DEPARTMENT OF PHARMACOLOGY

FACULTY OF MEDICINE
ASSIUT UNIVERSITY

LECTURE NOTES

IN

PHARMACOLOGY

FOR NURSING

VOLUME I FOURTH EDITION

Editors

Prof. Safwat Mangoura Prof. Ehab Eldesoky

Dr. Abeer M.R. Hussein

2020
 Pharmacokinetics
I- Definition
The pharmacokinetic process is concerned with the absorption, distribution,
metabolism and excretion (ADME) of drugs.
II Routes of drug administration.
Enteral:
1- Oral:
- Advantages: safe, most common and most economic.
- Disadvantages:
1- Not suitable for unconscious patients, or in the presence of vomiting
2- Some drugs are destroyed by gastric acidity or enzymes.
3- Slow onset of action. So, they are not suitable in emergency.
* Sublingual:
-Drugs are placed under the tongue to diffuse directly into the systemic circulation
(e.g. nitroglycerine used in acute attack of angina).
- Advantages:
1- Bypass the liver and liver metabolism (first pass effect).
2- Drug can be effective in much lower doses.
3- Very rapid therapeutic effect.
* Rectal:
-50 % of rectal blood drains into the systemic circulation & bypass the hepatic portal
circulation.
- Advantages:
1- Avoidance of first-pass metabolism in the liver.
2- Avoidance of gastric irritation by the drug.
3- Useful when the drug cannot be given by mouth as in unconscious patients or
vomiting.
B) Parenteral (injections):
Advantages:
1- Rapid effect. So, suitable in emergency conditions
2- Effective dose can be accurately determined

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3- Suitable route when drugs are poorly absorbed orally or lose efficacy when given
orally e.g. insulin.
4- Suitable for treatment of unconscious patients who cannot swallow and in
vomiting.
Disadvantages: possibility of introducing infection, pain during injection, relatively
expensive and difficulty of self-medication.
Types:
* Intravenous (I.V.):
Systemic availability of the drug in the blood is 100%
No probability of first-pass metabolism.
Once the drug is injected, there is no retreat.
* Intramuscular (IM):
Absorption of drug is faster than SC route particularly for water soluble drugs.
Absorption from IM route may be retarded by the use of thick oils
* Subcutaneous (SC):
The rate of absorption is usually constant but slow to supply sustained effect.
Some hormones are given by this way for contraception
* Intra-articular. The injection of drugs directly into the joint space produces a rapid
and local effect e.g. intra-articular injection of corticosteroids in rheumatoid arthritis.
* Intrathecal. The drugs are injected directly into the spinal subarachnoid space as in
spinal anesthesia.
C) Other routes of drug administration:
i) Inhalation.
Used for drugs that can be dispersed in an aerosol e.g. β-adrenergic agonists in
bronchial asthma or vaporize easily e.g. gaseous and volatile anesthetics.
It provides rapid delivery of the drug across the large surface area of the alveolar
membrane and can produce actions almost as rapidly as iv injections.
It avoids first-pass effect in the liver.
The main disadvantages of this route are poor ability to regulate the dose and
irritation of the pulmonary epithelium. Also, in case of bronchial asthma, it may be
difficult to the patient to use the inhaler properly.

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ii) Topical.
It includes application of the drug for local effect to the skin and mucous membranes
of conjunctiva, ear, nose, throat, rectum and vagina.
Systemic absorption into the circulation of locally applied drug is significantly
increased when there is tissue destruction

III- Absorption of Drugs

(A) It describes the rate and extent of transfer of drug from its site of administration
to systemic circulation (central compartment).
(B) Factors affecting drug absorption:
1- Blood flow to the absorption area e.g. intestine has greater blood supply than
stomach which favors the absorption from intestine.
2- Surface area available for absorption e.g. the wide surface area of the intestine
favors efficient absorption of drug in comparison to the stomach.
3- Gastrointestinal motility. Reduced gastric motility may delay the rate of
absorption of a drug as in migraine where severity of pain may delay absorption of
the analgesic drug paracetamol and its analgesic effect. That is why metoclopramide
drug which stimulates gastrointestinal motility is added.
4- Food. Variable effect, e.g. food may enhance absorption of drugs like hydralazine
and propranolol or reduce them as milk impairs tetracycline absorption by the
formation of an insoluble compounds
5- First pass metabolism: It involves the metabolism of the drug if given orally and
before reaching the systemic circulation. Examples are. benzyl penicillin and insulin
which are inactivated by gastric acid and proteolytic enzymes if given orally,
therefore, they are given always parenterally.
6- Lipid Solubility of the drug. Highly lipid soluble drugs e.g. CNS drugs cross the
membranes better than drugs with lower lipid solubility.

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 IV Drug distribution.
# Following absorption or systemic administration into blood stream, a drug
distributes into interstitial and intracellular fluids.
# Factors affecting drug distribution:
1) Plasma protein binding:
a) In blood, drugs bind to plasma proteins, mainly albumin, but other proteins include
α-1 acid glycoproteins, lipoproteins and globulin.
b) The binding is usually reversible
2) Regional blood flow:
Organs with rich blood supply like heart, kidney or liver tend to accumulate drugs to
greater extent than poorly perfused organs such as skin, fat and bone.
3) Lipid solubility:
Drugs which are highly lipid soluble canl distribute more readily to tissues than polar
compounds (water soluble).
Distribution of drugs across special membranes:
- Placental transfer of drugs:
- Drugs cross the placenta primarily by simple diffusion.
- The fetus is exposed to nearly all drugs taken by the mother.
- It is better for pregnant women to avoid drug intake as much as she can to protect
the fetus from possible congenital anomalies especially in the first trimester of
pregnancy (period of organogenesis).
(V) Biotransformation of drugs (drug metabolism).
1-The metabolism of drugs is a process usually occurs in livers to change drugs from
active to be inactive metabolites easily eliminated.
2- However, in some cases, metabolism leads to generation of metabolites with potent
biological activity or toxic properties.
3- Drug metabolism may occur in other organs e.g. insulin and vitamin D in the
kidney.
Factors affecting drug biotransformation (metabolism):
(a) Hepatic metabolizing enzymes: In some individuals drug biotransformation
may occur so rapidly and extensively by the enzyme (i.e. extensive metabolizers).
Consequently, reduced efficacy of the drug is expected in these individuals. In others,

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biotransformation of the same drug by the same enzyme can be so slow and weak
(i.e. poor metabolizers) and toxic effects of the drug can develop with standard
(usual) dose. Enzymatic activity is under genetic control of each subject.
(b) Hepatic blood flow
Reduction of hepatic blood flow as in heart failure decreases the hepatic clearance of
some drugs.
(c) Liver disease.
The capacity of the liver is so great that liver disease must be extensive before it can
alter drug metabolism. In advanced liver cirrhosis the clearance of some drugs like
warfarin is reduced.
(d) Age.
In extremes of age (very young babies and very old people), the capacity of the liver
to metabolize drugs is reduced.
(VI) Drug excretion.
1- The kidney is the main route of drug excretion. However, other routes include: the
lungs, bile, saliva, stool, and breast milk.
2- Renal excretion of drugs (through kidney) occurs mainly by the following
processes:
(i) Glomerular filtration. Through glomerular filtration
(ii) Passive tubular reabsorption:
Some drugs during their passage in the renal tubules are passively reabsorbed into the
circulation.
(iii) Active tubular secretion:
In the proximal renal tubule of the kidney, some drug are transported from blood into
renal tubular fluid..

