives & Purgatives

Are drugs which evacuate the bowel by increasing frequency of


defecation or fecal volume or consistency.
 Laxatives (or aperients) promote the elimination of soft formed
stools.
 Purgatives (or cathartics) produce a more fluid evacuation.
(A) Luminally-active agents (bulk purgatives)

1- Hydrophilic colloids & undigestible fibres as agar, psyllium (plantago) seed,


methyl cellulose & bran, by increasing bulk they stimulate peristalsis.

2- Osmotic agents absorb water & swell forming emollient gel.

 Cellulose & hemicellulose fermented by gut bacteria to volatile fatty


acids that exert osmotic effects.

136
 Saline purgatives as Mg-sulphate (Epsom salt), Na-sulphate (Glauber`s
salt), K-Na-tartrate (Rochelle salt), Mg-oxide (Milk of magnesia) & Mg-
citrate. They are poorly absorbed from gut so retain water increasing
bulk. Act after 1-2 hours. Given before breakfast on empty stomach in
isotonic solution. Contraindicated in pregnancy & chronic
constipation.
 Non-digestible sugar-alcohols lactulose, sorbitol & manitol are
hydrolyzed in the intestine to organic acids which acidify luminal
contents & draw water stimulating colonic motility. By saccharolytic
microflora acetic acid, lactic acid, etc. are formed lowering pH.
 Lactulose used for treatment of hepatic encephalopathy by
acidification of large intestine favors the formation of the non-
absorbable ammonium ion than the readily-absorbable ammonia
molecule, which requires detoxification in the liver by the urea cycle,
hyperammonemia is thus prevented, other toxic amines absorption
also is reduced.
3- Emollients & wetting agents (lubricant purgatives)

 Liquid paraffin; mineral oil; produce softening of the stools & easier
evacuation, act in 10 hours so given overnight, used in chronic habitual
constipation wherein saline agents are contraindicated.
Side effects

I. Interference with absorption of fat-soluble vitamins &


interaction with oral anticoagulants.
II. Foreign-body reaction if absorbed.
III. Lipid pneumonia if reach lungs.
IV. Anal polypi on prolonged use.
V. Delay healing of ano-rectal wounds. vi- leakage from anus &
pruritis ani.
 Wetting agents as dioctyl-Na sulphosuccinate which lowers surface
tension & facilitates penetration of water into stools.
(B) Irritant; Stimulant; Contact Purgatives Stimulate motility
& secretion.

1- Mild irritant

 Figs & prunes (bulk & irritant).

137
 Castor oil which when taken orally is transformed by pancreatic lipase
into glycerol & the hi-irritant ricinoleic acid which increases intestinal
motility yielding complete evacuation of the gut. Act in 2~6 hours at
dose range of 15~ 60 & is inactive in obstructive jaundice &
contraindicated during pregnancy.
 Linseed oil & olive oil are less irritant & act by the respective
formation of linoleates & oliveates (the Na & K salts of the released
fatty acids) which are irritant soaps.
2- Moderate irritant

 Anthracene (senna, cascara, aloe & rhubarb) release active compounds


( emodin?) which stimulate colonic motility.
Untoward effects include secretion into milk affecting suckling babies,
& into urine producing yellowish-brown discoloration of acidic urine
& reddish-brown in alkaline urine.
Colic & pigmentation of colonic mucosa are not uncommon.
 Derivatives of diphenylmethane; Phenolphthalein & bisacodyl are
dissolved by alkalinity in intestine, little is absorbed & excreted in urine
& bile. Directly stimulate colon for a period made long by their entero-
hepatic circulation. Redden alkaline urine & may trigger skin rash.
3- Severe purgatives as croton oil are not clinically used.

(C) Neuromuscular purgatives


Neostigmine, physostigmine, bethanechol, & carbachol. Other substances
that stimulate visceral smooth muscle contraction include vasopressin,
oxytocin, PGF2α & other PGs.

Indications of purgatives

1- Constipation.
2- Drug & food poisoning.
3- Before operation or radiography.
4- In treatment of helminthes.
5- To prevent straining as in heart failure or hernia.
(7) Enemata

 Evacuant enema; large volume given rapidly at hi-pressure &


38ºC.

138
 Retention enema; nutrition, basal narcotic, MgSO4 & in
treatment of some parasitic diseases. Small volume slowly given
at low head pressure.
(8) Treatment of constipation

 Proper diet; dietary fibres.


 Bowl training; conditioned reflux.
 Treat cause.
 Mild laxative.
(9) Treatment of food or drug poisoning

 Water or milk intake.


 Charcoal.
 Tincture ipecacuanha.
 Saline purgative.
(10) Treatment of diarrhea

1. Oral rehydration therapy.


2. Specific treatment of cause.
3. Symptomatic treatment;
 Adsorbants & absorbants; bismuth carbonate & subgallate,
chalk & Kaolin.
 Astringents ppt. surface proteins; tincture krameria & catecho
which release tannic acid.
 Opium derivatives; diphenoxylate (lomotil)R, loperamide
(imodium)R which have no CNS actions & are not addictive.
 Mebeverin direct action on musculature & used also in irritable
bowel syndrome.
 Atropine & other anticholinergic agents.
(11) Treatment of inflammatory bowel syndrome

1. Steroids.
2. Sulphasalazine, sulphapyridine & 5-amino-salicylic acid which act to
inhibit leukotriene synthesis.
3. Azathioprine.
(12) Uses of Magnesium sulphate

Dependency of pharmacologic action on the route of drug administration;

139
1. Cholagogue, small oral dose.
2. Bulk purgative, large oral dose.
3. A dehydrating agent, rectally.
4. Anticonvulsant (in eclampsia); hypotensive & calcium antagonist,
parenterally.
(13) Drugs used in hepatic encephalopathy

 Neomycin sterilizes colon inhibiting ammonia producing


organisms.
 Lactulose.
(14) Hepatotoxic drugs

 Heavy metals, alcohol, chloroform & tetracyclines inflict direct injury.


 Chloroform, hydrazine, MAO & halothane induce lesions similar to
viral hepatitis.

 Methyl testosterone, phenothiazines (chlorpromazine),


chlorpropamide & anti-thyroid drugs (thiouracil) produce a cholestatic
injury.

 Methyl dopa may cause allergic chronic hepatitis.

(15) Cholagogues

Are evacuants of the gallbladder.

 Mg-sulphate acts by the relaxation of the sphincter of Oddi.

 Cholcystokinin acts by the contraction of the wall.

(16) Choleretics

Stimulants of bile- secretion by liver cells.

(17) Hydrocholeretics

Increase volume but not total solids of bile, salicylates or benzoates,


contraindicated in acute hepatitis.

140
(18) Spasmolytics

Parasympatholytics or direct spasmolytics e.g. volatile oils, papaverine,


nitrites, khellin & aminophylline.

(19) Chenodeoxycholic acid & ursodeoxycholic acid

Are used to dissolve cholesterol gallstones.

(20) Octreotide

 A synthetic analog of somatostatin given parenterally.


 Inhibits gastric acid secretion, gastrin, secretin, VIP, & smooth muscle
contraction.
 Used to treat symptoms of gut tumors; carcinoid, insulinoma, &
gastrinoma, & in refractory diarrhea.

(21) Peptic ulcer

It is a non-malignant injury of mucosal barrier that result in diffusion of


H+ and ulceration in part of the digestive tract which is exposed to gastric
secretion.

141
a) Acute Ulceration and Erosions:
1. Related to acute gastritis due to predisposition to aspirin, excess
alcohol & bile reflux.
2. Related to shock: severe pain, major trauma, cerebrovascular
accident, septicemia, ACTH or corticosteroid therapy.
3. Ulceration is usually multiple and asymptomatic.
b) Chronic Peptic Ulcers; usually single and penetrate muscularis
mucosa.
c) Pathophysiology: ↑ aggressive forces or factors including HCL,
pepsin & Helicobacter pylori &/or ↓ protective or defense
mechanisms including prostaglandins, mucus & bicarbonates.
d) In gastric ulcer the acid secretion is normal or reduced suggesting an
impaired mucosal resistance. The pain is less regular (½-1hr) after
meal.
e) In duodenal ulcer there are excess acid and pepsin secretions with
tendency to nocturnal hyper-secretion. Typically pain relieved by
taking food.
f) Goals of therapy: 1- relief of pain. 2- promotion of healing . 3-
prevention of recurrence.
(22) Treatment of Peptic ulcer
a) Measures to relief pain
 General measures.
 Antacids.
 Anticholinergics.
b) Measures to promote healing:
 General measures.
 Drugs:
1- Large doses of antacids.
2-Antisecretory (drugs which inhibit acid secretion): H2
blockers, proton pump inhibitors, anticholinergics, gastrin
antagonist (proglumide) and prostaglandins (misoprostol) .

142
3- Mucosal protective agents: sucralfate, colloidal bismuth
cpd, carbenoxolone, prostaglandins.

c) Measures to prevent recurrence:


 General measures.
 Sedation if indicated by diazepam.
 Maintenance treatment (eradication of Helicobacter pylori)
General Measures
1) Rest and sedation; can heal gastric ulcer and may spontaneously
improve duodenal ulcer.
2) Stop smoking; smoking lowers the rate of ulcer healing and tends to
increase the relapse.
3) Diet; avoiding spices and taking regular meals in order to buffer
intra-gastric acidity.
4) Avoidance of Irritants such as caffeine, alcohol, NSAIDs,
corticosteroids, reserpine…etc.
Drugs to relief pain
a) Antacids: small, usual doses relief pain.
Mechanism of Action:

143
Neutralize gastric acidity → relief of pain.
Increase pH of the stomach → ↓ proteolytic activity of pepsin .
Some (in large doses) →↑PGs and eradicate H. pylori.
Classification :
Are classified as chemical or physical anti-acids .
1- chemical anti-acids :
a- Systemic antacids: soluble and absorbable; can produce systemic
alkalosis e.g. NaHCO3.
b- Non-systemic (insoluble and non-absorbable); like salts of Al+++,
Mg++ and Ca++ .
Uses:
1- Peptic ulcer→ relief of pain.
2- Gastro-esophageal reflux and heart burn.
3- Gastritis.

4- To ↑ urinary excretion of weak acidic drugs e.g.


salicylates and barbiturates.

5- To ↑ urinary excretion of uric acid → treat gout.


Adverse actions:
1. Changes in bowel habits (Ca++ and Al+++ cause constipation, and
Mg++ causes diarrhea)
2. High Na+ content can harm cardiac, renal or hepatic patients.
3. Systemic alkalosis with large doses of systemic antacids.
4. Ca-based may cause rebound hyper-secretion
5. Milk-alkali syndrome with high Ca++ intake
6. Mg++ or Al+++ may be retained in renal failure
7. Al+++ salts (not phosphate) leads to phosphate depletion
Contraindications:

144
1. Ca, Mg and Al decrease tetracycline absorption
2. Al(OH)3 decreases absorption of digoxin, phenytoin, warfarin,
etc
3. Antacids decrease absorption of anticholinergics, phenothiazine
& iron preparations.
4. Systemic antacids increase excretion of acidic drugs and decreases
excretion of basic drugs.
Drug interactions:
a) affect bioavalability of other drugs e.g. Ca, Mg and
Al↓absorption of tetracyclines; Mg and Al ↓absorption of
warfarin,digoxin, iron, theophyline, ketoconazole and
quinolones
b) change pH of bowel contents
c) adsorption or chelation
d) change gastric emptying or transit time
Preparations:
 NaHCO3: is the only useful water-soluble antacid. It acts rapidly but
has a transient action (short duration) and absorbed bicarbonate in
higher doses may cause
1. systemic alkalosis,
2. CO2 release→ abd.distention→ discomfort, dissolve
mucus,
3. alkalinization of urine: a- precipitates phosphate stones . b-
↓excretion of weak basic drugs e.g. ephedrine.
4. hypernatremia which is contraindicated in heart failure
and hypertension.
 Al(OH)3: has a relatively slower action. Al+3 ions form complex with
certain drugs like tetracycline & constipation, a mixture of Al(OH)3
and Mg(OH)2 may be used to minimize the effect on motility.
 Mg(OH)2: insoluble in water and has a fairly rapid action. Mg++ has a
laxative effect → diarrhea.
 GavisonR: (alginic acid, Mg tri-silicate, Al(OH)3 gel, NaHCO3). The
alginic acid in presence of saliva reacts with NaHCO3 to produce a
high viscous foaming solution of Na alginate in which librated CO2

145
is trapped. This material swells and floats on gastric contents as a
chaff which usually prevents gastric reflux.

146
b) Anticholinergics:
 Their unwanted effects (dry mouth, constipation, urinary retention,
tachycardia, excitement, glaucoma, etc) limit their uses.
 They also decrease the lower esophageal sphincter (LES) pressure,
increase the gastro-esophageal and delay the gastric emptying.
Mechanism of action:
1. ↓ gastric acid secretion
2. ↓motility and spasm by blocking muscarinic receptors in gut.
3. Are less effective alone but may be useful when combined with H2-
blockers or antacids.
They are of two types:
1) Non selective: Oxyphenonium (5mg tds) and propantheline (15mg
qid) Dicyclomine.
2) Selective M1-blockers: Pirenzepine (50mg bid orally for 4~6 weeks)
and telenzepine which are selective blockers of peripheral muscarinic
receptors near gastric parietal cells. They selectively inhibit gastric acid
secretion with minimal side effects.
Measures to promote healing
Antacids in high doses (patient compliance is poor)
Anticholinergics with H2-blockers or antacids.
Mucosal protective agents:
1) Liquorice Derivatives (carbenoxoloneR):
These are derivatives of glycyrrhizinic acid and have steroid-like molecules.
Mechanism of Action:
I. ↑ mucosal resistance as they slow down gastric epithelial turnover.
II. ↑secretion.
III. Alter its chemical composition decrease back diffusion of H+ ions
into mucosa.
Preparations:
I. Bio-gastrone for gastric ulcer

147
II. Duo-gastrone for duodenal ulcer (enteric caps act topically)
Side Effects:
Mineralcorticoid actions (↑Na, hypertension, edema, ↓K).
2) Sucralfate:
 It is an aluminum salt of sulfate sucrose.
 It promotes healing of duodenal ulcer and may also be used in
gastric ulcer.
Mechanism of Action:
 Acts topically by forming a complex with protein in ulcer to form a
protective barrier against the acid, pepsin and bile salts.
 Stimulates the release of prostaglandins (PGs).
 Requires an acidic pH to be activated and should be administrated
simultaneously with H2-blockers or antacids.
Dose:
1gm QID on an empty stomach or 1hour before meals.
Side Effects:
 Not absorbed systemically, it has few side effects like constipation.
 It decreases the bioavailability of tetracycline, digoxin and
phenytoin.

148
4) Colloidal Bismuth Compound (de-nolR):
It promotes healing of gastric and duodenal ulcers.
Mechanism of Action:
Acts locally combining with exudate and mucosa in the base of the
ulcer providing a protective coat.
Stimulates mucus secretion & inhibits Helicobacter pylori.
Dose:
As suspension 15mg or tablets 120mg QID before meals.
Side Effects:
Unpleasant ammoniacal odor, black stools and teeth discoloration.
In cases of chronic treatment, there may be encephalopathy especially
in renal failure.
4) Prostaglandin synthetic analogs (misoprostolR200mg tablets):
a. Provide mucosal cytoprotection.
b. Increase mucus and HCO3 secretion.
c. Maintain gastric blood flow.
d. Stimulate mucosal cellular renewal and regeneration.
e. A mild inhibitory effect on gastric acid secretion.

149
5) Histamine (H2 receptor) Antagonists:
 Reduce both daytime and nocturnal gastric acid secretion.
 Block acid secretion induced by histamine, gastrin, cholinergic drugs
and vagal stimulation.
Mechanism of Action:
Competitively inhibit histamine at H2-receptor of parietal cells.
1) Cimetidine (tagametR):
Rapidly absorbed from upper small intestine.
Excreted by kidney.
Adverse effects:
1) Diarrhea, nausea, vomiting, fatigue and skin rash.
2) CNS: headache, dizziness, elderly mental confusion and delirium.
3) Endocrine: hyperprolactinemia, galactorrhea and infertility in females
and gynecomastia in males.
4) Anti-androgenic action: loss of libido, impotence and decreased sperm
count.
5) ↑ serum transaminases, hepatitis, cardiac arrhythmias, bone marrow
depression & blood dyscrasias.
6) Slow metabolism of some drugs due to inhibition of cytochrome P-450
leading to ↑level & effect of warfarin, β-blockers, phenytoin,
diazepam & theophylline.

150
2) Ranitidine (zantacR):
Differs from Cimetidine in the following:
1) Chemically it is not an imidazole but a substituted furan.
2) 5~10 times more potent and more selective H2-blocker.
3) A slightly longer duration of action.
4) Less side effects and drug interactions.
5) Doesn’t inhibit CP-450 or block androgen receptors.
6) No evidence of CNS effect.
Dose: 300mg BID.
3) Famotidine (pepcidR): Is 8~10 times more potent.
4) Nizatidine (AxidR): Stronger than ranitidine, 100% bioavilable.
6) Proton Pump Inhibitors (omeprazole):
They are activated at acidic pH to sulfonamide derivatives that binds
irreversibly to H+-K+ATPase (an enzyme found at the secretory surface
of the parietal cells).
So, they inhibit the final transport of H+ via exchange with K+ ion in
gastric lumen.
They inhibit both basal and stimulated acid secretion.
Use & dose:
Peptic ulcer and Zollinger-Ellison’s syndrome.
20~40mg /day, orally.
Side Effects:
1) GIT: diarrhea & colic.
2) CNS: headache & dizziness.
3) Skin rash, leucopenia & transient ↑ in liver enzymes.
4) ↑ gastric pH leads to ↓ absorption of ampicillin, iron preparation,
ketoconazole, etc
5) Pronounced acid inhibition at extremely high doses leads to feedback
elevation of gastrin and subsequent enterochromaffin-like-cells change
of the stomach.

151
Preparations:
1. Omeprazole (losecR)20~40mg od .orally and I.V.
2. Lansopprazole (lanzorR):15~30mg od. Orally for 4 weeks(duodenal
ulcer)
3. Pantoprazole (controlocR) : 20-40mg od. Po and 8 weeks(gastric ulcer)
4. Rabeprazole (parietR): 20mg p.o.
Metoclopramide:
 It is a pro-kinetic drug.
 The main action is to prevent enterogastric reflux.
 More effective in gastric than duodenal ulcer.
 Prevents gastroesophageal reflux- in reflux esophagitis.

(23) Standard treatment regimen for peptic ulcer:


 Drugs used to treat infections caused by H. pylori.
 The most frequently prescribed agent is (1) amoxicillin or tetracycline
or clarithromycine plus (2) metronidazole or tinidazole in
combinantion with (3) bismuth .
 This triple-therapy for 10~14 days is effective but gives rise to frequent
side effects like nausea, diarrhea, etc. This regimen eradicates H. pylori
in about 70-80% of patients.
 Omeprazole, erythromycin or clarithromycine and metronidazole
eradicate H. pylori in 95-100% of patients in one week with fewer side
effects.
 Metronidazole resistance may be a problem.
Action of combinations of antibiotic ulcer therapy that must be used
• Clarithromycin – inhibits protein synthesis
• Amoxicillin – disrupts cell wall
• Tetracycline – inhibits protein synthesis
• Metronidazole – used often due to bacterial resistance to amoxicillin
and tetracycline, or due to intolerance by the patient
• Bismuth (Pepto-Bismol®) – disrupts cell wall of H. pylori

152
(24) Gastroesophageal reflux disease (GERD):
– Backflow of stomach acid into the esophagus
– Esophagus is not equipped to handle stomach acid => scaring.
– Usual symptoms are heartburn, an uncomfortable burning
sensation behind the sternum (MI often mistaken for GERD).
– More severe symptoms: difficulty swallowing, chest pain.
– Reflux into the throat can cause sore throat.
– Complications include esophageal erosions, esophageal ulcer and
narrowing of the esophagus (esophageal stricture).
– In some patients, the normal esophageal lining or epithelium
may be replaced with abnormal (Barrett's) epithelium. This
condition
(Barrett's esophagus) has been linked to cancer of
the esophagus.
– Primary treatment option are proton pump inhibitors.

153
Chapter 8

Drugs affecting the respiratory system


Drugs that affect the respiratory system either:
 Act directly on the bronchial airways to relax bronchial smooth
muscles or modify bronchial mucous secretion. or
 Centrally affect the CNS mechanism controlling respiration.
 These drugs belong to one of the following groups:
1) Anti-asthmatic for bronchodilation
2) Antitussive for suppression of cough
3) Drugs used for reducing respiratory tract secretion e.g. during
surgery
4) Expectorant & mucolytic for liquefying and removal of the
secretions from respiratory passage
5) Respiratory stimulants.
 Respiratory disorders are characterized by manifestations due to
bronchoconstriction, congestion and edema of bronchial mucosa
including:
o Reversible attacks of dyspnea
o Expiratory wheezing
o Chest tightness
o Cough
1. Asthma
 Asthma is a broad term that refers to a disorder of the respiratory
system that leads to episodic difficulty in breathing.
 It is defined as allergic condition or disease manifested by increased
responsiveness of trachea and bronchi to various stimuli.
 It is characterized by a wide spread narrowing of the airways.
 Air flow obstruction is due to inflammation of the bronchial wall
and/or contraction of the bronchial smooth muscles causing
shortness of breath, cough and wheezing.

154
Types of Asthma
A. Extrinsic or Allergic (early onset) Asthma: caused by extrinsic factor or
external stimuli. It is more common in children and precipitated by
known allergens resulting in antigen-antibody reaction. The antibodies
are of IgE type and attach to mast cells in bronchial mucosa. The
reaction leads to release of allergo-toxin mediators as histamine,
leukotrienes, Ach, PGs and kinins resulting in bronchoconstriction.
B. Intrinsic or Late-onset Asthma: is common in adulthood. The
symptoms being triggered by non-allergic factors like:
o viral infection (bronchitis)
o epithelial damage or mucosal inflammation
o emotional upset (thought to be mediated by excess
parasympathetic input; psychological troubles)
o exercise (thought to be due to water and heat loss from the
airways that triggers mediator release from mast cells)
Mechanism:

155
An asthmatic attack may be precipitated by inhalation of allergens such as
dust, pollen, animal dander,
industrial chemicals such as hair
spray, industrial trigger such as wood,
graven dust. These allergens interact
with mast cells coated with IgE
Allergen cross-links IgE
Production of antibodies (generated in response to
a previous exposure to the same
Specific IgE
allergen). Mast cells release mediators
such as histamine, leukotrienes and
chemotactic factors. These promote
(1) bronchial spasm & (2) mucosal
thickening from oedema and cellular
infiltration.

Mast cell

Activation and

Degranulation
Mediators

Asthma
a

There are two phases of asthma:


I. Immediate phase (bronchoconstriction) during which the forced
expiratory volume (FEV) is reduced. Responds to bronchodilators
(e.g. β2 agonists and
FEV methylxanthine).
II. Delayed phase
2.5 (inflammation e.g.
Immediat Delayed
2.0 e
Phase
1.5 156
Phase

Time hrs
bronchitis): a 2nd delayed FEV reduction following a return to the
normal. Responds to glucocorticoids.
 Both phases respond to sodium cromoglycate.
Pathophysiology:
Bronchi and bronchioles are supplied by sympathetic autonomic fibers and
not parasympathetic but contain muscarinic receptors.
Sympathetic stimulation of β2
Bronchodilation
receptors
Stimulation of muscarinic receptors Bronchoconstriction

 The bronchial muscle tone depends on the level of cAMP and cGMP:
• ↑ cAMP → bronchodilation
• ↑ cGMP → bronchoconstriction
ATP + Adenyl cyclase → cAMP + Phosphodiesterase → 5’AMP
 Adenyl cyclase is a surface enzyme associated with β receptors & can be
activated through:
I. Stimulation of β2 receptor by β2 agonists.
II. Inhibition of phosphodiesterase enzyme by theophylline.
GTP + Guanylate cyclase → cGMP
 This is less important since cGMP level is less than cAMP. Guanylate
cyclase enzyme is associated with muscarinic receptors. Its effect can be
brought about by parasympathomimetics and can be inhibited by
atropine (parasympatholytic). Elevation of cGMP leads to activation of
certain protein kinases ending in muscle contraction by enhancing the
activity of free Ca2+.
 There is evidence that the bronchial muscle contains α-adrenoceptors
in addition to β2 receptors. So, stimulation of α receptors leads to ↑
cGMP levels → bronchoconstriction. Accordingly, the use of α blockers

157
e.g. phentolamine as aerosol leads to bronchodilation and
improvement of the asthmatic attack in some cases.
Precipitating Factors in Asthma:
1) Hypersensitivity mechanism in many patients with allergic asthma.
2) Exercise-induced asthma; many patients with asthma especially
children become wheezing with severe exercise.
3) Respiratory infection precipitates asthmatic attack in all ages.
4) Non-specific irritants; cigarette smoke, dust, temperature change, etc.
5) Emotional factors; psychological stimuli e.g. stress and anxiety can
provoke or worsen bronchoconstriction and may affect the
effectiveness of bronchodilators used to treat asthma.
6) Drug-induced bronchial asthma:
o Cholinomimetic drugs.
o Histamine and histamine-releasing drugs e.g. morphine and
curare.
o Non-selective β adrenergic blockers. Also cardio-selective in
large doses.
o Prostaglandins especially PGE2.
o As part of allergic reaction to a drug e.g. penicillin.
o Salicylate and other NSAIDs e.g. aspirin, ibuprofen and other
prostaglandin synthesis inhibitors that lead to synthesis of
leukotrienes. These can induce asthma in patients with late
onset asthma through non-allergic mechanism.
o Inhalation of sodium cromoglycate is irritative and may induce
reflex airway obstruction. That is why it is contraindicated
during acute asthma.
o Morphine which is contraindicated in bronchial asthma (1)
releases histamine, (2) stimulates the vagal center and (3)
inhibits the respiratory and cough centers.
2. Lines of treatment of bronchial asthma:
1) Avoidance of the precipitating cause

158
1. Desensitization or avoidance of the Ag if known.
2. Treatment of respiratory infection.
3. Psychotic adjustment.
4. Avoidance or withdrawal of drugs precipitate asthmatic attacks.
2) Relief of bronchoconstriction; relaxation of bronchial musculature
1. Sympathomimetics (β adrenergic stimulant).
2. Theophylline derivatives (aminophylline).
3. Anticholinergic (ipratropium & deptotropine).
3) Relief of edema and congestion of bronchial mucosa; non- specific
reduction of the response to Ag-Ab reaction
1. Disodium cromoglycate.
2. Glucocorticoids.
3. Antihistaminics has been used but are ineffective.
4) Maintenance of good oxygenation
5) Expulsion of bronchial secretions
Expectorants & mucolytics render the mucous less viscid.

A. Bronchodilators:
I. β 2 agonists.
II. Xanthines derivatives.
III. Anticholinergics.
1. Sympathetic Bronchodilators:
β2 agonists are the first choice in the treatment of the immediate phase, they
act directly on β2 receptors and produce:
1) Relaxation of bronchial smooth muscles.
2) Inhibition of the release of mediators (bronchoconstrictor substances)
from mast cells.
3) Increase ciliary activity or affect the composition of mucous secretion
facilitating its transport.

159
 Non-selective β agonists as epinephrine, ephedrine, and isoprenaline
when used and cause cardiac stimulation via β1 receptors. In addition,
epinephrine is contraindicated in hypertensive patients.
 These have been replaced by selective β2 agonists with the advantages
of:
1. Long duration of action.
2. Less toxic effect on the heart. Effectiveness after oral
administration or inhalation.
Examples of Selective β2- agonist classified into:

1. Short acting: Salbutamol, terbutaline. Orally or by inhalation (as


aerosol, powder and nebulizer solutions) every 4~6 hrs.
2. Long acting: Salmeterol, formoterol inhalation, duration of action is
12 hrs.
3. Fenoterol, pirbuterol, rimiterol & bitolterol all are given by inhalation
but some may be given orally.

Side Effects:

• Tremor of skeletal muscles marked with oral preparation more than


inhalation (via β2 receptors), weakness.
• Nervousness, insomnia, dizziness, ↓ urine flow, nausea, headache,
tachycardia (cardiovascular effects).
• Hypokalaemia if used with xanthines and glucocorticoids.
• Tolerance can occur in asthmatic patients, but steroids reduce the
possibility of the development of tolerance
Contraindications:
• Cardiovascular disease, hyperthyroidism, diabetes mellitus.
• Used with caution in patients receiving MAOIs or tricyclic
antidepressants.

160
2. Methylxanthine derivatives:
These are Phosphodiesterase inhibitors; direct smooth muscle relaxants.
I. Naturally- occurring e.g. caffeine, theophylline and theobromine.
II. Synthetic derivatives e.g. aminophylline –a potent bronchodilator
which is a combination of theophylline, ethylene diamine and
Enprofylline.
Pharmacological actions:
 They have antihistamine-action.
 They reduce the immediate phase by direct bronchodilation.
 Reduce the delayed phase by an unknown mechanism.
Other actions:
 Positive inotropic, positive chronotropic,↑ COP ,↓ venous
pressure.
CVS  Dilate blood vessels EXCEPT cranial blood vessels which are
constricted.
 enprofylline doesn’t constrict cranial vessels
 Stimulate brain → ↑ alertness.
CNS  May cause tremor, nervousness.
 Interfer with sleep.
Renal ↑ Diuretic activity,↑ GFR.
GIT ↑ Acid & pepsin secretion.
 They have narrow therapeutic window due to the untoward effects
that include these wide range actions
 Theophylline has a narrow therapeutic window. The optimal
therapeutic effects are obtained with serum level of 10~20 μg/ml
(100~200 μmol/l). Adverse effects may appear with levels in excess
of 200 μmol/l. Careful monitoring of serum levels is therefore
essential to ensure efficacy and avoid toxicity.
Pharmacokinetic:

161
 Xanthine drugs are usually given orally as sustained release
preparations which have lower incidence of side effects and longer
duration of action.
 Aminophylline can be administered by slow intravenous or by
infusion.
 Theophylline and enprofylline are well absorbed from the GIT.
Theophylline is metabolized in the liver while enprofylline is
excreted unchanged in the urine.
 Half-life of theophylline is 8-12 hrs in adult and less than 4 hrs in
the children, while t1/2 of enprofylline is 2 hours.
 The t½ is prolonged in liver disease, heart failure, viral infection
and with erythromycin, contraceptives, ciprofloxacin and
cimetidine.
 The t½ is shortened by cigarette smoking, rifampicin, phenytoin,
phenobarbiton, carbamazepine & in patients with
hypothyroidism.
Mechanism of action:
1. They are thought to cause bronchodilation by blocking or
competing with adenosine receptor at A1 and P1 (Adenosine can
cause bronchoconstriction in asthmatics). Enprofylline is not an
adenosine antagonist but a powerful bronchodilator that lowers
cGMP.
2. Inhibition of phosphodiesterase enzyme -which catalyzes formation
of AMP from cAMP- leads to an increase of cAMP and broncho-
dilation is produced.

162
3. Increased strength of the skeletal muscle, diaphragm or improved
diaphragmatic contraction probably via mobilization of intracellular
calcium.
4. They may inhibit antigen-induced release of mediators as histamine.
Therapeutic iundications:
 Systemic relief of bronchial asthma. They are useful with other
drugs to treat prolonged attacks and in status asthmaticus.
 Treatment of reversible bronchospasm associated with chronic
bronchitis or emphysema.
Side Effects:
 Nausea, vomiting, epigastric pain and ulcerations that lead
GIT
to bleeding.
 Arrhythmia, palpitation, rapid i.v. may lead to cardiac
arrest.
CVS
 Dilation of blood vessels except cranial (constriction) and
hypotension.
 Psychological function disturbance (↓ blood flow to cranial
vessels), irritability, insomnia, nervousness and muscle
CNS
twitching (leads to generalized convulsions except
enprofylline)
Respiratory  Tachypnea, hyperventilation and respiratory arrest.
 Weak diuretic effect involves both ↑GFR and ↓
Renal
reabsorption in tubules except enprofylline.
 Seizures (antidote diazepam or phenytoin i.v.),
Toxic symptoms
 Severe emesis and agitation.

Contraindications:
Cardiac arrhythmia; myocardial infraction; hyperthyroidism; peptic ulcer;
hepatic and renal dysfunction .
3. Parasympathetic depressants (muscarinic antagonists):
Ipratropium bromide (AtroventR)

163
o Is isopropyl-atropine; better bronchodilator with less drying effect on
sputum. Actions are surmountable because acts by competitive
antagonism i.e. block muscarinic receptors.
o Prevents accumulation of cGMP and produce bronchodilation.
Indications:
o Used in asthmatic patients in whom sympathomimetics are
contraindicated; heart disease and thyrotoxicosis.
o Should not be given in glaucoma or prostatic hypertrophy.
o Safe, well tolerated and can be used in combination with β2-agonists.
Routes of administration:
o The drug is given by inhalation to limit systemic side effects.
o It has slower onset (peak effect 30 min) and more prolonged effects
(3~8 hrs) than β agonists.
Dose:
o Ipratropium as aerosol (20μg /puff/6hrs) or (1~2 puffs QID).
o Oxitropium 200μg BID.
B. Anti-inflammatory Agents or Prophylactic Agents:
I. Glucocorticoids.
II. Mast cell stabilizers.
Regular anti-inflammatory treatment (including corticosteroids and sodium
cromoglycate, etc.) must be given to patients who:
1. Require an inhaled bronchodilator more than once a day.
2. Have nocturnal symptoms.
I. Glucocorticoids:
 These include corticosteroids and ACTH. The present inhaled
corticosteroids are the drugs of choice in adults.
 Beclomethasone and budesonide are used at doses of 100~400 μg
BID. Higher doses are used if symptoms persist & inhaled
corticosteroid should be reduced -if possible- once symptoms and peak

164
expiatory flow have improved. It is an indicator in cases which does not
respond to bronchodilator in severe asthma and in status asthmatic.
 ACTH dose is 20-40 unit I/V.
 In case of status asthmatic, a dose of 200μg hydrocortisone is given
initially then repeated every four hours or according to the response.
Mechanism of Action:
1. ↑ Membrane stability of many cells e.g. endothelial cells, smooth
muscle cells and lysosomes membrane including mast cell granules.
This reduces the release of broncho-constrictor substance and inhibits
the response of smooth muscle to them. They may also inhibit synthesis
of mediators.
2. ↓ Capillary permeability and hence edema.
3. Suppress immune response and antibody synthesis.
4. Potentiate the endogenous catecholamines and sympathomimetic
bronchodilators by blocking non-neuronal uptake of catecholamines.
5. Direct relaxant effect on smooth muscles.
Preparations and routes of administration:

 Inhalation: Beclomethasone, Betamethasone, Budesonide,


Triamcinolone, Fluticasone & Ciclosenide; given as prophylactic in
the form of metered dose inhalers (MDIs). The full effect being
attained after several days so they are not useful in acute attacks. Their
action is limited to the respiratory passages because they are not
absorbed from the alveolar membrane. In less severe cases, aerosol
preparation is used e.g. beclomethasone dipropionate 1~2 puffs (each
puff 50 µg) QID up to (200 µg) QID.
 Oral: Prednisolone may be used in disabling asthma, repeated
nocturnal asthma & status asthmaticus, in severe or acute cases of
asthma. It is indicated combined with an inhaled steroid to reduce the
oral dose required. Prednisolone (10mg tablets) 60~80 mg/ day for

165
adults and 20~30 mg/ day for children in four-divided-doses. Then it is
reduced to 5-10 mg/ day and then alternate day therapy followed by an
aerosol preparation to avoid adrenal suppression.
 Intravenous: Hydrocortisone is given in cases of status asthmaticus,
followed by prednisolone. Methylprednisolone is a very effective
alternative.

Indications:
Indicated as prophylaxis against asthma that doesn’t respond well to non-
steroidal drugs.
Notes:

 Patients on oral corticosteroid therapy should NOT transfer


immediately to beclomethasone inhaler.
 Withdrawal of corticosteroids must be done gradually to avoid the
effect on the adrenal cortex.

Side effects:

With inhaled steroids the side effects are uncommon

 Oropharyngeal candidiasis (thrush).


 Dysphonia (voice problems).
 Regular large doses can produce adrenal suppression particularly in
children.
Side effects of prolonged oral steroid use:

 Supression of response to infection.


 Oesteoporosis.

166
 Supression of endogenous glucocorticoids synthesis → Iatrogenic
Cushing's syndrome.
 ↑ appetite.
 Metabolic actions; tendency to hyperglycemia and hypertension (due to
Na & water retention).

II. Mast Cell Stabilizers:


A. Disodium Cromoglycate (DSCG):
This is not used in acute bronchial asthma or status asthmaticus (doesn’t relax
bronchial muscles or other muscles), used as prophylactic treatment to ↓
frequency and severity of asthmatic attacks. The beneficial action appears after
several weeks.
Mechanism of Action:
It stabilizes mast cell membrane preventing the degranulation and release of
mediators of allergic reaction as follows:
 Prevents Ag-induced increase in Ca++ permeability.
 Inhibits phosphodiesterase enzyme leading to accumulation of cAMP
which lowers Ca++ permeability of mast cell membrane resulting in
inhibition of mediator release.
Preparations and dosage:
 It is given as a powder (spanhaler) or a solution (as nebulizer) 10mg/
ml in 2ml ampoules .The dose is 20mg to be inhaled orally by
nebulization QID and reduced gradually after stabilization.
 Also available as nasal spray powder or solution for hay fever and
allergic rhinitis (Ryncrom2% and Nasalcrom).
 Ophthalmic solutions e.g. Opticrom drops for allergic conjunctivitis.
 Oral capsules for ulcerative colitis (Nalcrom).
Pharmacokinetics:
t½ 80 min

167
Metabolism Non
Absorption <10%
Excretion 50% in bile and feces and 50%
urine
Side Effects:
 Direct irritation by the powder that leads to bronchospasm, wheeze,
cough, nasal congestion and pharyngeal irritation.
 Rarely, there could be laryngeal edema, urticaria, and eosinophilic
pneumonia.
Contraindications:
 Patients who show hypersensitivity.
 During acute attacks because it may aggravate the case due to irritation
by the powder.
B. Ketotifen:
 Used for prophylaxis of bronchial asthma, given orally.
 Similar to DSCG it inhibits the mast cells release of mediators but has
an additional anti-histaminic action.
 It may be used in allergic rhinitis and allergic skin disease.
 Used in the treatment of mild childhood bronchial asthma.
Dose:
 1mg tablets or capsules BID, effects appear after 3~4 weeks.
Side Effects:
Sedation, dry mouth, and dizziness at the begining of ttt.
C. Histamine antagonists (H1-receptor antagonists):

Azelastine

 Inhibits histamine release from basophils & inhibits oxygen free


radical production from neutrophils.