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 Pharmacodynamics
Definition: Pharmacodynamics studies the biochemical and physiological effects of
drugs and their mechanisms of action.
Mechanism of drug actions:
1- Receptor-mediated:
- Most of drugs act by binding to specific receptors located on the cell membrane
(e.g. adrenoceptors & cholinoceptors) or inside the cells (e.g. steroid receptors).
- Following this binding, certain biochemical and physiological events occur within
the cell that produce drug actione.
2- Non-receptor mediated:
- Some drugs act by direct chemical interaction, such as antacids which neutralize
gastric acidity and used in the treatment of peptic ulcer.
- Other drugs act through their physicochemical properties e.g. purgatives and
osmotic diuretics which owe their action to osmotic effect.
Pharmacological basis of drug-receptor interaction
1- “Agonist”: a drug that binds to receptors and produces an action.
2- “Antagonist”: a drug that binds to a receptor and reduces or blocks the action of
an agonist.
3- “Partial Agonist”: occupies all receptors, but give a partial agonist response.
4- “Affinity”: it is the tendency of a drug to bind to a receptor is called Affinity.
5- “Efficacy”: The ability of a drug-receptor complex to produce a pharmacological
response.
Receptor regulation:
1- Down-regulation:
In some cases, continued stimulation of the receptors with the same dose of agonist
results in a state desensitization or adaptation, or down regulation) of the receptors
and the effect of the drug is reduced.
2- Up-regulation:
Prolonged contact of receptors with an antagonist leads to formation of new receptors
and creates a state of supersensitivity of receptors to agonist once the antagonist
leaves the receptor binding. An example is the worsening of angina pectoris in some
patients following sudden withdrawal of a β-adrenergic receptor antagonist after long

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exposure. On withdrawal of the blocker the β-adrenergic receptors are up-regulated
and become supersensitive to the stimulatory effect of the normal concentration of
circulating catecholamines leading to cardiac stimulation in patients with angina.
Drug antagonism:
1- Physiological antagonism:
When a drug produces an effect opposite to the physiological effect of an agonist, it is
called a physiological antagonist. Example is injection of epinephrine to increase
blood pressure in patients who develop anaphylactic shock due to penicillin
hypersensitivity reaction. The release of histamine in the body due to allergy to
penicillin causes vasodilatation and severe hypotension which can by antagonized by
epinephrine injection subcutaneously.
2- Chemical antagonism: It occurs when two substances chemically interact to
neutralize the action of each other. Example is protamine sulphate (positively
charged) is an antidote to heparin (negatively charged anticoagulant) in is
3- Pharmacological antagonism:
a) Competitive antagonism (reversible binding)
Both agonist and corresponding antagonist bind reversibly to the receptor. When
antagonist inhibits the action of agonist, then administration of agonist in a dose
higher than antagonist, it can compete with the antagonist at receptor site removing
the antagonist and the agonist binds to produce its effect again.
b) Non-competitive antagonist (irreversible binding):
When an antagonist binds irreversibly to a receptor (e.g. by covalent bond) its effect
is not reversed by excess agonist.
Dose-response curve
It is an S-shape curve on a logarithmic scale (Figure. 2) which shows the relation
between dose (or corresponding drug concentration) & response. The log scale allows
a wider display of doses on the dose axis. The following characteristics can be
defined on the dose response curve: potency, maximal efficacy and slope.

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Figure. 2: Dose response curve: Log concentration versus effect
a) Potency: Dose size that produces a maximal effect. The most potent of two drugs
is the one which can be used in a smaller dose to give the same effect, i.e. the lower
the dose required to produce maximal effect, the higher the potency of the drug.
b) Maximal efficacy: It is the maximal therapeutic effect of the drug (ceiling effect)
after which there is no increase in therapeutic response even if the dose is increased.
c) Slope: It is the slope of the central linear part of the dose response curve (figure 2).
When the slope is very steep (figure 12), minor change in the dose can lead to toxic
effects (i.e. The drug has a narrow margin of safety.
Therapeutic index (TI):
In humans, TI is a ratio between median toxic dose (TD) and median effective dose
(ED) in 50% of population i.e. TI= TD50 / ED50. It is a measure of drug safety.
Drug tolerance:
- Following the repeated administration of some drugs, the intensity of response may
decrease during the course of therapy. In this condition, increased concentration of
the drug is required to get the same response as seen with addicting drugs. This is
called tolerance. Development of addiction to drugs like morphine is an example.

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 DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM (ANS)
Definitions:
- Autonomic nervous system (ANS) is a part of the nervous system that originates
from the central nervous system (CNS).
- It plays an important role in maintenance of life such as circulation, respiration,
digestion, body temperature …… etc.
- It is automatic in its function and not under conscious control.
Types of nerves in the ANS:
The nerves in the ANS may be:
- Parasympathetic nerves
- Sympathetic nerves

Difference Sympathetic Parasympathetic

Origin All thoracic and upper 3 Lumbar III, VII, IX, X cranial nerves,
2nd , 3rd and 4th of sacral

Ganglion Ganglia are closed to spinal cord Ganglia are away from spinal
(shorter pre-ganglion, longer post- cord (Longer pre-ganglion and
ganglion fibers). shorter post-ganglion fibers).

Physiological Not essential for life. It acts mainly Essential for life, it regulates
Function under stress and emergency vital function as digestion ..etc.
condition.

chemical mediator Generally norepinephrine (NEP) Generally acetylcholine (ACh)

Chemical transmission in ANS:

It is the process by which nerve impulse transmitted across a synaptic cleft in
autonomic synapses. Two main chemical transmitters are involved and include:
A) Acetylcholine (A Ch),
B) Nor epinephrine (NEP)

Sites at which ACh acts as a chemical mediators:

1) All pre-ganglion fibers of parasympathetic nerves.
2) All pre-ganglion fibers of sympathetic nerves.
3) All post-ganglion fibers of parasympathetic nerves.
4) Only sweat gland as a post-ganglion fiber of sympathetic nerve.
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5) Adrenal medulla in which post-ganglion fibers that secretes EP and NEP.
6) Motor end plate (neuromuscular junction) of skeletal muscles.
Sites at which NEP acts a chemical mediator:
All post-ganglion fibers of sympathetic nerves except sweat gland
AUTONOMIC DRUGS
Definition:
- They are the agents that affect the autonomic function.
- They are usually used to treat the autonomic disturbed function either
Classification of autonomic drugs:
Two different systems for classification of the autonomic drugs:
1- According to innervations
A- Parasympathomimitic drugs
B- Parasympathlytics drugs
C- Sympathomimetic drugs
D- Sympatholytic drug
2- According to chemical mediator
A- Cholinergic drugs
B- Cholinergic blocking agent
C- Adrenergic drugs
D- Adrenergic blocking agent

Parasympathetic Nervous System

Definition:
It is a system which contains ACh as a chemical mediator. (Cholinergic System)
Cholinergic receptors:
Two types of receptors:
1- Muscarinic (M) receptors. 2- Nicotinic (N) receptors.
1- Muscarinic receptors (M):
These receptors stimulated by ACh and named muscarinic because they stimulated
also by muscarine "alkaloid present in certain mushroom".
Three main types of muscarinic receptors are distinguished M1, M2 and M3
according to their response by the agonists and antagonists.