168
 Inhibits the synthesis of LTc4 and blocks the effect of Ach,
serotonin, LTc4 and histamine.
 Decreases the response to allergic agents.
 Inhibits moderately exercise-induced asthma & ↓ daily asthmatic
attacks & the concomitant therapy needed.
Terfenadine & Astemazole

 Long acting antihistaminics block antigen produced asthma, cold


air induced asthma and inhibit mast cell mediator release. They
inhibit cough and wheezing.
 Are given orally as supplementary with β2-agonist in the early phase
of bronchial asthma.
D. Leukotrienes Antagonists:
I. Leukotriene receptor blockers (new bronchodilators): Montelukast ,
Zafirlukast (AccolateR) and Pranlukast are selective inhibitors of LT 1
or LTD4-receptor blockers.
II. Leukotriene synthesis inhibitors (new anti-inflammatory drugs): e.g. 5-
lipoxegynase inhibitors: Zileuton.

Both groups are beneficial when used alone in mild and moderate asthma or
in combination with β2 agonists for exercise or aspirin-induced asthma or in
patients with poor compliance with inhaled drugs because of poor inhalation
techniques.
3. Severe acute asthma; or status asthmaticus:

The term is used to describe a very severe and sustained attack of asthma
which fails to respond to treatment with the usual measures. Early and
extensiventreatment is required:

169
1. Humidified oxygen or oxygen/helium mixture to relief hypoxia
and to reduce respiratory distress and dyspnea.
2. Treatment of dehydration orally or by IV fluid.
3. Systemic steroid: IV hydrocortisone 200 mg repeated every 4~6 hrs
until the acute attack is controled, then continue with 5 mg
prednisolone 6 hourly, the dose then gradually reduced.
4. Inhalation salbutamol in oxygen given by nebulizer or IV
(salbutamol may be given with intermittent positive pressure
breathing).
5. Or I/V infusion of aminophylline.
6. Expectorant and bronchial aspiration.

170
171
172
4. Cough
Cough is a protective reflex mechanism which serves the purpose of expelling
sputum and other irritant material from the upper part of the respiratory
airways.
• Irritant, & perhaps chemo- & stretch receptors initiate the cough reflex
• Bronchoconstriction is the most frequent & important cough
stimulus.
There are essential 2 types of cough:
1. Dry cough (unproductive) e.g. smoker`s cough, due to local irritation.
2. Productive cough that effectively expels secretion and exudates from
the respiratory passages.
Treatment of dry cough
I- Peripheral antitussives
Suppress the irritated sensory nerve ending
1. Demulcents: to relieve cough due to sore throat & pharyngitis e.g.
Liquorices lozenges.
2. Steam inhalation in tracheo-bronchitis: half a litre of boiling water +
tea spoonful tincture of benzoin or menthol.
3. Drugs with local anaesthetic activity e.g. benzonatate.
II- Central antitussives suppress the medullary cough centre
1- Non-addicting narcotics
a- Codeine
• It is natural opium alkaloid.
• It has less liability to cause dependence.
• It has mild analgesic effect.
• It causes constipation.
• It decreases bronchial secretions which thickens sputum.

173
• It inhibits ciliary activity which reduces clearance of thickened sputum.
b- Hydrocodone
• More potent than codiene.
• Less respiratory depressant effects.
c- Phlocodine
• Pholcodine mainly used as antitussive.
• It has no analgesic or euphoric action.
• Its addictive liability is less than that of codeine
2- Addicting drugs
• These are not commonly used as antitussive because of their addicting
properties e.g. morphine, heroin, methadone, dihydromorphine.
3- Non-narcotic antitussives
 Dextromethorphan
• It is a synthetic morphine substitute.
• It has no analgesic or addictive properties.
• Its antitussive potency is equivalent to codeine
• With less constipation and inhibition of mucociliary clearance.
 Narcotine:
• Natural opium alkaloid with an antitussive action mainly.
4- Non-opiate synthetic derivatives: Chlorphedianol, carbetapentane,
oxeladin, benzonatate, caramiphenethane disulphonate, diphenhydramine.
Treatment of productive cough
1- Expectorants
a- Sedative expectorants:

174
Stimulate the secretion of protective mucus & increase the fluidity of
sputum & help it expectoration by cough.
b- Alkaline expectorants e.g. Na & K citrate and acetate.
c- Nauseant expectorants e.g. tincture ipecacuanha & ammonium chloride.
d- Saline expectorants e.g. creosote, cuaiacol, & terpene hydrate.
2- Mucolytic agents:
They liquefy viscid bronchial secretions and enhance the therapeutic effect
of expectorants.
Acetylcystein:
 It has free sulphydryl (SH) group that opens disulphide bonds in the
mucus & reduces its viscosity.
 Administered by inhalation - as an aerosol- or by direct instillation into
the tracheal tree through bronchoscope.
Bromohexine:
• It reduces the viscosity of the bronchial secretion by depolymerization
(fragmentation) of the mucopolysaccharide which forms the ground
substance of the bronchial secretion.
Carboxymethylcysteine:
• In addition to its mucolytic property it reduces the mucus gland
hyperplasia which usually is associated with chronic bronchitis.
3- Decongestants
The indications include
• Sinusitis of allergic or viral etiologies & reverse sneezing or
• Other complications of postnasal drip.
Two drug categories are commonly used as decongestants
 H1 receptor antagonists e.g. Dimenhydrinate Diphenhydramine &
Chlorpheniramine.
 Sympathomimetic drugs i.e. α-agonists e.g. Ephedrine,
Pseudoephedrine & phenylepherine.

175
Chapter 9

The pharmacology of drugs affecting


the autonomic nervous system (ANS)

The ANS, with the endocrine system, coordinates the regulation and
integration of the body functions. The endocrine system sends signals to
target tissues by varying the level of blood-borne hormones. By contrast, the
nervous system exerts its influence by the rapid transmission of electrical
impulses over the nerve fibers. Drugs that produce their primary therapeutic
effects by altering the function of the ANS are called autonomic drugs which
act either by stimulating portions of the ANS or by blocking the action of the
ANS.
Introduction to the Nervous System

An Overview of the
Nervous System:

Peripheral Nervous
Central Nervous
System
System
-Brain
-Spinal Cord

Sensory Neurons Motor Neurons


-carry messages -carry signals
towards spinal cord away from CNS
from sensory receptors

Somatic System: Autonomic System:


Voluntary Nerves Visceral, Involuntary
--neurons control --heart, blood vessels,
skeletal muscles digestive organs,
smooth muscle

Sympathetic Division
--“fight or flight” Parasympathetic
--activated by stress Division:
--Routine

Anatomically and physiologically the ANS is divided into two parts:

176
Sympathetic Parasympathetic

Thoraco-lumber outflow Cranio-sacral outflow

Pre-ganglionic fibers originate from Pre-ganglionic fibers originate from


lateral horn cells of T1~L3 CNS’s nuclei III, VII, IX and X and
S2~S4

Short preganglionic fibers and long Long preganglionic fibers and short
postganglionic fibers postganglionic fibers

Ganglia are found in a chain on Ganglia are close to or even


either side of the vertebral column embedded in the effector organs

Activated in response to stressful Usually acts to oppose or balance the


stimulation; trauma, fear, action of sympathetic division
hypoglycemia, cold and exercise

Effects like:↑ HR ↑Bp

↑ blood flow to skeletal muscle &


heart while diverting flow from the
skin & internal organs

dilation of pupil and bronchi

Changes experienced by the body Generally dominant over the


during emergencies has been referred sympathetic, “rest or digest”
to as the “fight or flight” response stimulation

Tends to function as a unit & often Doesn’t have a function entity as such
discharge as a complete system e.g. and never discharge as complete
severe exercise & reaction to fear system. If it did, it would produce
massive, undesirable and unpleasant

177
symptoms. Instead parasympathetic
fibers are activated separately and
function to affect specific organs such
as the stomAch or eye

Reactions are triggered by both direct


sympathetic activation and
stimulation of the adrenal medulla to
produce EN and to a leaser extent
NE. These hormones enter the blood
stream to promote responses in
effector organs that contain
adrenergic receptors

With its diffuse distribution of It is involved in activities like


postganglionic fibers it is involved in accommodation for near vision,
a wide physiologic activities. movement of food, urination, etc.

It is NOT essential for life It is essential for life

Central Control: ANS is controlled by:

 Hypothalamus: posterior part controlling sympathetic activity and anterior


part regulating the parasympathetic
 The cortex
 Also by: spinal cord, medulla, mid-brain and the limbic system
Functions:

 The two divisions are usually antagonistic in function


 Activation of one is the same as inactivation of the other
 EAch involuntary organ usually receives a dual nerve supply, sympathetic
and parasympathetic
 Some receive only sympathetic supply e.g. dilator papillae muscle & all
blood vessels of the limbs
 Other receive only parasympathetic innervations like constrictor papillae
muscle

178
The Main Peripheral Effects of the ANS:
Sympathetic Parasympathetic
Organ
Receptor Response Response
SA node β1 ↑ rate Slow rate
Atrial β1 ↑ conduction ↑ conduction
muscle velocity velocity
β1
A.V. node ↑ conduction Slow conduction
Heart velocity velocity (AV
β1 block)
Ventricular
muscle ↑ contractility,
conduction velocity No effect
and automaticity
Arterioles
-Skeletal α Constriction No effect
muscle β2 Dilation No effect
Blood Constriction No effect
α
vessels -Skin &
mucous
α Constriction No effect
membranes
β2 Dilation
Veins
Smooth β2 Dilatation M-receptor
Bronchi
muscle Contraction

Smooth α1β1 ↓ Motility ↑ Motility


muscle α1 Constriction Dilatation
GIT
Sphincter No effect ↑ Secretion
Glands

Urinary Detrusor β2 Relaxation Contraction

179
bladder Trigone and α1 Contraction Relaxation
sphincter
Iris
-Radial α1 Contraction -
muscle (mydriasis) Contraction
Eye -Circular - (miosis)
muscle - Contraction
Ciliary
muscle
Male sex organ Α Ejaculation Erection
α,β Thick viscous Profuse watery
Salivary glands
secretion secretion
Kidney β1 Renin secretion No effect
β2 Glycogenolysis No effect
Liver
Gluconeogenesis

180
Types of Nerve Fibers
These are based on the transmitter molecules released from their terminals
1) Cholinergic Fibers:
These fibers release Ach that acts on Ach receptors (cholinoceptors) on
effector cells; smooth muscles, cardiac muscles and glands.
Ach is the transmitter of:
 All preganglionic fibers; sympathetic and parasympathetic.
 All postganglionic parasympathetic fibers.
 Some postganglionic sympathetic fibers such as those to the sweat glands
and sympathetic vasodilator fibers supplying blood vessels in skeletal
muscles.

181
 Preganglionic fibers (greater splanchnic nerve) to the adrenal medulla
which can be considered as modified sympathetic ganglia.
 Certain neurons within the CNS.

so
m
Motor Skeletal
fiber Ac
sy muscles
h
m
Smooth muscles
Preganglion Postganglion
ic Ac ic N Cardiac muscles
sy h E
m Gland cells

Preganglion Postganglion Sweat


ic Ac ic Ac
sy gland
h h
m s
Preganglion
N
ic Ac E
par h
Adrenal
a E
medulla Postga
Preganglion N n-
ic Ac Ac
h glionic
h

2) Noradrenergic & Adrenergic Fibers:


Most –but not all– postganglionic sympathetic neurons release nor-
epinephrine NE that acts upon NE receptors or adrenoceptors on the effector
cells.
The two major exceptions are: (1) the postganglionic sympathetic neurons
to thermoregulatory sweat glands and (2) vasodilator sympathetic neurons
supplying blood vessels in skeletal muscle.
N.B. some receptors that respond to autonomic drugs are not innervated.
The most important of these are cholinoceptors of the vascular bed.
3) Dopaminergic Fibers:

182
These fibers release dopamine. They are present in the extra-pyramidal &
the limbic system.
4) Histaminergic Fibers:
These release histamine from mixed somatic nerves (e.g. sciatic) and dorsal
nerve roots.
5) Serotoninergic Fibers (5-HT):
This fibers release serotonin in autonomic ganglia and mainly in the
hypothalamus.
6) Purinergic Fibers:
These fibers release ATP and/or adenosine. They mediate inhibitory
responses in the smooth muscles of the gut, lung and blood vessels. They are
excitatory in the urinary bladder.

transmitt
effector
Neuro-
Gangli

mitter
trans
onic

Preganglionic Postganglionic

er
CNS:
neuron neuron
Brain Synaptic connection = ganglion Effector organ:

Spinal An aggregation of cell bodies in the peripheral Involuntary


Organization
cord of the Nervous system tissues that
nervous system
Types of Receptors
Functions as relay station between pre and are innervated
1) Cholinergic Receptors: are classified into twobyreceptor
post-ganglionic neurons CNS types muscarinic
and nicotinic:
a) Muscarinic Receptors:
o They are also known as Atropine-sensitive Receptors or Peripheral
Cholinergic Receptors.
o They are called muscarinic or M-receptors because muscarine gives
the same action of Ach on these receptors. Also they are called
atropine-sensitive receptors because they are blocked by atropine.
o Five types of muscarinic receptors have been cloned; M1~M5 but
three of them are pharmacologically defined: M1, M2 and M3 (found
post-synaptically in the parasympathetic system).

183
They are present in:
o The heart
o Exocrine glands
o Smooth muscles (eye, bronchi, GIT, urinary bladder and blood
vessels).
 Autonomic ganglia; sympathetic and Selective agonist:
parasympathetic neurons
oxotremorine
M1  CNS neurons
Selective antagonist:
 Some presynaptic sites particularly in
pirenzepine, telenzepine
stomAch
Selective agonist:
 Heart pilocarpine
M2  Presynaptic cholinergic fibers (inhibit Selective antagonist:
Ach release) gallamine, methodramine,
himbacine
 Smooth muscles
M3
 Secretary glands

b) Nicotinic Receptors:
o They are also known as Central Cholinergic receptors.
o They are called N-receptors or nicotinic receptors because nicotine –
in small doses– produces the same effect of Ach on these receptors.
They are found in:
 Sympathetic and parasympathetic ganglia.
 Neuromuscular junction (NMJ) of motor end plate.
 The spinal cord.
They are classified according to the blocking agents into:
Neuronal NN:  In autonomic ganglia
Etamon sensitive  Supra-renal medulla

184
receptors
Muscular NM:
 Neuromuscular junction (NMJ)
Curare sensitive receptors

Autonomic Drugs
Are classified into adrenergic & cholinergic drugs. Each drug is either an
agonist i.e. stimulant (mimetic), or antagonist i.e. blocker (-lytic).
Cholinergic Drugs
CAA Cholinergic Drugs
Direct

Acting Cholinergic agonist Cholinergic


musca nicoti
rinic •Gangli
nic antagonist
cholines onic
•NMJ
Aceticterester Carbamic Cholinergic stimulant
of ester
Cholinergic
alkaloi
choline of choline blocker
Naturald Synthetic Cholinoceptor
•Ach •carbAchol agonist
•Muscarine
methAcholi ••bethanchol
Oxotremori
•ne Indirect
Nicotine, ne Cholinoceptor
Lobeline •DMPP
ShortActing
acting
•Pilocarpine
Long acting antagonist
(Min) •Organophosp
Reversible Irreversible
hate Cholinoceptor
•Edrophonium •Echothiopha stimulant
(Hrs) teee Cholinoceptor
Cholinester •Isofluropha
Carbamate:
ase te
blocker
e.g.

•Physostigm
oxime
Re-
•Parathion Ach receptor agonist
•Suramin
ineactivators
•Neostigmin
e
Ach receptor
Ach receptor antagonist
stimulant

185
Ach receptor blocker
Parasympathomimetic

Parasympatholytic
Cholinomimetic

Cholinergic Agonists
According to the mechanism of action cholinomimetic agents can be
classified into
(1) direct acting and
(2) indirect acting cholinomimetics.
According to the receptor type or spectrum of action cholinomimetics can be
classified into
(1) muscarinic and
(2) nicotinic.
They are also called Cholinergic Acting Agents CAA. They are classified into
(1) direct acting cholinomimetic,
(2) indirect acting cholinomimetic and
(3) cholinesterase re-activators or regenerators.
Neurotransmission
Synthesis and release of Ach from cholinergic neurons involve 6 steps:
1) Synthesis : transport of choline from extracellular into the neuron through
Na co- transporter system and reacts enzymatically (choline acetyl
transferase) with activated acetate (acetyl-CO A) to form Ach ( transport of
choline is inhibited by hemicholinium).
2) Uptake into storage vesicles: Ach is protected from degradation in storage
vesicle.
3) Release of neurotransmitter: entrance of Na creates an action potential that
leads to a depolarization which results in opening of Ca channels that
increase intracellular Ca which results in fusion of vesicular membrane

186
with the terminal membrane and release of Ach (release is blocked by
bottulinum toxin. Spider venom causes release of Ach
4) Binding to receptors: postsynaptic receptor is activated by binding of
neurotransmitter.
5) Degradation of : Ach is rapidly hydrolyzed by ChE in the synaptic cleft to
choline and acetate.
6) Recycling of choline: choline is taken up by neuron.

Choline Choline

Na Na AcCoA

Ach

Synaptic vesicle

Ca++ Presynaptic

receptor

choline

acetat
e

Intracellular

response

187
Acetylcholine (Ach)
Ach is a neurotransmitter of parasympathetic or cholinergic nerves. It is a
quaternary ammonium (polar) ester of choline with acetic acid. It is rapidly

188
hydrolyzed by both true and pseudo-cholinesterase. It has both muscarinic
and nicotinic action.
Ach is of little therapeutic importance because of:
 Multiple actions (M & N actions).
 Rapid inactivation by cholinesterase enzymes.
 Irregular absorption.
Mechanism of Action:
Ach acts by activation of muscarinic and nicotinic receptors. The esteratic
site of the receptor receives the acetyl group of Ach. The cationic head of Ach
(tri-methylamine) which has strong positive charge combines with the negative
charge at the anionic site of the receptor by a weaker ionic bond.
CH3
Acetyl group
CH – C – CH2 – CH2 – N+ – CH3
Amine group CH3
O

esteratic site anionic site

Activation of the parasympathetic NS modifies organ function by two major


mechanisms:
 First: Ach released from parasympathetic nerves can activate muscarinic
receptors on effector organs to alter organ function directly.
 Second: Ach released can interact with muscarinic receptors on nerve
terminals (presynaptic M2-R) to inhibit them from releasing their
neurotransmitters.
Hydrolysis of Ach:
The protein molecule of ChE enzyme resembles the receptor, and may be
considered to have anionic and esteratic site.Ach is rapidly hydrolyzed by ChE
in two steps:
Initial Ach+ enzyme active site → hydrolyzed → choline + acetylated
step enzymes

189
2nd step Acetylated enzyme → acetate is released + enzyme is set free

Cholinesterase Enzymes
I, True ChE, II, Pseudo ChE,
AchE Butyryl-ChE,
Specific: responsible for hydrolysis of Non-specific: hydrolytic enzyme
Ach released in the cholinergic which hydrolyzes esters.
transmission.
Essential for life
Presents in : Presents in:
 At the terminals of cholinergic fibers  Plasma type
 RBCs, type  Skin
 Nervous tissue  Intestine
 Some sites in the CNS.
Very slow turnover: Rapid turnover:
120 days to regenerate Synthesized in liver (2~3 wks)
Proper substrate: Proper substrate:
 Ach  Butyrylcholine
 MethAcholine  Succinylcholine
 Benzyl-choline

Actions of Ach
Muscarinic Ach Actions:
1) CVS:
 Heart: ↓HR (bradycardia) and ↓COP. It mimics the effect of vagal
stimulation reducing the rate of firing at SA node. The vagal activity is
regulated by release of Ach at SA node.

190
 Blood vessels: causes vasodilation.
 BP: ↓the BP due to ↓ COP and vasodilation, but large I/V dose will ↑
BP due to (1) stimulation of adrenal medulla that releases catecholamines
and (2) activation of sympathetic ganglia that release noradrenaline and
adrenaline from postganglionic neurons.
2) GIT:
 ↑Motor activity and peristaltic activity.
 ↑Motility (↑frequency and amplitude).
 Relaxation of most sphincters.
 ↑Secretions (polyuria and diarrhea).
3) Respiratory:
 Contraction of the bronchial muscle leading to bronchospasm.
 ↑bronchial secretions.
4) Urogenital:
 Promotes micturition by stimulation of the bladder wall:
1) Contraction of the detrusor muscle.
2) Relaxation of the sphincter and/or trigone muscle.
 Contraction of the ureter.
 Contraction of smooth muscles of the uterus (humans are less sensitive).
5) Eye:
 Stimulates ciliary muscle contraction for accommodation for near vision.
 Constriction of the papillary sphincter muscle, which causes miosis.
These effects facilitate aqueous humor outflow (opening of Schlemm’s
canal).
 Lowers intraocular pressure IOP.
 ↑Lacrimation.
6) Exocrine Glands:
 ↑Secretion of salivary, lacrimal and sweat glands.
It enhances salivation, lacrimation, urination and defecation (SLUD).

191
Nicotinic Ach Actions:
1) NMJ:
 Stimulates the N-receptors in NMJ resulting in skeletal muscle contraction.
 At high concentration, the membrane depolarization becomes sustained
and neuromuscular blockade may occur (flaccid paralysis of skeletal
muscle).
The muscle contraction induced by Ach could be blocked by
neuromuscular blocker e.g. d-tubocurarine or succinylcholine.
2) Autonomic Ganglia:
 Stimulates both sympathetic and parasympathetic ganglia (preganglionic).
The initial response is a mixture of both sympathetic and parasympathetic
effects.
The N-receptor at the ganglia is blocked by ganglionic blockers e.g. Tea.
3) CNS:
Brain is a muscarinic site while the spinal cord is enriched with nicotinic
receptors.
 Ach is excitatory transmitter in the basal ganglia:
1) Small amounts (tobacco smoke) → slight alteration.
2) High concentrations → convulsions that terminate in fatal coma.
 Stimulates the release of ADH by hypothalamus.
4) Endocrine:
 Stimulates adrenal medulla to release catecholamines.
Direct Acting Cholinomimetics
A cholinergic agonist mimics the effects of Ach by binding directly to
cholinoceptors. It could be:
 A synthetic ester of choline (choline esters) e.g. Ach and methAcholine.
 Carbamic ester of choline or carbamoyl choline: as carbachol and
bethanchol.
 Naturally occurring alkaloids: such as pilocarpine, muscarine, nicotine,
lobeline.

192
 Few synthetic agents: as oxotremorine and dimethylphenylpiperazinium
(DMPP). These are of interest in pharmacological researches.
Chemistry & Pharmacokinetics
 They are permanently charged and relatively lipid insoluble because they
contain the quaternary ammonium group [N+-(CH3)3] therefore poorly
distributed to the CNS.
 They are all hydrolyzed in the GIT so are less active by oral route.
 They look like Ach but slightly differ in their susceptibility to hydrolysis by
ChE enzymes in the body. The carbamic esters of choline as carbachol and
bethanchol are extremely resistant to hydrolysis by ChE enzymes and have
a corresponding longer duration of action.
 They also differ in their action in muscarinic and nicotinic receptors.
However, the presence of the β methyl group in methacholine and
bethanchol reduces the potency of the drug at the nicotinic receptors
(more muscarinic in action).
 Advantages of synthetic choline esters (bethanchol, carbachol and
methacholine) over Ach:
1) They have longer duration of action.
2) They are effective orally as well as parentraly.
3) They are more selective in their action.
Properties of Choline Esters
Choline esters ChEs susceptibility M effects N effects
Ach ++++ +++
++++
Methacholine ++++ Trace
Carbachol +++ +
Negligible
Bethanchol +++ None

Properties of Alkaloids
 The tertiary alkaloid cholinomimetics pilocarpine, nicotine and lobeline
are well absorbed from the site of administration.

193
 Nicotine is lipid soluble & crosses the skin.
 Muscarine is a quaternary amine less absorbed from the GIT. It is toxic
when ingested in certain mushrooms. Excretion is renal and accelerated by
acidification of urine.
 Oxotremorine is a potent synthetic muscarinic agonist that is used in
research. It is well distributed to the CNS.
 Lobeline is a plant derivative (Indian tobacco) with lower potency than
nicotine but has similar spectrum of action.
 DMPP is a potent synthetic nicotinic stimulant with little access to CNS. It
is a research tool used for selective stimulation of ganglionic nicotinic
receptors.
Methacholine
Mecholyl, acetyl β- methyl choline: the drug is incompletely absorbed from
GIT therefore the oral dose is 20 times the parentral dose. It is hydrolyzed by
true ChE enzyme only (in slower rate). Therefore, it is more stable than Ach.
Chemically, it differs from Ach by addition of methyl group to β position of
choline that results in:
 It becomes more muscarinic in action (insignificant in nicotinic).
 It resists hydrolysis by cholinesterase but is hydrolyzed in slower rate by true
ChE enzyme. So, it has longer duration of action.
Actions
Its actions are similar to Ach but its muscarinic actions are more prominent
especially on the CVS (bradycardia and vasodilation) than GIT and urinary
tract.
Therapeutic Uses
It was formerly used in the following conditions:
 Relief of attacks of paroxysmal atrial tAchycardia (15~25 S/C).
 As a vasodilator in treatment of peripheral vascular disease e.g. Raynaud’s
disease.

194
 Diagnosis of paroxysmal hypertension due to phechromocytoma (15~25
S/C). During the normotensive phase, it produces a rise in both systolic
and diastolic Bp instead of the usual depressor response in normal persons.
Carbachol
Doryl or carbamyl choline: the drug is completely absorbed from GIT and
the oral dose is thus nearly equal to the parentral one. It is not suitable to
hydrolysis by both true and pseudo cholinesterase .
Actions
Carbachol differs from Ach in the following:
 It has longer duration of action.
 Its muscarinic effects are more prominent on the eye, GIT, and urinary
bladder.
 It has nicotinic effects similar to Ach.
Therapeutic Uses
It is rarely used therapeutically because of
1) Its high potency
2) Long duration of action (1hr).
3) Exception is the use in the eye as a miotic agent or in glaucoma
(0.75~5% eye drops).
Adverse Effects
It causes a generalized cholinergic stimulation including: sweating, salivation,
flushing, a decrease in blood pressure, nausea, abdominal pain, diarrhea,
bronchospasm, etc.
Bethanechol (Bethanecholine)
 It is a carbamic ester.
 Chemically it has structure features of both methacholine &
carbachol.
 It has a long duration of action (about one hour).

195
 It is mainly muscarinic in actions. Its major action is on the smooth
muscle of the bladder and GIT (with no significant action on CVS).
Actions
It directly stimulates the muscarinic receptors causing:
 Increased intestinal motility and tone.
 Stimulation of the Detrusor muscle of the bladder causing expulsion of
urine.
Therapeutic Uses
 Urological treatment: often used to stimulate the atonic bladder
particularly postpartum or postoperative urinary retention.
 Abdominal distension.
 Esophageal reflux.
Adverse Effects
It causes a generalized cholinergic stimulation as mentioned above.
Pilocarpine
It is a tertiary amine alkaloid which is less potent than Ach and its
derivatives.
Its action is similar to methacholine.
It has mainly muscarinic activity and is unaffected by ChE enzyme.
Actions
Causes miosis and a decrease in the intraocular pressure (↓IOP).
By opening the trabecular meshwork around the Schlemm’s canal, it
leads to immediate drop in IOP as a result of the escape of aqueous
humor.
Therapeutic Uses
It is used in the treatment of glaucoma (the drug of choice in both
narrow (closed) angle glaucoma and wide (open) angle glaucoma).
The action lasts a few hours and can be repeated. It is used topically
as eye drops (0.5 % solution) to prevent the systemic effects.

196
Adverse Effects

 It can enter the brain and cause CNS disturbances.


 It also stimulates sweat secretion
Indirect Acting Cholinomimetics
Anti-cholinesterases or cholinesterase inhibitors
 These compounds provide cholinergic action indirectly by binding
to ChE and thereby reversibly inhibiting the hydrolysis of Ach.
 This results in accumulation of endogenous Ach in the synaptic
space.
Classification
Reversible (short acting)
With quaternary ammonium group e.g.
(1) Simple alcohol
edrophonium
With quaternary ammonium group e.g.
(2) Carbonic acid
neostigmine
ester
With tertiary ammonium group e.g.
physostigmine
Irreversible (long acting)
(3) E.g. DDT, diisopropyl fluorophosphates, DFP,
Organophosphates isofluorphate, ecothiophate and nerve gases.

Mechanism of Action
1) Edrophonium
It binds reversibly by weak electrostatic forces mainly to the anionic site of the
enzyme. The enzyme-inhibitor complex is thus short lived (2~10 min). Used
in the diagnosis and treatment of myasthenia gravis. Also used in the
differentiation between myasthenia gravis and cholinergic crisis.

197
2) Carbomic esters
They bind to both anionic and esteratic sites of the enzyme. They undergo a
two-step- hydrolysis by the enzyme similar to Ach. However, the covalent bond
of the carbamylated enzyme is more resistant to the second hydration process
which is prolonged (at least 2~4hrs).
Reversible Anti-cholinesterases ( Carbomates)

Physostigmine (Esrine) Neostigmine


(Prostigmine)
1-Source and Natural plant alkaloid obtained Synthetic.
from plant Physostigma venosum
Chemistry (calabar beans). A quaternary ammonium
compound.
A tertiary amine.
2. Kinetics
a- Complete absorption from GIT Partial and irregular
Absorption absorption (GIT)
b- Pass BBB, avoided in Can not cross BBB
Distribution Parkinsonism

3- Pharmaco- -Ant-cholinesterase ↑ Ach 1-Anticholine esterase↑


producing: Ach
Dynamics
a-Muscarinic mainly eye a-Muscarinic mainly GIT,
Urinary
b- Nicotinic; muscle twitches
b- Nicotinic; Muscle
no direct action twitches
c-CNS -Stimulation Direct stimulation a+b
powerful muscle
-Convulsions in high stimulation
dose
c-CNS:No action (can't
cross BBB)

198
4.- Uses 1. Eye drops : (miosis, contraction 1. Eye: miotic in
of the cillary M. Accommodation glaucoma
for near object, ↓IOP,
2. GIT: paralytic ileus
lacrimation, twitches of the eye
lid (N. action)-uses : 3. Urinary: post operative
urine retention
a- glaucoma
4. Skeletal muscles:
b-counteract action of mydriatics
myasthenia gravis
c- alternatively with mydriatics to (diagnosis and treatment )
cut recent adhesion between iris
5. Others
and lens
Antidote to curare
2. treatment of:
toxicity
a) atropine- poisoning:
(antagonize central and peripheral
actions of atropine).
b) phenothiazine and tricyclic
antidepressants overdose
3 treatment of Alzheimer disease
"dementia" due to deficiency of
cholinergic neurons in CNS
5- Toxicity Anti Ch E
- Muscarinic: bradycardia, ↓BP, bronchospasm,
vomiting, diarrhea ,↑secretion and miosis
- Nicotinic: sk muscle twitches, eye lid, facial, trunk
CNS convulsions, collapse, Absent
Coma and death from depression
of Resp. Center
6- treatment StomAch wash ,Oxygen and artificial respiration
of toxicity
Atropine 1mg + anticonvulsant ( diazepam )

199
Irreversible Anticholineserases
Organophosphorous (organo-phosphate) Compounds
These compounds are designed as high lipid soluble to be absorbed
through the insect and distribute to its CNS very rapidly.
They are:
 Mainly used as insecticides.
 Used as nerve gases
 Few of them (as echothiophate) have limited effect in glaucoma.
They include:
 diisopropyl fluorophosphates (DFP)
 isofluorphate
 ecothiophate
 malathion (thiophsphate)
 parathion
 As well as sarin and somarin. They have been studied for use in war
as nerve gases.
All of them except ecothiophate are highly lipid soluble and well absorbed
from skin, lung, gut and conjunctiva, can cross BBB. Poisoning with these
agents, therefore, includes important effects in CNS.
Toxicity of Organophosphate
Causes of organophosphate poisoning are usually outside clinical practice e.g.
agriculture, industrial, transport accidents, etc.
Manifestations
 Excessive muscarinic stimulation (salivation bronchial secretion,
bronchospasm, abdominal cramps, urination and defecation, sweating and
hypotension), nicotinic (respiratory muscles Paralysis) and CNS effects
(convulsion, etc.).
 Paralysis of respiratory muscles due to :
1) Peripheral neuromuscular blockade

200
2) Excessive bronchial secretions and bronchospasm causing respiratory
failure.
 Death due to respiratory failure and CNS effects (convulsion, etc.)
 Chronic exposure to certain organophosphates causes neuropathy
associated with de-mylination of the nerve axons.
Treatment
1) Decontamination:
This is to prevent further absorption by removal of the clothes, washing of the
skin (sodium bicarbonate) and gastric lavage if any of the substances has been
ingested.
2) Maintenance of the vital organs:
 Aspiration of bronchial secretion, endotrAcheal intubation, oxygen or
artificial respiration may be needed.
 Stimulation of the heart by adrenaline.
3) Atropine:
It is given in large doses to compensate the muscarinic and CNS effects.
1-2mg dose is given every 15 minutes until signs of adequate atropinization
occur (dry mouth, HR 70b/min, etc).
The patient should be kept fully atropinized for at least 24hrs.
4) Antidote:
Antidote as cholinesterase re-activator e.g. oxime is given.
5) Diazepam:
It may be needed for convulsions.
Mechanism of Oxime Agent Action
The oxime has very high affinity to the phosphorus atom.
It is attAched to the unoccupied anionic site of the enzyme and the free
oxime end attAches the phosphorus atom from the esteratic site of the
enzyme. Oxime displaces the enzyme and binds to the organophosphate
compound. Oxime agents are able to hydrolyze the enzyme if the complex has
NOT aged. Thus, it should be administrated within 12hrs of poisoning.

201
Examples of oximes include pralidoxime (PAM), diacetylmonoxime (DAM)
and obidoxime.
Pralidoxime can regenerate ChE associated with NMJ. DAM and obidoxime
have an advantage that they can cross BBB and regenerate some of CNS
ChEs.
Dose of DAM:
I/V infusion 1~2mg over 5~30min. additional dose may be given if muscle
weakness persists.
Myasthenia Gravis
Many theories are applicable to this condition:
 Circulating curare-like substances.
 Defective rate of Ach synthesis.
 Excessive amount of acetyl-cholinesterase in the NMJ.
 Autoimmune disease which is the main theory.
 Drug-induced myasthenia.
It is an autoimmune process which causes production of antibodies that
decrease the number of functional nicotinic receptors on the post-junctional
end plate.
It is characterized by weakness extraocular muscles, bulbar, muscles of the
neck, followed by other muscles. It shows muscle weakness and fatigability
resulting from failure of neuromuscular transmission.
Diagnosis
 Edrophonium test:
Give 2mg I/V. After 45 seconds, if no reactions occur, give additional 8mg
in one or two-divided dose.
A positive test is dramatic relief of muscle weakness.
 Neostigmine:
Give 1.5mg neostigmine plus 0.6mg atropine (to abolish muscarinic
action).
If the muscle weakness is improved, the diagnosis of myasthenia is
confirmed.

202
Treatment
a) Symptomatic treatment:
 Pyridostigmine: 60mg orally given every 6hrs. The dose is increased if
necessary. Pyridostigmine is preferred because its action is smoother than
neostigmine.
 Neostigmine: 15mg orally given every 6hrs. The dose is increased if
necessary. It has faster onset of action and is useful for morning weakness.
Atropine may be needed to control muscarinic side effects.
b) Immunosuppressive drugs:
They are used to eliminate Ach-receptor antibiotics.
 Steroids: start with small dose of prednisolone (10mg/day) to avoid
worsening of muscle weakness as steroids render ChEIs more effective and
cholinergic crisis may be provoked. The dose should be increased slowly.
Steroids are indicated in:
1) Seriously ill patients prior to surgery.
2) Patients unsuitable or not benefited from thymectomy.
3) Those with poor response to anticholinesterase.
 Other immunosuppressive drugs e.g. cyclosporine.
c) Other measures
 Thymectomy for patients under 40yrs and those who have thymomas.
 Plasmapheresis to remove antibodies.
Myasthenia crisis Cholinergic crisis
Muscle weakness due to Muscle weakness due to excessive
exacerbation of myasthenia: anticholinesterase treatment.
1. Inadequate treatment
2. Drug-induced myasthenia
3. Infection
Diagnosis: positive edrophonium Worsened by edrophonium.
test. Muscarinic symptoms are present
No Muscarinic symptoms

203
Treatment: Treatment:
 Ant cholinesterase  Withdrawal of ant cholinesterase
 Mechanical respiration is  Mechanical respiration is required
required  PAM 0.5mg I/V infusion may be
 Early and effective antibiotic tried
therapy (for infection)  Atropine to block excess
 Plasmaphoresis has been tried muscarinic effects

Cholinergic Antagonists
 They are also known as cholinergic blockers, anticholinergic drugs or
Ach receptor antagonists.
 They are referred to as parasympathatolytic because they selectively
reduce or abolish the effect of parasympathetic stimulation.
 All of them are competitive antagonists of Ach at muscarinic or
nicotinic receptors. They bind to choline receptors but do not trigger
the usual receptor mediated intracellular effect.
 They selectively block the muscarinic and nicotinic synapses of the
parasympathetic nerves and the actions of sympathetic stimulation are
left unopposed.
 Because of importance of Ach as neurotransmitter, the drug that blocks
Ach receptor has very important clinical applications. This includes
drugs acting at muscarinic and nicotinic sites.
Classification
They are classified according to their affinity to receptors into:
Anticholinergic
Antimuscarinic Antinicotinic
Synthetic
Natural Ganglionic blockers NMJ blockers
Semi-synthetic
Antimuscarinic Agents

204
They are called muscarinic antagonists or atropine-like drugs.The
effectiveness of antimuscarinics varies with the
(1) source of antagonist and
(2) the tissue under the study.
They are subdivided on basis of their ability to distribute in the CNS into
(1) quaternary and
(2) tertiary amine groups.
They include:
 Natural Agents (alkaloids):
1) Atropine: di-hydro-scyamine in Atropa belladonna and Datura
stramonium.
2) Scopolamine: hyoscine in Hyoscyamus niger.
 Synthetic and semi-synthetic: They are atropine’s substitutes mainly three
groups:
1) Mydriatic and cycloplegic.
2) Anti-secretary and antispasmodic.
3) Anti-parkinsonism.
Pharmacokinetics
 The tertiary drugs are well absorbed from the gut, conjunctiva and
skin. In contrast, (10~30%) of a dose of a quaternary agent is
absorbed after oral administration reflecting the decrease in lipid
solubility.
 They rapidly disappear from the blood within (t½ = 2hrs) and (60%)
excreted unchanged in urine.
 The effect of the drug declines rapidly from all organs (4hrs) except
the eye (72hrs~days).
Mechanism of Action
 They cause competitive blockade of the action of Ach at muscarinic
receptors.
 The antagonist could be overcome by increasing the concentration of
Ach at receptor sites of the effector organs e.g. by anticholinesterase.

205
Atropine
Mechanism of Action
 It competes reversibly with Ach at muscarinic receptor.
 At very high concentrations, it blocks Ach at ganglionic synapses and
motor nerve endings.
 It antagonizes the action of Ach in CNS.
Pharmacological Effects
1) CVS:
 Heart: it produces divergent effects depending on the dose (initial
bradycardia followed by tachycardia).
1) Low dose (0.5 mg): decrease COP and bradycardia due to
activation of vagal afferent outflow.
2) High dose (1 mg): blocks cardiac muscarinic receptors M2 resulting
in tachycardia. This is more apparent in young athletes with high
vagal tone than in old patients or infants.
 Bp: since blood vessels have no cholinergic innervation, blood pressure
is unaffected. Oral or I/M doses have little effect but I/V dose will
increase heart rate and that causes arterial blood pressure to increase.
 Atropine has a direct vasodilating effect on small blood vessels due to
prevention of calcium passage through the blood vessel wall.
 Toxic doses: lead to marked dilation of cutaneous blood vessels
(Atropine Flush).
2) CNS:
Atropine produces both stimulant and depressant actions in CNS:
 Stimulant actions:
1) Therapeutic doses stimulate the cardio-vagal center leading to
bradycardia.
2) Very large doses stimulate the cerebral cortex leading to restlessness,
hallucinations and delirium.
This central excitation is followed by depression.
 Depressant actions: manifested by

206
1) Decreased tremors and rigidity in Parkinsonism.
2) Antiemetic action in some cases of motion sickness (hyoscine is
better).
3) Counteraction of the central excitatory action of eserine and
organophosphate compounds.
4) Reduction of electric activity of the brain.
3) GIT:
 It decreases the amplitude and frequency of peristaltic contractions
and reduces the tone of the stomach, small intestine and colon
(antispasmodic action).
 It reduces gastric acid secretion in both volume and total acid
content.
4) Other Involuntary Muscles:
 Relaxation of biliary tract smooth muscles.
 Relaxation of bronchial smooth muscles. It prevents reflex
bronchoconstriction during anesthesia by bronchodilation action and
reduction of bronchial secretion (reduces the risk of airway
obstruction and pneumonia).
 Reduces contraction of the sphincter and trigone leading to retention
of urine.
 In ureter, it is antispasmodic.

5) Secretions:
All secretions (salivary, lacrimal, bronchial and sweat secretion) EXCEPT
milk are diminished.
 Dry mouth is common.
 Bronchial secretion is reduced and becomes viscid.
 Thermoregulatory sweating is suppressed causing atropine fever which
is not dangerous except in warm environment especially in infants and
children.

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 In large doses (over 1 mg), gastric acid secretion is decreased. It
reduces pepsin and mucous and volume out put. The gastric pH is
little affected.
6) Eye:
 Atropine locally or systemically blocks Ach response of the:
1) Ciliary muscle of the lens producing cycloplegia (inability to focus for
near vision).
2) Circular smooth muscle of the iris producing mydriasis (dilatation of
the pupil).
Both effects precipitate acute attack of glaucoma in patient with narrow
anterior champer.
 Loss of normal pupillary reflexes which may last for two weeks.
 Reduction of lacrimal secretions leading to dry eye or sandy eye.
 May cause rise in IOP due to closure of Schlemm’s canal and obstruction
of space of Rontana. This is dangerous in patient with glaucoma.
Tolerance of Atropine:
Natural tolerance to atropine is present in certain species e.g. rabbits which
naturally have atropinestease enzyme in the blood and liver that destroys the
alkaloid! In man, however, tolerance to atropine occurs to a limited extent in
patients with Parkinsonism following prolonged use of the drug.
Therapeutic Uses
1) CNS disorders:
 Pre-anesthetic medication: atropine is administrated half an hour before
general anesthesia in order to:
1) Decrease salivary and bronchial secretions which are usually increased
with certain irritant anesthesia as ether. It also causes bronchodilation.
2) Protect the heart from excessive vagal tone which may occur with
halothane anesthesia.
3) Counteract the inhibitory effect of morphine on respiratory center.
4) Antiemetic.

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 Parkinsonism: to reduce rigidity, tremor and autonomic effect. Synthetic
substitutes are better.
 Motion sickness: 0.3-0.6mg injection.
2) GIT & genitourinary tract disorders:
 Dicyclomine is used in hypermotility induced by drugs such as
anticholinesterase (reduces gut motility).
 Widely used to reduce gastric acid in patients with peptic ulcer
(synthetic substitutes are better). Histamine antagonists have
replaced them all.
 As antispasmodic in cases of intestinal, biliary and renal colic.
 In irritable bowel syndrome.
 In traveler’s diarrhea.
 In sensory urgency.
 In nocturnal enuresis (tricyclic antidepressants are preferable).
3) Ophthalmic uses:
 In fundus examination.
 Accurate measurement of refractive errors especially in young children.
(Aids in ophthalmoscopic examination of the retina).
 In cases of iritis and corneal ulcer to prevent adhesions formation
(synechia).
 Used in alteration with mitotic to break down recent adhesions
between the iris and the lens.
 Homatropine, cyclopentolate and tropicamide are drugs developed
specifically for ophthalmic uses.
4) CVS disorders:
 Severe bradycardia and syncope associated with hyperactive carotid
sinus reflex.
 Heart block due myocardial infraction or overdose of digitalis or
propranolol.
5) Respiratory:

209
 Ipratropium bromide is an effective bronchodilator in bronchial
asthma but the sputum become viscid and more difficult to expel.
6) Cholinergic poisoning:
 As antidote to parasympathomimetic e.g. organophosphate poisoning.
 In mushroom poisoning.
 Tertiary members are preferable to reverse central and peripheral effects
7) Other:
 In hyperhidrosis (excessive sweating).
 In urolithiasis to relief the smooth muscle spasm caused by passage of
stone.
Adverse Effects
o Dry mouth.
o Blurred vision and photophobia.. sandy eye and Loss of normal
pupillary reflexes
o Acute glaucoma in patients with narrow anterior champer.
o Tachycardia.
o Flushing and hyperthermia especially in infants.
o Retention of urine in old patients with enlarged prostate and
constipation.
Contraindications
Patients with glaucoma.
Elderly men with history of prostate (urine retention).
Patients with peptic ulcer because it delays gastric emptying. So,
treatment of ulcer with antacid and H2 blocker is preferable.
Atropine Poisoning
The symptoms appear quickly and may proceed for some days.
(1) Parasympathetic Depressant Symptoms:
These include: dry mouth, mydriasis, blurred vision, hot and dry skin, flush
in addition to hyperthermia.
(2) CNS Symptoms:

210
They include: restlessness, confusion, hallucination, delirium and mania
followed by depression.
The patient is described as:
“Dry as a bone” Dry mouth
“Hot as a hare” Inhibition of sweating
“Red as a beet” Tachycardia and coetaneous vasodilation
“Blind as a bat” Blurring of vision
“Mad as a hen” Hallucination and delirium

Treatment of Atropine (and other Antimuscarinic) Poisoning:


 Gastric lavage if atropine is taken orally.
 Artificial respiration and oxygen.
 To control parasympathetic depression with parasympathomimetics as
physostigmine 1~3 mg I/V slowly. This is reversed for patient with severe
supra-ventricular tachycardia or hypertension. It can antagonize both
central and peripheral effects.
 Diazepam 10mg I/V to control central excitation.
 Treatment of hyperthermia by cooling blankets, ice bags and alcohol
sponges to reduce fever (but not aspirin).
Scopolamine (Hyoscine)
It is structurally related to atropine. It is an alkaloid and an ester tropic
acid with organic base scopine.
This belladonna alkaloid produces peripheral antimuscarinic effect
similar to atropine but differ from it by:
1) It is MORE potent than atropine in:
o Producing mydriasis and cycloplegia.
o Decreasing bronchial, salivary and sweat gland secretions.
o Sedative effect.
2) It is LESS potent than atropine in its effects on:
o The heart.

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o Bronchial muscles.
o Intestine.
3) CNS action:
o Atropine has longer duration of action and in therapeutic doses it does
not depress the CNS. Hyoscine is chiefly a CNS depressant and may
some times causes excitement.
o It produces amnesia.
o Hyoscine is preferable than atropine in pre-anesthetic medication
because of amnesia effect, depression of CNS, strong anti-secretary
action and strong antiemetic action. In addition, it counteracts
respiratory depressant of morphine.
Therapeutic Uses
 They are similar to that of atropine but it is excellent for treatment
of motion sickness.
 It is more useful as prophylactic than as treating the condition after
it occurs. It is mainly used as antiemetic and antispasmodic.
 The dose is 0.5~1.0 mg orally or parenterally.
Atropine Substitutes
 They are also known as synthetic or semi-synthetic antimuscarinic
drugs.
 They include (1) tertiary and (2) quaternary ammonium compounds.
 The tertiary antagonists are used often for their effect on the eye and
CNS.
 The quaternary members are developed to reduce CNS effects. They
are mainly used for GIT and genitourinary disorders. They are poorly
lipid-soluble with lower CNS effects and their distribution is mainly
extra-cellular. In addition, they have ganglionic blocking activity.
Atropine Substitutes for Ophthalmic Use
They produce mydriasis and cycloplegia (for short duration) which are
easier to be antagonized.
 Homatropine (1.2~0.5%drops). It has short duration of action than
atropine (1~3days) and is less likely to cause serious rise in IOP. It is

212
unreliable in children in whom atropine is preferred. It is used to produce
cycloplegia and mydriasis for ophthalmic refraction.
 Eucotropine is used as mydriatic in acute iridocyclitis.
 Tropicamide (mydracil 0.5~1.0%). It has short duration of action (1hr). It
produces mydriasis but is inadequate cycloplegic.
 Cyclopentolate (cyclogyl 0.5~2.0%). It has shorter duration of action than
homatropine. It is thought to be act by direct relaxation of muscle rather
than competitive antagonist of Ach at muscarinic receptor.
Atropine Substitutes for GIT & Genitourinary Use
They are mainly used against muscle spasm and hypermotility. Examples
include:
 Propantheline (7.5~15mg orally)
 Clidinium.
 Hyoscine (N-butyl-bromide buscopan 10mg).
 Oxyphenonium.
 Isoprpamide (5mg orally).
 Pirenzepine (gastrozepine) and telonzepine are M1 blockers that are
preferable in treatment of peptic ulcer than antimuscarinic blockers.
 Emepronium (cetiprin 200mg orally). It is used to reduce the bladder
motility and capacity.
 Ipratropium bromide (20mg). It is a synthetic quaternary analogue of
atropine, which is used by inhalation as bronchodilation. It has a little
effect on mucous viscosity.
Nicotinic receptor antagonists
NiThese drugs affect the neurotransmission at either the ganglia or the
effector organs
Nicotine
Nicotine is a toxic and addictive drug derived from tobacco leaves. It is the
active ingredient of tobacco.
It acts by depolarizing the ganglia resulting first in (1) stimulation followed by
(2) paralysis of ganglia i.e.:

213
 In low doses: causes ganglionic stimulation by depolarization.
 In high doses: causes ganglionic blockade by persistent depolarization,
The effects are complex including:
 ↑ COP and Bp.
 ↑peristalsis and secretion.
Pharmacokinetics
 Absorbed through oral mucosa, GIT and skin.
 Cigarette contains 6~8 mg of nicotine and the lethal dose is 60 mg.
 Nicotine substitution therapy as chewing gums (contains 2 mg) or
nicotine patch reduce withdrawal symptoms.
Mechanism of Action
 It is highly lipid soluble, penetrate and stimulate CNS, then depresses
the vital medullary and respiratory centers.
 Low doses: Relaxation; improved attention, learning, reaction time,
problem solving and some degree of euphoria.
 High doses: Respiratory paralysis; severe hypotension caused by
medullary paralysis; & complex peripheral effects including a fall in
blood pressure, cessation of GIT and urinary activity.
Pharmacological Actions
 ↑Heart work due to increase in the rate and force of contraction.
 ↑FFA level in blood causes vasospasm.
 ↑Gastric acid secretion.
 ↑Incidence of pre-eclampsia due to constriction of blood vessels and
↑neonatal mortality.
 Lowered ciliary reactivity of bronchi.
 Induction of liver microsomal enzymes.
 ↑Incidence of cancer.
 ↑Incidence of CVDs.

214
 It decreases the oxygen carrying capacity of blood and causes amblyopia
(rare) which is characterized by decreased visual activity due to spasm of
retinal blood vessels.
Adverse Effects
 CNS: irritability and tremor.
 Peripheral: intestinal cramps, diarrhea, increase heart rate and blood
pressure.
 Accelerate drug metabolism: increases rate of metabolism of number of
drugs.
 Withdrawal symptoms: physical dependence of nicotine develops
rapidly including: irritability, anxiety, restlessness, difficulty in
concentration, headache and insomnia, appetite often affected, and
GIT pain may occur.
Ganglionic Blockers
These drugs act on nicotinic receptors on autonomic ganglia.
They block both sympathetic and parasympathetic ganglia WITHOUT
selection i.e. block the entire output of ANS at nicotinic receptors.
The effects observed are complex and widely spread making it
impossible to achieve selective actions. So rarely used therapeutically
today. They are not effective as neuromuscular blockers.
Presynaptically:These drugs block synthesis and/or release of Ach.
Postsynaptically: block nicotinic receptors in both sympathetic and
parasympathetic ganglia.
1) Depolarizing Ganglionic Blockers
o These include large doses of ganglionic stimulants that block the
ganglia by persistent depolarization.
o They have no therapeutic application.
o Examples include nicotine, lobeline, DMPP and TMA.
2) Non-depolarizing Ganglionic Blockers
o These are competitive blockers
o Examples include trimethaphan, mecamylamine, etc.

215
Actions of ganglionic blockers
1) Blockade of sympathetic ganglia:
 Drop in blood pressure due to (1) peripheral vasodilation & (2)
decreased venous return.
 Postural and exercise hypotension due to blockade of cardiovascular
reflex.
 Sexual function impairment (failure of erection and ejaculation).
2) Blockade of parasympathetic ganglia:
 In the eye: mydriasis, cycloplegia and increased IOP.
 Tachycardia.
 Reduction of GIT secretion and motility with constipation.
 Urinary retention.
 Impotence.
 Sweat gland thermoregulatory block leading to hyperthermia (a
problem except in hot environment) but cutaneous vasodilation
maintains normal body temperature.
Therapeutic Uses
 Treatment of hypertension; trimethaphan is used to control blood
pressure.
 In autonomic hyper-reflexia in patients with spinal cord injury
characterized by sweating, flushing and severe headache that may be
associated with a marked rise in arterial blood pressure, bradycardia
and confusion.
 TEA is used for diagnosis of pheochromocytoma. 100ml is given I/V to
produce a lowering in blood pressure due to direct stimulant action on
the tumor as a result of ganglionic blockade.
 In acute pulmonary edema. By causing peripheral vasodilation blood is
shifted from the pulmonary circulation to the peripheral.
Trimethophan (Arfonal)
This is a short acting, non-depolarizing (competitive), ganglionic blocker. It
lowers the blood pressure by:

216
 Ganglionic blockade.
 Direct vasodilation.
 Histamine release.
Therapeutic Uses
 A single administration lasts 1~2min, a continuous infusion (0.1%
solution in 5% dextrose in water) lowers blood pressure instantly.
 Used to control blood pressure (1) during surgery, (2) in malignant
hypertension and (3) hypertension caused by pulmonary edema.
Mecamylamine hydrochloride (inversin)
It produces a competitive nicotinic block of ganglia.
Duration of action is 10hrs after a single administration.
Absorption is good in contrast to trimetaphan.
It reaches CNS producing tremor and mental confusion.
A dose of 25mg orally achieves the hypotensive effect.
Drugs Acting at the NMJ
Skeletal Muscle Relaxants
1- Neuromuscular blockers (NMB).
2- Spasmolytics.
1) Neuromuscular blockers NMB
Are drugs that interfere with NM transmission. They act pre-synaptically or
post-synaptically.
A) Pre-synaptic (pre-junctional) agents:
Are drugs that depress Ach output from motor nerve terminal (interfere
with synthesis and\or release of Ach) they may act by the following ways:
a) inhibition of Ach synthesis:
They block the uptake of choline by the nerve terminal, hence,
blocking Ach synthesis .e.g. Hemicholinium, triethylcholine.
b) Inhibition of Ach release: This may be activated by:
i. Lack of Ca++, or excess of Mg++ or phosphate ions.
ii. Local anesthetics e.g. procaine {as they depress the nerve action
potential}.

217
iii. Botulinium toxin.
B) Postsynaptic(post-junctional) agents:
They prevent action of released Ach on receptors, either by competition
or depolarization:
c) non-depolarizing (competitive reversibly) NMBs:
They compete with Ach for N-receptors preventing depolarization of
motor end plate {MEP} by Ach, leading to failure of transmission
and muscle paralysis .e.g tubocurarine, pancuronium,
gallamine…etc
d) depolarizing (non-competitive) NMBs:
They have same action of Ach, but instead of initiating
depolarization, they produce prolonged depolarization {fasciculation
followed by muscle paralysis} e.g. succinylchloine, decamethonium
A. Non-depolarizing NM blockers:
Mechanism of action:
1. At low doses: they combine with N-receptors preventing binding of
Ach, thus preventing depolarization of muscle cell membrane and
inhibit muscle contraction.They are called competitive because they
compete with Ach on N-receptors.Their action can be overcome by
increasing the concentration of Ach on synaptic cleft by administration
of anticholinesterases as neostigmine and edrophonium.
2. At high doses: they block channels of MEP (Na+ channels, not Ca++
channels) leading to further weakening of NM transmission and
reduced ability of anticholinesterases to reverse their action. Muscles
affected are:
i. Muscles innervated by the cranial nerves
ii. Muscles of the limbs and trunk
iii. Intercostal muscles and diaphragm. Death from toxic doses is
due to paralysis of respiratory muscles.
3. They have weak ganglionic action, i.e., large doses are required to block
autonomic ganglia than for blocking NM transmission.
4. They have histamine releasing action leading to bronchospasm,
hypotension, and excessive bronchial and salivary secretion.
Hypotension is due to:
i. Peripheral vasodilatation due to histamine release.

218
ii. Sympathetic ganglionic blockade
iii. Diminished venous return due to loss of skeletal muscle tone.

Pharmacokinetics:
 Since they are quaternary ammonium compounds (alkaloids) they do
not enter CNS, oral absorption, so they have to be given parentally.
 Many of these drugs are not metabolized and are excreted unchanged
in urine.
 Most of them have a relatively long duration of action ranging from
30min~1 to2 hrs
Therapeutic uses:
Used as adjuvant drugs in surgical anesthesia.
Adverse effects:
Only tubocurarine may cause bronchospasm, skin wheals due to release of
histamine.

Toxicity:
Profound and prolonged muscle relaxation with consequential respiratory
paralysis and hypoxia.
Treatment of toxicity of all members:
1. Artificial ventilation
2. Antidote neostigmine 1~8mg I.V preceded by 0.6mg atropine to
prevent excessive bradycardia, or edrophonium 10mg repeated as
required owing to its short duration of action.
3. Anti-histamine to counteract the signs caused due to histamine release.
Drugs interactions:
The action is potentiated by:
1. Halogenated hydrocarbon anesthetics as halothane and ether that
enhance NM blocking by exerting a stabilizing action at NMJ.

219
2. Antibiotics (streptomycin, polymixine) that inhibit Ach release
from cholinergic nerves by competing with Ca++, they synergize with
tubocurarine and other competitive blockers enhancing the block.
3. local anesthesia, anti-arrhythmic drugs , quinidine ,quinine , K+
depleter (diuretics) ,cholorpromazine, Ca++ channels blockers that
increase NM block of tubocurarine and other competitive blockers
as well as depolarizing blockers.
Their action is antagonized by anticholinesterases. K+…..etc
Tubocurarine:
Pharmacokinetics:
o Highly ionized, so, it does not cross membranes and have limited Vd.
o 50%-60% of it is excreted through bile.
Pharmacological action:
1. paralysis of skeletal m.:
IV dose cause muscle weakness more than muscle flaccidity and
inexcitibility to stimulation. Not all muscles are equally sensitive to
blockage by competitive blockers, that is, small rapid contractile
muscles of the face and the eye are more susceptible and paralyzed
first followed by finger muscles, neck and trunk muscles, and
intercostals muscles, and lastly the diaphragm.
Duration of action: 20min~1 to2 hrs after a single administration
(depending on the dose).
2. other effects:
a) A small degree of ganglionic blockade by block N-
receptors at autonomic ganglia.
b) The adrenal gland may be blocked.
c) A fall in BP by release of histamine.
Dose:
Initially 10~15mg IV, then supplement accord to response.
Adverse effects:
Hypotension, bronchospasm, and allergy, effect of diplopia may persist for
few days.

220
Toxicity:
Profound and prolonged muscle relaxation with consequential respiratory
paralysis and hypoxia.
Preparation and dosage:
1. D-tubocurarine chloride (tubarine) 15~20mg IV: a test dose of
5mg is given first to test the patient susceptibility.
2. Dimethyl tubocurarine iodide (metubine): a semi synthetic
derivative of D-tubcurarine which is 3 times more potent.

Gallamine triethiodide (flaxedil):


A synthetic curare substitute with similar actions, but differ in the following:
1. Has 1/5 of activity of curare on NMB with shorter duration of
action.
2. Has much weaker ganglionic blocking activity.
3. Has much weaker histamine release activity
4. Has a selective parasympathetic depressant (atropine-like) action
on the heart and thus produce tAchycardia (contraindicated in
cases of thyrotoxicosis).
5. Produce slight or no effect on BP.
6. Excreted by kidney, so contraindicated in renal failure. Dose:
1.5mg/Kg IV.
Other members:
Pancuronium:
 Dose: 4~5mg IV.
 Drug of choice to patient susceptible to hypertension.
Alcuronium chloride and Benzoquinonium
B. Depolarizing (desensitizing) NM blockers:
Their action involves 2 phases:
1) Phase I block(depolarizing):
 They interact with N-receptor on postsynaptic membrane
producing depolarization of end plate causing generalized
contraction of the muscle (initiate fasciculation).

221
 The depolarization persist because succinylcholine is not rapidly
hydrolyzed, the resulting muscle paralysis is flaccid.
2) Phase II block (desensitization):
 With repeated or prolonged administration of succinylcholine,
phase I block changes to phase II block.
 The end plate membrane becomes repolarized. It does not
respond to Ach, so the membrane is said to be desensitized to the
effects of Ach (desensitization block).
Succinylcholine (suxamethonium) Sch:
 The only member of this group commonly used clinically.
 It is a dicholine ester (2molecules of Ach linked end to end) which
attachs to N-receptors and acts like Ach to depolarize NMJ.
Pharmacokinetics:
Has a short duration of action (5~10 min) due to rapid hydrolysis by pseudo
cholinesterase (butyl cholinesterase), hydrolysis occurs in 2 steps:
1. initial rapid step: conversion of Sch to succinylmonocholine (a much
weaker NMB).
2. slow prolonged step: conversion of succinylmonocholine to succinic
acid and choline (inactive products).
Pharmacodynamic:
1. Skeletal muscles: IV administration causes transient fasciculation
followed by paralysis, this affect the arms, neck, leg, pharyngeal
muscles, and lastly respiratory muscles.
Post-operative muscle pain may follow paralysis.
2. Autonomic ganglia: Stimulation, leading to a transient bradycardia &
salivation (parasympathetic action) followed by tachycardia & increase
in BP (sympathetic action).
3. Histamine release (particularly in high doses).
4. A transient increase in intra-ocular pressure due to the transient
vasodilatation and contraction of extra-ocular muscles.
5. Occasionally, an increased intra-gastric pressure due to fasciculation of
abdominal muscles that may cause regurgitation of gastric contents.
Dose:
1. 0.5~1.0 mg/Kg IV for short duration (relaxes muscles for 5min).

222
2. IV infusion 0.1~ 0.2% solution in 5% dextrose (or 0.9% saline) at the
rate of 2~ 4ml/min (relaxes muscles as long as required).
Adverse effects and toxicity:
1. Post-operative muscle pain
2. Malignant hyperthermia
3. Bradycardia, cardio muscular collapse, and cardiac arrest.
4. Hyperkalemia
5. Increased intra-ocular pressure
6. Salivation.
Treatment of overdose:
1. Artificial respiration until the muscle power returns.
2. Fresh blood transfusion in case of lack of cholinesterase enzyme in
the plasma (when phaseI block is present).
3. No specific antidote is available.
4. When phaseII block is present, IV anti-cholinesterase may be used;
edrophonium 10 mg, neostigmine 2~5mg, atropine 1 mg.
Sch- apnea:
It is a prolonged apnea produced by Sch use, due to lack of
peudocholinesterase which may be:
1. Genetically abnormal: the enzyme is either totally unable to split
Sch or its activity is less than normal or totally absent.
2. Acquired: low plasma level of enzyme activity and/or amount as
in cases of liver diseases, malnutrition, organophosphate
poisoning…etc
3. During pregnancy its level decreases by 25%, pregnant women
are more susceptible to Sch- apnea.
Contraindications:
1. Patient with abnormal plasma pseudo cholinesterase.
2. Patient with history of malignant hyperthermia.
3. Patient with acute narrow angle glaucoma, or penetrating eye
injuries.
4. Patient with allergy to Sch.
5. During pregnancy.
Indications:

223
1. Adjustment in general anesthesia to prolong muscle relaxation
during operation and decrease the amount of anesthesia
required
2. Facilitation of endotracheal intubation, laryngeoscopy,
bronchoscopy, and oesophageoscopy.
3. Controlling convulsions (used in the symptomatic treatment of
all convulsions states as tetanus).
4. Prevent cough and laryngeospasm during operation.

2) Spasmolytics:
A. Centrally acting muscle relaxants
 They act on spinal cord and brain inhibiting multi-synaptic reflexes
involved in producing and maintaining muscle spasm of varied
etiology.
 They do not relax tense muscles directly.
Diazepam (valiumR):
Facilitates GABA-mediated pre-synaptic inhibition (by opening Cl-
channels producing hyper-polarization reducing neuronal excitability).
At high doses, it may suppress NM transmission.
Baclefen (LioresolR):
1. An orally active GABA-mimetic agent that acts on pre-synaptic
GABA receptors leading to inhibition of the release of excitatory
transmitter in the brain and the spinal cord.
2. It inhibits mono- and poly-synaptic reflexes
3. It can also inhibit release of substance P in the spinal cord
reducing pain in patients with spasticity.
4. Is less sedative than diazepam.
5. It does not reduce general muscle strength as does dantrolene.
6. It benefits some cases of trigeminal neuralgia. Dose:15 mg twice
a day.
B. Direct acting spasmolytics:
Dantrolene (DantriumR):
Does not act on central suppressor of NMJ

224
Mechanism of action:
1. Acts directly on muscle, preventing release of activator Ca++ from
sarcoplasmic reticulum interfering with excitation-contraction
coupling.
2. Main action on skeletal muscles, but cardiac and smooth muscles
may be affected.
Uses and dosage;
1. Spastic state e.g. tetanus 25~100 mg orally/day.
2. Malignant hyperthermia 1~2 mg/Kg IV.
Adverse effects:
1. Generalized weakness.
2. Sedation and hypotension.
3. Constipation.

Adrenoceptor Acting and other Sympathomimetic Drugs


Classification; adrenoceptor stimulants or sympatho-mimetics are classified
into:
1) According to the source
Norepinephrine (NE), Epinephrine (E). Dopamine (DM)
Natural
Some of their metabolites, which are not potent.
Synthetic Isoproterenol Old synthetic, very potent, Ephedrine, amphetamine, etc
2) According to their chemical structure
Catecholamine Contains catechol nucleus: NE, E, DM and isoproterenol
Non- Ephedrine, Amphetamine, Tyramine, etc.
catecholamine
3) According to the site of action
Directly on adrenoceptor NE, E, DM, Isoproterenol, Methoxamine
causing release of NE from noradrenergic neurons
Indirectly
Amphetamine, Tyramine, Ephedrine
Mixed-action by both mechanism Other synthetic agents
directly and indirectly

225
also dopamine and ephedrin
4) According to selectivity on adrenergic receptors (type of receptors)

α-agonists defined by their affinity to α-receptor:


(compounds which stimulate α- α1 postsynaptically
receptors) α2 presynaptically
defined by their affinity to NE and E:
β-agonists (compounds which
β1 has equal affinity to both.
stimulate β-receptors)
β2 has higher affinity to E than for NE.
 NE has α and β effects, but α is more predominant.
 E has α and β effects with equal molecular potency
 E can not differentiate between β1 and β2, where as NE can differentiate
(β1-selective).
 Dopamine has its own receptors D1and D2 and has some action on β1 and
α1 adrenoceptors.
 Isoproterenol has a selective action on β1 and β2, but has no action on α-
receptors.
The Adrenergic Neuron
The adrenergic neurons release NE as a neurotransmitter.
These neurons are found (1) in CNS and also (2) as part of the
sympathetic nervous system & serve as links between preganglionic
neurons and effector organs.
The adrenergic neurons and the receptors (located on the effector
organs) are the sites of action of adrenergic drugs.
The Classification of Adrenoceptors
o The main pharmacological classification, into α and β subtypes, is
based originally on the order of potency among agonists and later on
selective antagonists.
o Both α and β adrenoceptors comprise subtypes: α1, α2 and β1, β2 and
β3 that are similar in structure and belong to a super-family of G-
protein-coupled receptors.
Effects: The main effects of receptor activation are:

226
Vasoconstriction, increase in PVR. Increased Bp. Relaxation of GIT
α1 smooth muscle. Salivary secretion. Mydriasis. Hepatic glycogenolysis.
Closure of the internal sphincter of the urinary bladder
Inhibition of NE and Ach release from autonomic nervous system.
α2
Platelet aggregation.
Increase cardiac rate and force. Relaxation of GIT smooth muscle.
β1
Lipolysis.
Bronchodilation. Vasodilatation and slight decrease in PVR. Relaxation
β2 of visceral smooth muscle. Hepatic glycogenolysis. Muscle tremor.
Relaxation of uterine smooth muscles .

Effect control by G-protein:


Two pathways are controlled by receptor via G-proteins.
Both can be activated or inhibited by pharmacological ligands
depending on the nature of the receptor and G-protein.
Mechanism of action of Adrenoceptor Agonists:
 This depends on (1) type of receptor and (2) type of the second
messenger.
 The effects of catecholamines are mediated by cell surface receptors,
which are coupled to G-protein via the transmembrane signaling
pathways. These transduce the effects of the drug receptor
interaction.
 G-protein serves as intermediate between the receptors and various
effector proteins whose activity is regulated by those receptors.
1) G-proteins make up the family of GTP- binding proteins that has four
members at least. Each G-protein is a heterotrimer consisting of α-, β-, and
γ-subunits. Each G-protein has its distinctive α subunit.
2) The activation of G-protein coupled receptors by CA promotes the
dissociation of GDP from the α-subunit of the appropriate G-protein.
3) GTP then binds to this G-protein causing the α-subunit to dissociate from
the βγ-dimer.

227
4) The activated GTP bound α-subunit then regulates the activity of its
effectors. These effectors of activated α-subunit include adenylyl cyclase/
cAMP system, cGMP, phospholipase C/ inositol phosphate system and ion
channels.
The inactivation of α-subunit occurs due to hydrolysis of the bound
GTP to GDP + PI and the consequent re-association of α-subunit
and β-γ dimer.
The α1 receptors differ greatly from α2 in their physiology.
1) The α1 receptors are mediated by second messenger phospholipase C,
which increases intracellular Ca++ and leads to activation of protein kinase
and hence the physiological response.
2) The α2 and β receptors act on another enzyme which is adenylyl cyclase
that leads to conversion of ATP to cAMP.
β-receptors are coupled to stimulating type of G-protein (Gs) whereas
the α2-receptors are coupled to inhibitory type of G-protein (Gi).
They cause stimulation and inhibition, respectively, of the target
enzyme adenylyl cyclase.
So, the effects of β-receptor stimulant are brought about by
activation of adenylyl cyclase via (Gs) with consequent increase in
intracellular cAMP that initiates a sequence of enzymatic β-effects. In
addition, Gs proteins directly enhance the activation of voltage
sensitive calcium channels in plasma membrane of skeletal and
cardiac muscles.
The α2-receptors produce their effects by inhibiting adenylyl cyclase
via (Gi) reducing intracellular cAMP. The Gi proteins also activate
potassium conductance and inhibit voltage sensitive calcium
channels.
Neurotransmission:
Uptake and Degradation (Fate) of Catecholamines:
 Catecholamines differ markedly from Ach in the way by which their
action is terminated.
 There is no sympathetic enzyme as AchE that rapidly degrades
catecholamines.

228
 The main mechanisms by which the released transmitter is inactivated
are:
1) Reuptake of NE by adrenergic nerve terminals and by other cells.
2) Circulating NE and E are degraded enzymatically but much more slowly
than Ach. The two main enzymes MAO and COMT are located in the
intracellular so, uptake into cells necessarily precedes metabolic
degradation.
Reuptake:
 It is a major mechanism by which the released NE is removed from the
vicinity of autonomic endings.
 The sympathetic nerve uptakes amine from circulation and releases it
again as a transmitter by sympathetic stimulation.
1) Neuronal uptake; uptake Ι:
 Amine pumps actively transport NE into the neuronal cytoplasm.
 It is blocked by cocaine, tricyclic antidepressant as desipramine or
imipramine and chloropromazine.
 It is a high-affinity system with a relatively low maximum rate of
uptake.
 Substrates uptake is relatively selective for NE (specificity NE >E).
2) Extra-neuronal (non-neuronal) uptake; uptake II:
 NE is taken to muscles and into gland cells prior to destruction.
 It is blocked by steroid hormone or glucocorticoids,
phenoxybenzamine, normetanephrine and metanephrine.
 It has low affinity for NE, but much higher maximum rate.
 The substrate specificity accumulates epinephrine and isoprenaline
(E>NE).
3) Granular uptake:
 It actively transports cytoplasmic NE into the storage resides.
 It can be inhibited by reserpine.
 (N.B. uptake I and II are the major mechanisms).
Enzymatic Catabolism (metabolic degradation:

229
Endogenous and exogenous catecholamines are metabolized mainly by two
enzymes;
a. monoamine oxidase (MAO) and
b. catechol ortho- methyl transferase (oxidant COMT).
Direct Acting Adrenergic Agonists
Epinephrine (Adrenaline)
It is one of the three natural catecholamines which is synthesized from
tyrosine in the adrenal medulla and released with small quantities of
NE in the blood stream.
It interacts with both α and β receptors.
At low doses → β-effects on the vascular system predominate.
At high doses → α-effects are stronger
Pharmacological Actions:
a) Local Actions: When applied to mucous membranes or surfaces, it leads to
vasoconstriction and accordingly it produces:
1. Local haemostatic action when applied to a bleeding surface.
2. Decongestive action.
3. Delay in the absorption of associated drugs when injected s/c.

b) General Actions or Systemic Actions:

Theses actions are classified into:


1. Sympathomimetic action.
2. Metabolic action.
3. Adrenocortical actions.
4. Skeletal muscle action.
5. Antihistamine and antiallergic action.
6. Action on blood coagulation.
7. Action on the CNS.
1) Sympathomimetic actions: It stimulates both α and β adrenoceptors
producing:

230
CVS Actions:
 Increased heart rate; positive chronotropic action (β1 effect).
 Increased force of contraction; positive inotropic action (β1 effect).
 Increased excitability leading to extra systolies.
 Increased cardiac output so increased oxygen demand of the
myocardium.
 Vasoconstriction of the arteriolar blood vessels of the skin and mucous
membranes (α1effect).
 Vasodilatation of the skeletal muscles and coronary blood vessels (β2
effect).
N.B.
 The cumulative effect is in systolic pressure due to increased COP and
there is a slight change in diastolic pressure.
 The increase or decrease depends on the final effect on peripheral
resistance that depends on the ratio of α and β activity on vascular
beds. If α is blocked there would be a fall in Bp since there is only β
effects.
Respiratory system
 Stimulation of respiratory system through a central mechanism.
 Powerful bronchodilation (β2 effect). In bronchial asthma it acts
directly on smooth muscle and relives all known allergen- or histamine-
induced bronchoconstriction.
 In acute asthmatic attack, it rabidly relieves the dyspnea (labored
breathing) and increases the tidal volume (volume of gas inspired and
expired).
Urinary bladder
 It relaxes the detrusor muscle (β2-effect).
 It contracts the sphincter and trigone (α1-effect)
Uterus
 In experimental animal it has variable actions on the uterus depending
on the species and stage of the cycle.