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Types of muscarinic receptors:
This table illustrates the differences

Difference M1-Receptors M2-Receptors M3-Receptors

Location - Gastric parietal cells - Myo cardium - Smooth muscles

-CNS. - Smooth muscles - Exocrine glands

Agonists Ach, Methacholine Ach, Methacholine ACh, Methacholine

Carbachol Carbachol Carbachol

Antagonists Atropine, Pirenzepine Atropine Atropine

2- Nicotinic receptors (N):-

Two types of N-receptors are distinguished NN and NM according to their agonist
and antagonists. The following table illustrates the differences
Difference NN-receptors NM-Receptors
Location Autonomic ganglia, Adrenal gland. Skeletal neuromuscular junction

Agonists ACh and low conc. of nicotine Ach and high conc.of nicotine

Antagonists High conc. Nicotine&hexamethonium D-tubocurarine and galamine

Parasympathomimetics
Classification
According to mechanism of action
1-Directly acting cholinergic drugs
Choline estersNatural alkaloid
••Methacholine •• Pilocarpine ••Carbacol ••Bethanecol
2-Indirectly acting cholinergic drugs
Reversible: •• Physostigmine •• Neostigmine ••Edrphonium
Irreversible •• Organophosphorous compounds like DFP
Pharmacological Effects of ACh:
According to the type of cholinergic receptors, two types of actions are known:

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 Parasympathomimetic Drugs
Definition:
These drugs produce an effect similar to Ach.
Generally they are used in diseases due to Ach deficiency.
Classification:
I-Directly acting parasympathomimetics:
Bethanichol is only clinically used choline ester.
It is used in:
1- GIT disorders: in intestinal atony (paralytic illus).
1- Urinary tract disorder: acute and chronic urine retention.
Side effects and toxicity of bethanichol:
Side effects are related to GIT and urinary bladder.
Tightness of urinary bladder.
Transient complete heart block and hypotension.
Visual disturbance, headache and dyspnoea.
Nausea, vomiting and abdominal cramps.
Antidote: Atropine
Pillocarpine
Pharmacological actions:
1- Direct muscarinic agonist with very weak nicotinic effect.
2- Locally on the eye, miosis and spasm of accommodation and decrease IOP.
3- Potent stimulator of secretions: sweat, tears, and saliva.
Therapeutic uses:
1- Treatment of glaucoma.
2- Increase saliva secretion to treat the dry mouth.
Adverse effects:
Exaggerated parasympathetic stimulation.
Antidote: Atropine.

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 II- Indirect parasympathomimetics (Anti-cholinesterases)
Mechanism of action:
They produce their pharmacological actions by inhibiting the enzymatic hydrolysis of
ACh.
Classification
According to the reversibility, two different groups are known
I- Reversible Anticholinesterases:
These drugs are classified according to the duration of action into:
A- Long acting (about 2-8 hours), carbamate derivatives:
Physostigmine, neostigmine and pyridostigmine: they attach at both sites of the
enzyme, the anionic and esteratic sites.They inhibit (both true and pseudo ChE)
resulting in accumulation of the endogenous
Differences between physostigmine and neostigmine:
Differences Physostigmine Neostigmine
Nature Natural Tertiary ammonium Synthetic Quaternary ammonium
Kinetics 1- Well absorbed orally. 1- Irregular oral absorption.
2- Passes BBB. 2- Does not pass BBB.
3-Rapid metabolism by ChE. 3-Slow metabolism by ChE.
4- Short duration 4- Long duration.
Dynamics 1-Stimulate M&N receptors. 1- Stimulate M&N receptors.
2- Specific on eye. 2- Specific on GIT and UB.
3- CNS stimulant. 3- Direct Sk.M stimulant.
Uses 1- Eye drops: 1- Myasthenia gravis.
Glaucoma. 2- Curare poisoning.
b- To counteract mydriatics. 3- Paralytic lleus.
2- IV in atropine poisoning. 4- Urine retention
3- Alzheimer disease.
Toxicity 1- Exaggerated ACh-like 1- Exaggerated ACh-like action.
actions. 2- No convulsions in CNS.
2- CNS convulsions
Management 1- Atropine. 1- Atropine only.
2- Anticonvulsants.

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 Other carbamate esters
B- Short acting (10-20 minutes), non carbamate: (Edrophonium)
Its short duration of action is mainly due to its binding with ChE at the anionic site
only (weak and rapidly hydrolyzed bond).
II- Irreversible anti-cholinesterase's (Organ phosphorus compounds):
These agents bind covalently to the enzyme.
Many of these drugs are extremely toxic and were developed by military as nerve
toxic agents.
They are mostly used as: Insecticide(e.g.parathion).
Organ phosphorous poisoning:
Acute toxicity:
Causes:
1) Local exposure via contact with skin or inhalation.
2) Agricultural insecticides.
3) Intentionally suicide or homicide.
Symptoms:
1) Muscarinic effects: lacrimation, miosis, salivation, bradycardia, hypotension,
bronchospasm, excessive secretion, colic and diarrhea and urination.
2) Nicotinic effects: initial skeletal muscle twitches followed by paralysis.
3) CNS: convulsions followed by coma and death.
Cause of death is respiratory failure due to peripheral and central mechanisms.
Treatment:
1) Atropine is the lifesaving drug.
2) Removal the toxic agent by
A) Gastric lavage if taken orally.
B) Clean the skin from the toxic agent.
3) Respiratory supports.
4) Fresh blood transfusion.
5) Reactivation of acetylcholinesterase (Oximes): as rapidly as possible. Example
Pralidoxime (PAM) and Diacetylmonoxime (DAM).

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 Parasympatholytics (Cholinergic Antagonists)
Definition:
These drugs are cholinergic blocking agent that blocks the actions of Ach
Atropine
Mechanism of action:
It blocks selectively by competition the muscarinic receptors (M1, M2 and M3).
Therapeutic uses:
1- In preanesthetic medication: Decrease salivary and bronchial secretions.
2- In ophthalmology: fundus examination
1- In GIT:Reduce the gastric acidity. Reduce intestinal motility (antispasmodic).
2- Antidote in organophosphorus compounds toxicity.
Contraindications:
1- Fevers. 2- Glaucoma.
3- Tachycardia. 4- Constipation and paralytic ileus.
Atropine Poisoning
Symptoms:
1- Dryness of mouth, very difficult talking and swallowing.
2- Hot dry skin and increased body temp.
3- Disturbance in vision (passive mydrasis + cyclopelgia).
4- Weak pulse and rapid palpitation.
5- Difficulty in micturation.
6- Abdominal distension.
7- Restlessness, excitement and confusion, disorientation and hallucination.
8- In severe cases circulatory and respiratory failure and death.
Treatment:
1- Stomach lavage.
2- Physostigmine I.V. can be repeated if required.
3- Symptomatic treatment:
a) If marked excitement → diazepam is used.
b) Artificial respiration.
c) Ice bag.
d) Dark room to avoid marked photophopia.

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 Sympathetic Nervous System (Adrenergic Nervous System)
Definition
It is the system in which NEP is the main chemical mediator.
NEP:
It is a chemical mediator at all the postganglionic fibers of sympathetic nerves except
sweat glands.
EP:
It is the emergency hormone secreted from the adrenal medulla.
Adrenergic drugs
Definition:
These are drugs that affect the adrenergic nervous system.
Classification:
These drugs are classified according to their main effects into:
1- Sympathomimeties "adrenergic agonist"
2- Sympatholytics "adrenergic antagonist"
Sympathomimetics
Definition:
These drugs produce an effect similar to the adrenergic nerve stimulation
Classification:
These drugs are classified according to the chemical structure into:
1-Catecholamine "contain catechol nucleus" NEP, EP, dopamine and dobutamine.
2-Non catecholamines "with no catechol nuclus" Ex.ephedrine, amphetamines …etc.
Adrenergic receptors:
Two main types of adrenergic receptors are known:
A- Alpha (α) adrenergic receptors:
1- Alpha 1 (excitatory except that of GIT)
2-Alpha 2 (inhibitory as its stimulation decreases NEP release).
B- Beta (β) adrenergic receptors:
1- Beta 1 ,β1(on the heart and it is an excitatory receptors)
2- Beta 2 ,β2 ( inhibitory receptors)

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 Adrenergic agonists
Definition:
They are drugs give an action like adrenaline& nor adrenaline.
Classification:
These agents can be classified according to their mechanism of action into
A- Direct-acting agonists:
These drugs act directly on α or β receptors and produce effects similar to those occur
following stimulation of sympathetic nerves.
Examples:
1- Epinephrine.
2- Norepinephrine.
3- Isoproterenol.
4- Phenylephrine.
B- Indirectly acting sympathomimetics:
They are taken up into the nerve end and cause the release of the sympathetic
neurotransmitter from the nerve terminals
e.g. Amphetamine.
C- Mixed-action agonists:
These agents act by both mechanisms:
e.g. Ephedrine.
1- Epinephrine (Adrenaline)
It is the catecholamine which is present in higher concentration in the adrenal
medulla (80%-85%). It acts on both types of adrenergic receptors
Pharmacokinetics:
Not given orally due to:
1- Poor absorption from the GIT. 2- Rapid destruction by intestinal juices.
Administration
It must be stored in dark glass ampoules because if exposed to light it is oxidized to a
very toxic compound, adrenochrome.
It is used by the following routes:
1- S.C. producing local vasoconstriction leading to slow absorption.
2- Inhalation in bronchial asthma.

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Therapeutic uses (5 different uses)
1-Subcutaneous injection with local anesthetics: decreases their absorption and
decreases their systemic toxicity.
2-Hemostatic: in epostaxis.
3-Cardiac arrest (intracardiac injection).
-4Acute bronchial asthma (emergency conditions only).
5-Allergy: urticaria and anaphylactic shock.
Contraindications (3 different contraindications)
1) Coronary diseases.
2) Hyperthyroidism.
3) Hypertension.
Adverse effects and toxicity:
Alpha effects:
Hypertension, may cause cerebral hemorrhage.
Beta effects:
Tachycardia, palpitation and angina.
Cardiac arrhythmia.
2. Norepinephrine (Noradrenaline)
Therapeutic uses:
Therapeutically it is used in:
1- Acute hypotension (IV).
2- Treat shock due to increase blood pressure,
Contraindications:
Similar to those of epinephrine
Isoproterenol (Isoprenaline)
Therapeutic Uses:
Heart block
Rarely used in acute bronchial asthma.
Adverse effects: Similar to those of epinephrine especially the beta effects:
tachycardia, palpitation, angina and arrhythmia. Also, tremors can occur.
Contraindications: Similar to those of epinephrine: coronary heart disease and
thyrotoxicosis.

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 Dobutamine
It is a selective β1- agonist.
Therapeutic uses:
Heart failure and heart block.
Selective beta 2 agonists (Salbutamol)
Given mainly by inhalation as bronchodilator to control acute symptoms of bronchial
asthma.
Indirect-Acting Agonists:(Amphetamine)
Properties:
-It is non-catecholamine.
- Administered orally
- Passes BBB producing central effects.
- It elevates blood pressure.
- Its CNS effects have led to its use in therapy of depression, narcolepsy, and appetite
control.
Mixed-Action Agonists (Ephedrine )
Therapeutic uses:
1- As analeptic in toxicity with CNS depressants.
2- Mydriatic eye drops.
3- Nasal decongestant.
4- Prophylaxis in bronchial asthma.
5- Hypotension; may be used before spinal anaesthesia.
Adverse effects :
1- CNS: insomnia, anxiety, tremors and convulsions.
2- CVS: hypertension, tachycardia, palpitation, and arrhythmia.
3- Urinary retention

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 Sympatholytics Adrenergic Antagonists
Definition:
They are drugs that block the effects of NEP and other adrenergic agonists.
Classification:
They are classified according to their site of antagonism into
I- Adrenergic receptor blockers:-
They act at the receptors of the effect organs:-
According to the types of adrenergic receptors they are classified into.
Alpha adrenergic blocking " ά - blockers "
Beta adrenergic blocking " β - blockers "
Mixed alpha and beta blockers.
II- Adrenergic neuron blockers:-
They act on adrenergic nerve end.
They inhibit the biosynthesis, storage and/or the release of the adrenergic chemical
transmitter.
Adrenergic receptor blockers
A- Alpha Adrenergic Blockers (α- Blockers )
Classification:
Alpha adrenergic blockers may classify according to:
I- Reversibility of binding:
A- Irreversible alpha blockers: bind covalently to α receptors e.g.
phenoxybenzamine.
B- Reversible alpha blockers: bind reversibly to α receptors phentolmine, tolazoline and
prazosin
Phenoxybenzamine.
A- It decreases the BP.
B- The pressor effects of EP are reversed by this drug.
C- It results in reflexed tachycardia in response of its peripheral vasodilatation
and hypotension.
Therapeutic uses :
Treatment of pheochromocytoma, a catecholamine-releasing tumor of the adrenal
medulla.

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Prazosin
It decreases the peripheral vascular resistance and lower arterial blood pressure by
causing relaxation of both arterial and venous smooth muscles.
Therapeutic uses :-
1- Control of acute hypertension.
2- Treatment of begnin prostatic hyperplasia (BPH)
Beta adrenergic Antagonists ( β- Blockers)
-These drugs inhibit the effects mediated by epinephrine on the β adrenergic
receptors .
Classification:
These blockers are classified according to their selectivity to block only one or both β
1 and β 2 receptors. (Non-selective and selective β blockers).
Non selective beta adrenergic blocker (Propranolol)
It is taken as a prototype of non-selective beta adrenergic blockers.
Therapeutic uses:-
1-Treatment of hypertension. 2- Prophylaxis in cases of angina pectoris.
Adverse effects:-
Heart failure, Because propranolol blocks β2-receptors.
It must be used with caution in asthmatics because it may cause bronchospasm.
Other non-selesctive β-blockers(Timolol)
Timolol reduces the production of aqueous humor, so it is used in glaucoma.
Selectiv β1-blockers (Cardio-selective) Atenolol and Metoprolol
-They are used for the treatment of cardiac disorders and hypertension in patients
with bronchial asthma and diabetes mellitus.
Drugs that Reduce Central Sympathetic Outflow:
Clonidine (catapress)
Clonidine activate α2- adrenergic It is mainly used as antihypertensive agent.
Methyldopa (aldomet)
α methyl NEP is also stimulate α2adrenergic receptors. It is mainly used as
antihypertensive agent especially in pregnancy as it is safe on fetus .

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 Drugs acting on the cardiovascular system (CVS) Diuretics
Diuretics are drugs that increase:
A- The rate of urine flow. B- Sodium excretion.
Classification of diuretics
Loop diuretics.
Thiazide diuretics
Potassium sparing diuretics.
Osmotic diuretics.
Other classification based on their efficacy:
1- High efficacy:
e.g Loop diuretics … they are the most powerful diuretics
2- Moderate efficacy:
e.g thiazide …. Have moderate diuretic activity.
3- Low efficacy:
e.g Potassium sparing diuretics and osmotic diuresis… have low diuretic activity.
Loop diuretics
Examples:
A) Furosemide.
B) Ethacrynic acid.
Mechanism of diuretic action:
Inhibition of sodium-potassium-chloride co transport mechanism in thick ascending
limb of loop of henel leading to sodium loss and water loss.
Pharmacological properties:
Highest efficacy as diuretics (high ceiling diuretics) with rapid onset and short
duration of action.
So, it is the diuretic of emergency.
Therapeutic uses:
1) Acute pulmonary edema.
2) Essential hypertension.
3) Edema of nephritic syndrome.
4) In patient with drug overdose to induce forced diuresis and rapid drug
elimination.