231
 It relaxes the pregnant human uterus.
Eye
 It has limited effect on the size of the pupil (local application) for two
reasons:
1) It is partly destroyed by the alkalinity of tears.
2) It causes vasoconstriction of the conjunctiva blood vessels and thus
hinders its own absorption.
 It lowers IOP in open angle glaucoma.
GIT
 Stimulation of both α and β receptors, leads to inhibition of tone and
motility of GIT smooth muscles.

2) Metabolic actions:
 Adrenaline increases blood glucose level (hyperglycemia) by two
mechanisms:
a) By β2 effect; enhancement of glycogenolysis in liver and increased
release of glucagon. It also decreases uptake of glucose by peripheral
tissues.
b) By α- effect; decreased release of insulin.
 Initiates lipolysis through β1 activity.
 Increases blood concentration of free fatty acids as a result of increased
breakdown of triglycerides in adipose tissue.
 Increases metabolism (has a calorigenic action). This is evidenced by
increased oxygen consumption 20~30% after the usual doses.
 Produces a transient rise in plasma potassium followed by a prolonged
fall.
3) Adrenocortical actions:
 It stimulates anterior pituitary to secrete ACTH, which enhances the
secretion of hydrocortisone from the adrenal cortex.
4) Skeletal muscle action:

232
 Adrenaline facilitates neurotransmission and hastens recovery from
fatigue.
5) Antihistamine and antiallergic action:
 Adrenaline is the physiological antagonist of histamine.
6) Action on blood coagulation:
 Adrenaline accelerates blood coagulation by increasing factor V
activity.
7) Action on the CNS:
 Adrenaline has a weak stimulatory action on the CNS.
 It may cause restlessness and tremors.
Clinical indications:
1. Bronchospasm; produces bronchodilation and reduction of congestion
and edema of bronchial mucosa.
2. Glaucoma; decreases IOP.
3. Anaphylactic shock (hypersensitivity reaction).
4. Shock; decreases hyperkalemia (promotes K+ uptake).
5. Anesthesia; to prolong duration of action of infiltration anesthesia;
localizes the action and decreases bleeding.
6. Cardiac arrest; restores cardiac activity.
7. Insulin hypoglycemia.
8. Epistaxis; as local haemostatic, the nose is packed with cotton or wool
soaked with adrenaline solution.
Adrenaline Reversal:

α effect β effect
It is the fall (instead of elevation) in
α-blockage
blood pressure produced by adrenaline
when given following blockade of α-
adrenergic receptor; the vasodilation reflects the ability of adrenaline to
activate β2 receptors which, in vascular smooth muscle, are inhibitory.

233
Pharmacokinetics:
 It has a rapid onset and brief duration of action.
 It is inactive orally because of:
 poor absorption from GIT
 rapid destruction by digestive juices
 rapid metabolism by the liver
 By subcutaneous injection, it has slow absorption due to local
vasoconstriction (α effect).
 Absorption is more rapid after intramuscular injection, but can be
delayed by admission of the drug in oil.
 Its strong solutions as nebulizer or inhalant are used locally in
respiratory tract.
Side Effects:
 Minor side effects; Anxiety, restless, headache, tremors and palpitation.
 Anginal pain in patients with angina pectoris due to increased cardiac
work.
 Cardiac arrhythmias occur when adrenaline is employed during
anaesthesia with chloroform, trichloroethylene, cyclopropane, or
halothane. These lead to potentiation of adrenaline excitability
leading to ventricular fibrillation or extra systole, which could be
treated by β-blockers.
 Large doses raise Bp leading to cerebral hemorrhage.
 Severe vasoconstriction or even gangrene of fingers or toes may follow
infiltration anesthesia containing adrenaline.
 Pulmonary edema which leads to pulmonary hypertension
Contraindications:
1. Coronary diseases because it may induce anginal attacks.
2. Hyperthyroidism
3. Hypertension
4. Chloroform and some other anesthesia

234
5. In patient receiving digitalis therapy (adrenaline and other
sympathomimetics as ephedrine).
Preparations:
1) Adrenaline HCL: solution 1/1000 in distilled water 0.5 ml.
2) Adrenaline HCL: 1% solute by oral inhalation from nebulizer.
Drug Interactions:
 Hyperthyroidism: epinephrine shows enhanced cardiovascular actions
in patients with hyperthyroidism, so the dose must be reduced. The
mechanism is by increasing adrenergic receptors.
 Cocaine: it produces exaggerated cardiovascular action in presence of
cocaine.
Norepinephrine (Noradrenaline)
NE is a neuromediator of adrenergic nerves that stimulates all types of
adrenergic receptors.
It has similar effect of that done by adrenaline but its α-effect is more
than β-effect (β2 is stimulated to a lesser degree).
Actions:
1) Produces intensive vasoconstriction so it increases peripheral resistance
(α-effect) and both systolic and diastolic Bp are increased
2) Baroreceptor reflex: In isolated cardiac tissue, NE stimulates cardiac
contractility but in vivo little effect is noted. This is due to NE-induced
increase in vagal activity by enhancing baroreceptor activity
3) Effect of atropine pretreatment: Atropine blocks the transmission of
vagal effects so NE stimulates the heart and produces tachycardia
Pharmacokinetics:
NE like adrenaline is ineffective orally. It is given by i.v. infusion ONLY. It is
not given s/c or i/m because of its strong vasoconstrictor effect that produces
necrosis and sloughing.
Therapeutic Uses:
It is used as a hypertensive agent. However, dopamine is better because it
does not reduce blood flow to the kidney (other uses are not considered
clinically significant).

235
Side Effects:
1) Anxiety, headache and bradycardia are common side effects.
2) NE may cause severe hypertension in excessively sensitive persons e.g.
hyperthyroidism patients.
3) Necrosis and sloughing.
Isoproterenol (Isoprenaline)
It is a direct acting synthetic catecholamine; isopropyl-noradrenaline.
It is a powerful direct stimulant of the β-adrenoceptor and very weak
stimulant to α-receptor.
Actions:
1. CVS:
It produces intensive stimulation in heart leading to increase in its rate and
force of contraction. These increase cardiac output. So, it is used in treatment
of atrioventricular block or cardiac arrest. Also, it dilates the arterioles of
skeletal muscle (β2-effect). Because of cardiac stimulation, it may increase
systolic Bp slightly but reduces mean arterial and diastolic Bps.
2. Respiratory system:
Its pulmonary effect is rapid bronchodilation.
3. Other effects:
It increases blood sugar and increases lipolysis (β-effect).
Clinical Uses:
It is used in (1) acute bronchial asthma and (2) heart block.
Side Effects:
Similar to epinephrine, it causes palpitation, arrhythmias, anginal pain,
flushing of skin, headache and tremors.
Administration:
Can be absorbed systemically by sublingual and more reliably absorbed
parentally as inhaled aerosol.
Dopamine
It is a naturally occurring catecholamine.

236
It is the immediate precursor of NE.
It has a transmitter role in the CNS (dopamine receptors D1 and D2).
Peripherally, it acts on α and β receptor as well as dopaminergic
receptors (not influenced by α and β blockers).
Stimulation of D1 leads to relaxation of muscles.
Stimulation of D2 leads to increased NE.
Also it stimulates β1 i.e. it has both positive inotropic and positive
chronotropic effects.
Low doses → decrease VPR
High doses → activate α-receptor leading to vasoconstriction.
Via dopaminergic receptor it dilates renal and splanchnic arterioles
leading to increase in blood flow to kidney and other viscera (this
action is not affected by α and β blockers).
The increased blood flow to the kidney enhances the GFR and causes
sodium dieresis, dopamine is superior to NE which diminishes blood
supply to kidney and may cause kidney shutdown.
Uses:
It is used in the treatment of shock due to many causes as myocardial
infarction or congestive heart failure, trauma and septicemia.
Adverse Effects:
Overdose produces sympathetic stimulation.
It is rapidly metabolized but adverse effects include nausea,
hypertension and arrhythmias. All are short lived.
Dobutamine
It is a synthetic, direct acting catecholamine.
a β-receptor agonist that increases cardiac contractility and output,
with few vascular effects and little effect on arterial Bp.
Chemically, it is related to isoprenaline. It differs from isoprenaline
by producing a lesser fall in peripheral vascular resistance and a lesser
rise in heart rate for a given increase in cardiac output.
Unlike dopamine, it has no renal vasodilator effect.

237
The drug also stimulates α-receptors to some extent (in high dose).
Therapeutic Uses:
 In shock due to myocardial infarction; cardiogenic shock
 Used to increase cardiac output in congestive heart failure (oxygen
demand, etc)
Kinetics:
It is not absorbed orally. The t½ is two minutes and is given I/V.
Adverse Effects:
It should be used with caution in arterial fibrillation since the drug increases
atrioventricular conduction. Other side effects are similar to those caused bys
epinephrine.
Metaproterenol
 It is a more selective β2-agonist with longer duration of action.
 It is used as bronchodilator and to reduce uterine contraction in
premature labor.
Ritodrine
It is a selective β2-agonist used to relax uterine contraction of premature
labor.
Salbutamol and Terbutaline
They are selective β2-agonists used in bronchial asthma.
Albuterol
 Selective β2-agonist with properties similar to terbutaline.
 It is used to relief bronchospasm
Phenylephrine
 It acts directly on α-receptor, but α1- is favored over α2-receptor.
 Actions in CVS include vasoconstriction that rises systolic and
diastolic Bp.
 It has no effect on heart.
 When taken orally, it produces reflex bradychardia.
 Used topically as mydriatic agent.

238
Therapeutic Uses:
 Nasal decongestion
 Used to raise Bp and to terminate episode of supraventricular
tAchycardia.
 Mydriatic
Adverse effects include hypertension and cardiac irregularities when used in
large doses.
Methoxamine
 It is a direct acting sympathomimetic binds to α-receptor, but α1- is
favored over α2-receptor.
 It stimulates α1 causing vasoconstriction that increases total
peripheral resistance.
 Adverse effects include hypertension, headAche and vomiting.
Clonidine
 It is an α2-agonist which is used to lower Bp & to minimize
symptoms of withdrawal of opiates. or benzodiazepines.
 Acts centrally to produce inhibition of sympathetic vasoconstriction
centers.

Indirect-acting Adrenergic Agonists


Amphetamine
It is a synthetic non-catecholamine. It is rapidly absorbed from GIT and
parental sites, not destroyed by MAO, partly destroyed by liver and partly
excreted unchanged in urine. The extent is increased by acidification of urine.
It produces two main actions:
1) Sympathomimetic Action: It stimulates α and β receptors through an
indirect mechanism
↑Bp (α); both systolic and diastolic
Heart rate is usually reflexly slowed. Large
CVS doses may produce cardiac arrhythmias
Tachyphylaxis usually occurs due to CV effects
on repeated administration

239
Smooth muscle Bronchi: insignificant action
Relaxation of detrusor muscle
Urinary bladder
Contraction of sphincter
GIT Relaxation in spastic states
Eye Local application leads to mydriasis
2) Central Actions:
It stimulates the cerebral cortex, reticular activating system, vital medullary
centers and spinal cord. This stimulation is more potent than that of
ephedrine.
a) Psychic stimulation: This includes euphoria, wakefulness, alertness
and increased mental and physical activity. (Psychic stimulation is
followed by depression)
b) Anorexigenic Action: It depresses appetite and reduces food intake
through:
 Central action on the hypothalamic feeding center
 Reduction of acuity of smell and taste
 Facilitation of mono- and poly-synaptic transmission in the spinal
cord
Uses:
 Obesity, narcolepsy and Parkinsonism (to elevate the mood)
 Narcotic and barbiturate poisoning
 Mental and physical fatigue
 Psychic depression
 Nocturnal enuresis(the drug is given at night to lighten sleep )
 Chronic alcoholism
 Hyperkinetic syndrome in children (to calm)
It can be used as decongestive but because of its strong central activity it
becomes neglecting.
Tyramine

240
It is a natural non-catecholamine compound. It acts indirectly causing release
of endogenous transmitters (E, NE and DM) leading to hypertension followed
by little decrease in Bp due to the effects in β2-receptors. It does not bind to
receptors.
 It can be found in cheese, fish, ferminted food as ripe, cheese, wine,
tears, beers, especially old substances.
 It is metabolized by MAO.
 If it is taken in food by persons using MAOI, it leads to hypertension
e.g. (cheese reaction → hypertension crisis).
 So, tyramine is contraindicated in MAOI usage.
Mixed-action Adrenergic Agonists:
Ephedrine:
• It is an alkaloid obtained from Ephedra plants. It is also prepared
synthetically.
• It is not a catecholamine poor susceptibility for COMT and MAO.
• It has an excellent absorption orally and from parental sites and has
long duration of action. Greater part is excreted unchanged in urine. It
can penetrate CNS.
Actions: Having a wide variety of actions, it is similar to epinephrine but is
less potent.
Cardiac stimulation; raises both systolic and diastolic blood
CVS
pressure
bronchi: bronchodilation but less potent than epinephrine
Smooth
muscles Used as prophylactic to prevent attack rather than to treat
acute attack
GIT Inhibition of the smooth muscles of the gut
Relaxation of the bladder muscle and constriction of
Urinary tract
sphincter and trigone
Eye Mydriasis
Uterus Varied with species and cycle - It relaxes human uterus
Skeletal Facilitates neuromuscular transmission (used in myasthenia

241
muscles gravis)
Enhances contractility and improves motor function
Stimulates CNS like amphetamine but the action is lesser
Mild stimulation; increased alertness, decrease fatigue and
CNS
prevent sleep
Used to improved athletic performances

Uses:
 As prophylactic to prevent asthmatic attack
 Nasal decongestion (vasoconstriction)
 Mydriasis
 To prevent fall in Bp during spinal anesthesia or to raise Bp in GA
 Myasthenia gravis
 Heart block
 Nocturnal enuresis and narcolepsy
Side Effects:
They are similar to adrenaline. In addition, it produces insomnia
(counteracted by barbiturate) and urine retention.
Metaraminol
It is a mixed-acting agonist having similar actions to norepinephrine.
It is used
(1) to treat shock (when infusion with NE or dopamine is not possible) and
(2) to treat acute hypotension (given parentally as single dose).
It enhances cardiac activity and produces vasoconstriction
Adrenergic Antagonists; Adrenoceptor Blocking Drugs
Adrenergic antagonists
The effect of sympathetic nerve stimulation can be blocked or inhibited
through one of the following mechanisms:

242
1- Adrenergic receptor blockers:
A. α adrenergic blockers
B. β adrenergic blockers
C. α and β adrenergic blockers
2- Adrenergic neuron blockers or anti-adrenergic drugs:
A. Peripherally acting drugs (interfering with release or storage)
1- Drugs interfering with release e.g. guanethedine and bretylium
2- Drugs interfering with storage e.g. reserpine (deplete of NA)
B. Centrally acting drugs (inhibition of VMC = α2 agonist)
Stimulation of presynaptic α2-receptor→ inhibit NA release e.g. α methyl
dopa , clonidine
3- Ganglionic blockers: block the transmission in the sympathetic ganglion
Note:
1. NE: inhibit tyrosine hydroxylase{rate-limiting step in NE synthesis}
2. α- methyl tyrosine: inhibit conversion of tyrosine into Dopa by inhibiting
tyrosine hydroxylase enzyme which is essential for biosynthesis of NE.
3. Chemical sympathectomy occurs by 6-hydroxy dopamine.
1- Adrenoceptor- blocking drugs:
α1 Prazosin, doxazosin, terazosin
α1- α2 Phenoxybenzamine, phentolamine
α2 Yohimbine, tolazoline, idazoxan
α– β Labetalol
β1 atenolol, alprenolol, acebutolol, metoprolol, esmolol
Β1- β2 Propranolol, timolol, andolol, pindolol
β2 Butoxamine

243
α- Blockers:
Classification of α- blockers:

1. Imidazoline derivatives: phentolamine and tolazoline.


2. β- haloalkylamines: phenoxybenzamine , terazosin, doxazosin (long-
acting).
3. Selective α1-blockers: prazocin, trimazosin, indoramin .
4. α2 –blocker: yohimbine.
5. Block α1 and β respectively: lahetolol, carvedilol.
6. Ergot alkaloid: ergotamine, ergotoxine.
7. Other α– blockers:
1. Chloropromazine: have multi-pharmacological actions (one of
them is α-blocking).
2. Piprocaine: used for the diagnosis of pheochromocytoma.
3. Ketanserin.
These drugs block α-adrenoceptors and have profound effects on blood
pressure. Since neuronal sympathetic control of the vasculature occurs in
large part through α-adrenoceptor action, blockage of these receptors reduces
sympathetic tone of the blood vessels resulting in fall of peripheral vascular
resistance. This induces reflex tachycardia that results from decreased Bp.
These agents with the exception of prazosin and labetalol have limited
clinical uses.
Pharmacological Action:
 In CVS; α-blockade decreases PR + Bp resulting in reflex tachycardia. The
drugs have been unsuccessful in maintaining lowered Bp in hypertensive
patients, so have been discontinued. (decreased blood pressure due to
decreased peripheral resistance, the fluid in peripheral blood will increase
the hydrostatic pressure and colloid pressure producing fluid retention).
Blocking of α2 –receptors will increase NE release.
 Postural hypotension; orthostatic hypotension due to α- blockade. When
individuals stand rapidly, blood pools in the lower extremities causing
faintness.
 Epinephrine reversal; α-blockade leads to decrease in Bp due to β-action.
All α- blockers reverse the α–agonist action of epinephrine and not
norepinephrine.

244
 Sexual function is adversely affected by α-blockade leading to inhibition of
ejaculation with the possibility of retrograde ejaculation (inability of
internal sphincter of the bladder to close during ejaculation).
 Produce nasal stuffiness and decrease adrenergic sweating.
 Dilate blood vessels in the skin, mucous membranes, and sex organs
{increasing sexual desire (aphrodisiac), increase ADH release, & a local
anesthetic action that may improve symptoms in painful diabetic
neuropathy.
Therapeutics uses:
1. Primary hypertension; selective α1 –blockers.
2. Hypertension due to excess Catecholamines; pheochromocytoma
and sudden clonidine withdrawal.
3. Peripheral vascular diseases (Ca++ channels blockers can also be
used).
4. Reverse severe vasoconstriction due to leakage of NE during IV
infusion.
5. Treatment of neurogenic vascular dysfunction in which internal
sphincter closes spontaneously during micturition and urine
stagnates in bladder because of incomplete voiding.
6. Treatment of patients with spinal cord injuries (paraplegia) who
may suffer from hyper-reflexia, which results in increased
sympathetic activity to the blood vessels and causes high blood
pressure. Thus, predisposes paraplegics to strokes. The drug blunts
this response and aids to normalize paraplegic Bp.
7. Treatment of patients with benign prostatic hypertrophy (reduces
the size of the prostate and antagonizes smooth muscles
contraction in enlarged prostate by selective α1 –blockers).
8. Phentolamine is injected with papavrine to induce erection in
male sexual dysfunction (PGE can also be used).
Note:
Sildenafil (ViagraR) inhibits phosphodiesterase-5, so increase cGMP, it is
given orally to increase erection.

245
Alhpa- blockers
Ergot Imidazoline Phenoxybenz prazocin Yohim
alkaloids amine e bine
tolazoline phentola
mine
Select α1– α2 α1– α2 α1– α2 α1– α2 α1 α2
ivity
Mech Partial Competiti Competiti Non- Competi Comp
anism agonist ve ve competitive tive etitive
antagonist antagonist irreversible antagoni antago
antagonist{slo st nist
w onset and
long duration
of action}
additi 1.smooth 1.histami 1. α – 1.close 3 phosphd 1-
onal muscle ….. ne-like blocker,5t other iesterase aphro
actio imes more receptors: inhibitor disiac
n vasoconstr 2.periphe histamine.5H {increase
potent
iction ral T,muscarinic cAMP 2-
sympatho2.much and ADHr
oxytocic mimetic 2.block elease
less in cGMP}
2.CNS:{++ 3.sympath other uptake 1 and
uptake2 of 3-local
CIC,CTZ,-- omimetic actions. anesth
R.C,VMC} NE
etic
Uses Acute Periphera 1.PVD 1.PVD hyperten 1.aphr
attack of l vascular sion odisiac
migraine diseases{P 2.diagnosi 2.diagnosis of
VD} s of pheochromoc 2.diab
pheochro ytoma etic
mocytoma neuro
3.shock pathy?
Side - -peptic Less than Hypotension -1st dose -
effect tingling,ga ulcer tolazoline phenom increas
e

246
s ngrene -angina enon ADH
-angina - -angina -edema
hypotensi
- on -edema
hypertensi
on -allergy

-abortion
-
nausea,vo
miting
CIC= cardio inhibitory centre CTZ=chemoreceptor trigger zone
RC=respiratory centre VMC=vasomotor centre
++ = stimulation -- = Inhibition

Note:

Phenoxybenzamine:
 The only mechanism by which the body can overcome the block is the
ability to synthesize new α-adrenoceptors in one day.
 Therefore, the action of this drug lasts 24 hours after a single
administration. When the drug is injected, the actions delay for few
hours before α-blockade develops because drug undergoes change to
the active form.
Clinical pharmacology of α-receptor blocking drugs:
 Phaeochromocytoma (Phenoxybenzamine + β-receptor antagonist e.g.
atenolol)
 Hypertensive emergency (labetalol)
 Chronic hypertension (prazosin, doxazosin, terazosin)
 Peripheral vascular disease as Raynaud's syndrome (phentolamine,
tolazoline)
 Local vasoconstrictor excess (phentolamine)
 Urinary obstruction (phenoxybenzamine).

247
Classes of β- blockers
Non- Solubility Metaboli Durati Local I. S. Uses
Selective sm on anesthet A.
ic
action
Propranolo Lipophilic Hepatic Short + No Angina, arrhythmia,
l (CNS (extensiv 4~6hr hypertension.
action) e) s
Nadolol Hydrophili Renal Long No No Angina, hypertension.
c 12~24
hrs
Oxprenolol Lipophilic Hepatic Short + ++ Angina, arrhythmia,
hypertension. Not used
with hypersensitive R
Pindolol Lipophilic Hepatic Short + + Not used with
hypersensitive R
Sotalol Hydrophili Renal Long No No Antiarrhythmic, addition
c class III action
Timolol Lipophilic Hepatic Short No + - WA-glaucoma, eye
drops.
- Absorbed systemically,
avoided in heart block.
- Does not affect
accommodation.

Selective β1 Solubility Metabol Durati Local I. S. Uses- special notes


ism on anesthet A.
ic
action

248
Metoprolol Lipophilic Hepatic Short + No Angina, arrhythmia,
hypertension.
Atenolol Hydrophili Renal Long No No Angina, hypertension given
c once a day.
Acebutolol Lipophilic Hepatic Short + ++ Angina, arrhythmia,
hypertension.
Bisprolol Angina, arrhythmia,
hypertension.
Esmolol Esterase Ultras No No Supraventricular
in RBCs hort arrhythmia & severe
(T1/2E hypertension, IV;
10min) 50~400μg/kg/min.

Pharmacokinetic:
 Most of them are well absorbed.
 Rapidly distributed and have large volume of distribution.
 Half-lives between 2~5 hours.
Mechanism of action (Pharmacodynamic):
The effect is due to occupation and blockade of β-receptors, however some
effects may be due to other mechanisms.
Effect on C.V.S.:
 Lower blood pressure.
 Negative inotropic and chronotropic.
 Slow atrioventricular conduction with increased PR interval on ECG
Effect on the respiratory tract:
 Blockade of β2-receptor increases the airway resistance in patients with
asthma
Effects on the eye:
 Reduce intraocular pressure
Metabolic and endocrine effects:
 Inhibit lipolysis
 Inhibit glycogenolysis
Therapeutic indications of β-blockers:
CNS:

249
1. anxiety
2. prophylaxis against migraine
Eye:
3- open angle glaucoma
CVS:
4. angina pectoris
5. acute phase of myocardial infarction
6. arrythmia
7. cardiomyopathy
8. essential hypertension
9. hypertension due to pheochromocytoma{in combination with alpha
blockers}
B.vessels:
10. vascular surgery
11. prevention and treatment GIT bleeding{oesophgeal varicies }
Endocrine:
12. hyperthyroidism
13. other: antiparkinsonism{reduce the tremors}

Clinical advantages of selective β1-blockers:


1) less in producing increase in peripheral resistance{Raynaud's
phenomenon}
2) less in producing bronchospasm
3) less in producing hypoglycemia
4) less in producing lipoproteins change
5) less in producing potassium change
Note:
Cardio-selectivity {β1-selectivity} is not absolute and is lost with high doses.
Adverse reactions:
1- Fatigue, dizziness, GIT disturbances and muscle aching with normal doses
2- Heart failure (in case of inadequate myocardial function)
3- Heart block may be worse and even cardiac arrest may occur in case of
partial AV block due to digitalis therapy or heart disease. Atropine may be
used as antidote.

250
4- Hypotension and severe bradycardia
5- Bronchospasm
6- Augmentation of the hypoglycemic action of insulin and masking of
symptoms.
7- Allergic reactions (skin rash, fever & purpura).
8- Hallucinations & nightmares.
9- Cold hands due to vasodilatation in cutaneous vessels.
10- Abrupt discontinuation of propranolol or other β-blockers lead to a
withdrawal syndrome (sever exacerbation of angina attacks and myocardial
infarction), so it should be stopped gradually.
Contraindications:
1- Bronchial asthma.
2- Congestive heart failure.
3- Partial heart block.
4- Hypotension.
5- Angina due to vasospasm.
6- IDDM.
7- Pregnancy.
8- Peripheral vascular disease.
Side effects & Contraindications of β- blockers
System Side effects Contraindications
CNS Sedation, depression & nightmares.Severe depression
(only the lipophilic β- blockers (use hydrophilic β- blockers).
that cross the BBB).
Eye Oculumucu-cutaneous syndrome withNot used any more.
practolol
CVS- - Heart failure in cases of inadequate- Varient angina.
A) Heart myocardial function as MI. - CHF.
- Heart block ( atropine is - H block & severe bradycardia.
the antidote) - Not used with verapamil or
diazepam → contraction &
conduction → HF or H block.
B) BVs Cold extremities, Raynaud`s phenomenon &
Rynaud`s phenomenon, numbness, other Peripheral vascular
tingling & intermittent claudication. diseases.
C) BP Hypertension. Hypertension.
Respiration Precipitate acute attacks of BA inBronchial asthma

251
asthmatics. (β1 are used).
Metabolism - Hypoglycemia (severe in patientsHypoglycemia
receiving insulin or (with hypoglycemics).
Oral hypoglycemic).
- Atherosclerosis (↓HDL).
- Hyperkalemia especially in uremic
patients.
Others If given with supersensitive receptorsUse β- blockers without ISA
(sympatholytics, with supersensitive receptors.
MAOI…) → exaggerated
sympathomimetic action
(only in β- blockers with ISR).
- Sudden discontinue (withdrawal) →
sympathetic over-
activity & precipitation of anginal
attacks or even MI.

2-Drugs that affect noradrenergic neurons


A. Drugs that affect noradrenaline synthesis:
α- methyl- tyrosine
 Inhibits tyrosine hydroxylase.
 It has been used in the treatment of phaeochromocytoma.
Carbidopa
 Inhibits dopa decarboxylase.
 Used as adjunct to the treatment of Parkinsonism with L-dopa. It reduces
the peripheral side effects of L-dopa (conversion of L-dopa to dopamine
and NA).
 Carbidopa does not enter the brain.
Methyldopa:
 In the CNS (taken up by adrenergic neurons) methyldopa is converted to
α–methyl-noradrenaline which forms a false transmitter.
Methylnoradrenaline is not metabolized by MAO.
 Methylnoradrenaline is less active on α1-receptor and thus a less
vasoconstrictor, but more active on α2 receptors so more strong inhibitory
feed-back mechanism.

252
 Methyldopa is a dopa decarboxylase inhibitor & prevents the conversion
of dopa to dopamine.
Pharmacological action:
1- Bradycardia
2- Hypotension
3- Sedation (due to depletion of 5HT)
Therapeutic uses:
Treatment of hypertension usually in combination with a diuretic, because
renal blood flow is not reduced with its use.
Side effects:
1- Central effect: sedation, vertigo, parkinsonism and psychic depression.
2- GIT: dry mouth, nausea, vomiting and diarrhea.
3- Hypersensitivity: fever, reversible liver damage, granulocytopenia,
thrompcytopenia and autoimmune haemolytic anaemia.
4- Postural hypotension
5- Salt and water retention and weight gain.
6- Hyperprolactinaemia, gynaecomastia, and galactorrhoea.
B. Drugs that affect noradrenaline storage:
Reserpine:
An alkaloid excreted from the root of Rawulfia serpentine.
Mechanism of action:
 At low conc. reserpine blocks the transport of NA into synaptic vesicles.
Accordingly, NA may leak into the cytoplasm where it is rapidly
metabolized by MAO enzyme.
 Reserpine impairs the uptake of dopamine by the granules and thus
inhibits the synthesis of NA therein.
Pharmacological action:
C.V.S: hypotension and bradycardia through:
 Peripheral action: reserpine interferes with the uptake and retention of
noradrenaline by the tissue storage sites and with its intraneuronal storage
leading to depletion of catecholamine stores in sympathetic nerve ending
and in peripheral tissues. Consequently the symp. tone of the blood
vessels falls with a resultant drop in blood pressure.
 Central action: reserpine causes vasomotor depression leading to a
decrease in the peripheral resistance. It also depletes catecholamine and 5-
HT stores in the CNS, leading to sedation and lowering of blood pressure.

253
Therapeutic uses:
1- Small dose for hypertension (0.25 mg).
2- Large dose for psychotic states (5~10 mg).
Side effects:
1- Parasympathetic effects: salivation, cutaneous vasodilatation, nasal
stuffiness, diarrhea, and bradycardia. Activation of peptic ulcer.
2- Centrally: psychic depression, Parkinsonism, suicidal tendencies,
nightmares.
3- Weight gain due to an increased appetite and sodium and water retention.
4- Endocrine disturbances: such as feminization, with loss of libido and
impotence.
5- Prolonged use may increase the incidence of carcinoma of the breast.
Contraindication:
 Psychic depression.
 Peptic ulcer.
Drug interactions:
1- MAO inhibitors reverse the hypotensive action of reserpine.
2- The use of general anaesthesia in patients taking reserpine may cause
hypotension.
C. Drugs that affect noradrenaline release:
1- Noradrenergic neuron blocking drugs e.g. guanethidine, bretylium,
bethanidine and deprisoquin.
2- Indirect acting sympathomimetic amines e.g. ephedrine, tyramine and
amphetamine.
3- Interaction with presynaptic receptors that enhance release e.g. dopamine
or inhibit release e.g. α2-agonist.
4- By increasing or decreasing available stores of NA e.g. reserpine and MAO
inhibitors.
Guanethidine:
 It is incompletely absorbed from the GIT and excreted by the kidney.
 It is too polar so not effective centrally.
 The drug is cumulative since it is stored then slowly released from the
tissue.
Pharmacological actions:
 Guanethidine inhibits the release of noradrenaline from adrenergic nerve
fibres.

254
 It depletes NA from its tissue stores
 Is taken up by adrenergic nerves by the same mechanism involved in NA
uptake. It then accumulates in the storage granules and displaces NA from
them.
 It does not penetrate BBB & does not affect the level of NA in the brain.
 It does not antagonize injected catecholamines.
Effect on C.V.S:
Rapid IV administration produces:
 An initial rapid fall in B.P. associated with increase COP and decrease
peripheral resistance due to direct action on the arterioles.
 This is followed by a rise in blood pressure due to the release of
catecholamines from their stores in the peripheral tissues.
 Finally the drug causes hypotension associated with bradycardia, decrease
pulse pressure and decrease COP.
Oral administration produces:
 A fall in systolic and diastolic B.P and bradycardia.
 Hypotension is more marked in the ambulant patient than the supine
one.
Other effects:
Increased GITmotility, increased gastric acid secretion, failure of ejaculation,
miosis and lowering of intraocular pressure in case of glaucoma.
Therapeutic uses:
1- Treatment of severe hypertension (usually with diuretics or other
hypotensive agents).
2- Treatment of glaucoma by local application.
Side effects:
1- Postural hypotension and exertional hypotension
2- Nasal congestion & stuffiness.
3- Fluid retention with heart failure.
4- Failure of ejaculation without impotence.
5- Parotid gland pain and diarrhea.

255
Chapter 10

Drugs affecting the CNS


The basic functional unit of the nervous system is the nerve cell or neuron
consisting of 3 parts the cell body, dendritic tree & axon. The CNS comprises
billions of neurons linked to form a diffuse network. The complex
arrangement enables that impulses may be:
A. Blocked during transmission from a neuron to another.
B. Changed from a single to repetitive impulses.
C. Integrated with impulses from other neurons to generate highly
intricate pattern of impulses.
 Nerve impulses are transmitted from one neuron to the next via the
specialized structures synapses.
 Synapses determine the pathway of signal spread, specific areas in the
nervous system can alter function sometimes facilitating transmission
by opening synapses for transmission & at other times closing them
rendering them as sites for control of signal transmission.
 Although there are two types of synapses the chemically mediated &
the electrical, the vast majority of synapses in the CNS are chemically
mediated characterized by transmission of signals in one direction.
1. The transmitter release is initiated by an impulse action potential that
activates the voltage-gated Ca channels.
2. Ca ions then flow into the presynaptic terminal catalyzing a reaction
that liberates the NT in a concentration proportional to the number of
Ca ions entering the terminal.
3. NT released from the presynaptic vesicles into the synaptic cleft diffuses
to bind Rs in the post-synaptic membrane.
4. Receptor proteins have 2 important components; a binding component
& an inophore component;
5. Type one inophore component is ion channels. i- Cationic
channels allow Na (& sometimes K or Ca) passage & serve to excite
post synaptic membrane i.e. these channels open to excitatory NTs.

256
ii- Anionic channels allow mainly chloride ions to pass & are opened
by inhibitory NTs.
6. The other type of inophore component is a 2nd messenger activator
that generates prolonged neuronal responses (seconds to months).

Neurotransmitters in the CNS

ACh

1- Same mechanism of action & hydrolyses by esterase as in peripheral


nerves.
2- Although M1~ M5 exist, M1 are predominant coupled to G-protein &
function primarily to close K, Ca or chloride channels depending on
cell type i.e. inhibitory & excitatory.
3- Presynaptic receptors exist.
Noradrenaline

1- Unlike ACh has an uneven CNS distribution.


2- 2 regions are the most important the brain stem & the reticular
formation ;from neurons arising in these locations axons innervate
target cells in cortical subcortical & spino-medullary fields.
3- Activates excitatory Rs in control of sleep & wakefulness, mood &
emotional behavior & temperature.
Adrenaline

1- Neurons of the medulla reticular formation,


2- Pharmacological properties poorly understood.
Dopamine

1- Precursor for the synthesis of noradrenaline.


2- Basal ganglia & the limbic system.
3- Primarily inhibitory function linked to the fine control of movement,
disturbances of behavior & hypothalamic-pituitary endocrine system.
4- D1 & D5 postsynaptic Rs activate adenylyl cyclase increasing cAMP.
5- D2, 3 & 4 located both post & presynaptically inhibit (or have no effects
on) cAMP synthesis.
6- D3 is of particular role as a therapeutic target for treatment of
schizophrenia & drug abuse.
5HT

257
1- Increases K conductance.
2- Inhibits pain pathways in the spinal cord.
3- Pons & upper brain stem & projects to many brain & spinal cord
areas.
4- Serotoninerigc neurons control sleep & wakefulness, mood &
emotion, temperature, appetite & neuroendocrine control.
5- Presynaptic autoreceptors.
6- Nerve terminals that release other NTs e.g. dopamine.
Histamine

1- H1, 2 &3 mainly in the posterior hypothalamus.


2- Uncertain but involved in regulation of arousal, temperature &
vascular dynamics.
GABA

1- Is the major inhibitory transmitter receptor in the CNS & controls


spinal & cerebellar reflexes & is involved in the induction of
convulsions & in anxiety states.
2- Many neuroactive substances (e.g. alcohol, barbiturates &
benzodiazepines) facilitate GABAA on Cl conductance.
3- GABAB receptor acts via a G-protein to increase conductance in K
channels.
Glycine

1- Inhibitory NT between spinal interneurons & motor neurons.


2- Act by increasing conductance of Cl channels.
3- Restricted to the spinal cord.
Glutamate

1- Is the major excitatory NT in the CNS.


2- Involved in neurophysiological & pathological processes.
3- Is selectively blocked by ketamine & phencyclidine which are clinically
useful in the inhibition of epilepsy & brain ischemia.
Nitric oxide

1- Is responsible for long-term behavior & memory.


2- Synthesized almost instantly as needed.
3- Does not alter membrane potential (excitability) but act by changing
intracellular functions.

258
Neuropeptides

1- Present in smaller amounts but far more potent.


2- Synthesis is directed by mRNA in ribosomes. The biologically-inactive
prohormone is packaged in vesicles in the smooth ER & transported to
nerve terminals for latter release by Ca-dependant mechanism.
3- Inactivated by enzymatic breakdown.
4- Although some NTs act on identified specific Rs, most are released
with & act on concert with small molecule NTs enabling the
transmission of an enriched message (strengthening or prolongation).
Substance-P

1- Prolonged duration excitatory action on dopaminergic neurons in the


brain in response to afferent nerve fibres in the spinal cord.
2- Mediates sensations of noxious stimuli.
Opioid peptides

An endorphin is a chemical substance naturally-formed in the body


that exhibits the pharmacologic properties of morphine. They are
categorized in 3 families;
1- Pro-opiomelanocortin-derived; e.g. the most potent β-endorphin.
2- Pro-enkephalin-derived e.g. metenkephalin & leuenkephalin.
3- Pro-dynorphin-derived e.g. dynorphin.
 Enkephalins are short-acting & are NTs.
 Endorphins are relatively long-acting & have modulatory hormonal
effects.
 Both mediate analgesia.