23
Side effects:
1) Hypokalemia.
2) Hyperglycemia.
3) Hyperuricemia.
4) Hyponatremia (excess sodium loss) and hypotension.
1- Thiazide diuretics
Examples:
A) Chlorothiazide.
B) Hydrochlorothiazide.
C) Chlorthalidone.
Mechanism of diuretic action:
Inhibition of sodium-chloride cotransportmehanism in distal renal tubules
increase sodium, chloride and water excretion.
Therapeutic uses:
1) Edema.
2) Hypertension.
Side effects:
1) Hypokalemia.
2) Hyperuricemia.
3) Hyperglycemia.
3- Potassium sparing diuretics
Examples:
A) Spironolactone which is aldosterone receptor antagonist.
B) Triametrine which is described as an inhibitor of renal epithelial sodium channels
in collecting tubules.
They both are weak diuretics.
Mechanism of action:
Spironolactone (aldoctone) is a compititive antagonist to aldosterone hormone at
aldosterone receptors.
Triametrine and amiloride inhibit active sodium reabsorption in the collecting tubules
causing increased sodium and cholride excretion.

24
Therapeutic uses:
Hypertension.
Heart failure.
Side effects:
Hyperkalemia .
Nausea and vomiting.
3- Osmotic diuretics
Examples :
Mannitol.
Mechanism of action :
Mannitol is an inert substance.
In renal tubules particularly proximal tubules and loop of henel( which are highly
permeable to water) it raises osmotic pressure relative to osmotic pressure in blood.
This causes withdrawal of fluids from blood to renal tubules to keep the balance in
osmotic pressure between blood and renal tubules.
Therapeutic uses:
1- Acute renal failure.
2- Cerebral edema and elevation of intracranial pressure.
3- Increase IOP in glucoma.

25
 Angina pectoris
Chest pain due to transient myocardial ischemia
Ischemia: imbalance between cardiac work (O2 need) and coronary flow (o2 supply)
Chest pain: sterna or retro sterna, compressing, stapping, radiating to lt arm,
shoulder, jaw
Mainly ppt by effort
Types
1- Effort, stable, classic, exertion
Commonest. Occur in exertion
Aet: atherosclerosis
2- Prinzmetal (variant, vasospastic. Atypical) angina
Occur at rest, ass with arrhyth
Aet: coronary V.C
3- Mixed
4- Un stable: occur at rest or mil exertion
Aet: coronary occlusion
Drug treatment
1- Nitrites & nitrates
2- Ca channel blockers
3- Beta- blockers, dipyridamol
4- Anti-thyroid drugs
Nitrites nitrates
In organic Na nitrite nitroglycerine
organic Amyl nitrite Isosorbid dinit
Useful in cyanide Erythrityl tetra N
poisoning
Therapeutic uses:
1- All types of angina
*Angina of effort (↓ cardiac work
↓o2 consumption)
*Variant angina: coronary V.D
*Mixed-unstable: ↓work, V.D

26
A-Acute attack of prophylaxis
Used before exercise and during stress
Sublingual (nitroglycerine- isosorbide)
B-Long term prophylactic treatment
To overcome extensive hepatic first pass metabolism
-T.D.S -ointment -patch
Advantage: 1- allow 8-10 hours
Nitrate free→avoid tolerance
2-Never stop therapy →avoid infarction
C- Add B.B in stable and unstable angina to avoid tachycardia
2-Acute M.I & acute pulm oedema
Nitroglycerine infusion→↓preload
↓pulm congestion
3-Biliarry colic
4-Bronchial asthma
5-Contraction ring of uterus
6-cyanide poisoning
Na nitrite I.V
Amyl nitrite inhalation
Others:
1- H.F
2- Hypertensive emergency
3- Diffuse esophageal spasm
S.E
1- Headache, flushing, ↑i.o.p
2-hypotension
Reflex symp stim→short diastolic perfusion of coronary
Addition of B.B or verapamil
3-hypersensitivity
4-tolerance: depletion of SH group
Avoided by: long term treatment
Alteration therapy with other Antianginal drug/2 WK

27
 5-dependence
Abrupt withdrawal→angina, infarction
6-met-haemoglobinemia
7-carcinogenic effect (nitrates+aminogroup)→nitrosamines
B- Adrenergic blocker
Effect:
1- reduce myocardial o2 req during exertion and stress
↓ H.R ↓ cardiac contractility
1- hypotension
Indication:
1- exertional angina
2- first line therapy in most patients with chronic angina
3- coronary dis -post myocardial infarction
N.B: B.B induce worsening of prinzemetal`s angina
(un opposed effects of catecholamines acting on alpha receptors →↑coronary
resistance
C.I:
bronchospasm – bradyarrhythmias- H.F
Drugs:
propranolol, nadolol, atenolol, metoprolol
Calcium channel blockers
Types:
1- receptor operated ca-channels
Site: excitable cells activated by changes in memb pot
Types
1- T ( transient)
2- N (neural)
3- L (long-lasting) slow inactivated
Only L-type is sensitive to ca-channel blockers
Classifications:
1- Hydropyridines( nifedipine, nicardipine, nimoldipine
2- Non- hydropyridines ( verapamil, dilitazem)

28
 Congestive heart failure
Defention
Heart is unable to pump sufficient blood to meet the needs of the body.
Aetiology
1. Atherosclerosis
2. Heart disease
3. Hypertension
4. Valvular heart disease
5. Congintal heart disease
6. Anemia
7. Thyrotoxicosis
Main clinical picture
1. Dyspnea
2. Rapid fatigability
3. Odema of lower limb
4. Congested pulsating neck veins
Treatment
1. Rest in bed
2. Salt restriction
3. Drug treatment
a. Vasodilator captopril
Enalapril
Sodium nitro prusside
b. Diuretics frosemide
Hydrochlorothiazide
c. Inotropics digitalis
Digoxin
d. Treatment of cause

29
 Cardiac glycosides
Specific and powerful stimulant action on myocardium
1. Positive inotropic effect (increase contraction )
2. Increase cardiac output (not accompany by increase oxygen consumpation )
3. Negative chronotropic effect slowing heart rate
4. Increase conductivity
5. Diuretic action
Therapeutic uses
1. Congestive heart failure
1. Decrese cardiac size
2. Decrease cardiac rate
3. Decrease venous pressure – congestion
4. Decrease dyspnea - cyanosis
5. Relief oedema
2.Atrial fibrillatin
Reduce ventricular rate
3.Atrial flutter
Toxicity
1. GIT: Anorexia, Nausea, Vomiting , Diarrhea
2. CNS: Yellow vision, Hallucinations , Delirium , Headache
3. Cardiac: Brabycardia, Heart block, Arrhythmia (ventiricular or atrial)
Treatment
1. Stop digitalis
2. Kcl orally or i.v When serum k is normal decrease binding of digitalis to
heart
3. Phenytoin : Decrease atrial + ventricular arrhythmia
4. Specific binding Ab (digibind )
Contraindication
1. Ventriculae tachycardia
2. Partial heart block
3. Recent myocardial infarcation

31
 Hypertension:
Normal blood pressure 120/80
Increase blood pressure above 140/90
Types: 1- Primary: idiopathic
2- Secondary: due to known cause
- Renal disease
- Toxemia of pregnancy
- Use of certain drugs

Classification
1- Mild: diastolic 95-105
2- Moderate 105-115
3- Severe 115
Antihypertensive drugs
Drugs used to normalize blood pressure
Classification
I- Diuretics
II- Depressants of sympathetic activity
A. Stimulation of α2 receptor centrally: Methyldopa and Clonidine
B. Blocking action of transmitter of receptor site
1- Beta-adrenergic blockers
Non selective: propranolol (B2-B1)
Selective: atenolol (B1)
2- Selective α1 adrenergic blockers prazosin
3- α and B blockers labetalol
C. Depressants of ganglionic transmission trimetaphan.
III- Direct vasodilators:-
1- Arteriodilators: Hydralazine and Diazoxide
2- Arterio and venodilator: Sodium nitroprusside
IV- Angiotensin converting enzyme inhibitors: Captopril, Enalapril, Lisinopril
V- Calcium channel blockers: Verapamil , Nifedipine, Diltiazem, Amoldipine

30
III- Direct vasodilators
A- Arterial dilators
1- Hydralazine:
Indications: Moderate to severe hypertension
Side Effects: 1- Headache - Palpitations – Sweating – Nqusea.
2- Salt and water retention
3- Reflex tachycardia → Provocation of angina attacks and ischemic heart disease
4- Lupus – Erythgematosus like syndrome
It should combined with → Diuretics and Beta – blocker
To avoid 1) Salt –water retention and 2) Reflex symp
2- Minoxidil:-
1- Used orally in severe hypertension more efficacy than hydralazine .
2- Topical use to stimulate hair growth .
Side effects:
1) Reflex sympathetic stimulation.
2) Sodium – water relention
3) Hypertrichosis
3- Diazoxide:
Used by rapid I.V injection in: - Hypertensive emergency
- Hyperinsulinomas
Side effects:
1- Severe hypotension → shock – myocardial infarction.
2- Reflex sympathetic stimulation.
3- Hyperglycemia (due to inhibition of insulin release)
2- Arterial and venous vasodilators
Sodium nitroprusside
Indications:
- Hypertensive emergency
- Provide controlled hypotension during anesthesia used by I.V infusion kept in dark bottles
Side effects:
1- Severe hypotension 2- Cardiac dysrhythmia.
3- Acidosis. 4- Tubular necrosis.

32
IV- Calcium channel blockers
Verapamail , Diltiazem , Nifedipine used orally
Indications
1- Treatment of hpertension
2- Cardiac arrhythmia.
3- Angina pectoris
Advantage:
Safe in patient with : - Diabetes mellitus - Renal dysfunction
Side effects:
1- Dizziness hypotension flushing.
2- Pedal edema – cough.
3- Bradycardia after I.V use
Contra - indications
1- A.V block.
2- Heart failure
Angiotensin converting enzyme inhibitors (ACEIs)
Captopril
Enalapril
1- Orally effective.
2- Refractory hypertension
Side effects:
1- Dry cough
2- Severe hypotension
3- Hyperkalemia.
4- Skin rash
5- Renal insufficiency
Angiotensim II Receptor antagonists
e.g losartan
advantage: not cause dry cough or edema.

33
 Antidysrhythmic Drugs
Definition
Drugs suppress abnormalities of cardiac rhythm and conduction by blocking ion
channels or altering autonomic functions
Classifications
1- Class I: sodium channel blockade
A: quindine
Procainamide
B: lidocaine
Phenytoin
C: propafenone
Flecainide
2- Class II: beta adrenergic blockers ( propranolol, atenolol, timolol)
3- Class III: K channel blockers
Amiodarone
Sotalol
4- Ca channel blockers
Verapamil
Dilitiazem
Class IA
1- Qunidine:
Direct cardiac depressants
Therapeutic uses
1- Supra ventricular dysrhythmia
Paroxysmal supra-ventricular tachycardia
Atrial flutter-fibrillation
2- Ventricular dysrhythmia
Side effects
1- Cardiac toxicity
A-V block
↓ Myocardial contractility→ Qunidine syncope

34
 2- GIT: nausea- vomiting- diarrhea
3- Cinchonism: tinnitus- hearing loss-vomiting-diarrhoea- severe headache,
diplopia, photophobia, confusion, psychosis
4- Hypersensitivity: fever-rash-thrombocytopenia-hepatic dysfunction
5- Hypotension
Class B:
Lidocaine: local anesthetic, anti-arrhythmic
Used by i.v injection in
1- Myocardial infarction
2- Digitalis intoxication
3- Open heart surgery
Side effects:
Parasthesia, dizziness, convulsions, respiratory failure, decrease hearing
3- Phenytoin
Used in * acute- chronic suppression of ventricular dysrhythmias
* Tachycardia due to digitalis toxicity
Side effects:
1- CNS: Drowsiness, vertigo, nystagmus, ataxia
2- Gingival hyperplasia
3- Megaloblastic anemia
4- Nausea-vomiting
5- Lupus like syndrome
Class C:
Propafenone
Orally used
Uses
1- Paroxysmal supraventricular tachycardia
2- atrial flutter-fibrillation
Class ii: b adrenergic blockers
Class iii: potassium channel blocker
1- Sotalol
Uses: ventricular tachycardia

35
 Side effects: as b- blockers
2- Bretylium
Uses: resistant ventricular dysrhythmia
Complicating
- Myocardial infarction
- Cardiac surgery
- Resistant cases to other drugs
Side effects:
Postural hypotension
3- Amiloride:
Uses: resuscitation from ventricular fibrillation
Cardioversion failure
Side effects
1- Reversible pulmonary fibrosis
2- Bradycardia, A-V block
3- Photosensitivity
4- Corneal deposits
5- Hyper or hypothyroidism
6- Hepatic injury
Class: ca channel blockers
Uses: 1) paroxysomal supraventricullar tachycardia
2) Atrial flutter+ fibrillation
Anticoagulants
Drug preventing blood coagulagtion
1. Parenteral; heparin
2. Oral : warfarin
Heparin
Rapid anticoagulant effect (within minutes )
Administration
Rapid i.v - s.c (subcutaneous)
Therapeutic uses
1. Deep venous thrombosis

36
 2. Pulmonary embolism
3. Prophylactic use to prevent post-operative thrombosis
4. Acute myocardial infarction
5. Dialysis mechanism
6. Patient with prosthetic valves
Side effect
1. Bleeding complication (need monitoring of bleeding time )
2. Hypersensitivity : fever ,urtcaria
3. Thrombocytopenia (decrease number of platlet )
Warfarin
Rapid oral absorption
Side effect
1. Bleeding disorder
2. Drug interaction
Not use during pregnancy because it is
Tetratogenic
Haemorrhage due to
Heparin :antagonized by protamine sulphate
Warfarin blood transfusin
Frozen plasma
Vitamin k
Agent used in treatment of anemia
A) Iron deficiency anemia (microcytichypochromic )
Requirments of iron : 5-10 mg in food
Prepration
 Oral ferrous sulphate, Ferrous gluconate, ferrous fumarate
shouldgiven after meals and shouldcontinues 3-6 months
side effect
1. git irritation
2. abdominal colic
3. constipation
parenteral : iron dextran (imferon ), iron sorbitol – citric acid complex

37
side effect
 pain at site of injection
 skin discolouration
 local inflammation
4. systemic toxic effect
headache -malasia -muscle and joint pain
Brocho spasm -hypotensin
convulsion -alleragy
In casec of iron toxicity : Treatment is carried out by
1. Gasricleavage
2. i.v fluid to treat collapse and dehydration
3. sodium biocarbonate
4. barbiturates :to treat convulsin
5. iron cleating agent (desferrioxamine )
B. MEGALOBLASTIC ANEMIA
Failure of stomch to secrete the intrinsic factor which is required for the absorption
of cyanocobalamine (vit b12)
Characters
1. macrocytic hyperchromicanaemia
2. glossitis
3. diarrhea
4. peripheral neuritis
5. ataxia
preparation andadminstration
1. cyanocobalamine injection
2. vit b12 with intrinsic factor oralprepration (capsule or tablet )
3. hydroxocobalamine
c- folic acid deficiency anemia
treatment folic acid 10-20mg \ day orally