Drug Action in the CNS

A- Specific

By specifically modifying some step or mechanism in the chemical


synaptic transmission of nerve impulses, e.g.
1. Impulse conduction can be prevented by application of a local
anesthetic to a nerve fibre.

259
2. Pre-synaptic transmission can be depressed by halting NT release or
synthesis; reserpine interferes with intracellular storage of
monoamines therein limiting their availability for immediate release.
3. Amphetamine increases the release of the NT.
4. Cocaine affects the uptake of the NT.
5. Physostigmine affects the degradation of the NT.
6. Post-synaptically drugs may mimic the action of the NT on receptors
e.g. opioids, or block the R.

B- Non-specific

Drugs may affect the CNS by diverse or poorly-understood mechanisms


e.g. inhaled anesthetics.

Drugs that depress the CNS

(1) Narcotic a drug which induces narcosis i.e. drowsiness or


sleep especially with analgesia.
(2) Hypnotic a drug that induces sleep i.e. hypnosis.
(3) Anaesthetic a drug that induces absence of sensation, general
or local.
(4) Sedative a dose of a drug that calms or sooths without
inducing sleep though it may cause sleepiness. A small dose
of a hypnotic or tranquilizer always suffices.
(5) Tranquilizer a drug that quitens a patient without impairing
consciousness, it does not cause sleepiness e.g.
phenothiathines or butryphenones.
Ataractic has the same meaning & is derived from a Greek
word meaning "indifferent".
(6) Neuroleptic (antipsychotic) a drug which is more powerful
than a tranquilizer (literally = nerve-seizing).
(7) Psycholeptic a depressant of mental function.
(8) Psychodysleptics produce a disturbed mental state; perception
& behavior e.g. hallucinogens & psychomimetic agents such
as lysergic acid diethylamide (LSD), mescaline &
phencyclidine.
(9) Psychoanaleptics stimulants of mental function e.g. caffeine.

260
(10) Thymoleptics drugs that alleviate the symptoms of depressive
illness i.e. maintain or stabilize an euthymic mood e.g. the
antidepressants TCA & MAO-inhibitors.
(11) Analgesics pain killers.
(12) Anticonvulsants prevent or suppress convulsions.

Narcotics & Anaesthetics

 Narcosis is a state of CNS depression which borders on anaesthesia &


may be achieved by the use of sub-anaesthetic doses of barbiturates,
chloral hydrates or by the administration of morphine opium-extract.
 Narcosis is due to the physicochemical properties of the drug, there is a
relationship between the lipid solubility & the narcotic potency due to
the high lipid content of the nervous tissue which has a particular
affinity for substances which are highly lipid soluble.

1. Ethyl alcohol CH3CH2OH

 Has narcotic, disinfectant & dietary properties, a good solvent, can


precipitate protein, stringent & antibacterial.
 Application of 70% ethanol can cause 75% reduction of cutaneous
bacterial count, does not kill spores therefore not used for sterilization.
 Rapidly absorbed from GIT & is metabolized by dehydrogenation
producing acetaldehyde + acetate & finally CO2 + H2O.

2. Methyl alcohol CH3OH

 Hypnotic effect less than ethanol, toxic effects are due to the metabolic
formation of formaldehyde which can cause blindness.
 Used in disinfection but not sterilization.
 Alcohols are not clinically useful hypnotics because of their diuretic
effect & variation of sleep pattern, both interfere with normal sleep.

3. Chloral hydrates CCl3-CH(OH)2

261
 A crystalline chemical substance with sedative & hypnotic actions,
metabolized in the liver to trichloroethanol which is pharmacologically
active.
 When absorbed it is distributed to most body tissues, also is oxidized in
the liver to trichloroacetic acid for 1~2 days, it also is conjugated to
glucouronic acid to form urochloraic acid which is excreted in urine.
 Sedative effects in 1/2 hr, plasma T1/2E 6hrs. Does not depress reflexes
so is not anticonvulsive.
 Clinically useful as a light sedative & a basal narcotic before
anaesthesia.
 Contrindicated in CS as it crosses placenta & depresses fetal
respiration.

4. Barbiturates

Obtained by combining derivatives of malonic acid with urea to form


the barbituric acid nucleus. Substitutions give the different agonists.
Type of barbiturate Examples

Long-acting -Barbitone, Phenobarbitone

Moderately-acting -Amobarbital, Pentobarbitone

Short-acting -Thiopentone, Methohextone, Thialbarbital

Ultrashort-acting -Secobarbital Na, Thiamylal Na

Structure-activity relationship

 The increase in fat solubility of barbiturate molecules is associated with


hypnotic potency, speed of onset of anaesthesia, duration & metabolic
degradation.
 Branching of the molecule also increases the lipid solubility but
decreases stability = shorter action e.g. Thiopentone › Pentobarbitone ›
Phenobarbitone.

262
 The phenyl group at C5 confers a selective anti-convulsive effect e.g.
Phenobarbitone. A small change in the barbiturate molecule can
otherwise generate a convulsive state.
Pharmacology

1. Absorption in the GIT is rapid.

2. Metabolism is accomplished in 3 successive phases;

i. Physical redistribution which is especially important with


the hi-lipid soluble S.A.B. wherein metabolism may take
up to 3hrs, redistribution from the brain to other body
compartments, fats in skin & muscles is accomplished in
15 ~ 30 mints.
ii. Metabolic degradation; except Barbitone, most are
transformed in the liver by oxidation to inactive
metabolites, the process takes longer time in impaired
hepatic function. Enzyme induction; Phenobarbitone,
apart from its narcotic potency, can stimulate liver enzyme
system leading to tolerance by increased oxidative
enzymes, a state wherein larger doses are needed to deduce
the same therapeutic effects. Chloramphinicol & glucose
potentate the activity of barbiturates.
iii. Renal excretion; the Bs with the longest actions are those
excreted in urine e.g. Barbitone.
Phenobarbitone is partly excreted unchanged in urine &
partly degraded in the liver.
Mode of action

1. All Bs depress the CNS, they differ only in degree, they possess no pain
killing effect.
2. Depress the utilization of O2 by the brain, cerebral O2 consumption is
decreased by 55%.
3. Prevent the synthesis of ACh in the brain by blocking the conversion of
pyruvate to acetate.

(a) Enhance the effect of GABA by binding Bs receptor portion of


GABAA receptor decrease the rate of dissociation of GABA &

263
increased chloride conductance is maintained ( GABA-
mimetic sedative & hypnotic effect e.g. Pentobarbitone).
(b) GABA-independent direct activation of Cl-channels at hi
concentrations thereby depressing sensory areas of the brain (
anaesthesia e.g. Thiopentone).
(c) Depress motor areas in the brain & thereby used to control
seizures e.g. Phenobarbitone.
(d) The direct effect (increased membrane conductance) can be
suppressed by GABA antagonists such as picrotoxin &
penicillin.
(e) GABA, benzodiazepines & barbiturate receptors are associated
together in many ways.
4. Depressant effects on respiration.

Clinical uses

1) Thiopentone is used to induce anaesthesia.


2) L.A.B. are used as anticonvulsants.
3) I/v administration is used to avoid irritation & to adjust the dose, care
should be taken not to depress the respiratory centre. Overdose can
cause pulmonary oedema (or death), increased blood Pco2 & hypoxic
effects on the chemoreceptors. At therapeutic levels Bs do not affect the
cardiovascular system although large doses can cause shock. Bs can
reduce the basal metabolic rate. Cross placenta in CS & depress
newborn respiration.
4) Treatment of overdose is by use of analeptics to counter-react the
respiratory function e.g. couramine (nikethamide), picrotoxin &
doxapram.

Analgesics (pain killers)

Pain can be relieved by

1. A local anaesthetic.
2. A counter irritant.
3. Certain centrally acting drugs.
4. The use of certain anti-pyretics.

264
Analgesics
Analgesics are drugs that relieve pain. They are usually divided into two
groups:
1- Opioid (narcotic) analgesics
2- Non-opioid (non-steroidal anti-inflammatory-NSAIDs) analgesics
Other drugs relief certain types of pain, but are not regarded as proper
analgesics include: Local anaesthetics, carbamezapine (for trigeminal
neuralgia), ergotamine (for migraine), colchicines (for gout), rubefacients and
counterirritant such as camphor & capsicum, obtundants e.g. clove oil,
physical protectives e.g. demulcents & emollients.

Classification of opioid analgesic drugs:

1- Morphine analogues: structurally related to morphine

 Agonists: morphine, heroin and codeine.


 Partial agonists: nalorphine, levallorphan
 Antagonists: naloxone.
2- Synthetic derivatives: structurally unrelated to morphine

 Phenylpipereidine series: pethidine, fentanyl


 Methadone series: methadone, dextropropoxyphene
 Benzomorphan series: pentazocine, cyclazocine
3- Semisynthetic thebaine derivatives: etorphine, buprenorphine.

Morphine receptors (opioid receptors):

There are 4 types: μ, δ, Ќ and σ.

They are receptors for endogenous opiates including endorphins,


enkephalins & dynorphins.

265
Pharmacological actions of morphine:

1. Activates opioid receptors producing a mixture of both stimulant &


depressant actions on CNS depending on receptors, dose & the
presence or absence of pain.
2. Depresses the higher function of the brain, stimulates then depresses
medullary centres. Individual effects may vary from purely depressant
(rabbit) generating analgesia, sleep & coma, to analgesia, excitement,
insomnia & delirium.
3. Hyperexcitement can be prevented by the administration of CNS
catecholamine-depleters e.g. reserpine or dopaminergic blockers e.g.
chlorpromazine or haloperidol, insomnia is reversed by naloxone.
Depression Stimulation

Analgesia General excitement

Sedation Nausea

Respiratory depression Vomiting & defication

Depression of cough reflex Addiction

1- Analgesia: Morphine suppresses all types of pain acute or chronic. It


suppresses pain sensation as well as distress. It is not effective in pain of
neuropathic origin such as phantom limb pain & pain of trigeminal
neuralgia.

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2- Euphoria: euphoria is a strong feeling of contentment and well being,
codeine and pentazosine do not cause euphoria while nalophrine
causes dysphoria.
3- Respiratory depression: All types of opioids cause varying degrees of
respiratory depression. This effect is thought to be due to a decrease in
the sensitivity of medullary respiratory centre to Pco2, It causes death
from over dose. Bronchial secretions are stimulated then depressed.
4- The cardiovascular centre is the least affected, stimulate the vagal
centre slowing the pulse.
5- Depression of cough reflexes: opioids depress cough reflexes and use in
treatment of cough. Codeine suppresses cough in subanalgesic doses so
used in cough medicine.
6- Nausea and vomiting: which is common and transient.Apomorphine is
the prototype central emetic drug.
7- Papillary constriction: opioids constrict pupil. They produce pin-point
pupils, used as diagnostic feature of morphine addiction or coma
produced by morphine. This effect is centrally through stimulation of
the oculomotor centre.
8- GIT effects: opioids increase tone of GIT & decrease motility. They
cause constipation. They contract the muscles of the gall bladder and
constrict the sphincter so increase intra-biliary pressure, so morphine
not used in gall bladder colic. Other effects include contraction of the
uterus, urinary bladder sphincter & constriction of the urethra.
9- Histamine release: they release histamine which leads to local itching
and urticarial and systemic effects including bronchoconstriction and
hypotension. Cutaneus vasodilatation due to release of 5HT causes

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hypothermia. Catalepsy & hypothermia can be prevented by
thyrotropin-RH.
10- Immunosupressant action: with chronic use.
11- All the actions on opioid receptors are antagonized by naloxone.
Pharmacokinetics:

 Morphine is irregularly absorbed in GIT, is given I.V or I.M. codeine is


given orally and is well absorbed.
 Morphine undergoes first pass effect. It is metabolized by conjugation
to glucouronic acid. Pethidine is metabolized by N-demethylation.
 They all are excreted by the kidney.

Side effects:

1- Respiratory depression.
2- Sedation, physical and psychological dependence.
3- Constipation, nausea and vomiting.
4- Pupil constriction
5- Bronchoconstriction and hypotension. Local itch and
urticaria.
6- Acute overdose lead to coma, respiratory depression &
pupil constriction. This is treated by naloxone. In case of
addiction naloxone precipitates withdrawal syndrome.
Heroin

Heroin is diacetyl morphine. It is 3 times as potent as morphine as analgesia.


It is highly lipid soluble and cross BBB rapidly with shorter duration of action

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(2 hrs). Less emetic action synthesis of heroin is stop in many countries. It
causes more dependence.

Codeine

It is methyl morphine. Less potent than morphine, better absorption in GIT.


20% of the analgesic activity of morphine. It has lower efficacy even by
increasing dose. Used in mild pain like headache, antitussive. It causes little
euphoria, addiction is rare.

Pethidine

 1/10 of morphine analgesic potency, but has antimuscarinic action


 Very weak antitussive, similar euphoria like morphine.
 Duration of action is shorter. Metabolized by N-demethylation so can
be given to newborn and during delivery. Metabolites cause
hallucination and convulsion in high dose. When administered with
MAOI it causes excitement, hyperthermia and convulsion.
Apomorphine

Derived from morphine but of less narcotic potency. Stimulates the vomiting
centre the CTZ action when injected I/v.

Fentanyl

It has the same analgesic effect like morphine. It used for anaesthesia to cause
neuroleptanalgesia.

Etrophine

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It is a semi-synthetic drug 1000 times more potent than morphine. It is used
in arrow darts to immobilize the wild animals.

Methadone

As potent as morphine. Half life is more than 24 hours due to high binding
to extravascular tissues. It causes less sever abstinence withdrawal syndrome
thus uses to treat withdrawal syndrome of morphine.

Pentazocine

It is mixed agonist and antagonist. In low dose it has similar analgesic effect of
morphine. In high dose it cause dysphoria, night mares, hallucination and
increase blood pressure. It has less- tendency to cause dependence.

Opioid antagonist

Nalorphine

At high dose it causes morphine like action while in low dose it antagonizes
the effects of morphine. Used as antidote to morphine overdoses. It
precipitates the physical dependence of morphine and heroin addicts. It
causes respiratory depression.

Naloxone

 It antagonized the effect of opioid and endogenous opioid peptide. It


has high affinity to the receptors. Naloxone causes hyperalgesia in case
of stress when endogenous opioid are produced such as in dental
surgery, in case of acupuncture analgesia.

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 It uses in treating respiratory depression cause by opioid overdoses. In
neonate after delivery to reverse the effect of opioid on their
respiration.
 It administered I.V 2-3 times daily. In addict it precipitates withdrawal
effect.
Naltroxone

It is similar to naloxone but longer duration of action.

Non-steroidal anti-inflammatory drugs

(NSAIDs)

 The main anti-inflammatory agents are the Glucocorticoids and


NSAIDs. Others are antirheumatoid agents; drugs that treat gout and
H1-receptor antagonists.
 NSAIDs are described also as analgesic antipyretics. Their effects are
related to inhibition of cyclo-oxygenase pathway of arachidonic acid
metabolism, which lead to inhibition of prostaglandin (PG) and
thromboxane (TX) production.
Pharmacological actions:

 Antipyretic effect: (lowering a raised temperature) Fever associated


with inflammation or infection result from enhanced formation of
interleukin-1, which stimulates production of PGE2 in the
hypothalamus. NSAIDs promote the return of the set-point to normal
by inhibition of PG synthesis, allowing the temp regulating
mechanisms to operate.

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 Analgesic effect: (reduction of certain sorts of pain) PGE1 and E2
sensitize nociceptive receptors to the action of certain mediators such as
bradykinin, histamine and 5-HT. NSAIDs are effective mainly against
pain associated with inflammatory processes of mild to moderate
intensity e.g. pain associated with arthritis, headache, toothache or
dysmenorrhoea, in which conditions there is an increased production
of PGs.
 Anti-inflammatory effects: (modification of the inflammatory reaction)
PGs are one of many factors playing a role in inflammation. NSAIDs
inhibit the synthesis of PGs but one NSAID may be more effective than
other against a certain inflammatory condition if it happens to affect
more the mediators involved in that particular condition.
Mechanism of action:

 The main action of NSAIDs is inhibition of arachidonate cyclo-


oxygenase.
 Two forms of cyclo-oxygenase termed cyclo-oxygenase 1 and 2 (COX-1
and COX-2). COX-1 is a constitutive isoform found in most tissues,
including blood platelets, stomach and kidney. COX-2 is induced by
inflammatory processes and mediators.
 An ideal NSAID should inhibit COX-2, therein relieving inflammation
without affecting COX-1 or causing major side effects on the stomach
and kidney.
 Most NSAIDs act as non-selective reversible inhibitors of both
isoenzymes, but vary in the degree of inhibition of each. New

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compounds with a selective action on COX-2 such as meloxicam show
potent anti-inflammatory activity with minimal gastric side-effects.
 Aspirin binds covalently to both COX-1 and COX-2, thus resulting in
irreversible inhibition of cyclo-oxygenase activity.
Classification of NSAIDs

1- Salicylic acid derivatives: aspirin, diflunisal, benorylate.


2- Pyrazolone derivatives: phenazone, phenylbutazone,
oxyphenbutazone, azapropazone.
3- Carboxy- and heterocyclic acetic acids: indomethacin, sulindac.
4- Phenylacetic acid derivatives: diclofenac, alclofenac, fenclofenac
5- Propionic acid derivatives: ibuprofen, ketoprofen, naproxen,
tiaprofenic acid.
6- Oxicams: piroxicam, tenoxicam.
7- Fenamic acid derivatives: mefenamic & flufenamic acids
8- Acetanilide derivatives: phenacitin & paracetamol.
9- Selective COX-2 inhibitors: meloxicam, nimuselide, celecoxib.
Salicylates

Salicylic acid is irritant and therefore only used locally. The derivatives e.g.
acetylsalicylic acid (Aspirin)R is less irritant and used systemically.

Pharmacokinetics:

 Orally administered salicylates are absorbed partly from the stomach,


but mainly from the small intestine. Absorption being favoured by a
low pH.

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 Aspirin is absorbed and rapidly hydrolyzed in tissues and plasma to
salicylic acid. 50~ 90% bound to albumin.
 Salicylate is partly excreted unchanged and partly undergo conjugation
with glycine or glucouronic acid before excretion. Excretion is relatively
slow and is mainly renal and increases in alkaline urine.
Pharmacological actions:

I- Local actions: salicylic acid and methyl salicylic acid have a local irritant
action on the skin and mucosa. Salicylic acid has keratolytic, antiseptic
and fungistatic properties.
II- General actions: sodium salicylate and aspirin are used systemically and
produce the following actions:
1- Analgesic action: they are effective in relieving dull aching pain e.g.
headache, myalgia, arthralgia and toothache. Chronic use does not
lead to tolerance or addiction.
2- Antipyretic action: salicylates lower the elevated temp to normal,
but does not affect normal body temp. Toxic dose raises body temp
especially in young children. Hyperthermia is due to uncoupling of
oxidative phosphorylation.
3- Anti-inflammatory and anti-rheumatic action: this action is due to
one or more mechanisms: inhibition of PGs synthesis, inhibition of
the kallikrein system, inhibition of fibrinolysin, inhibition of
chemotaxis and uncoupling of oxidative phosphorylation.
4- Aspirin in low doses inhibits platelet aggregation and prolongs the
bleeding time.

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5- GIT: salicylates irritate gastric mucosa leading to epigastric distress,
nausea and vomiting. In high doses, gastric ulceration and bleeding
may occur.
6- Kidneys: small doses depress uric acid secretion resulting in uric acid
retention, while large doses inhibit the tubular reabsorption of uric
acid and increase its excretion.
7- Respiration: large doses cause stimulation of the respiratory centre
leading to hyperventilation and respiratory alkalosis due to excessive
CO2 loss.
8- Metabolism: although salicylates generally lower blood glucose level,
large doses can cause hyperglycaemia due to depression of aerobic
glycolysis & increased adrenal cortical activity wherein
hydrocortisone stimulates glycogenolysis & gluconeogenesis. Serum
cholesterol is reduced by hi dose taking at least 2 weeks. Cellular
enzymes are inhibited; i)
uncoupling oxidative phosphorylation decreasing the BMR &
arresting formation of ATP (the formation of a haemostatic plug
depends on the release of ATP from platelet);
ii) inhibition of the transaminases & the dehydrogenases.
9- Associated hypoprothrominaemia responds to vitamine K.
Therapeutic uses:

Local uses:

1- Keratolytic agent: for the removal of corns and warts.


2- Fungistatic: in combination with benzoic acid
3- Hyperhyderosis (excessive sweating): SA in talcum powder.

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Systemic uses

1- Antipyretic
2- Analgesic for headache, myalgia, arthralgia and toothache.
3- Common cold
4- Gout: 5-6 g/day
5- Rheumatoid arthritis:
6- Acute rheumatic fever in patients not suffering from heart failure.
7- Reducing the risk of myocardial infarction, stroke and venous
thromboembolism.
Side effects:

1- GIT: Gastric irritation, epigastric discomfort, heartburn and nausea.


Gastritis and focal erosion and bleeding.
2- Hypersensitivity reactions: allergy in form of bronchoconstriction,
angioneurotic oedema and urticarial.
3- Hepatotoxicity: mild and asymptomatic
4- Reye's syndrome: characterized by sever hepatic injury and
encephalopathy. It occurs following the use of a drug to control fever in
viral infections e.g. chicken pox and influenza in children.
5- Renal toxicity: by long term abuse
6- Salicylism: by repeated large doses. Symptoms are headache, mental
confusion, ringing in the ears, dimness of vision, sweating,
hyperventilation, nausea, vomiting and diarrhea. Symptoms disappear
by cessation of the drug.
Acute poisoning:

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 CNS: Restlessness, vertigo, tremors, delirium, hallucination,
convulsion, and coma.
 Skin eruption
 GIT: Anorexia, nausea, vomiting
 Metabolic acidosis in children and respiratory alkalosis in adults.
 Haemorrhagic phenomena
 Hyperpnoea, hyperpyrexia and dehydration.
Treatment:

 Gastric lavage with sodium bicarbonate


 Correction of hyperthermia by cooling with cold water or ethylalcohol.
 I.V fluids, Vitamin K or blood transfusion
 Alkalinisation of urine, haemodialysis in severe cases.
Drug interactions:

 It extensively binds plasma proteins. It potentially increases the effect of


warfarin, dicoumarol, sulphonylureas, sulfonamides, penicillin and
phenytoin.
 The gastric ulcerogenic effect of aspirin may be enhanced by alcohol,
corticosteroids, indomethacin and phenylbutazone.
 Drugs that inhibit the analgesic effect of aspirin include barbitone
(enzyme inducer), reserpine and B-blockers.
 Salicylates inhibit the anti-inflammatory effect of indomethacin,
fenamates, propionic acid derivatives and pyrazolone derivatives.
Contraindications:

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 Peptic ulcer, aspirin hypersensitivity, bleeding tendency (haemophilia,
hypoprothrombinaemia)
 Patient taking oral anticoagulants & children with viral infections.
Paracetamol (Acetamenophen)

 It is one of the most commonly used non-narcotic analgesic-antipyretic


agents. It has weak anti-inflammatory activity.
Pharmacokinetics:

 It is completely absorbed from the GIT. Peak achieved after 30-60 min.
it is conjugated in the liver to glucouronic acid or sulphate. Half life is
2-4 hours.
Therapeutic uses:

 Used as analgesic and antipyretic drug, does not produce gastric


irritation, erosion or bleeding.
Unwanted effects:

 In therapeutic doses, side effects are few and uncommon.


 Allergy may occur.
 Regular prolonged use increases risk of kidney damage.
 Toxic doses cause hepatic damage leading to liver necrosis. The initial
symptoms are nausea and vomiting, while hepatotoxicity appears after
24-48 hours. Treatment by gastric lavage and activated charcoal; then
I.V acetylcysteine (increases glutathione formation) or oral methionine
(activates conjugation if given early).
Benorylate:

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 It is the aspirin-paracetamol ester. It has the same pharmacological
action of aspirin with less GIT disturbances and less hepatotoxicity, but
there is increased risk of kidney damage.
Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen, Tiaprofenic acid,
oxaprozin & Fenoprofen

- They are propionic acid derivatives.

 They have analgesic, antipyretic and anti-inflammatory properties. They


are firmly bound to plasma protein and extensively metabolized in the
liver. GIT irritation and bleeding occur but less frequent than aspirin.
 Side effects: GIT irritation, rash, pruritus, tinnitus, dizziness, headache,
anxiety, fluid retention, agranulocytosis and aplastic anaemia. Acute
renal failure, interstitial nephritis and the nephrotic syndrome.
 Their use with aspirin decreases the anti-inflammatory effect. They are
contraindicated in patients with nasal polyps, angioedema and
bronchospastic reactivity to aspirin.
Diclofenac

 It is a potent COX inhibitor with analgesic, antipyretic and anti-


inflammatory properties. Well absorbed orally, metabolized in the liver
and has a short half-life.
 Diclofenac is used in rheumatoid arthritis, osteoarthritis, acute
musculo-skeletal disorders, dysmenorrhoea & the prevention of
postoperative ophthalmic inflammation.
 Side effects include GIT irritation, ulceration, bleeding (minimized by
coating) & hepatotoxicity (rare).

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Indomethacin

 Indomethacin has potent anti-inflammatory, analgesic and antipyretic


actions. Invetro, it is the most potent of the inhibitors of prostaglandin
synthesis, but more toxic.
 It is well absorbed orally and highly bound to plasma proteins (90-
98%), metabolized in the liver by conjugation, undergoes extensive
enterohepatic circulation, excreted in bile and urine.
Clinical uses:

 Not generally used for analgesia. Should not be used in children. Used
in acute gout, rheumatoid arthritis, ankylosing spondylitis and
osteoarthritis.
 Used in the management of patent ductus arteriosus in premature
infants, being kept patent by continuous production of PGs, and
closure is accelerated by I.V infusion indomethacin.
Adverse effects

 GIT: anorexia, nausea, abdominal pain, diarrhea and ulceration with


perforation and haemorrhage, pancreatitis and hepatitis.
 CNS: headache, vertigo, dizziness, confusion, depression and rarely
psychosis with hallucination.
 Hypersensitivity: rashes, urticaria, itching and acute asthma.
 Haemopoietic reactions: neutropenia, thrombocytopenia and aplastic
anaemia.
 Visual effects: corneal vasoconstriction and blurred vision.
 Hyperkalemia

280
Contraindication:

 Pregnancy (it may be teratogenic)


 Renal disease, psychiatric patients, epilepsy and Parkinsonism.
 Peptic ulcer.
Sulindac:

 It is a prodrug, converted in the liver to sulphide which is excreted in


bile then reabsorbed from the intestine. Sulphide interferes with both
cyclooxygenase and lipoxygenase pathways, but has little or no effect on
renal PGs synthesis.
 The indications and side effects are similar to other NSAIDs.
Piroxicam

 It is well absorbed orally and has a long half life allowing once daily
dosing. It is metabolized by conjugation to glucouronic acid.
 It has potent anti-inflammatory properties and is used in the treatment
of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.
 The common side effects are GIT symptoms, headache, tinnitus,
dizziness and rash.
Mefenamic acid & Flufenamic acid

 They have antipyretic and potent anti-inflammatory actions. Mefenamic


acid has an analgesic effect.
 The side effects include GIT disturbances therefore they should be
given after meals. Elevated hepatic transaminases. Skin rashe and
haemolytic anaemia. They should not be used for longer than 1 week.
Dipyrone

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 It is a pyrazolone derivative.
 It produces agranulocytosis.
 It can be given by oral, IM or IV routes.
Phenylbutazone

 Absorption is rapid and complete from GIT. Plasma protein binding


98%, metabolized by microsomal enzymes to oxyphenbutazone (has
anti-rheumatic effects) and gamma- hydroxyphenylbutazone (has
uricosuric & no anti-rheumatic effects).
 The drug has potent anti-inflammatory and anti-rheumatic action. It
has weak analgesic and antipyretic action. Uricosuric action through
inhibition of uric acid re-absorption.
Therapeutic uses:

 Rheumatoid arthritis, acute gout and acute superficial


thrombophlebitis.
Toxicity:

 GIT: nausea, vomiting, epigastric distress and peptic ulcer with


haemorrhage and perforation.
 Na and water retention leading to oedema.
 Agranulocytosis, aplastic anaemia and thrombocytopenia.
 Liver and kidney damage. Skin rashe.
Contraindication:

 Peptic ulcer, hypertension, cardiac, hepatic and renal disease and


elderly patients.

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 The drug increases the effects of sulfonamides, anti-coagulants and oral
hypoglycaemic drugs by displacing them from protein binding.
Selective COX-2 inhibitors (Meloxicam & Celecoxib)

 They have minimal adverse effects on the GIT.


General Anaesthetic agents
Act on C.N.S. producing unconsciousness and prevening awareness of pain.
1) Inhalation: either gases e.g. nitrous oxide & cyclopropan, or volatile liquids
e.g. halothane.
2) I.V anaesthetics e.g. thiopentone.
Effect of anaesthetics on the nervous system:
 General anaesthesia inhibits action potential conduction, and inhibit
synaptic transmission (an excitatory transmitter is usually more
susceptible).
 This inhibition is produced by: (1)
Reduction of transmitter output "e.g. the output of ACh is decreased by
G.A." (2) inhibition of
the postsynaptic action of transmitter (3) or reduction of
postsynaptic response to excitatory transmitter.
 Unconsciousness produced by damage to brainstem reticular formation,
the hypothalamus or the thalamus.
 Activity of reticular formation responsible for arousal and wakefulness.
 Anaesthetics cause short-term amnesia, this is due to interference with
hippocampal function (hippocampus is responsible for short-term
memory).

283
If conc. of G.A. is increased other sites of brain are affected including
motor control and reflex activity, respiration and autonomic regulation
leading to respiratory and myocardial depression.

Stages of anaesthesia
If a slow acting G.A. is applied then four well-defined stages will be generated:
Stage I voluntary movement (Stage of analgesia):
 Patient is conscious but drowsy, amnesia has not developed but there is
reduced responsiveness to painful stimulation.
 This stage reflexes the inhibition of sensory interneurons of the dorsal
horn and spinothalamic pathways.
 Analgesia occurs gradually and the sense of hearing is increased during
this stage.
 In some cases of anaesthesia for obstetric purposes it stops in this stage.
Stage II involuntary movement (Stage of excitement and delirium)
 Patient is unconscious and responds to painful stimuli
 The subject may move, talk, choke or vomit. Signs may include irregular
respiration, rapid pulse, increased blood pressure, the pupils are dilated
but reactive. There also is increased muscle tone (involuntary movement)
 This stage is due to inhibition of inhibitory pathways in brain (looks like
excitation).
 This stage is dangerous and should be shortened or avoided (new
anaesthetics eliminate this stage)
Stage III (Stage of surgical anaesthesia)
 In this stage muscle tone is reduced, the involuntary movements disappear
and respiration becomes regular.

284
 The pupil is no longer dilated, roving movement of the eye ball may be
observed and there is loss of eyelid and conjunctival reflexes.
 Respiration becomes progressively shallower as anaesthesia deepens, until
it finally ceases due to failure of the intercostals muscles followed by the
diaphragm
 This stage is due to inhibition of ascending pathways of the reticular
formation.
Stage IV (Stage of medullary paralysis)
 In this stage depression of respiratory and cardiovascular system takes
place, followed by death.
 The pupils are fully dilated with no response to light, the eyes become
fixed, the blood pressure very low, skin becomes grey, cold and covered by
clammy sweat.

Anaesthesia for clinical purpose consists of 3 components:


1- loss of consciousness
2- loss of reflexes (muscle relaxation)
3- analgesia
These components are not achieved by G.A. alone but by a combination of
drugs.
 Rapid production of loss of unconsciousness by an I.V induction agent
e.g. thiopentone. Consciousness loss within 20 seconds to avoid stage II
and maintain anaesthesia.
 Maintenance of the unconsciousness and production of analgesia by
adding one or more inhalation anaesthetics such as halothane and nitrous
oxide.

285
 Analgesia is maintained by analgesic agents e.g. opiate.
 To produce muscle relaxation use a neuromuscular blocking agent e.g.
tubocurarine.
Effects of G.A. on the cardiovascular and respiratory systems:
 All G.A. depress the isolated heart, but in vivo their effects vary according
to the action on the sympathetic nervous system.
 Some agents, e.g. nitrous oxide, increase plasma noradrenaline conc.
thereby increasing blood pressure, while halothane and other halogenated
G.A. oppose this effect and decrease blood pressure.
 Halothane produces cardiac dysrhythmias, particularly ventricular
extrasystolies which may develop into ventricular fibrillation if plasma
level of NA is high.
 The mechanism of dysrhythmia is not known but is thought to be due to
sensitization of heart to the action of NA, this effect is especially harmful
in the case of operations with excessive release of NA (e.g.
phaeochromocytoma) wherein the use of halothane becomes dangerous.
 All anaesthetic except nitrous oxide and ketamine depress respiration.
Inhalational anaesthetics
Pharmacokinetic aspects:
The main factors that determine the speed of induction and recovery are:
1- Properties of the anaesthetic
- Blood: gas partition coefficient
- Oil: gas partition coefficient
2- Physiological factors
- Alveolar ventilation rate
- Cardiac output.

286
 Solubility of G.A in the blood is expressed as blood: gas partition
coefficient which is defined as: "Fraction of gas dissolved in blood" so the
lower the blood: gas partition coefficient the faster is the induction and
recovery e.g. nitrous oxide.
 Oil- gas partition coefficient: Anaesthetics have to pass from blood into
tissue and lipid. In the normal subject about 20% of weight is fat, also
anaesthetics have to pass through brain
 Oil- gas partition coefficient reflexes the potency of anaesthetics. The high
the oil: gas partition coefficient the high the potency.
 Oil- gas p.c. accounts for anaesthetic distribution in the body fat i.e.fat acts
as a reservoir from which it is slowly released. This prolongs the recovery
period and prolongs the hangover period: “the period of semi-
consciousness which follows anaesthesia due to slow release of the
anaesthetic from fat deposit".
 The higher the pulmonary ventilation the faster the induction. This is of
little importance considering a drug with low blood solubility.
 The greater the pulmonary blood flow (increase in cardiac output), the
slower the rise in arterial tension. In patients with circulatory shock, the
combined effects of decreased COP and increased ventilation may
accelerate the induction of anaesthesia with some anaesthetics (least likely
occurs with nitrous oxide).
Metabolism and elimination:
- Most inhalation anaesthetic are eliminated unchanged through the lungs
 50% of methoxyflurane is metabolized to fluoride ions, and oxalate,
leading to renal impairment.

287
 30% of halothane is metabolized, in the liver, to bromide ions and
fluoroacetic acid (immunogenic compound). The combination of
fluoroacetic acid and liver proteins lead to immunologic interactions
generating hepatic damage.
Minimum Alveolar concentration (MAC):
The MAC of inhalation anaesthetics is regarded as the least concentration of the
anaesthetic in the lungs that would permit a surgical incision to be performed
without pain or involuntary reflexes in 50% of patients.
The lower the MAC value, the more potent would be the anaesthetic agent.
1- Diethyl ether
- A colourless volatile liquid with irritant odour.
- Of little use now because it is very explosive in a mixture with oxygen.
- Diethyl ether is a relatively safe anaesthetic agent with a large therapeutic index.
The ratio between the dose that produces cardiac & respiratory depression and
the anaesthetic dose is large.
- It has analgesic effect but weak neuromuscular action.
Disadvantages:
 Irritant to respiratory tract leading to copious secretion of mucous leading
to post-operative infections.
 Induction & recovery are slow, with a prolonged hangover period during
which nausea and vomiting may take place.
2- Halothane
- Halothane is a colourless volatile liquid halogenated ether.
- Non-inflammable, non-explosive and non-irritant to respiratory tract.
- It has low solubility in blood so produces smooth, rapid induction and a
relatively rapid recovery.

288
- May produce bradycardia due to increased vagal activity and depression of the
sinoatrial node.
- Causes cardiac arrhythmias due to myocardial sensitization to adrenaline.
- Decreases blood pressure due to vasodilatation, cardiac depression and
vasomotor centre depression. It also potentiates the action of ganglion blockers.
- Relaxes uterus so is contraindicated during labour.
- Decreases motility of the GIT, produces bronchodilatation and respiratory
depression.
- About 30% of absorbed halothane is metabolized in the liver to trifluoroacetic
acid which reacts with proteins to form immunogenic compounds leading to
hepatotoxicity.
3- Nitrous oxide
 The Laughing Gas
 A colourless, odourless, non-inflammable and non-explosive gas
 Rapid action due to low blood: gas partition coefficient
Pharmacological actions:
 Induction is rapid, consciousness is lost in 20-30 seconds and recovery is
rapid.
 Low potency, if administered for continuous 2 minutes it produces
cyanosis, a rise of blood pressure and slow pulse.
 This is avoided by mixing 80% nitrous oxide in 20% oxygen.
 However this conc. can not produce loss of consciousness, therefore, it is
usually used to induce anaesthesia in combination with other potent G.A.
e.g. thiopentone and halothane.
 Nitrous oxide has analgesic effect in low conc. (35%) so useful for
producing analgesia during childbirth.