38
 Drug therapy of bronchial asthma
Bronchial asthma is a chronic inflammatory disorder of the airways characterized
clinically by difficulty in expiration (expiratory dyspnea). It occurs in the form of
recurrent attacks of wheezing, chest tightness, and cough.
The strongest predisposing factor for the development of asthma is atopy (allergy).
When the sensitive patient is exposed to certain allergens e.g. by inhalation, and
sometimes drugs like aspirin, the airway inflammation and symptoms of airway
obstruction appear.
Antiasthmatic drugs can be classified as follows:
1- Selective β2-adrenergic agonists
2- Anticholinergic drugs
3- Phosphodiesterase inhibitors (Methylxanthines)
4- Antiinflammatory which include:
a) Cromolyn sodium
b) Corticosteroids
c) Leukotriene antagonists
1- Selective β2-adrenergic agonists:
They are classified into:
Short acting: e.g. Salbutamol (albuterol) and terbutaline:
 These drugs stimulate 2 adrenergic receptors in the bronchi leading to
bronchodilatation.
 They can be given by inhalation and orally.
 They have rapid onset and short duration of action (3-6 hours).
Therefore, they are the preferred treatment for rapid symptomatic relief of dyspnea
associated with asthmatic bronchoconstriction
b) Long acting: e.g. salmeterol and formoterol:
 They are similar in action to short acting group on bronchi, but their
broncodilator effect has a slow onset and longer duration of action (up to 12
hours).
 They are indicated as a maintenance treatment of asthma but not for acute
cases and they are given usually by inhalation.
2- Anticholinergic drugs:

39
 Example is ipratropium bromide which is a derivative of atropine, but free of
atropine side effects.
 Mechanism of action: it reverses vagal (cholinergic)-mediated bronchospasm in
patients with chronic bronchitis or emphysema where cholinergic tone is high.
 The drug is given by inhalation usually in asthmatic patients intolerant to β2
adrenergic agonists and in β-blockers induced bronchospasm.
3- Phosphodiesterase inhibitors (Methylxanthines)
 Example is theophylline.
 Mechanism of action:
Adenyl cyclase Phosphodiesterase
ATP  cyclic AMP  AMP

Inhibition of phosphodiesterase enzymein bronchial smooth muscle membrane by

theophylline leads to accumulation of cyclic adenosine monophosphate (cAMP)
which causes bronchodilatation.
 Side effects are dose related. In therapeutic dose, theophylline causes gastro-
intestinal discomforts, insomnia, and palpitation. At higher doses it may cause
seizures, hypotension and arrhythmia that may be fatal especially if the drug in
given i.v. in a rapid way. So, theophylline administration i.v. should be given
slowly.
 Therapeutic uses: 1- Moderate and severe asthma. Sustained release theophylline
preparations are effective in controlling nocturnal asthma.
2- Premature infants with prolonged apnea to guard against occurrence of hypoxia
and neurological damage in infant.
4- Antiinflammatory:
a) Cromolyn sodium:
 It is a prophylactic treatment given in between attacks but not during an attack
 Mechanism of action: stabilization of bronchial mast cell on exposure to allergens
preventing their destruction and release of their bronchoconstrictor chemical
mediators (e.g. histamine, bradykinin and slow reacting substances of
anaphylaxis)that cause bronchoconstriction

41
 They are given by inhalation and also as nasal spray in treatment of allergic
rhinitis, and topically as eye drops in treatment of allergic conjunctivitis.
b) Corticosteroids:
* Mechanism of action:
1- Inhibition of the formation of cytokines like interleukins which are secreted in
asthma by T-lymphocytes, macrophages and mast cells.
2- Decrease eosinophil cells related to allergy
3- Inhibition of expression of multiple inflammatory genes in airway epithelial
cells.
4- Decrease vascular and airway edema
5- Inhibition of mucus secretion from airway submucosal glands
* Corticosteroids may be given by inhalation or systemically according to severity of
asthma..
* Inhaled corticosteroids:
(i) They are preferred as first line agents for patients with persistent asthma
chronic asthma.
iii) Maximum response from inhaled corticosteroids takes time.
(iv) Oropharyngeal side effects such as candidiasis are common at higher
doses of inhaled corticosteroids. These side effects can be minimized if the
patient uses a large volume spacer device and washes his mouth with
water after inhalation. Hoarseness of voice may be another side effect from
continued inhalation procedure of the drug.
 Systemic corticosteroids (oral or parenteral):
(i) Oral corticosteroids (e.g. prednisone) should only be used if symptom
control cannot be achieved with maximum doses of inhaled bronchodilators
including inhaled corticosteroids.
(ii) Once the patient has improved, it is preferred to reduce the dose of the
drug gradually for discontinuance within 1-2 weeks.
(iii) Different side effects related to systemic prolonged use of steroids are
expected like osteoporosis, gastritis, edema, etc...
c) Leukotriene antagonists:

40
* Leukotrienes are biochemical mediators that are produced by mast cells, basophils,
eosinophils and neutrophils to cause asthma.
* Zafirlukast & montelukast: are drugs that selectively and reversibly inhibit
leukotriene receptors blocking their allergic effect on bronchi. They are used as a
prophylactic treatment in mild asthma. especially in aspirin-induced asthma.
* Side effects may be elevation of liver enzymes
Anticough drugs
 Cough is a reflex action that serves to clear the respiratory passages of foreign
material and excess secretions.
 Antitussives: drugs used to stop or reduce dry (nonproductive) coughs. They
include the following:

a) Opiates: They inhibit cough center centrally. e..g. codeine and pholcodine
Side effects include sedation, constipation and tendency to tolerance and addiction
with prolonged use of codeine.
b) Dextromethorphan: It may also antagonize opioid receptors. Although it is
included in many over the-counter cough suppressants but it is poorly effective in
treating cough.
Hallucinations at higher doses and abuse potential have been recorded with the drug
Expectorants
These are drugs that aid in the removal of mucus and reduce the viscosity of
secretions. Guaifenesin is recognized as safe and effective expectorant.

42
 Peptic ulcer

Peptic ulcer occurs when there is an imbalance between the damaging effects of
gastric acid and pepsin, and the defense mechanisms, which protect the gastric and
duodenal mucosa from these substances (Fig. 1). A major cause of peptic ulcer is use
of NSAIDs, particularly in the elderly. Smoking is a major environmental factor and
patients who smoke should be advised to stop.
Treatment of peptic ulceration has based on to neutralize gastric acid, to inhibit its
secretion, or to enhance mucosal defenses. More recently, recognition of the
important role of H. pylori has revolutionized treatment.

Fig.1 Factors involved in maintaining acid balance

ACID SECRETION BYTHE STOMACH

Gastric acid is secreted by the parietal cells in gastric mucosa. The basolateral
membranes of these cells contain receptors for the three main stimulants of acid
secretion, namely gastrin, histamine and acetylcholine. In contrast, receptor binding
of prostaglandin E2 and somatostatin diminish gastric acid production. Gastrin and
acetylcholine act by inducing an increase in intracellular calcium levels. Histamine
binding causes activation of adenylyl cyclase, whereas binding of prostaglandin E2
inhibits this enzyme (Figure.2).

43
 Figure .2 Effects of acetylcholine, histamine, prostaglandin E2, & gastrin on gastric
acid secretion by the parietal cells of stomach.

INHIBITION AND NEUTRALISATION OF GASTRIC ACID

I-Proton pump inhibitors (PPIs)
Example: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.
Mode of action: Omeprazole is a prodrug, in common with all PPIs. It enters the
parietal cell from the blood by nonionic diffusion but becomes ionized in the acid
midia. In this form it is a highly reactive species which binds to sulphydryl groups on
Na+/K+ ATPase. This irreversibly inactivates the enzyme causing profound
inhibition of acid secretion: a single 20 mg dose reduces gastric acid output by 90%
over 24 h. Omeprazole is degraded at low pH and must be given in enteric coated
tablets.
Therapeutic uses:
 The superiority of the PPIs over the H2 antagonists for suppressing acid
production and healing peptic ulcers has made them the preferred drugs for
treating erosive esophagitis and active duodenal ulcer and Zollinger-Ellison
syndrome.
 They are approved for the treatment of GERD. They are also successfully used
with antimicrobial regimens to eradicate H. pylori.