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Toxic effects:
 During recovery from nitrous oxide anaesthesia the gas diffuses rapidly
outwards lowering the oxygen conc. in the alveolar air, producing hypoxia
especially in patient with respiratory disease, wherein oxygen has to be
supplied during recovery.
 Produces oxidation of cobalt in vitamin B12, which is required to co-factor
methionine synthetase. This enzyme serves as a methyl donor in the
synthesis of DNA & other proteins. Exposures to nitrous oxide lead to
inhibition of cell division, which results in anaemia and leucopenia.
 Single administration of nitrous oxide does not produce these effects
because the bone marrow has sufficient reserve.
 Prolonged exposure to nitrous oxide even in low conc. has been suspected
to be a cause of abortion and foetal abnormality among female theatre
staff.
4- Methoxyflurane
 Non-explosive, does not produce respiratory irritation or postoperative
vomiting.
 A very potent G.A. with high lipid solubility, i.e. high blood- gas part.
coefficient, therefore slow induction and recovery.
 Comparable with halothane produceing similar effects on the
cardiovascular & respiratory system.
 More analgesic effect & less uterine relaxant activity.
 Metabolites produce nephrotoxicity so has been replaced by enflurane and
isoflurane.
5- Enflurane

290
 A halogenated ether, non- inflammable and faster in action than
halothane.
 Less liable to accumulate in body fat
 Produces better muscle relaxation
 Metabolized to a minor extent so does not cause kidney damage.
 At high conc. it causes seizures during induction and following recovery,
therefore should be avoided in patients with EEG abnormalities or with
history of seizures.

6- Isoflurane
 Non-inflammable and not metabolized with few signs of toxicity
 Not convulsive.
 Enhances the action of neuromuscular blockers
 Very expensive.
 Increases the incidence of coronary ischemic attacks so avoided in patients
with coronary heart diseases.
7- Desflurane:
 Similar to isoflurane but faster in induction and recovery.
8- Sevoflurane:
 Resembles desflurane in excellent control of anaesthetic depth and rapid
recovery.
 Less irritant to the respiratory tract and does not increase cardiac rate.
Intravenous anaesthetics
 These agents are not used to maintain anaesthesia, only used as induction
agents.

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 Rapid onset of action, ease of administration, no irritation of respiratory
passages.
 They subclasses into:
1- Induction anaesthesia: rapid onset action (20 seconds) e.g. thiopentone
2- Basal anaesthesia: onset 2-3 minutes used to produce sedation e.g.
ketamine, diazepam.
1- Thiopentone
 A barbiturate but instead of (O2) atom has (S) atom.
Pharmacokinetics:
 Highly lipid soluble with a rapid transient action.
 Onset 10 seconds, duration 10 minutes.
 Once injected I.V. a rapid decline in plasma concentration takes place due
to redistribution of drug into high blood flow tissues (brain, liver, kidney),
followed by slow decline due to slow uptake of drug by fat tissues (physical
redistribution).
 Adipose tissues act as a reservoir leading to a prolonged hangover so
thiopentone can not be used to maintain surgical anaesthesia.
 Metabolized by oxidation followed by glucouronic conjugation.
 Highly bound to plasma protein (70% binds to albumin), binding is
reduced in case of liver & kidney disease & malnutrition.
Pharmacodynamics and side effects:
 Induce rapid hypnosis and loss of consciousness.
 No analgesic or neuromuscular blocking action.
 Depresses the respiratory centre and may cause bronchospasm.
 Therapeutic doses may cause transient hypotension, laryngeal spasm,
cough & sneezing. Excessive doses associated with abrupt fall in blood

292
pressure due to depression of cardiac contractility and reduction of COP,
hypothermia & profound cerebral impairment.
 Sodium salt used is highly soluble and very potent, alkaline, but not stable
so prepared immediately before I.V injection.
 If injected outside a vein, causes tissue necrosis, procaine should
immediately be injected by the same needle as antidote.
 Thiopentone may precipitate prophyria in susceptible subjects.
Indications
 Induction of general anaesthesia.
 Anaesthesia of short duration.
 Reduction of raised intracranial pressure if ventilation controlled.
 Status epilepticus.
Contraindications
 Inadequate resuscitative facilities.
 Inconfidence of ability to maintain a batent airway as in the presence of a
tumor in the pharynx or larynx.
 Cardiovascular, pulmonary or hepatic impairments.
 Acute porphyria.
 Myotonic dystrophy.
 Breast feeding.
 Caution in pregnancy & surgery of the mouth, pharynx or larynx.
2- Etomidate (Hypnomidate) R
 It has a large therapeutic index, a large margin between the anaesthetic
dose and the dose producing respiratory and cardiovascular depression.
 More rapidly metabolized than thiopentone. No hangover effect.

293
 Etomidate may cause involuntary movement during induction and
recovery, can be minimized by an opioid analgesic or a short acting BD
given before induction.
 May cause postoperative nausea and vomiting.
 Prolonged use leads to adrenal cortex suppression which may cause death
in very ill patients
 Used mainly as induction agent in patients with risk of circulatory failure.
Indications
 Induction of general anaesthesia.
Contraindications
 As in other I/v anaesthetics.
 Use for maintaince (adrenal suppression).

3- Propofol (DiprivanR)
 Similar in action to thiopentone.
 Rapidly metabolized, no hangover.
 Convulsions, anaphylaxis & delayed recovery. Special caution after day
surgery is advised for delayed convultions.
 I/v antimuscarinic prevent an occasionally profound bradycardia.
 Can be used continuously by infusion to maintain anaesthesia.
 No involuntary movement or adrenal cortex suppression.
5- Ketamine (KetalarR)
 Structural analogue of phencyclidine a psychotomimetic drug.
 Less liable to cause euphoria & sensory distortion compared to
phencyclidine.

294
 Both drugs block NMDA receptor of glutamate (block activation of
excitatory receptor)
 Administered I.V or I.M or infusion to produce dissociative anaesthesia
 The eyes remain open but the patient does not respond to external stimuli
without loss of consciousness.
 Analgesia, muscle paralysis and amnesia are marked.
 Ketamine increases blood pressure and heart rate but respiratory system is
not affected.
Unwanted effects:
 It causes hallucinations, delirium and irrational behavior during recovery.
Children are much less susceptible to these phenomena, so used in
combination with diazepam for minor operation in pediatric surgery.
6- Midazolam
 A short acting benzodiazepine. Has slower onset and recovery.
 Does not depress respiratory or cardiovascular system
Neuroleptanalgesia:
 A combination of neuroleptic and analgesic drugs to produce a state of
deep sedation and analgesia. The patient responds to simple commands &
questions, but not to painful stimuli.
 Further reading Conscious sedation in the provision of Dental care,
w.w.w.dh.gov.uk.

Neuroleptic agents

Are also known as antischizophrenic or antipsychotic drugs. Are agents


clinically useful in control of psychotic illness & modification of behavior.

295
Mental disorders

1. Psychosis (endogenous) includes; A) Schizophrenia. B) Affective


disorders (depression & mania). C) Mental disturbances (head injury,
alcoholism & drug addiction).
2. Neurosis: abnormal reaction to external circumstances.

1) Phenothiazines & related tricyclic cpds

A. Phenothiazines e.g. chlorpromazine.


B. Thioxanthenes e.g. flupenthixol
C. Dibenzodiazepenes e.g. clozapine & carbamazepine(tegretol)

2) Butryphenones related to cannabis & pethidine e.g. haloperidol.

3) Benzamides e.g. metclopramide & sulpride.

Mechanism of action

A) Mechanisms related to the general pharmacologic property of antagonizing


the actions of dopamine;

1) Antipsychosis (D2 receptors).


2) Antiemetic activity by antagonizing dopamine & agonists such as
apomorphine on CTZ.
3) Motor disturbances; Parkinson`s-like syndrome characterized by
muscle rigidity, loss of mobility & tremor & is reversible; tardive
dyskinesia characterized by involuntary movements often of face &
tongue but also of trunk & limbs, a disabling & irreversible condition.
4) Endocrine effects; increased prolactine leading to breast enlargement
& lactation, decreased GH, increased aldosterone leading to water
retention & thirst are not uncommon.

B) Mechanisms related to blocking the actions of the following;

1) mAChR; blurring of vision, increased IOP, dry mouth & eyes,


constipation & urine retention.

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2) α; orthostatic hypotension, & contributing to the sedative
action of the class.
3) H1; sedative & antiemetic property.

Pharmacokinetics

1) Erratically absorbed after an oral dose.


2) Absorption delayed due to selective tissue-binding.
3) Correlation between plasma level & clinical effects variable e.g.
chlorpromazine EPC 30~300 ng/ml.
4) T1/2e 15~30 hrs, hepatic clearance by oxidation & conjugation.
5) I/m not uncommon, sustained release formulations available e.g.
fluphenazine.

Clinical use

1) Treatment of SZP.
2) Antiemetic ttt of uraemia, iatrogenic nausea, & vomiting caused by
radiation.
3) Ttt of Huntington chorea (e.g. haloperidol).
4) Ttt of depression (e.g. sulpiride).

Side effects

Postural hypotension, idiosynchratic reactions including hypersensitivity &


jaundice (e.g. chlorpromazine), leucopenia & skin- reactions.

Drugs used in the treatment of affective disorders

Anti-depressants and mood- stabilizers

Depression results from a functional deficit of monoamine transmitters,


noradrenaline & serotinine, at certain sites in the brain, mania results from a
functional excess.

1) TCA e.g. Imipramine & amitriptyline.


2) MAOI e.g. phenelzine & tranylcypromine.
3) Atypical antidepressants e.g. nomifensine.

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4) Lithium.
5) SSRI e.g. flouxitine (Prozac).

Tri- cyclic antidepressants

Closely related to phenothiazines, prototype compound imipramine closely


related to promazine, other cpds include amitriptyline, nortriptyline,
protriptyline, desipramine, clomipramine & doxepin.

Mechanism of action

Block the reuptake of amines by nerve terminals. This leads to in-


coordination, sedation & confusion in the first few days of therapy.

Pharmacokinetics

 Rapidly absorbed from an oral dose.


 Strong binding to plasma albumin 90~ 95% & extravascular tissues.
 Hepatic N-de-methylation & hydroxylation to active metabolites,
glucouronidation & urinary excretion, t1/2e 15~ 20 hrs.

Side effects & toxicity

 The most frequently used drugs in attempted suicide, excitement,


delirium, convulsions followed by coma & respiratory depression.
 Atropinic effects, dysrhythmias, sudden death from ventricular
fibrillation are common, ttt by physostigmine.

MAO Inhibitors

 Cause rapid sustained increase in serotonin, noradrenaline &


dopamine in brain, heart, liver, intestines & plasma.
 This increase at nerve terminals generates immediate euphoria,
excitement & increased motor activity.
 Rapid biochemical responses are followed by the delayed
antidepressant effect.

Side effects

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Hypotension, excessive central stimulation (tremor, excitement &
convultions), wt gain, atropinic effects, hepatotoxicity.

Interactions

1. Cheese reaction due to tyramine content.


2. Hypotensive episodes with TCA.
3. Hyperpyrexia, restlessness, coma & hypotension with pethidine.

Lithium

The drug of choice in the prophylactic control of manic-depressive illness.

Mechanism of action

 Resembles Na in excitable tissues permeating the generation of hi-


voltage action potentials.
 Increases noradrenaline & serotonin turnover in the brain.

Pharmacology

Excreted by the kidney, t1/2e 12hrs, renal disease or Na- depletion


potentiates the likelihood of toxicity, mainly;
1. Renal; polyurea with thirst.
2. Thyroid enlargement associated with hypothyroidism.
3. Neurologic toxicity; nausea, vomiting, tremor, confusion, coma,
convulsions & death.

Selective serotonin- reuptake inhibitors (SSRIs)

Citalopram, escitalopram, flouxetine, fluvoxamine, paroxetine & sertraline


selectively inhibit the reuptake of serotonin.

Cautions & contraindication

 Epilepsy, cardiac disease, DM, CA-glaucoma, history of mania &


bleeding disorders.
 Contraindicated if the patient enters a manic phase.

Withdrawal

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 GI disturbances.
 Headache, anxiety, dizziness, paraesthesia, sleep disturbances, fatigue,
influenza-like symptoms & sweating on abrupt withdrawal.

Side effects

 Less sedating & fewer antimuscarinic or cardiotoxic effects.


 Include GI & hypersensitivity symptoms.

Indications

Depressive disorders, panic attacks, obsessive compulsive disorder, social


anxiety disorder, bulimia nervosa & post-traumatic stress disorder.

Anxiolytics

1- The Benzodiazepines

Short-acting T1/2e ≤ 24hrs Long-acting T1/2e ≥ 24hrs


Lorazepam (Ativan) Diazepam (Valium)
Oxazepam Chlordiazepoxide (Librium)
Temazepam Flurazepam (Dalmane)
Nitrazepam (Mogadon)
Clonazepam

Mechanism of action

1) Produce anxiolytic, sedative, hypnotic, anticonvulsant &


musclerelaxant effects by enhancing the action of GABA.
2) The BD-receptor is a modulatory site on the GABAA receptor that
allosterically regulates the postsynaptic chloride channels gating that
occurs at the interaction of GABA with GABAA receptors.
3) Different actions may be a function of blood levels with the anxiolytic
effect occurring at lower levels, sedation & unconsciousness occurring
with increasing blood levels.
4) While barbiturates prolong the channel lifetime, BDs increase the
frequency of opening.

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CNS

The principal site of depression is the brain stem reticular formation.

Cardiopulmonary

Some respiratory depressant effects, minimum effect on CVS, in patients with


IHD coronary blood is maintained or improved following diazepam induced
anaesthesia.

Skeletal muscles

The central muscle relaxant action principally affects polysynaptic reflexes at


the supraspinal level due to spinal cord depressant action at the interneuronal
level as well as inhibitory effect on ACh release at the presynaptic level.

Drug interactions

1) Potentiate the actions of other CNS depressants & non depolarizing


muscle relaxants.
2) Cimitidine impairs hepatic microsomal oxidation of diazepam
prolonging its halflife.
3) Use with ketamine is referred to as ataranalgesia or ataranaesthesia, the
combination prevents side effects of ketamine such as CV
complications, elevated intracranial pressure & psychmimetic
responses, a longer recovery period must be accepted.

Pharmacokinetics

1) Completely absorbed from oral administration, I/v not uncommon,


I/m slow absorption.
2) Peak plasma level after 1hr, strong protein binding, may accumulate in
body fat.

Indications

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1) Reduction of anxiety & aggression, maintenance of verbal contact
during certain diagnostic & outpatient procedures.
2) Sedation & induction of sleep. Decrease the time taken to get to sleep
& increase its total duration especially in subjects sleeping less than
6hrs. Improve the quality of sleep by not interfering with REM periods.
3) Reduction of muscle tone.
4) Anticonvulsant.
5) Tapering diazepam is used in ttt of dependence.

Acute toxicity

Overdose generates prolonged sleep, subject rousable, no serious


respiratory or CVS depression.
Therapeutic side effects

Tolerance & dependence.


Tetratogenesis & carcinogenesis

Diazepam has neoplasm promoting activity inasmuch as extensive


prolonged use.
2- β-blockers

 Do not affect psychological symptoms of anxiety such as worry, fear &


tension but reduce autonomic symptoms such as palpitation & tremor
(not muscle tension).
 Indicated in patients with predominantly somatic symptoms.

3- Buspirone

Buspirone HCl (Buspar)

 Act on specific serotonin receptor 5HT1A, short term use.


 Side effects are nausea, dizziness, headache, nervousness & excitement,
palpitation, confusion & fatigue.

Contraindications

Epilepsy, acute porphyria & pregnancy.

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4- Meprobamate

 Less effective, more hazardous, cause dependence.


 Not recommended.

Anticonvulsants

Are those drugs used to control motor disorders e.g. convulsive seizures,
epilepsy, Parkinsonism & spasticity.

A. Convulsive seizures

Usually are caused by

1. Altered neuronal membrane function.


2. Increased excitatory NT, e.g. glutamate, in the CNS.
3. Decreased inhibitory NT, e.g. GABA, in the CNS.
4. Altered extracellular calcium level↓, or potassium level ↑, or both.

Mechanism of action of anticonvulsant agents

1. Pharmacological modification of the GABA or glutamate mediated by


enhancing the inhibitory effect of GABA at the GABA-receptor-
chloride channel complex, e.g. phenobarbitone & the
benzodiazepines.
2. Antagonists of the excitatory amino acids are similarly anticonvulsants,
whereas the excitatory amino acids themselves, or agents that increase
their synaptic effectiveness act as convulsants.
(A) Diazepam: see anxiolytics.
(B) Phenytoin: is chemically related to the barbiturates. Is well-absorbed
when given orally, 80~90% bound to albumin, undergo hepatic
clearance by the oxidase system, excreted as the glucouronide
conjugate, hepatic enzyme inducer, T1/2e 20 hrs. There is a
considerable individual variation in plasma concentrations achieved
with a given dose. Side effects include vertigo, ataxia, headache,
nystagmus (but not sedation), confusion & intellectual deterioration.

303
The gradual side effects include hyperplasia of the gums &
megaloblastic anaemia. Hypersensitivity reactions are not uncommon.
(C) Phenobarbitone, primidone, ethosuximide, trimethadione:
Phenobarbitone is well absorbed orally, 50% of the drug in the
plasma is bound to albumin, T1/2e 50~140 hrs, 25% is excreted
unchanged in urine, excretion increases if urine is made alkaline, 75%
is oxidated & conjugated. The drug is a particularly effective hepatic
enzyme inducer. Primidone pharmacological actions are due to the
formation of phenobarbitone as the active metabolite. Ethosuximide
has been developed by the modification of the barbituric acid
structure. It closely resembles trimethadione which was the first drug
effective in the control of absence seizures (often in children), causes
hypersensitivity reactions including aplastic anaemia & may produce
foetal abnormalities.
(D) Valproate: is a simple monocarboxylic acid, not a class relative, that
causes a significant increase in the GABA content of the brain by
inhibiting the 2 enzyme systems that inactivate GABA, the
transaminase & the dehydrogenase. Is well-absorbed orally & excreted
as the glucouronide, T1/2e 15hrs, relatively free of untoward effects
other than the thinning & curling of hair, in about 10% of the
patients, & an increase in SGOT. Has been a drug of choice in
infantile epilepsy due to the lack of toxicity & of sedative effects.
(E) Carbamazepine (Tegretol) R & oxacarbazepine: are the drugs of
choice in partial, primary & secondary generalized tonic- clonic
seizures, trigeminal neuralgia or other neuropathic pain states & the
prophylaxis of bipolar disorder unresponsive to lithium. Side effects
include vomiting, drowsiness, headache, confusion, agitation, visual
disturbances especially diplopia, leucopenia & other blood disorders,
& rash. Contraindicated in AV conduction abnormalities & history of
marrow depression.
(F) Gabapentin & pregabalin: are
indicated in partial seizures & peripheral neuropathic pain. Side
effects are GI symptoms, hypertension, cough & rhinitis, depression

304
confusion & hostility, diplopia, paraethesia, amnesia, impotence &
urine incontinence.
(G) Lamotrigine: indications similar to carbamazepine, side effects similar
to gabapentin.

B. Epilepsy
A neurological disease due to abnormal bioelectrical activity in the brain
which might be focal, localized or spread all over the brain thereby generating
focal seizures involving one finger or a facial muscle (according to
representation) or generalized grand-mal epilepsy characterized by:
 Aura.
 Loss of consciousness & falling down.
 Tonic phase, clonic phase then plateau (all taking 3 min).
 Patient regains consciousness or sleeps.
 Retrograde amnesia.
Absence petit mal epilepsy:
Mainly in hyperactive children with brief absence of consciousness
without falling or tonic clonic phases.
Narcolepsy:
Patient suddenly falls asleep (in mid-sentence).
Temporal loop psychomotor epilepsy:
SZP symptoms, change of behavior during sleep; grinding of teeth;
yawning; walking with stereotypy, sleeps & awakes amnestic.
Status epilepticus:
Seizures continue in a series without regaining consciousness, can be fatal.
1. Emergency treatment is instituted IV using;
 Phenytoin Na.
 Diazepam.
 General anaesthesia.
2. Long term therapy (for 3 uninterrupted yrs) includes:
 Carbamazepine 200 mg BID.
 Na valproate 200 mg BID which can be combined with clonazepam
(ClonitrilR).
3. Amphetamine

305
Is used in the treatment of hyperkinetic children (paradoxical) & in the
treatment of narcolepsy.

C. Parkinson`s diease
Is an acquired progressive motor disorder characterized by

 Tremor & muscle rigidity.


 Hypokinesia (↓frequency of voluntary movements).
 Inherent inertia (motor activity is difficult to initiate as well as
difficult to stop).
 Dementia.

Drug-induced Parkinsonism is usually due to

1) Dopamine reducers e.g. reserpine.


2) Dopamine receptor blockers e.g. chlorpromazine & other neuroleptics.
3) Methyltetrahydropyridine (MPTP) destruction of negro-striatal
dopaminergic neurons. The antagonist of MPTP is selegiline.

Drugs used in the treatment of Parkinsonism

 The symptoms of Parkinsonism result from an imbalance between the


excitatory effects of ACh & the inhibitory effects of dopamine in the
corpus straiatum (the caudate & lenticular nuclei plus the internal
capsule).
 Drug treatment is aimed at restoring this balance i.e.

1. Drugs that replace dopamine e.g. levodopa.


2. Drugs that mimic the actions of dopamine e.g. bromocriptine.
3. Drugs that releae dopamine e.g. amantadine.
4. Drugs that antagonize ACh e.g. benztropine.

(A) Levodopa:

 Dopamine itself does not cross the BBB, so levodopa was introduced as
the 1st line treatment.

306
 It has to be given in large & frequent doses amounting 3~8 gms/day in
3~4 doses. Well-absorbed from small intestine by active transport,
much inactivated (by MAO) in intestinal wall, T1/2e 2hrs, 95% is
converted to dopamine in peripheral tissues, ≤ 1% enters brain wherein
rapid decarboxylation occurs.

Pharmacologic effects:

 80% of the patients show improvement, 20% restore normal motor


function.
 Effectiveness gradually declines reflecting the natural progress of the
disease since the drug does not affect the ongoing underlying
pathological process.

Side effects:

1. Excessive activation of dopamine-Rs develops involuntary choreiform


movements.
2. Fluctuation of clinical state i.e. an on-off effect.
3. Acute effects;
I- Nausea & anorexia (CTZ- stimulation).
II- Hypotension (peripheral vasodilator action) & dysrhythmia.
III- Schizophrenia- like syndrome with hallucinations & delusions,
confusion, disorientation, insomnia or nightmares.

Domperidone:

 Is a dopamine antagonist which does not cross the BBB.

Carbidopa:

 Is a dopamine- derivative that inhibits dopa-decarboxylase & does not


penetrate the BBB.
 Both are used as adjunct to levodopa therapy to antagonize the
peripheral effects of the drug & /or to minimize the dose.

Selegiline:

307
 Is a MAOI that acts to facilitate dopaminergic transmission & is used
in mild cases or as adjunct to levodopa.

(B) Bromocriptine:

Is an ergot alkaloid agonist at D2-receptors in the CNS with very


similar effects & disadvantages to levodopa & a T1/2e 6~8hrs, but is
expensive.
(C) Amantadine:

May increase dopamine release, inhibit amine uptake or directly act at


dopaminergic receptors, less effective & with considerably less severe
side effects.
(D) Acetylcholine antagonists:

 Atropine & related drugs suppress the excitatory muscarinic Ach


effects exerted by receptors on the striatal neurons.
 Such agents diminish tremor but not rigidity or hypokinesia.
 Troublesome atropinic effects are inevitable, benztropine side effects
are limited to drowsiness & confusion.
I. Anticholinergic e.g. procyclidine, biperiden, cycrimine &
trihexphenidyl.
II. Antihistaminics e.g. diphenhydramine & orphenadrine.
III. Anticholinergic-antihistaminic e.g. benztropine & ethopropazine.

CNS Stimulants

Convulsants & Psychomotor Psychotomimetic drugs


respiratory stimulants stimulants
- Doxpram. - Amphetamine - Diethylamide
- Nikethamide. - Caffeine. lysergic acid.
- Leptazol. - Cocaine. - Cannabis.
- Strychnine. - Phencyclidine.
- Reflex - ↑ mental - ↑thought
excitability. function. pattern.
- Activate - Behavior. - Perception &
respiratory & - ↓fatigue & mood.
vasomotor ↑motor activity. - Schizophrenic

308
centres. effect.
- Convulsions.

1) Convulsants & respiratory stimulants

Bicuculline & picrotoxin (fish poison)

 Block the action of GABA on chloride channels.


 Convulsive.
 Had use against barbiturate overdose.

Nikethamide & leptazol

 Very similar pharmacologically.


 Mode of action unknown.
 Cause initial respiratory stimulation & raise blood pressure at doses
somewhat lower than cause convulsions.

Amphenazole & doxapram

 Have larger margin of safety between respiratory stimulation &


convulsion.
 Cause nausea, coughing & restlessness, I/v infusion allows regulation
of level of respiratory stimulation.

2) Psychomotor stimulants

Amphetamine, dextroamphetamine, methylamphetamine &


methylphenidate
 Act by releasing monoamines from nerve terminals in the brain;
noradrenalin, dopamine & serotonin.

Pharmacologic effects

1) Locomotor stimulation (busier than brighter).


2) Alertness & euphoria.
3) Stereotyped behavior.
4) Anorexia.

309
5) Peripheral sympathomimetic actions including a rise in blood pressure
& inhibition of GI motility.
6) Fenfluramine is a particular agonist that causes anorexia without
stimulation due to release of serotonin rather than noradrenalin or
dopamine.

Tolerance & dependence

 Tolerance rapidly develops to the sympathomimetic & anorectic effects.


 Dependence is a consequence of the unpleasant aftereffect. No physical
withdrawal syndrome.

Pharmacokinetics

 Amphetamine is rapidly absorbed from the GIT, freely penetrate the


BBB, mainly excreted unchanged in urine particularly if made acidic.
 Methylamphetamine is partially metabolized in liver to amphetamine,
t1/2e 5~20~30 min. depending on urine flow & pH.

Clinical uses

1) Hyperkinetic children (paradoxical).


2) Minimal brain dysfunction in children (some countries).
3) Narcolepsy (an epileptic disorder wherein the subject suddenly fall
asleep).

Side effects

1) Hypertension.
2) Insomnia.
3) Tremors.
4) Precipitation of schizophrenia.
5) Dependence.

Cocaine

310
 Is a potent inhibitor of catecholamine uptake by noradrenergic nerve
terminals.
 Strongly enhance sympathetic activity with similar effects in CNS to
amphetamine.
1) Euphoria, garrulousness & ↑ motor activity.
2) In excessive doses there is tremor, convulsions & respiratory & motor
depression.
3) Peripheral sympathetic effects include tachycardia, vasoconstriction & a
raised blood pressure.
4) Body temperature is increased by increased motor activity & reduced
heat loss.
5) T1/2e of an I/v dose is 15min.
6) No appreciable physical withdrawal syndrome, a psychological
dependence ensues characterized by depression & dysphoria.

Use

1) Topical use as ophthalmic local anaesthetic.


2) Street drug that, upon inhalation, causes necrosis of the nasal septum
due to prolonged vasoconstriction.

Methylxanthenes; caffeine & theophylline

1) CNS stimulation; insomnia, improved concentration & flow of


thought, ↓ reaction time, improved performance of motor activities
particularly in fatigued subjects.
2) Dieresis.
3) Myocardial stimulation.
4) Relaxation of smooth muscles especially bronchial.

Mode of action

1) Inhibit phosphodiesterase responsible for intracellular cAMP


metabolism.

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2) Antagonizes some of the effects of adenosine.
3) Dieresis results from vasodilatation of the afferent glomerular arterioles
↑ GFR.

Clinical use

1) Caffeine is incorporated with aspirin & ergotamine in preparations for


headache & migrane.
2) Theophylline is used as a bronchodilator in severe asthmatic attacks.

Untoward effects

Mutagenesis & teratogenesis.

3) Pschotomimetic agents

Affect thought, perception & mood without causing psychomotor


stimulation or depression.
LSD, Psilocin & Mescaline

Agents Derived from Chemically resemble


Fungi Catecholamines &
LSD - Ergot lysergic acid. serotonin.
Psilocin - Psilocybin.
Mescaline Mexican cactus Amphetamine.

 The main effect of these drugs is on mental function, most notable


alteration of perception in such a way that sights & sounds appear
distorted & fantastic.
 Hallucinations; visual, auditory, tactile or olfactory also occur. Sensory
modalities may become confused so that sounds are perceived as
visions.
 Inspite of these dramatic psychological actions, LSD & class has few
other actions & are remarkably not toxic.
 Tolerance & cross tolerance develop quite quickly, no physical
withdrawal syndrome.

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 Bad trips: Are more persistent mental disorders in which altered
perception & hallucinations have lasted for 3 weeks following a single
dose of LSD, the disorder may recur later after initial response to
antipsychotic therapy.

Phencyclidine

 The I/v general dissociative anaesthetic agent that produce in many


subjects a period of disorientation & hallucination following recovery
of consciousness.
 Effects are similar to psychotomimetic agents in addition to analgesia.
 Tendency as LSD to cause bad trips.

Cannabis

 Source: Cannabis sativa.


 Active principal: tetrahydrocannabinol (THC).
 Marijuana: the dried leaves & flower heads smoking mixture.
 Hashish: the extracted resin.

Pharmacodynamics

A mixture of psychotomimetic & sedative effects.

1) A feeling of relaxation & wellbeing.


2) A feeling of sharpened sensory awareness.
3) Time passes extremely slowly.
4) Increased appetite.
5) Impaired psychomotor performance, learning, memory tasks &
incoordination (confidence & creativity not reflected on actual
performance).
6) Aggressive behavior is not enhanced nor is sexual activity (contrary to a
common popular belief).
7) Analgesia & catalepsy.
8) Peripheral effects include
A) Tachycardia.

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B) Vasodilatation (especially scleral & conjunctival vessels).
C) Reduced IOP.
D) Inhibition of nausea & vomiting.
E) Bronchodilation.

Mechanism of action

Is not well understood though related to the lipid soluble anaesthetics.


Dependence

Anxiety, depression & irritability.

Tolerance

Non.

Adverse effects

Tertatogenisis & mutagenesis.

Local Anaesthetics (L.A.)


L.A. are drugs that cause reversible block of nerve conduction when applied
to nerve tissue in appropriate concentration.
Chemistry of local anaesthetics
- L.A. consist of lipophilic group (Normally aromatic ring) connected by
intermediate chain (either ester or amide) to hydrophilic (ionizable) group
usually a tertiary amine.
- Optimum activity requires balance between the lipophilic and hydrophilic
groups. Moreover there is stereochemical specifity, some isomers more active
than others.

314
- Ester linkage is essential for susceptibility to metabolic degradation by
pseudocholinesterase in plasma or liver. Therefore drugs with ester linkages
have shorter duration than those with amide bridges.
- L.A. are weak bases (Pka 8-9) so at acidic pH or physiological fluids they are
partially ionized.
- The uncharged form is important for penetration of biologic membranes;
however the cationic form is important for binding with channel receptor to
produce blockade.
- This explains the observation by dentists & surgeons that L.A. are less
effective in infected tissues (infection = low pH, so L.A. in ionized form).

Classification of L.A.:
1- Esters:
 Ester of benzoic acid: cocaine
 Ester of P.aminobenzoic acid: Procaine (Novocaine), Tetracaine
(Pontocaine), Benzocaine (Americaine), Chloroprocaine (Nesacaine).
2- Amides: Lidocaine (Xylocaine), Dibucaine, Mepivacaine (Carbocaine),
Prilocaine (Citanest), Bupivacaine (Marcaine), Etidocaine (Duranest),
Ropivacaine (Noropin).
Methods of administration of L.A.:
1- Surface anaesthesia:
- This refers to the local anaesthesia produced by direct application of the drug in
a suitable form to an accessible surface e.g. wounds, ulcers, burns, mucous
membrane of the eye, nose, pharynx, trachea, urinary tract. Surface anaesthesia
does not work well on the skin which is better anaesthesized by ethylchloride
aerosol which evaporates rapidly causing freezing of skin.

315
Example: lignocaine, tetracaine.
- If the drug is applied in high dose on a large area it may cause systemic toxicity
therefore a vasoconstrictor is added e.g. adrenaline or phenylephrine to prolong
the duration of action and limit delocalization.
2- Infiltration anaesthesia:
- The drug is injected in the subcutaneous tissues to reach a nerve terminal, used
in minor surgery.
- Adrenaline is added to prolong duration of action but it is contraindicated in
toes because it causes ischemic tissue damage.
3- Nerve block anaesthesia:
L. A. is injected close to a nerve trunk e.g. intercostals or dental nerves. Used for
surgery, dentistry, analgesia.
4- Spinal anaesthesia:
L.A. is injected in the subarachnoid space in the lumbar region. The drugs
diffuse in the C.S.F to act on spinal roots and spinal cord. Used for abdominal,
pelvis or leg surgery when general anaesthesia can not be used.
The level of spinal anaesthesia depends upon:
 Posture of the patients
 Specific gravity of the injection solution (relative to CSF) isobaric,
hyperbaric or hypobaric. Controlling specific gravity by controling the
conc. of glucose.
Side effects:
1- Hypotension due to blockade of preganglionic sympathetic nerves
2- Headache
3- If the drug reaches to the phrenic nerve supplying diaphragm, respiratory
arrest ensues.

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4- Septic meningitis may occur due to bacterial contamination.
5- Epidural anaesthesia
The drug is injected into epidural space. Used as for spinal anaesthesia but the
side effects are less due to reduced longitudinal spread of L.A.
6- Paravertebral block:
L.A. is injected around spinal roots from the paravertebral formina. This used to
relief postoperative pain and to produce painless childbirth.
7- Intraarticular.
8- Regional intravenous block using a tourniquet.
Mechanism of action:
 L.A. prevents both generation and conduction of nerve impulses. Their
site of action is the cell membrane. They block conduction by interference
with the permeability to Na+ by stabilization of the cell membrane and
blocking Na+ transport along Na channels.
 Blocking of the channels has use-dependent property, i.e. the depth of
block increases with the level of activity of the channels and with the
number of open channels,
 Na+ channels exist in 3 functional states: activated (open), resting (closed)
and inactivated. In the resting state the nerve is less sensitive to the local
anaesthetics (L.A. does not bind to receptor). It binds to the receptor
when the channel is active or inactive, but it has higher affinity to the
channel in the inactive state and it stabilizes it. The more inactivated the
channel the more is the degree of blockade.
 L.A in the charged form can only gain access to receptor when the channel
in active (open) state.

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 Elevated extracellular Ca+2 partially antagonize the action of L.A. while
elevation of extracellular potassium enhances their effect.
 L.A. has differential blockade: smaller diameter fibers are more susceptible
to the action of L.A. than larger ones. They block myelinated nerve before
unmyelinated nerves of the same diameter.
 Pain Aδ fiber & C fiber which are unmyelinated and have small diameter
are more susceptible to L.A. Sensation of pain is blocked before sensation
of pressure & touch. Motor activity (autonomic or skeletal) transmitted by
motor neurons which have large diameter fibers are the last nerve blocked
by L.A. Recovery of conduction occurs spontaneously.
Pharmacological actions:
1) Local anaesthetic action.
2) In the central nervous system: restlessness, agitation, tremor and
convulsions. Central stimulation is followed by depression. Death may
occur from respiratory failure. They may cause euphoria e.g. cocaine.
3) In the cardiovascular system; myocardial depression due to blockade of
Na+ channel leading to decreased the intracellular Na+ which is
exchanged with Ca+2, thus Ca+2 is reduced.
4) On blood vessels L.A. cause dilatation (except cocaine) decreasing blood
pressure which if sudden may be detrimental.
Side effects:
1) Restlessness & convulsions followed by respiratory depression.
2) Hypotension, cardiac arrest.
3) Hypersensitivity reactions (rare).
Pharmacokinetics:

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1) L.A. vary in their ability to penetrate membranes which affect the
onset of action and recovery and also affect the application sites, e.g.
procaine has poor penetration so it is not useful as a surface
anaesthetic. Rapidness of onset of action may be aided by the
addition of bicarbonate to the L.A. solution or the mucolytic
enzyme hyaluronidase.
2) Increased systemic absorption & higher peak level in blood is
correlated to overall dose injection into sites of hi vascularity. The
concurrent use a vasoconstrictor such as adrenaline ( e.g. at a conc.
ratio of 1:200 000) reduces the peak blood levels of the shorter
acting drugs (e.g.Lidocaine) but a lesser pronounced effect on the
more lipophilic & longer acting agents (e.g. Etidocaine).
3) Drugs with ester linkage have limitd distribution & short duration
of action (minutes) because they are rapidly metabolized by
cholinesterase e.g. procaine. Pregnancy reduces plasma
cholinesterase activity prolongs clearance & increases the potential
for toxicty. Subarachnoid administration effects will continue until
the the drug is systemically absorbed due to lack of
pseudocholinesterase activity in the CSF.
4) Products of hydrolysis undergo hepatic biotransformation or
otherwise can be directly excreted by the kidney (e.g.nearly 25% of
diethylaminoethanol from the hydrolysis of procaine). Para-
aminobenzoic acid (PABA) is a breakdown product of esters
responsible for allergic reactions in some patients.
5) Amide– type local anesthetics are widely distributed following I/v
absorption following a 2 or 3compartment model. Anatomic,

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pathologic & physiologic factors influence their distribution. Lung
extraction limits the amount of drug reaching the systemic
circulation & downstream sensitive sites. Conversely hypercapnia &
resulting acidosis in the CNS will likely increase regional blood flow
& therefore increase local anesthetic conc in the brain & risk of
toxicity. Protein binding influences the free drug available for both
activity & clearance by the liver, toxic plasma level is inversely
proportional to degree of protein binding.
6) Drugs with amide linkage are metabolized in the liver by N-
dealkylation and their metabolites are pharmacologically active.
7) Changes in hepatic or renal function or blood flow influence
clearance of these drugs.
8) Cocaine is an atypical ester that undergoes significant hepatic
metabolism & renal excretion.

ClassificationnnPotency Onset DurationpKa % Non- % Lipid


of (mints) ionized protein solubility
Action pH7.4 binding

Esters
Procaine 1 Slow 60 8.9 3 6 0.6
Chloprocaine 3 Rapid 45 8.7 5 - -
Tetracaine 8 Slow 180 8.5 7 76 80
Amides

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Lidocaine 2 Rapid 120 7.9 25 70 2.9
Mepivacaine 1.5 Intermed180 7.6 39 77 1
Bupivacaine 8 Intermed480 8.1 15 95 28
Etidocaine 8 Slow 280 7.7 33 94 141
Prilocaine 1.8 Slow 120 7.9 24 55 0.9
Ropivacaine 8 Intermedi480 8.1 15 94 28

Cocaine:
Cocaine is a naturally occurring alkaloid obtained from the leaves of Erythroxylon
coca a tree indigenous to Chile, Peru & Bolivia. It is an ester of benzoic acid.
Pharmacological actions:
I. It stimulates the central nervous system
II. It has sympathomimetic action because of blocking the neuronal
CA uptake so it produces tachycardia, vasoconstriction and
increases blood pressure.
III. It has anti-fatigue action thus coca leaves were chewed by mountain
people living in South America to allay hunger, fatigue and produce
psychic stimulation & euphoria.
IV. Used only for surface anaesthesia of eye and larynx.
V. Absorbed from all sites of application including mucous
membranes, metabolized by liver and partly excreted unchanged in
the urine.
VI. Causes psychic dependence. No tolerance develops to its action.

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VII. Poisoning symptoms include excitement, hyperpyrexia, tachycardia,
convulsions and finally coma. Death may result from respiratory
failure.

Procaine
 Procaine is a synthetic derivative of PABA.
 Little is absorbed from mucous membranes so it is effective only by
injection for infiltration, nerve block and spinal anaesthesia.
 It causes vasodilatation so is commonly combined with adrenaline to
limit its diffusion and prolong duration of action.
 Is given as hydrochloride by I.V infusion to relieve pain in arthritis and
burns.
 The amide derivative (procainamide) is used as an antiarrhythmic drug.
 Procainamide is metabolized in liver to PABA and diethylaminoethanol.
PABA antagonizes the action of sulfonamides.
Lidocaine
Is effective as L.A. for surface, infiltration, nerve block and spinal
anaesthesia. Is also used as an antidysrhythmic.
Lignocaine
 More potent as L.A. than procaine
 Has a rapid onset of action
 Useful for surface anaesthesia because it penetrates mucous
membranes.
 It is most popular in dental anaesthesia
 Duration of action is longer than procaine
 It is class I antidysrhythmic.

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 It stimulates C.N.S and may cause convulsions.
Chloroprocaine:
Resembles procaine but less allergenic.
Tetracaine:
Is a potent L.A. suitable for surface and injection L.A.
Dibucaine:
Extremely potent L.A. but is very toxic. It is used as solution or ointment
for surface anaesthesia. It is well-absorbed from mucous membranes. It
must be used in very dilute solution when injected.
Bupivacaine:
Long acting L.A.
Prilocaine:
Resembles lidocaine pharmacologically, but with a longer duration of
action and a delayed onset. Its metabolites cause haemoglbinaemia after-
effect toxicity.

Chapter 11

ANTI-RHEUMATIC DRUGS

Disease- Modifying Anti-rheumatic Drugs (DMARDs)

Actions

o DMARDs are drugs that suppress the rheumatic disease process by


affecting the progression of the disease in contrast to NSAIDs or

323
corticosteroids which mask the symptoms of the disease by their
analgesic and anti-inflammatory actions.
o DMARDs can improve not only the symptoms of inflammatory joint
disease but also extra- articular manifestations such as vasculitis.
o DMARDs reduce the ESR, C- reactive protein, titre of RF and may
retard erosive damage as judged radiologically.

Gold salts: Auranofin and Na- aurothiomalate

Indications

o Active progressive rheumatoid arthritis.


o Na- aurothiomalate is also indicated in juvenile idiopathic arthritis.

Contra- indications

o Hx of blood disorders or BM aplasia.


o Exfoliative dermatitis.
o SLE.
o Necrotizing enterocolitis.
o Pulmonary fibrosis.

Side effects

o Anaphylactic reactions.
o Stomatitis, mouth ulcers and taste disturbances.
o Colitis, hepatotoxicity with cholestatic jaundice.
o Pulmonary fibrosis.
o Peripheral neuropathy.
o Nephrotic syndrome and proteinuria.
o Blood disorders.
o Gold deposits in eye, skin reactions and alopecia.

Penicillamine:

Indications

o Severe active rheumatoid arthritis.

324
o Wilson`s disease.
o Autoimmune hepatitis.
o Cystinuria.

Contra- indications

o SLE.
o Caution with concomitant nephrotoxic drugs and gold.
o Caution with renal impairment and pregnancy.

Side effects

o Nausea and anorexia. Rashes and fever are also initial side effects.
o A 6 weeks loss of taste after 6 weeks of initiation of therapy.
o Blood disorders including thrombocytopenia, leukopenia,
agranulocytosis and aplastic anaemia.
o Proteinuria, nephrotic syndrome, rarely haematuria, and haemolytic
anaemia.
o Stomatitis, mouth ulcers, skin reactions and alopecia.
o SLE- like syndrome, myasthenia gravis- likesyndrome, polymyositis
which may involve cardiac muscles, Goodpasure`ssyndrome, and
Stevens- Johnson`s syndrome.
o Bronchiolitis and pneumonitis.
o Male and female breast enlargement.

Chloroquine and hydroxychloroquine (antimalarials):

Indications

o Rheumatoid arthritis of moderate inflammatory activity.


o Mild SLE particularly involving the skin and joints.

Contra- indications

o Caution in hepatic and renal impairments.


o It is not necessary to withdraw therapy during pregnancy, but breast-
feeding should be avoided.
o Epilepsy, severe GIT disorders and G6PD deficiency.

325
Side effects

o Better tolerated than gold salts.


o Retinopathy.
o Convulsions and other CNS disturbances.

Mepacrine (anti-giardial drug):

Indications

o Discoid lupus erythematosus.


o Giardiasis.

Contra- indications

o Hepatic impairment and elderly.


o Hx of psychosis.
o Psoriasis.

Side effects

o GIT disturbances.
o Transient acute toxic psychosis and CNS stimulation.
o Yellow discoloration of skin and urine and chronic dermatosis.

Other Anti-rheumatic Drugs

Glucosamine

Is a natural substance found in mucopolysacharides, mucoproteins and chitin,


its mechanism of action is not understood.

Indications

Symptomatic relief of mild to moderate osteoarthritis of the knee.

Contra- indications

o Allergy.
o Pregnancy.

326
o Breast feeding.

Side effects

o Nausea, abdominal pain, indigestion, diarrhea, constipation.


o Fatigue and headache.
o Allergy.
o Hypercholestrolemia and impaired glucose tolerance.

Drugs affecting the immune response

Indications

o Moderate to severe RA.


o Moderate to severe RA not responding to other DMADs.
o Severe active RA.
o RA with severe systemic manifestations.
o Connective tissue disease especially with active vasculitis.
o Severe cases of SLE.
o Severe or progressive renal disease (together with corticosteroids).
o Polymyositis refractory to corticosteroids therapy.
o In patients whose corticosteroids requirements are excessive i.e. for
their corticosteroid- sparing effects.
o Psoriatic arthritis affecting peripheral joints.

Contra- indications

o Severe immunodeficiency, severe hypoprotienaemia or severe


infection.
o Hepatic or renal impairment.
o Breast- feeding and pregnancy wherein active metabolites are
teratogenic.

Side effects

o GIT upset including vomiting, diarrhea, pain, and oral mucosal


disorders.

327
o Raised BP, leucopenia, anemia, hyperlipidemia, hypokalemia and
hypophosphatemia.
o Headache, dizziness, asthenia and paraesthesia.
o Rash, pruritus, rare hepatitis or jaundice, alopecia and dry skin.
o Tenosynovitis, tendon rupture or interstitial lung disease.

Measures taken in serious side effects

1. Discontinue therapy.
2. Wash- out procedures including administration of colestyramine and
activated charcoal before starting other DMARD.

Methotrexate

o DMARD indicated in moderate to severe RA.


o Given orally once a week.
o Monitor blood counts, hepatic and renal functions and give folate to
avoid side effects.

Azathioprine

o More toxic DMARD indicated in moderate to severe RA not


responding to other DMADs.
o Has a corticosteroid- sparing effect, used in polymyositis.
o Given daily in divided doses.
o Monitor blood counts.
o Vomiting, diarrhea and Herpes zoster infections are common.

Leflunomide

o A toxic DMARD with therapeutic effects onset in 4- 6 weeks improving


over 4- 6 months. Active metabolites persist for a long period.
o Used when sulfasalazine or methotrexate cannot be used.
o Used in Psoriatic arthritis affecting peripheral joints where
Methotrexate and Azathioprine are also indicated.
o Side effects may include BM toxicity maximizing the risk of infection
and malignancy.

328
Ciclosporin

o Indicated in active severe RA not responding to other DMADs.


o Retards the rate of erosive progression and improve symptoms control.

Cyclophosphamide

o Indicated in RA with severe systemic manifestations, and in connective


tissue disease especially with active vasculitis.
o Given OD orally or IV repeated initially, fortnightly then monthly
according therapeutic response and side effects.
o Toxic, close monitoring is required.

Gout and Hyperuricaemia

Acute attacks of gout

Are usually treated with one or more of the following:

o Hi-dose NSAIDs such as diclofenac, indometacin, ketoprofen,


naproxen, or sulindac but not aspirin.
o Colchicine.
o Corticosteroids.

Colchicine

Mechanism of action

o Uricosuric effect maximizes uric acid secretion in urine.

Indications

o Acute attacks of gout.


o Prophylaxis of familial Mediteranian fever.

Contra- indications

o Pregnancy and breast- feeding.


o Renal impairment.

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Side effects

o Nausea, abdominal pain, indigestion, profuse diarrhea and GIT


bleeding with large doses.
o Hepatic damage.
o Peripheral neuritis and myopathy and alopecia.
o Inhibition of spermatogenisis.
o Blood disorders.

Long term control of gout

Indications

o Frequent recurrence of cute attacks of gout.


o Presence of tophi.
o Signs of chronic gouty arthritis.

Allopurinol

Mechanism of action

Inhibits the metabolic enzyme xanthine oxidase leading to decreased


formation of uric acid from purines.

Indications

o Prophylaxis of gout.
o Prophylaxis of uric acid and of calcium oxalate renal stones.
o Prophylaxis of hyperuricaemia associated with cancer chemotherapy.

Contra- indications

o Acute attacks of gout.


o Renal and hepatic impairment.
o Caution in pregnancy and breast- feeding.

Side effects

o Rash and other hypersensitivity manifestations.

330
o Seizures, headache, vertigo, drowsiness, visual and taste disturbances
(all rare), paraesthesia and neuropathy.
o GIT disorders.
o Alopecia and gynaecomastia.
o Blood disorders including thrombocytopenia, leukopenia,
agranulocytosis and aplastic anaemia.

Sulfinpyrazone

Mechanism of action

o Uricosuric effect maximizes uric acid secretion in urine.

Indications

o Prophylaxis of gout.
o Hyperuricaemia.
o Indicated instead of Allopurinol or in conjunction with it in cases that
are resistant to treatment.

Contra- indications

o Acute attacks of gout.


o Hx of blood disorders.

Side effects

o Rash and other hypersensitivity manifestations


o GIT disorders, ulceration and bleeding, hepatitis and jaundice.
o Acute renal failure.

Probencid and Rasburicase

Mechanism of action

o Uricosuric effect maximizes uric acid secretion in urine.

Indications

331
o Probencid is used to prevent nephrotoxicity associated with Cidofovir
therapy.
o Rasburicase is indicated in the prophylaxis and treatment of
hyperuricaemia associated with initial chemotherapy of haematological
malignancy.

332
Chapter 12
Chemotherapy
Is the treatment of disease by use of pure chemicals which have a specific
antagonistic effect on the organism causing the disease.
Paul Erlich is the father of chemotherapy, in 1900 he stated that “A
chemotherapeutic agent should be maximally parasitotropic & minimally organotropic”,
thereby establishing the modern concept of assessment of the therapeutic value
using the therapeutic index represented by the ratio: Median LD/ Median curative
dose. The greater the TI, the more valuable is the drug. The aim of the modern
chemotherapeutic index is to a special mechanism of an organism metabolism
which is not common to that of the host, having found that, a compound is
found which utilizes that peculiarity in attacking the organism without affecting
the metabolism of the host.
Chemotherapeutic agents are chemical substances that elicit a selective toxicity
against the parasitic cells e.g. bacteria, fungi, protozoa, helminthes & cancer cells.
Antibiotics are substances produced by certain microorganisms that kill or
inhibit the growth of other microorganisms.
Classification of antibiotics:
1- According to spectrum
a- Broad spectrum: e.g. tetracycline & chloramphenicol
b- Narrow spectrum: e.g. penicillin & streptomycin.
2- According to whether they kill or inhibit microbial growth:
a- Bactericidal: causes death of the microorganism e.g. penicillin, cephalosporin,
streptomycin, aminoglycosides & polymixin

333
b- Bacteriostatic: inhibits growth of microorganisms e.g. tetracyclines,
chloramphenicol & sulfonamides.
3- According to the mechanism of action:
a- Antibiotics acting on the microbial cell wall:
- Inhibitors of the D-alanine linkage e.g. cycloserine
- Inhibitors of peptidoglycan biosynthesis e.g. bacitracin & vancomycin
- Blockers of transpeptidation e.g. penicillins & cephalosporins
b- Antibiotics increasing the permeability of the cytoplasmic membrane e.g.
polymyxin, nystatin & amphotericin
c- Antibiotics interfering with protein synthesis
- aminoglycosides, streptomycin, gentamycin, kanamycin & tetracyclines bind
to the 30S subunit of the microbial ribosomes.
- chloramphenicol, erythromycin & clindamycin bind to the 50S subunit of
microbial ribosomes.
d-Inhibitors of nucleic acid synthesis e.g. rifampicin, pyrimethamine,
trimethoprim, sulfonamides, quinolones & griseofulvin.
4-Antibiotics limited by toxicity
The drugs discussed under this heading are considered to be suitable for treating
generalized infection only in desperate situations, nevertheless, they share the
following advantages:
a) Highly bactericidal.
b) Slow development of resistance.
c) Not absorbed from the gut.
I. Neomycin.
II. Polymixin A~ E, except B.
III. Bacitracin.

334
IV. Erythromycin.
V. Tylosin, bactriostatic, especially active against mycoplasma. Particularly
distributed to lungs in RI due to hi lipid solubility.
VI. Lincomycin.
VII. Griseofulvin used for ttt of wring worm, ineffective as local application,
passes from blood to newly formed keratin enabling skin & hair to resist
fungal attack. Contraindicated 6 month before, & during, pregnancy.
VIII. Nystatin effective against yeast & Candida albicans infections &
superinfection following use of broad spectrum antibiotics such as
tetracycline.
Choice of a suitable antibacterial drug:
The clinician must consider 2 factors:
(1) The patient: history of allergy, renal & hepatic function, age, sex, severity of
illness & resistance to infection.
(2) The known or likely causative organism and its antibiotic sensitivity
Empiric antimicrobial therapy:
In many cases wherein the causative pathogen or its specific antibiotic
susceptibility is unknown the use of antibiotic is known as empiric therapy
(presumptive therapy) i.e. initiated based on the experience.
Bacteriological identification and sensitivity tests:
Properly obtained and processed specimens for culture frequently yield reliable
information about the causative microorganism.
Principles of Antiobiotic Therapy
1) Do not use antibiotics for trivial self-limiting conditions which are better
left to natural defense mechanism & development of immunity.

335
2) Use a specific narrow spectrum antibiotic, where possible, to avoid
disruption of normal resident bacteria.
3) In general continue treatment for 24~ 48hrs after disappearance of
symptoms because if the infection is not completely eliminated there may
be a relapse or the infection may become chronic particularly in ttt of
pyogenic infections.
4) Use early in disease, in adequate dosage & by a route insuring effective
affected-tissue concentration.
5) Antibiotic combination may be used either in mixed or unknown
infection, or to attempt to achieve synergism.
6) Consider relative cost.
β-Lactam antibiotics
β-Lactam antibiotics share a mechanism of action & a β-Lactam ring in their
molecules. They include penicillins, cephalosporins, monobactams &
carbapenem.
Mechanism of action:
They are bactericidal & affect the microorganisms during their growth. After
binding to the receptor (penicillin-binding protein) on the bacterium they
inhibit cell wall synthesis by blocking the transpeptidation of peptidoglycan.
They also activate the autolytic enzymes in the cell wall leading to lysis of the
bacterium.
Penicillins
A large group of substances that share the basic structure 6-amino- penicillanic
acid. Some penicillins are obtained naturally from moulds of Penicillium spp.,
while others are semi-synthetic.

336
Resistance:
Certain bacteria e.g. staph., H. influenzae, & other G-ve species produce β-
Lactamase enzymes that inactivate the penicillin by breaking the β-Lactam ring
responsible for its antibiotic activity.
Spectrum:
G+ve: Streptococci, pneumococci, staph., Bacillus anthracis, C. diphtheria &
clostridia.
G-ve: Gonococci, meningococci
Spirochaetes: Treponema pallidum, actinomyces
Ampicillin also is effective against the G-ve bacilli shigella & salmonella.
Pharmacokinetics:
1- Benzylpenicillin (penicillin G)
 Destroyed by gastric juice so is administered parenterally, is completely
absorbed from I.V or I.M. administration, certain acid-resistant penicillins
are taken orally.
 Penetrates C.S.F with difficulty unless the meninges are inflamed, widely
distributed in body fluids, passing into the joints, pleural and pericardial
cavities, into bile, saliva, milk & across placenta.
 Protein binding is low with the exception of cloxacillin & dicloxacillin.
 Most are excreted rapidly by tubular renal mechanism. This excretion can
be blocked by probencid. Ampicillin excreted more slowly.
 Penicillin G T1/2e is 30~ 60 mints.
Unwanted effects:
 Penicillins are relatively free from toxic side effects.

337
 Hypersensitivity reactions are common with parenteral, but less marked
with oral penicillins. Symptoms include: skin rash, fever, urticaria,
asthma & in severe cases generalized oedema.
 Acute anaphylactic shock is rare but is dangerous.
 Broad spectrum penicillins particularly the oral forms cause GIT
disturbances & diarrhea.
Clinical use
 Is used in a water soluble salt form given only I.M or I.V because of
destruction by gastric acidity, must be freshly prepared.
 Has a short duration of action, T1/2 30 minutes, so is administered 4~
6 hourly.
 Destroyed by β–lactamases. It covers G+ve and some G-ve bacteria.
 Used in: meningococcal meningitis, respiratory tract infections,
tonsillitis, pharyngitis, pneumonia, gonorrhea & syphilis.
Long acting penicillin-G preparations:

 Are relatively insoluble & hence slowly absorbed from the injection
site, producing low but sustained plasma concentrations.
 Are usually given I.M only & never I.V.
A. Procaine penicillin: is given once or twice daily.
B. Benzathine penicillin: given 1~ 4 weekly, not used in acute
infections because of low blood level, used in chemoprophylaxis.
2- Phenoxymethyl penicillin (penicillin V):

 Orally active penicillin.


 Spectrum, distribution & excretion are similar to penicillin G.
 Less potent especially in gonorrhea & meningitis.

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3- β-lactamase-resistant penicillins:

A. Methicillin: parenteral, nephrotoxic.


B. Cloxacillin: oral or I.M, absorption increases with food, T1/2e 30~ 60
mints, rapidly excreted, less potent than benzyl penicillin.
C. Dicloxacillin: acid resistant, longer duration than cloxacillin.
D. Nafcillin: the most active β-lactamase resistant penicillin. Oral
absorption is incomplete, I.M is quicker with a higher Cp, reaches the
C.S.F in reasonable conc., 20% appear in urine & 80% in bile,
duration of action prolonged by enterohepatic circulation.
E. Flucloxacillin: oral, I.M or I.V.
4- Broad spectrum penicillins:

A. Ampicillin: acid resistant, given orally & parenterally, GIT absorption


is fairly good & decreased by food. β-lactamase sensitive. T1/2e 80 min.,
excreted in bile & urine, less active than penicillin on G+ve, but more
active against some G-ve bacteria, causes diarrhea.
B. Esters of Ampicillin (Pivampicillin, Talampicillin, Pacampicillin,
epicillin): are prodrugs releasing ampicillin in the liver by de-
esterification, absorption not decreased by food (better absorption), less
diarrhea than with ampicillin.
C. Amoxicillin: is better absorbed orally, T1/2e 80 min., similar
antimicrobial spectrum to that of ampicillin. β-lactamase sensitive so is
sometimes given in combination with a β-lactamase inhibitor
(clavulanic acid).
5- Antipseudomonal penicillins (extended spectrum penicillins):

339
A. Carbenicillin: given I.M or I.V. spectrum as ampicillin plus
pseudomonas and proteus, T1/2e 80 min., excreted in urine.
B. Ticarcillin: more active against pseudomonas, available in combination
with clavulanic acid.
C. Azlocillin, mezlocillin, piperacillin: more active against pseudomonas
& some klebsiella strains than carbenicillin & ticarcillin, , given I.V.,
T1/2e 60 min., excreted in bile & urine, indicated in serious G-ve
infections, used in combination with gentamycin to prevent the
emergence of resistant strains.
6- Reversed-spectrum penicillins:

A. Mecillinam: less potent against G+ve, but highly active against G-ve
bacteria including E. coli, klebsiella, salmonella & shigella,
pseudomonas are resistant. Given parenterally.
B. Pivmecillinam: a pro-drug of mecillinam, given orally, excreted in
urine & bile, used in typhoid fever.
β-lactamase inhibitors:

A. Clavulanic acid: a very powerful β-lactamase inhibitor without


antibacterial activity, when combined with amoxicillin it becomes
effective against infections due to β-lactamase producing organisms in
RT & UT.
B. Sulbactam combined with ampicillin
C. Tazobactam combined with piperacillin
Cephalosporins and Cephamycins

 Cephalosporins are derived from moulds of Cephalosporium spp.

340
 Cephamycins are derived from Streptomyces spp.
 Both have β-lactam ring structures.
 Are bactericidal, inhibit cell wall synthesis by inhibiting transpeptidase
resulting in failure of cross-linking of peptidoglycan.
 According to their resistance to β-lactamase, spectrum of activity,
administration & distribution, they can be classified into generations:
1) First generation cephalosporins:

 Active against G+ve cocci: Staph. aureus, Strep viridans, Strep.


pneumonia, Strep. pyogen, & G-ve : E. coli, Klebsiella pneumonia &
Proteus mirabilis, & the anaerobic peptococcus & peptostrptococcus.
 Do not cross the meninges.
 More stable to β-lactamase than penicillins.
 Cephalothin, Cephapirin, Cephazolin & Cephradine are
administered parenterally & excreted via the kidney, dosage have to be
adjusted in renal impairment.
 Cephalexin, Cephradine, Cephadroxil are administered orally, well
absorbed from gut, excreted mainly in urine. Probencid may increase
serum levels. In renal failure dosage must be reduced.
Clinical uses:

 Urinary tract infections.


 Surgical prophylaxis.
 Minor staph. Infections, cellulitits & soft tissue abscess.
2) Second generation cephalosporins:

 Cefuroxime, cefaclor, cefprozil, cephpodoxime: orally.

341
 Cefamandole, cefoxitin, cefotetan, cefonicid, cefuroxime, cefprozil,
ceforanide: parenterally.
 Wider spectrum of activity than first generation especially against G-ve
bacilli: enterobacter, klebsiella, indole +ve proteus.
 Cefamandol, cefuroxime, cefonicid, ceforanide & cefaclor are active
against H. influenza.
 Cefoxitin, cefmetazole & cefotetan are active against B. fragilis &
serratia.
 All are less active against G+ve than the first generation.
 More stable to β-lactamases than first generation.
 CSF penetration is unreliable except cefuroxime.
 In renal failure, dosage adjustments are required.
Clinical uses:

 Otitis media & sinusitis (cefaclor)


 Community-acquired pneumonia (cefuroxime, cefamandol)
 Meningitis (cefuroxime)
 Mixed anaerobic infections like peritonitis (cefoxitin, cefotetan)
3) Third generation cephalosporins:

 Cefoperazone, cefotaxime, ceftazidime, ceftriaxone, ceftizoxime,


cefixime & moxalactam.
 Wider spectrum, highly active against G-ve bacilli; enterobacter,
citrobacter, providencia, β-lactamase producing H. influenza &
Neisseria.
 Ceftazidime & cefoperazone have activity against Pseudomonas
aeruginosa.

342
 Ceftizoxime & moxalactam have good activity against B. fragilis.
 Highly resistant to β-lactamases.
 All are parenteral antibiotics except cefixime which is oral.
 All, except cefoperazone & cefixime penetrate BBB and attain high
CSF conc.
Clinical uses:

 Meningitis, sepsis
 Neutropenic & febrile immunocompromised patients (combined
with gentamycin).
 Gonorrhea due to penicillin-resistant gonococci.
 Mixed infections, involving chest, abdomen or pelvis.
4) Fourth generation cephalosporins:

 Cefepime, a new cephalosporin, is highly resistant to β-lactamases &


has excellent penetration into the CSF.
Adverse effects of cephalosporins:

 Hypersensitivity reactions: anaphylaxis, urticaria, bronchospasm, rash,


fever etc.
 Cross-allergenicity between penicillins & cephalosporins is uncertain
(6-18%), some individuals with a history of penicillin allergy may
tolerate cephalosporins. However, patients with a history of
anaphylaxis to penicillins should never receive cephalosporins.
 Local pain at the site of I.M injection. Thrombophlebitis after I.V
injection.

343
 Renal toxicity (interstitial nephritis, tubular necrosis) has been
reported following administration of the withdrawn cephaloridine.
 Bleeding due to hypoprothrombinaemia, thrombocytopenia and/or
platelet dysfunction occur with cephalosporins containing a
methylthiotetrazole group (cefamandole, moxalactam, cefoperazone,
cefotetan). They also can cause severe disulfiram-like reactions, so
alcohol must be avoided.
 Many second and particularly third generation agents are ineffective
against G+ve organisms especially staph. & enterococci. These
organisms plus fungi often grow and may induce super-infection.
Monobactams
 Are drugs with monocyclic β-lactam ring.
 Are resistant to β-lactamase and are active against G-ve bacteria including
pseudomonas and serratia, but have no activity against G+ve species or
anaerobes.
 Aztreonam is the most widely used and can be given I.V or I.M.
Carbapenems
 Imipenem has a wide spectrum against G-ve, G+ve species & anaerobes.
 Highly resistant to β-lactamase, but inactivated by dihydropeptidase in the
renal tubules.
 Administered, I.V or I.M., in combination with an inhibitor of renal
dihydropeptidase (Cilastatin).
 The most common side effects are nausea, vomiting, diarrhea & rash at
the infusion sites. High dose or high conc. in the plasma may cause
seizures.

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Aminoglycosides
Streptomycin, Neomycin, Kanamycin, Amikacin, Tobramycin, Sisomicin,
Netilmicin, Parmomycin etc. are produced by species of Streptomyces,
gentamycin is produced by the mould micromonospora pupurea.
 They are bactericidal drugs. They bind to the 30S subunit of the bacterial
ribosomes inhibiting protein synthesis.
 Water-soluble and more active at alkaline than at acid pH, poorly
absorbed from the intestine, when given orally their effects are restricted
to the GIT.
 Systemic effects are produced parenterally.
 Wide extracellular distribution, minimum plasma protein binding except
streptomycin, & a very limited penetration into CSF.
 Excreted mainly unchanged by the kidney.
Side effects:
 Ototoxicity: hearing loss, start with high-frequency tones or as vestibular
damage (vertigo), ataxia & loss of balance.
 Nephrotoxicity: aminoglycosides accumulate in the kidney in high conc.
especially neomycin (not used systemically) and gentamycin.
 In high doses, they produce a curare-like effect with neuromuscular
blockade leading to respiratory paralysis. (Treated by calcium gluconate
or neostigmine as antidote).
Streptomycin
 It is not absorbed orally, when given its actions are limited to infections
of GIT. It is rapidly absorbed after I.M. injection.
 Is excreted by glomerular filtration in the kidney, some may be excreted
in bile, milk, sweat & tears.

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 Crosses the placenta, & into the CSF only if the meninges are inflamed.
 Narrow spectrum bactericidal activity against Mycobacterium
tuberculosis, G-ve bacilli such as E. coli, H. influenza & some staph
strains.
 Maximum activity is achieved in a slightly alkaline medium & reduced at
pH of 6 or less.
Therapeutic uses:
1- Tuberculosis, usually in combination with antimycobacterials.
2- Tularemia, plague & brucellosis.
3- Bacterial endocarditis due to Streptococcus viridans or Strep. faecalis & G-
ve bacteremia e.g. Pseudomonas sp.
Adverse reactions:
1- Allergy: rash, fever & eosinophilia.
2- Pain at the site of injection.
3- Reversible disturbance of vestibular function (vertigo, nausea,
dizziness & loss of balance).
4- Pregnancy administration → newborn deafness.
5- Hi dose → respiratory paralysis due to NM blockade
Gentamicin
 Bactericidal effects against G-ve bacilli Pseudomonas aeruginosa, Proteus
spp., E. coli, Klebsiella pneumonia, Enterobacter spp. & the G+ve
staph., Strep. viridans & faecalis.
 Gentamicin + some penicillins → synergistic effect, but cannot be mixed
in one syringe or intravenous solution.

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 Most strep. are resistant to gentamicin. G-ve organisms aquire plasmid
governed gentamicin-inactivating enzymes. These organisms are often
resistant also to kanamycin, tobramycin, but infrequently to amikacin.
Therapeutic uses:
1- Severe infections caused by G-ve organisms resistant to other
less toxic drugs e.g. UTI, pneumonia, infected burns,
osteomyelitis & septicaemia.
2- Infective endocarditis combined with penicillin G.
3- Topically: in the treatment of septic wounds & burns.
4- Intrathecally in meningitis.
Side effects
Like streptomycin, it is highly nephrotoxic and ototoxic with irreversible loss of
hearing by prolonged hi drug levels.

Tobramycin
 Similar antibacterial spectrum to gentamicin but more active.
 There is cross-resistance between gentamicin & tobramycin.
 (80%) excreted by glomerular filtration.
 Slightly less nephrotoxic than gentamicin.
Amikacin
 Is a semisynthetic less toxic kanamycin derivative.
 Broader in spectrum than other aminoglycosides.
 Resists enzymes that inactivate gentamycin & tobramycin, used against
infections resistant to these drugs.
 Nephrotoxic & ototoxic.
Netilmicin

347
 Similar to gentamicin, not inactivated by many resistant bacteria.
 Less nephrotoxic and less ototoxic than other aminoglycosides.
The neomycin group
Kanamycin
 Active against G+ve & G-ve bacteria and some mycobacteria.
Pseudomonas & streptococcui are resistant.
 May be used orally for GIT infection, but usually parenterally for serious
infections.
 Dose reduced in elderly patients & in renal impairment.
 Ototoxic & nephrotoxic.
Neomycin
 Similar to kanamycin in spectrum & activity.
 Limited by nephro- & ototoxicity to topical or oral use.
 Topically effective against staph. & G-ve bacilli skin infections.
 Other agents e.g. bacitracin & polymyxin are usually combined in the
ointment to minimize the development of resistance.
 Prolonged local application may cause skin sensitization.
 Oral use for acute intestinal infections, preparation of the bowel for
surgery & in hepatic coma.
Parmomycin
 Effective oral use in enteritis.
 Effective against E. histolytica intestinal amoebiasis.
Spectinomycin
 Is an aminocyclitol antibiotic (related to aminoglycosides)
 I.M. effective against many G-ve & G+ve species.
 Alternative treatment for gonorrhea.

348
 Causes pain at the injection site, fever, nausea, nephrotoxicity & rarely
anaemia.
Polypeptide antibiotics
Polymyxins
 The group is active against G-ve bacteria including pseudomonas.
 The high nephrotoxicity limits use to polymyxin B & E.
 Bactericidal, disrupt the osmotic properties and transport mechanisms of
the bacterial cell membrane.
 Not absorbed orally, poor tissue distribution, urinary excretion.
 Polymyxin B may be used orally for intestinal infections, or in ointment
mixture with bacitracin & neomycin in skin, eye or ear infections. It
 Causes paresthesia, dizziness & in-coordination, nephrotoxicity &
respiratory paralysis at hi blood levels.
Bacitracins
 Not absorbed orally, nephrotoxic parenterally, limited to topical use.
 Highly active against G+ve & neisseria. Combined with other
antibiotics in creams & ointments for wound & skin infections.
Chloramphenicol & Tetracyclines
Chloramphenicol
 Isolated from Streptomyces venzuelae, is now produced synthetically.
Pharmacokinetics:
 Parenteral chloramphenicol succinate is highly water soluble & is
hydrolyzed in tissues to liberate free chloramphenicol.
 Oral chloramphenicol palmitate (a tasteless salt) absorption is rapid &
complete, GI hydrolysis liberates the free drug.

349
 Exists in different crystal shapes, a phenomenon known as
polymorphism, the particle size & shape of crystals play an important
role in absorption.
 Wide tissue distribution including CNS & CSF. (Cp = conc. in brain
tissue).
 30% is bound to plasma proteins.
 Reduced or conjugated to glucuronic acid in the liver.
 Metabolites, plus 10% in the active form, are excreted by the kidney.
Mechanism of action:
1) Bacteriostatic, attachment to the 50S subunit ribosomes inhibits protein
synthesis.
2) Inhibits mitochondrial protein synthesis in mammalian bone marrow
cells.
3) Broad spectrum antibiotic activity against a wide array of G+ve & G-ve
species, rickettsia & Chlamydia, some salmonella & bacteroids.
4) Gradual resistance due to the emergence of mutants, no cross resistance,
but plasmids may transmit multiple drug resistance (chloramph.,
tetracycline, streptomycin) from one bacterium to another by
conjugation, resulting from the production of chloramphenicol
acetyltransferase, which inactivates the drug.
Therapeutic uses:
1- Acute stage typhoid & paratyphoid fever, for 14~21 days, severe rickettsial
diseases.
2- Meningitis & other H. influenza infections including pneumonia or
laryngiotracheitis.
3- Life threatening sepsis, brain abscess and bacteroids infections.

350
4- Eye infections, topically.
Adverse reactions:
1- GI disturbances: nausea, vomiting and diarrhea.
2- Candidiasis.
3- An irreversible, fatal but rare marrow depression.
4- Grey baby syndrome with vomiting, flaccidity, hypothermia, grey color,
shock & collapse due to high blood level of the active drug in newborn
infants due to undeveloped hepatorenal elimination pathways.
Drug interaction:
1. Enzyme inhibitor that prolongs the T1/2e of tolbutamide, phenytoin &
warfarin.
2. Antagonizes the bactericidal action of penicillins or aminoglycosides.
Tetracyclines
 Tetracycline was isolated from Streptomyces spp.
 Chlortetracycline, oxytetracycline, tetracycline, demeclocycline,
methacycline, doxycycline & minocycline were recently developed new
tetracyclines for good absorption & prolong duration of action.
 Broad spectrum bacteriostatic against many G+ve and G-ve bacteria
including some anaerobes, rickettsia, Chlamydia, mycoplasma, & some
protozoa e.g. amoeba.
 Bind 30S ribosomal subunit interfering with protein synthesis.
Resistance:
 Some bacteria lack an active transport mechanism or passive
permeability to tetracyclines.
 Plasmid-transmitted by transduction or conjugation.

351
 Usually transmitted to multiple drugs e.g. aminoglycosides,
sulfonamides & chloramphenicol.
Pharmacokinetics:
 Incomplete oral absorption (30% of chlortetracycline, more
tetracycline, oxytetracycline & demeclocycline, & 100% of doxycycline
& minocycline).
 The pyrrolidino-methyl derivative of tetracycline is water soluble and can
be given intravenously.
 Absorption orally occurs in the upper small intestine and is best in the
absence of food.
 Combine with metal ions, e.g. Ca++, Mg++, Fe++ and Al+++ to form
insoluble chelates. The presence of these ions (e.g. in milk or antacid
preparations) tends to prevent absorption.
 Distributed throughout body tissues, including fetal circulation and are
excreted in milk. Low conc. reaches the CSF. High conc. of minocycline
reaches to tears & saliva useful in eradicating the meningococcal carrier
state.
 Variable protein binding, excreted mainly in bile & urine, bile
concentrations are high. Entero-hepatic recycling contributes to the
steady blood levels observed with these drugs.
 Deposited in growing bones & teeth, causing yellow discoloration of
teeth & dental enamel hypoplasia.
 Doxycycline & minocycline are almost completely absorbed from the
gut and excreted slowly, leading to prolonged duration of action.
 Doxycycline is mainly excreted in bile therefore a good risk in renal
failure.

352
Clinical use:
1- Chlamydia, rickettsia & mycoplasma infections
2- Mixed RT infections.
3- STD e.g. syphilis (tetracycline).
4- Brucellosis, tularemia & plague, in combination with
rifampicin (doxycycline).
5- Prophylaxis & treatment of Vibrio cholerae infections
(tetracycline).
6- Amoebic dysentery & Plasmodium falciparum
(oxytetracycline).
7- Inhibition of the action of ADH in the renal tubule in
chronic hyponatraemia due to inappropriate ADH secretion
(Demeclocycline).
Adverse reactions:
1- GI disturbances, nausea, vomiting and diarrhea.
2- Super infection with Candida albicans
3- Vitamin B complex deficiency.
4- Discoloration & increased susceptibility of teeth to caries, growth
inhibition of growing bones.
5- Impair hepatic function, especially during pregnancy or when given I.V.
6- Expired preparations cause acidosis and renal injury.
7- Administration with diuretics may produce polyurea, proteinurea or
nitrogen retention.
8- I.V. injection produces thrombosis, I.M. produces local irritation.
9- Photosensitization especially demeclocycline.
10- Dizziness, vertigo, nausea & vomiting may occur with minocycline.

353
Macrolides
 Erythromycin, clarithromycin & azithromycin inhibit bacterial protein
synthesis by binding to 50S ribosomal subunit, elicit bactericidal or
bacteriostatic actions depending on the conc. & the microorganism.
 Erythromycin, similar to penicillin in spectrum, is effective against G+ve
& spirochaetes, the G-ve N. gonorrhoea & to a lesser extent H.
influenza, mycoplasma, legionella & Chlamydia.
 Azithromycin is more effective against G-ve H. influenza & legionella. It
has excellent action against toxoplasma.
 Clarithromycin is as effective, and its metabolite is twice as active,
against H. influenza as erythromycin. Effective against Mycobacterium
avium cellular and Helicobacter pylori.
Pharmacokinetics:
 Azithromycin, clarithromycin, erythromycin stearate & ester are acid-
resistant, administered orally. Erythromycin gluconate is administered
parenterally.
 All diffuse into most tissues including prostatic fluid & placenta, but do
not cross BBB. T1/2e of erythromycin is 90 min, clarythromycin is 5~ 7
hrs & azithromycin is 40~ 60 hrs prolonged by concentration in tissues
& in phagocytes.
 Inactivated in the liver, erythromycin more than azithromycin,
clarithromycin metabolites are active. Excreted mainly in bile.
Resistance:
 A plasmid-controlled alteration of the binding site on the bacterial
ribosome (rRNA- methylation).

354
 Staph. rapidly develop resistance if treatment is prolonged more than 10
days.
Therapeutic use:
1- Corynebacterial diphtheria & sepsis.
2- Penicillin-sensitive patients with pneumococcal or
streptococcal infections.
3- Pneumonia caused by mycoplasma & legionella.
4- Chlamydia infections in pregnancy.
5- Clarithromycin & azithromycin are effective in suppressing
disseminated Mycobacterium avium intracellulare infections
in patients with AIDS.
6- Clarithromycin is used in peptic ulcer.
Adverse reactions:
1- GIT: anorexia, nausea, vomiting & diarrhea.
2- Hepatotoxicity: erythromycin estolate produces a reversible acute
cholestatic hepatitis (fever, jaundice, impaired liver function).
3- Allergic reactions.
4- Erythromycin inhibit cytP450 & increases the effects of warfarin, digoxin
& conc. of cyclosporine & antihistamines e.g. terfenadine & astemizole.
Lincomycin & Clindamycin
 Clindamycin is the chlorinated derivative of lincomycin the natural
isolate from Streptomyces lincolnensis.
 Lincomycin resembles erythromycin in activity, Clindamycin is more
potent. Both inhibit protein synthesis by binding to 50S ribosomal
subunits of bacteria.

355
 Clindamycin is active against G+ve cocci including penicillin-resistant
staph. & anaerobes such as Bacteroid spp.
 Orally or parenterally widely distributed in tissues & body fluids but not
CSF. T1/2e 21 hrs. Some is metabolized in liver, metabolites are active,
excreted in bile & urine.
Uses:
1. Bacteroides & staph. joint & bone infections.
2. Topical use for staphylococcal conjunctivitis.
Side effects:
GI disturbances, diarrhea & pseudomembranous colitis due to a
necrotizing toxin produced by the drug-resistant Clostridium difficile.
Treatment is by oral vancomycin & metronidazole.
Glycopeptide antibiotics
 Vancomycin is bactericidal inhibiting cell wall synthesis, effective against
G+ve spp. including methicillin-resistant staph. & enterococci. It
synergises with aminoglycosides.
 Not absorbed orally, given I.V., widely distributed, eliminated via the
kidney, T1/2e 8 hours.
 Use limited to pseudomembranous colitis, multi-resistant staph.
infections & endocarditis.
 Side effects include fever, rashes and local phlebitis.
 Ototoxicity, nephrotoxicity & hypersensitivity reactions are not
uncommon.

Quinolones

356
 Synthetic antibiotics, Nalidixic acid is the prototype agent, achieves
low systemic levels & narrow spectrum, useful only as a urinary
antiseptic.
Fluroquinolones

 Ciprofloxacin, Norfloxacin, Ofloxacin & pefloxacin.


 Block bacterial DNA synthesis by inhibiting DNA gyrase
(topoisomerase-II) required for normal transcription & duplication.
 Broad spectrum effects against G+ve and G-ve bacteria including:
Enterobacteriaceae, pseudomonas, Neisseria, H. influenza &
compylobacter. Strep. & pneumococci are less susceptible.
 Resistance is due to change in the permeability or change in the target
enzyme.
 Well absorbed orally, widely distributed in the body fluids & tissues,
T1/2e 3~ 10 hours. Pefloxacin & ofloxacin cross the BBB. Oral
absorption is impaired by Al+++ & Mg++ e.g. antacid.
 Ciprofloxacin & ofloxacin can be given I.V. pefloxacin is
metabolized to norfloxacin.
 Excreted by tubular secretion & glomerular filtration.
Clinical uses:

- UTI even when caused by multi-drug resistant bacteria e.g.


pseudomonas.
- Infectious diarrhea & typhoid. Soft tissue, bone & joint, intra-
abdominal & respiratory tract infections.
- STD & mycobacterial infections.

357
- Eradication of meningococci from carriers or prophylaxis in
neutropenic patients.
Adverse effects:

1. Nausea, vomiting & diarrhea.


2. Headache, insomnia & less frequently convulsions especially with
theophylline or NSAIDs.
3. Photosensitivity & hypersensitivity reactions.
4. Elevate theophylline level.
5. Damage growing cartilage, not given to patients under 18.
Sulfonamides

 Prontosil-red dye- is the precursor of sulphanilamide from which


many sulfonamides have been developed.
 Short acting, well GI absorption: sulphadiazine, sulphadimidine,
sulphamethoxazole.
 Long acting, well GI absorption: sulphametopyrazine.
 Poor GI absorption: sulphasalazine.
Mechanism of action:

1. Sulphanilamide is a structural analogue of P-amino-benzoic acid


essential for the synthesis of folic acid.
2. Sulfonamides act by competing with pABA for dihydropteroate
synthetase. This effect can be antagonized by adding excess PABA or
some local anaesthetics such as procaine.
3. Bacteriostatic, selective toxicity on the bacterial cell because human
cells utilize pre-formed folic acid.

358
4. Plasmid-mediated synthesis a mutant enzyme of lowered affinity for the
drugs generates resistance.
5. Effective against a wide array of G+ve & G-ve bacteria, Chlamydia &
Trichomonas.
Pharmacokinetics:

 Readily absorbed from GIT, usually not given topically (except silver
sulphadiazine) because of sensitization & allergic reactions.
 Distribution depends partly on plasma protein binding, cross placenta
& BBB.
 Acetylated in the liver to inactive form, excreted in urine.
Clinical uses: now are seldom

1- UTI.
2- Respiratory tract infections
3- STD.
4- Sulphasalazine in inflammatory bowel disease.
5- Silver sulphadiazine in infected burns.
6- Na-sulphacetamide locally in the eye for conjunctivitis.
7- Combined with pyrimethamine in the treatment of
toxoplasmosis and drug-resistant malaria.
8- Combined with trimethoprime in the treatment of
Pneumocystis carinii.
Side effects:

1- Nausea, vomiting, headache and dizziness, mild.


2- Cyanosis.

359
3- Crystalluria due to precipitation of the drug or its metabolites in the
urine, prevented by giving large volume of fluids & urine alkalinization.
4- Hypersensitivity including rash, fever & photosensitivity.
5- Hepatic injury.
6- Bone marrow depression.
Trimethoprim

 Trimethoprim & pyrimethamine resemble the pteridine moiety of


folate, taken by bacteria and protozoa & inhibit their dihydrofolate
reductase 50000 times than the human enzyme.
 Bacteriostatic activity against most common pathogenic bacteria,
mixtured with sulphamethoxazole (co-trimoxazole) the potentiated
combination reduces the side effects, has a bactericidal property &
decreases the frequency of development of resistance.
 Oral trimethoprime is well absorbed, widely distributed, reaches
CSF, lung & kidney, excreted in the urine, elimination increase by
decreasing urinary pH.
 Used in UTI, RTI & Pneumocystis carnii infections.
 Side effects are nausea, vomiting, rash & folate deficiency.

Anti- cancer chemotherapy


Cancer

 It is basically a disease of cells characterized by the shift in the control


mechanisms that govern cell proliferation and differentiation.
 The growth of both normal and cancerous cells is genetically controlled
by the balance or imbalance of oncogene, protooncogene, and tumor
suppressor gene protein products.

360
Carcinogenesis

 Carcinogenesis is a multi-step process that includes initiation,


promotion, conversion, and progression.
 Multiple genetic mutations are required to convert normal cells to
cancerous cells.
 Substances that may act as carcinogens or initiators include chemical,
physical, biologic agents, & some drugs and hormones used for
therapeutic purposes.

Drug or hormone Cancer Caused


Alkylating agents Leukemia
chlorambucil, mechlorethamine, melphalan,
nitrosoureas)
Anabolic steroids Liver
Analgesics containing phenacetin Renal, urinary
bladder
Anthracyclines Leukemia
doxorubicin
Antiestrogens Endometrium
tamoxifen
Coal tars (topical) estrogens Skin
Nonsteroidal Vagina/cervix,
diethylstilbestrol endometrium,
breast, testes
Steroidal e.g. estrogen replacement therapy & oral Endometrium,
contraceptives breast, liver

Epipodophyllotoxins Leukemia
etoposide & teniposide

Immunosuppressive drugs Lymphoma, skin


cyclosporine & azathioprine

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Oxazaphosphorines Urinary bladder,
cyclophosphamide & ifosfamide. leukemia

Special Characteristics of Cancer Cells

• Uncontrolled Proliferation

• Dedifferentiation and loss of function

• Invasiveness (Spreading)

• Metastasis (spread of cancer from its primary site to other places in the
body )

Management of Cancer

• Surgical

• Radiation

• Chemotherapy

• The neoplastic cell burden is initially reduced either by surgery and /or
radiation followed by chemotherapy or combination therapy.

• Surgery and radiation are local treatments. These modalities are likely
to produce a cure in patients with a truly localized disease but because
most patients with cancer have metastatic disease at diagnosis, localized
therapies often fail to completely eliminate the cancer. In addition,
systemic diseases such as leukemia cannot be treated with a localized
modality.

• Chemotherapy (including hormonal therapy) accesses the systemic


circulation and can theoretically treat the primary tumor and any
metastatic disease

Chemotherapy

362
• Adjuvant: Additional treatment after the primary treatment to lower
the risk that the cancer will come back.

• Neo-Adjuvant therapy: Treatment as a first step to shrink a tumor


before the main treatment.

• Concurrent therapy: When two or more therapies are given together,


such as chemotherapy and radiation.

Cell Cycle

• G0: A resting phase,the cell has stopped dividing.

• G1: Cells increase in size.

• S: DNA replication occurs.

• G2: Gap between DNA synthesis and mitosis, the cell will continue
to grow.

• M: Cell growth stops and cellular energy is focused on the orderly


division into two daughter cells.

Principles of cancer chemotherapy

1. Goal of treatment:

• The ultimate goal of chemotherapy is cure. i.e. long term disease free
survival.

• If cure is not attainable, then the goal becomes pallitation i.e.


alleviation of symptoms and avoidance of life-threatening toxicity.

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2. Indications for treatment:

• Chemotherapy is indicated when neoplasms are disseminated (Spread


over a large area)and are not cured by surgery.

• Chemotherapy is also used as a supplimental treatment to attack


micrometastasis following surgery and radiation treatment.

3. Tumor susceptibility and growth cycle:

• Rapidly dividing cells are generally more sensitive to anti cancer drugs,
therefore the fraction of tumor cells that are in replicative stage of their
cycle are most susceptible.

• Non proliferating cells usually survive the toxic effects of many of these
agents

4. Cell cycle specificity of drugs:

• The normal and tumor cells differ in the number of cells that are in
various stages of the cycle.

• Chemotherapeutic agents that are effective only against replicating cells


are called cell cycle specific (CCS) drugs.

• Others are said to be cell cycle non specific (CCNS) drugs.

• The non specific drugs have more toxicity in cycling cells and are
useful against tumors that have low percentage of replicating cells.

5. Tumor growth rate:

• The growth rate of most solid tumors in vivo is initially rapid, but
growth rate decreases as tumor size increases. Because of unavailability
of nutrients and oxygen.

• By reducing the tumor burden through surgery or radiation promotes


the remaining cells growth into an active proliferation and increases
their susceptibility to chemotherapeutic agents.

364
6. Treatment regimens and scheduling:

• Drugs are administered on the bases of body surface area.

• Destruction of cancer cell by chemotherapeutic agent follows first order


kinetics, i.e. given dose destroys constant fraction of cells.(Log kill)

• Combine drug therapy is more successful than single drug treatment.

• In combine therapy the drugs must have different toxicities,


Mechanisms of action.

7. Problems associated with chemotherapy:

• Resistance:

a) Inherent

b) Acquired

• Toxicities: Effects on the normal rapidly proliferating cells i.e. buccal


mucosa, bone marrow, GIT mucosa, and hair.

Side Effects

Bone marrow suppression

• Anemia

• Neutropenia

• Thrombocytopenia

Effects on GIT

• Vomiting

• Stomatitis

• Dysphagia

• Constipation

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• Diarrhea

Effects on skin:

• Skin dryness

• Sunburn

Effects on reproductive system:

• Decrease sperm count

• Decrease menstruation

Cancer Chemotherapeutic Agents

Cell Cycle Specific Drugs:

Effective for high growth-fraction-malignancies, such as hematological cancers.

• Antimetabolites

• Bleomycin peptide antibiotics

• Vinca alkaloids

366
Cell Cycle non-Specific Drugs:

Effective for both low-growth (solid tumors) and high growth fraction
malignancies.

• Alkylating agents

• Antibiotics (Dactinomycin)

• Cisplatin

1. Alkylating agents:

Cyclophosphamaide, Carboplatin, Cisplatin, Oxaliplatin, Dacarbazine

• Major interaction: Alkylation of DNA

• Binds to nucleophilic groups on various cell constituents. Including


DNA

367
• These drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and
phosphate groups of cellular constituents.

• Major Toxicity: bone marrow suppression

2. Antimetabolites:

5-Fluoro Uracil, Gemcitabine, Cyterabine, Methotrexate

 Structurally related to normal compounds that exist within the cell.

 Interfere with the availability of normal purine or pyrimidine


nucleotide precursors, either by inhibiting their synthesis or by
competing with them in DNA or RNA synthesis.

 Their maximal cytotoxic effects are in S-phase and therefore are cell-
cycle specific.

Folic Acid Analogs

Methotrexate

 Inhibitor of dihydrofolate reductase, the enzyme that catalyzes


conversion of folic acid to tetrahydrofolate.

Pyrimidine Analogs

 5-fluorouracil and cytarabine are commonly used.


 5-Fluorouracil must be converted to an active 5-fluoro−2′-deoxyuridine-
5′-phosphate form to bind the enzyme thymidylate synthetase and block
or inhibit DNA and RNA synthesis.
 This drug is considered S phase-specific.
 Cytarabine (cytosine arabinoside) is an analog of 2′-deoxycytidine and
must be activated by conversion to a 5′-monophosphate nucleotide.
Cytarabine may also inhibit DNA repair enzymes. This drug is S phase-
specific

Purine analogs

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 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used
occasionally. 6-MP is a sulfhydryl-substituted analog of hypoxanthine
that must be converted to an active form by hypoxanthine-guanine
phosphoribosyltransferase (HGPRT). The active drug inhibits synthesis
and metabolism of purine nucleotides and thus disrupts synthesis and
function of DNA and RNA. This is an S phase-specific drug.

3. Microtubule Inhibitors:

Vinca Alkaloids: Vincristine, Vinblastine, Vinorelbine

Taxanes: Paclitaxel, Docetaxel

o These are plant-derived substances.

o Cause cytotoxicity by affecting the equilibrium between the


polymerized and depolymerized forms of the microtubules.

o Vinca alkaloids inhibit microtubule polymerization and increase


microtubule disassembly. The mitotic spindle apparatus is disrupted,
and segregation of chromosomes in metaphase is arrested.

4. Antineoplastic Antibiotics:

Bleomycin, Doxorubicin, Dactinomycin, Daunorubicin

• Interacts with DNA, leading to disruption of DNA function.

• Also Inhibit topoisomerases (I and II) and produce free radicals.

• Cell-cycle nonspecific.

• Eg: Actinomycin D binds with double-stranded DNA and blocks the


action of RNA polymerase, which prevents DNA transcription.

5. Hormonal Agents:

Prednisone, Tamoxifen, Estrogens, Flutamide, Nilutamide, Bicalutamide

Commonly involves the use of glucocorticoids.

369
Direct antitumor effects are related to their lympholytic properties.

Glucocorticoids can inhibit mitosis, RNA synthesis, and protein


synthesis in sensitive lymphocytes.

Considered cell-cycle nonspecific.

Resistance to a given glucocorticoid may develop rapidly and typically


extends to other glucocorticoids.

6. Monoclonal Antibodies:

Rituximab, Trastuzumab, Cetuximab, Bevacizumab

 Antibodies that are made in the lab rather than by a person's own
immune system.

 Directed at specific targets and often have fewer adverse effects.

 Designed to recognise and find specific abnormal proteins on cancer


cells.

 Each monoclonal antibody recognizes one particular protein.

 Three types of monoclonal A-bodies:

1. Trigger the immune system to attack and kill cancer cells.


E.g. Rituximab (MabtheraR).

2. Stop cancer cells from taking up proteins E.g.


Trastuzumab (HerceptinR).

3. Carry cancer drugs or radiation directly to cancer cells.


These are called conjugated MABs. E.g. Ibritumomab
(ZevalinR).

Chapter 13

Addendum notes

Addendum notes 1:

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Disinfectants & Antiseptics

 Disinfectant: a substance that kills microorganisms in the inanimate


environment.
 Antiseptic: a substance that inhibits bacterial growth in-vitro & in-
vivo when applied to the surface of living tissue.
 Antibacterial action depends on conc., temperature & time. An ideal
disinfectant should be lethal in hi dilution, non-injurious,
inexpensive, stable, non-staining, odorless & rapid acting.
Alcohols

 Ethanol 70% is bactericidal at 30oC in 1~2 min, but less effective at


lower and higher conc.
 Ethanol 70% & isopropyl alcohol 90% are the most satisfactory
antiseptics for skin surface, but do not kill spores on instruments.
 For instruments 70% alcohol aerosol is disinfectant.
Aldehydes

 Formaldehyde 1~ 10% kills microorganisms and spores in 1~ 6


hours, irritating so use is limited to instruments.
 Formaldehyde 35% with methanol prevents polymerization.
 Glutaraldehyde 2% in 70% isopropanol is a liquid disinfectant for
instruments (optic & prosthetic). It kills microbes in 10 min & spores
in 3~ 10 hours.
 Methenamine is a urinary antiseptic. It releases formaldehyde into
acid urine.
Acids

371
 Boric acid 5% in water or as powder is used as antimicrobial on skin
lesions, highly toxic if absorbed, not advised.
 Benzoic acid 0.1% is a food preservative. Its esters are used as
antimicrobial preservatives of certain drugs.
 Acetic acid 1% is used in surgical dressing as antimicrobial. Acetic
acid 0.25~ 2% is antimicrobial in external ear and for irrigation of
the lower urinary tract, active against G-ve bacteria including
pseudomonas.
 Salicylic acid & other fatty acids act as fungicides on skin.
 Mandelic acid is excreted unchanged in urine if taken orally, lower
pH to 5 which is antibacterial.
Halogens and halogenated compounds

Iodine

 An effective germicide. 1:20000 solution of iodine kills bacteria in 1


minute and spores in 15 minutes.
 Iodine tincture USP contains 2% iodine and 2.4% Na iodide in
alcohol. It is the most effective antiseptic available for intact skin, safe
but may cause dermatitis avoided by removing the tincture using
alcohol.
 Povidone-iodine (iodine + polyvinylpyrrolidone) is a water soluble
complex used as a pre-operative skin antiseptic, kills bacteria &
spores, available in solution, ointment, aerosol, shampoo, skin
cleanser, cotton swabs..etc.
Chlorine

372
 Chlorine 0.25 ppm is effectively bactericidal.
 Organic matter reduces it antimicrobial effect.
 Used for disinfection of inanimate objects & purification of water.
 Halazone USP is chloramines available in tablet form for the
sterilization of drinking water.
 Sodium hypochlorite 0.5% solution is an irrigating disinfectant fluid
for contaminated wounds & as household bleaches containing
chlorine used as disinfectants for inanimate objects.
Oxidizing agents

 Hydrogen peroxide solution USP (3% H2O2 in water) has


antimicrobial action, used as mouthwash, cleansing of wounds &
disinfectant for smooth contact lenses.
 Hydrous benzoyl peroxide is bactericidal, keratolytic & skin irritant.
 Potassium permanganate 1:10000 conc. kills many microbes in 1
hour, used in the treatment of weeping skin lesions.
Heavy metals

Mercury

 Precipitates proteins & inhibits sulfhydryl enzymes in both bacteria &


human cell, highly toxic if ingested.
 Mercury bichloride NF (1:100) is used as disinfectant for
instruments.
 Ammoniated mercury ointment 5% is a skin antiseptic in impetigo.
 Organic mercury compounds are less toxic. Nitromersol, thiomersol
& phenyl mercuric acetate are available in liquid & solid forms as

373
bacteriostatic antiseptics & used also as preservatives in biologic
products.

Silver

 Precipitates proteins & interferes with essential metabolic activities of


bacteria. An inorganic salt is strongly bactericidal.
 Silver nitrate 1:1000 destroys most microbes rapidly, 1% ophthalmic
solution prevents gonococcal ophthalmic infections in newborns,
causes conjunctivitis so not used now.
 Silver salts are used in burns, irritating & have side effects.
Soaps

 Are anionic surface-active sodium or potassium salts of various fatty


acids. Dissolved in water they are strongly basic, excessive use will dry
normal skin.
 Remove dirt, surface secretions, desquamated epithelium & bacteria.
 For additional antibacterial action, certain disinfectant chemicals
(phenol, hexachlorophene) have been added to certain soaps.
Phenols & Related compounds

 Phenol denatures proteins, 1~2% phenol is antimicrobial, 5% is


irritating to tissues, mainly used for the disinfection of inanimate
objects e.g. Cresol, Resorcinol, Thymol & Lysol.
 Hexachlorophene powder is an effective bacteriostatic, also available
in liquid soap used in surgical scrub routines & as deodorant soap.

374
 Soap or detergents containing 3% hexachlorophene are effective in
preventing colonization of newborn's skin with staph. in hospitals,
not used due to its CNS toxicity if absorbed systemically.
 Carbanilides or Salicylanilides are also added to soaps as antiseptics.
 Chlorhexidine is antiseptic agent for G+ve bacteria, used as skin
cleanser in soap and as a mouth-wash.
 0.2% chlorhexidine gluconate can reduce plaque accumulation on
teeth and may be of some value in gingivitis. It is used for vaginal
flushing in prophylaxis against neonatal infections.
Cationic surface-active agents

 Bactericidal agents used as wetting agents and detergents in industry


& home, are antagonized by soap which is anionic, strongly adsorbed
by cotton and rubber.
 Benzalkonium chloride & cetylpyridinium chloride have
antibacterial activity, rarely used as disinfectants of instruments.
Nitrofurans

 2% nitrofuran is used as topical antimicrobial agents on superficial


wounds or skin lesions & as surgical dressing.
 Does not interfere with wound healing but 2% of patients may become
sensitized and develop reaction.
 Nitrofurantoin is a urinary antiseptic.
Addendum notes 2:

Antimicrobial drugs combination:


Combinations are generally indicated for one of the following purposes:

375
1- To achieve a synergistic effect e.g. penicillin + gentamycin in
bacterial endocarditis. Sulfamethoxazole + trimethoprim (co-
trimoxazole)R are often combined to obtain a bactericidal effect.
2- To delay development of bacterial resistance, especially in chronic
infections e.g. tuberculosis.
3- To treat mixed bacterial infections e.g. peritonitis, UTI.
4- To broaden the spectrum of antibacterial activity.
5- To treat urgent infections before bacteriological diagnosis has been
made.
6- To reduce the toxic effects of antibiotics by giving small doses of
each.
Rules in combination of antibacterial:
1- Bacteriostatic + Bacteriostatic drugs combinations → additive effect
(arithmetic sum of the effects of the individual drugs)
2- Bacteriostatic + Bactericidal drugs combinations → antagonistic effect (the
addition of a second drug actually diminishes the antibacterial
effectiveness of the first drug) e.g. tetracycline + penicillin. Bactericidal
agents kill mainly multiplying bacteria, but if the bacterial growth is
prevented by a bacteriostatic agent, the bactericide will no longer be able
to act efficiently.
3- Bactericidal + Bactericidal drug combinations → a synergistic effect (the
results is far greater than that of each drug alone & greater than could be
expected from simple addition effects) e.g. penicillin + gentamycin.
Addendum notes 3:

Resistance to antimicrobial drugs:

376
a- Non-genetic resistance: active replication of bacteria is required for
most antibacterial drug action. Consequently microorganisms that
are metabolically inactive (non-multiplying) may be resistant to
drugs e.g. mycobacteria.
b- Genetically inherited resistance: The majority of resistant microbes
have emerged as a result of genetic changes & subsequent selection
that may be either chromosomal or extra-chromosomal.
Chromosomal resistance develops as a result of spontaneous
mutation, with selective multiplication of the resistant strains till
they eventually dominate. Extra-chromosomal resistance involves
extra-chromosomal genetic elements known as "plasmids" which
are small circular bodies consisting of 2 helical DNA strands and
carrying up to 100 genes regulating the various metabolic processes
of bacteria. The R-plasmids are especially encoded to confer
antibiotic resistance upon the organisms which acquired them.
Genetic material and plasmids can be transferred from one
bacterial cell to another by one of the following mechanisms:
i. Transduction: the passage of DNA from one cell to another of the
same species by means of a bacterial virus "bacteriophage". Thus the
plasmid carrying the gene for β–lactamase production can be
transferred from a penicillin-resistant to a penicillin-susceptible
staphylococcus.
ii. Transformation: DNA released from one cell of a species to another
cell, thereby altering its genotype. This type is common to Gram-
positive bacteria.

377
iii. Conjugation: Through physical contact a unilateral transfer of
genetic material between two bacteria of the same or of different
species. This is important for the spread of plasmid-mediated
resistance.
iv. Translocation "transposition": An exchange of short DNA
sequences occurs between one plasmid and another or between a
plasmid and a portion of the bacterial chromosome within a
bacterial cell.
Biochemical mechanisms of resistance to antimicrobial drugs:
1- Microorganisms produce enzymes that inactivate the drug e.g.
staphylococci resistant to penicillin G produce a β–lactamase that
destroys the antibiotic, other G-ve bacteria produce β–lactamases.
2- Microorganisms become less permeable to the drug and can no longer
accumulate it e.g. tetracyclines which are normally transported actively
across cell membranes of susceptible bacteria & are accumulated within
the cell. Resistant strains do not accumulate tetracyclines. Resistance to
polymyxins also is associated with a change in permeability to the drugs.
3- Development of an altered structural target for the drug. Chromosomal
resistance of aminoglycosides is associated with loss of the specific
protein on the 30S subunit of the bacterial ribosome that serves as a
receptor in susceptible organisms. Erythromycin-resistant organisms also
have an altered receptor site on the 50S subunit.
4- Microorganisms induce changes in target enzymes rendering them less
susceptible to the antibiotic, while retaining their normal metabolic
function e.g. when the enzyme dihydropteroic acid synthetase of some

378
bacteria loses its affinity for sulfonamides while retaining its affinity for
PABA.
5- Development of an altered metabolic pathway that bypasses the reaction
inhibited by the drug e.g. some sulfonamide-resistant bacteria, which
develop certain enzymes that can utilize preformed folic acid and do not
required extracellular PABA.
Cross resistance: Microorganisms resistant to a certain drug may also be
resistant to other drugs that posses the same chemical nucleus e.g.
tetracyclines or the same mechanism of action e.g. neomycin ~ kanamycin.
Addendum notes 4:

Agents used in radiology and imaging

Contrast Materials

Contrast materials, also called contrast agents or contrast media. Are used to
improve pictures of x-rays, computed tomography (CT), magnetic resonance
(MR) imaging and ultrasound. They temporarily change the way x-rays or
other imaging tools interact with the body making certain structures or tissues
in the body appear different on the images than they would if no contrast
material had been administered. Contrast materials help distinguish or
“contrast” selected areas of the body from surrounding tissue. By improving
the visibility of specific organs, blood vessels or tissues, contrast materials help
physicians diagnose medical conditions.

Routes of administration

 Orally
 Rectally
 Intravenously or intra-arterially

Following an imaging exam with contrast material, the material is absorbed


and eliminated through urine stools.

379
CLASSIFICATION:

Compounds used in x-ray and computed tomography (CT)

When taken by a specific tissue, they block or limit the ability of x-rays to pass
through. As a result, blood vessels, organs and other body tissue that
temporarily contain iodine-based or barium compounds change their
appearance on x-ray or CT images.

a. Iodine-based compounds

These contrast materials can be injected into veins or arteries,


within the disks or the fluid spaces of the spine, and into other
body cavities. In some situations, iodine-based contrast materials
are substituted for barium-sulfate contrast materials for oral
administration.

b. Barium-sulfate

Is the most common contrast material taken orally. It is also used rectally
and is available in several forms, including: powder, which is mixed with
water before administration, liquid, paste, and tablet.

Are used to enhance x-ray and CT images of the gastrointestinal (GI) tract,
including: pharynx, esophagus, stomach, the small intestine, and the large
intestine.

C. Microbubbles and microspheres have been administered for


ultrasound imaging exams, particularly exams of the heart.

Compounds used in magnetic resonance (MR) exams

 Gadolinium: When this substance is present in the body, it alters the


magnetic properties of nearby water molecules, which enhances the
quality of MR images.

380
Intravenous Contrast Materials

 Iodine-based (x-ray and CT images)


 Gadolinium-based (MR images)

Typically they are used to enhance imaging of:

 viscera, including the heart, lungs, liver, adrenal glands, kidneys,


pancreas, gallbladder, spleen, uterus, and bladder
 gastrointestinal tract, including the stomach, small intestine and large
intestine
 arteries and veins, including vessels in the brain, neck, chest, abdomen,
pelvis and legs
 soft tissues, including muscles, fat and skin
 brain
 breast

Liver specific contrast media

Superparamagnetic iron oxide (SPIO) particles 30- 200 nm in size are


selectively taken by RE cells in liver spleen and BM. This magnifies the
contrast between normal liver and intrahepatic tumour, so lesions become
more conspicuous. Side effects are few and mild. Focal nodular hyperplasia is
the only liver tumor containing functioning RE- cells, some liver cell adenoma
and well- differentiated hepatocellular carcinoma may also contain a few of
these cells.

Hepatocyte agents

Protien- bound chelates of gadolinium Gd and manganese Mn are extracted


by functioning hepatocytes and contrast to liver tumours. Improved visibility
is 30- 60 mints after injection and lasts 4 hrs.

Focal lesions including hepatocellular carcinoma, focal nodular hyperplasia,


and regenerating nodules in cirrhosis may take up these agents and become
hyperintense to surrounding tissues in delayed images.

381
Use of contrast media in suspected perforation

Air

100 ml of air can be injected down an NG- tube and the film is taken after the
patient lies for 10 mints in lateral decubitus position. This allows passage of
air to the peritoneal cavity.

Alternatively 50 ml of non- ionic contrast may be used. A leak of contrast may


occur in ulcers which have perforated but do not show free gas.

Intestinal obstruction

Giving barium in suspected intestinal obstruction is not harmful due to the


large amounts of fluids present. It will not complete an otherwise incomplete
obstruction.

Paediatric

Barium is the most commonly used contrast in GIT- imaging in children. It is


safe, inexpensive and gives high- quality images.

It should be CI postoperatively, following rectal biopsy, or in conditions


where intraperitonial or mediastinal leakage might occur, also in patients at
high risk of aspiration.

In neonates water soluble contrasts are used instead of barium. Low osmolar
water soluble contrasts include iohexol and iopamidol. They have no adverse
effect if extravasated into peritoneum or mediastinum or aspirated into the
respiratory tract.

Earlier hyperosmolar water soluble agents such as meglumine/Na


(Gastrografin) and iothalamate meglumine were associated with risk of
dehydration due to fluid shift and haemodynamic compromise in infants, and
pulmonary edema if aspirated. Gastrografin only indication is in the enema
treatment of meconium ileus.

Administration of contrast media can be via a cup- and- straw, feeding bottle,
or syringed into the mouth if necessary. NG- tube allows better control of
contrast volume and bolus passage into the duodenal loop.

382
Water- soluble contrast enema is indicated in neonatal low GI obstruction
and post necrotizing enterocolitis strictures. Also in older children in
suspected Hirschsprung`s disease or after colonic surgery. In IBD
colonoscopy is better avoiding ionizing radiation and allowing taking biopsy.

The use of air enemas in reduction of intussusception is now established


practice.

Side effects and adverse and allergic reactions

Barium Sulfate Contrast Materials

 Stomach cramps
 Diarrhea
 Nausea
 Vomiting
 Constipation

Symptoms:

 Hives
 Itching
 Red skin
 Swelling of the throat
 Difficulty breathing or swallowing
 Hoarseness
 Agitation
 Confusion
 Fast heartbeat
 Bluish skin color

Patients at greater risk of an adverse reaction to barium-sulfate contrast


materials:

 History of asthma, hay fever, or other allergies.


 Cystic fibrosis, which will increase the risk of blockage in the small
bowel.
 Severely dehydrated, which may cause severe constipation.
 Intestinal obstruction or perforation.

383
Iodine-based Contrast Materials

Mild reactions include:

 Nausea and vomiting


 Headache
 Itching
 Flushing
 Mild skin rash or hives

Moderate reactions include:

 Severe skin rash or hives


 Wheezing
 Abnormal heart rhythms
 High or low blood pressure
 Shortness of breath or difficulty breathing

Severe reactions include:

 Difficulty breathing
 Cardiac arrest
 Swelling of the throat or other parts of the body
 Convulsions
 Profound low blood pressure

Contrast-Induced Nephropathy

Patients with impaired renal) function should be given special consideration


before receiving iodine-based contrast materials by vein or artery. Such
patients are at risk for developing contrast-induced nephropathy, in which the
pre-existing kidney damage is worsened.

At-Risk Patients of adverse reaction to iodine-based contrast materials


include:

 Previous adverse reactions to iodine-based contrast materials


 History of asthma

384
 History of allergy
 Heart disease
 Dehydration
 Sickle cell anemia, polycythemia and myeloma
 Renal disease
 The use of medications such as Beta blockers, NSAIDs, interleukin 2
 Having received a large amount of contrast material within the past 24
hours.

MR-Gadolinium

 Is less likely to produce an allergic reaction.


 Nephrogenic systemic fibrosis (NSF), a thickening of the skin, organs
and other tissues, is a rare complication in patients with kidney disease
that undergo an MR with contrast material. Gadolinium-based contrast
material may be withheld in some patients with severe kidney disease.

Pregnancy and contrast materials

 Many imaging tests and contrast material administrations are avoided


during pregnancy to minimize risk to the baby. However both may be
used when critical information must be obtained.
 Informed consent of the patient must be taken.

Intravenous Contrast Material (Iodine and Gadolinium) and Breast feeding:

 Mothers should not breast-feed their babies for 24 to 48 hours after


contrast medium is given.

385
Bibliography

Brunton, L., Chabner, B. and Knollman, B., (2010). Goodman &


Gilman`s: The pharmacological basis of therapeutics, 12th edition, pages:1-
1990, Mc Graw Hill Medical.

DiPiro, Joseph T., Talbert, Robert L., Yee, Gary C., Matzke, Gary R.,
Wells, Barbara G. and Posey, L. Michael, (2011). Pharmacotherapy: A
Pathophysiologic Approach, 8th edition, pages: 1- 403. McGraw-Hill
Education, Printed in China.

Jambhekar, Sunil S. and Breen, Philip J., (2009). Basic Pharmacokinetics, 1st
edition, pages:1- 400. Printed in Great Britain by J International, Padstow,
Cornwall, Published by the Pharmaceutical Press, 1 Lambeth High Street,
London SE1 7JN, UK, 100 South Atkinson Road, Suite 200, Grayslake, IL
60030-7820, USA Pharmaceutical Press.

Joseph I. Boullata, and Vincent T. Armenti, (2010). Handbook of Drug-


Nutrient Interactions, 2nd edition pages: 4- 13 / 158 / 167- 178 / 209- 223 /
427- 442. Humana Press 233 Spring Street, New York, NY 10013, USA.

Riviere, Jim E. and Papich, Mark G., (2009). Veterinary Pharmacology and
Therapeutics, 9th Edition, pages: 1-1544,Wiley-Blackwell John Wiley & Sons,
Inc.,1 Wiley Drive, Somerset, NJ 08875-1272, U.S.A, Telephone:
800.225.5945, Facsimile: 732.302.2300, Email: custserv@wiley.com

Sutton, D., (2007). Contrast media. Textbook of Radiology and Imaging, 7th
edition, volume 1, pages: 668, 671, 778, 849, 850, ELSEVIER CHURCHILL
LIVINGSTONE, Philadelphia, USA: phone: (+1) 215 239 3804, fax: (+1) 215
239 3805.

The British National Formulary (BNF – 65), (2013). Pages: 1- 1102.


Pharmaceutical Press c/o Macmillan Distribution (MDL), Brunel Rd,
Houndmills, Basingstoke, RG21 6XS, UK, Tel + 44 (0) 1256 302 699, Fax +
44 (0) 1256 812 521, direct@macmillan.co.uk, www.pharmpress

386
The British National Formulary (BNF – 57), (2009). Pages: 1- 978. BMJ and
RPS Publishing 1 Lambeth High Street, London, SE1 7JN, UK.

387