44
 For maximum effect, PPIs should be taken 30 minutes before breakfast or the
largest meal of the day.
 If an H2-receptor antagonist is also needed, it should be taken after the PPI for
best effect. The H2 antagonists will reduce the activity of the proton pump, and
PPIs require active pumps to be effective.
Adverse effects
 Nausea, headache, diarrhea, constipation and rash but are uncommon.
 Omeprazole inhibits cytochrome P450 system, decreasing the metabolism of
warfarin, diazepam, carbamazepine and phenytoin.
 In animal studies, the incidence of gastric carcinoid tumors increased, possibly
related to the effects of prolonged hypochlorhydria and secondary
hypergastrinemia. However, this has not been found in humans.
 Other side effects relate to reduced absorption of vitamin B12 and increased
susceptibility to GIT infections as a result of prolonged hypochlorhydria.
II-H2 receptor antagonists
Example: cimetidine, ranitidine, famotidine, nizatidine
Therapeutic uses:
 Peptic ulcers: these agents are equally effective in promoting healing of duodenal
and gastric ulcers.
 Acute stress ulcers.
 Gastroesophageal reflux disease.
Adverse effects:
 The most common side effects are headache, dizziness, diarrhea and muscular
pain. CNS effects (confusion, hallucinations) occur primarily in elderly patients.
 Cimetidine can also have endocrine effects, because it acts as antiandrogen
increase prolactin level; gynecomastia, impotence (Male) and galactorrhea,
infertility (Female).
 Cimetidine inhibits CYP 450 and there is potential for increased effect of some
drugs e.g. warfarin, phenytoin, lidocaine, propranolol and theophylline.
III- Antimuscarinic drugs, e.g. pirenzepine and telenzepine, formerly widely used
to suppress acid secretion, are now obsolete.

45
IV-Antacids
Antacids are basic substances that reduce gastric acidity by neutralizing HCL.
Antacids are salts of AL3 and Mg2, e.g, Al(OH)3 and Mg(OH)2, either alone or in
combination.
They are taken intermittently when symptoms occur. Side effects and inconvenience
limit their use as ulcer healing agents.
Magnesium oxide and hydroxide react quickly with gastric HCL, it cause diarrhea,
as do all magnesium salts (which are also used as purgatives).
Aluminium hydroxide reacts with HCL to form aluminium chloride. It tends to
produce constipation. Sufficient aluminum may be absorbed from the intestine to
create a risk of encephalopathy in patients with chronic renal failure.
Sodium bicarbonate reacts with acid and relieves pain within minutes. It is absorbed
and causes alkalosis which in short-term use may not cause symptoms. Sodium
bicarbonate can release enough CO2 in the stomach to cause discomfort and
flatulence. Excess sodium intake may be undesirable in patients with cardiac or renal
disease.
ENHANCING MUCOSAL RESISTANCE
Drugs can increase mucosal resistance by:
• Protecting the base of a peptic ulcer (bismuth compound, sucralfate)
• Cytoprotection (misoprostol).
I-Bismuth compounds:
These compounds effectively heal peptic ulcers. In addition to their antimicrobial
actions, they inhibit the activity of pepsin, increase secretion of mucus, and interact
with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater.
Bismuth agents should be used for only short periods and should be avoided in
patients with renal insufficiency. Prolonged usage of bismuth compounds may rarely
lead to bismuth toxicity resulting in encephalopathy.
II-Sucralfate
This complex of aluminum hydroxide and sulfated sucrose binds to positively
charged groups in proteins of both normal and necrotic mucosa. By forming complex
gels with epithelial cells, sucralfate creates a physical barrier that impairs diffusion of
HCL and prevents degradation of mucus by pepsin and acid. It also stimulates

46
prostaglandin release as well as mucus and bicarbonate output, and it inhibits peptic
digestion. Because it requires acidic pH for activation, sucralfate should not be
administered with H2-antagonists or antacids.
III-Misoprostol
Misoprostol is a synthetic analogue of prostaglandin E1 which protects against the
formation of gastric and duodenal ulcers in patients who are taking NSAIDs.
Adverse effects: Diarrhea and abdominal pain. Like other prostaglandins, misoprostol
produces uterine contractions and is contraindicated during pregnancy.
TREATMENT OF HELICOBACTER PYLORI INFECTION
Successful eradication of Helicobacter pylori infection usually results in long-term
remission of the ulcer. The organism is sensitive to metronidazole, amoxicillin,
clarithromycin, tetracycline and bismuth salts. Currently, either triple therapy
consisting of a PPI with either metronidazole or amoxicillin plus clarithromycin, or
quadruple therapy of bismuth subsalicylate and metronidazole plus tetracycline plus a
PPI, are administered for a 2-week course. Treatment with a single antimicrobial drug
is less effective, results in antimicrobial resistance and is absolutely not
recommended.
PROKINETIC AGENTS
1-Cholinomimetic Agents
Bethanechol stimulates M3 receptors on muscle cells. Bethanechol was used in the
treatment of GERD and gastroparesis. Due to multiple cholinergic side effects and
the advent of newer agents, it is seldom used now.
The acetylcholinesterase inhibitor neostigmine can enhance gastric, small intestine,
and colonic emptying. Intravenous neostigmine has used in clinical for the treatment
of hospitalized patients with acute large bowel distention.
2. Metoclopramide, Domperidone and Cisapride
Clinical Uses
 Gastroesophageal Reflux Disease(GERD).
 Impaired Gastric Emptying.
 Nonulcer Dyspepsia.
 Prevention of Vomiting: metoclopramide and domperidone are used for the
prevention and treatment of emesis.

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Adverse Effects
 The most common adverse effects of metoclopramide involve the CNS including
drowsiness, insomnia, anxiety, and agitation especially the elderly.
Extrapyramidal effects (parkinsonian features) due to central dopamine receptor
blockade.
 Elevated prolactin levels (caused by both metoclopramide and domperidone) can
cause galactorrhea, gynecomastia, impotence,and menstrual disorders.
 Domperidone is well tolerated. It does not cross the BBB, neuropsychiatric and
extrapyramidal side effects are rare.
 Cisapride was removed from the United States market due to cardiac arrhythmias.
3. Macrolides
Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on
GIT smooth muscle. Intravenous erythromycin is beneficial in some patients with
gastroparesis; however, tolerance rapidly develops.
ANTIEMETIC DRUGS
Antiemetics represent a variety of classes (Figure.3).
Antimuscarinic drugs, e.g , scopolamine and H1-receptor antagonists, e.g, meclizine,
and cyclizine, are very useful in motion sickness but are ineffective against
substances that act directly on the CTZ.
1-Phenothiazines: The first group of drugs shown to be effective antiemetic agents,
e.g, Prochlorperazine, they act by blocking dopamine receptors. Side effects:
hypotension, restlessness, sedation and extrapyramidal symptoms.
2-5-HT3 receptor blockers: ondansetron, granisetron, palonosetron & dolasetron.
This class is important in treating emesis due to chemotherapy. They selectively
block 5-HT3 receptors in the periphery and in the brain (CTZ).
3- Metoclopramide: It acts by blocking dopaminergic receptors. Antidopaminergic
side effects; sedation, diarrhea and extrapyramidal symptoms, limit its high-dose use.
Hyperprolactinemia may occur.
4. Butyrophenones: Droperidol and haloperidol act by blocking dopamine receptors.
Droperidol had been used most often for sedation in endoscopy and surgery, usually
in combination with opiates or benzodiazepines.

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5. Corticosteroids: Dexamethasone, is effective against mildly to moderately
emetogenic chemotherapy. Their antiemetic mechanism is not known.
6. Cannabinoids: Marijuana derivatives, including dronabinol and nabilone, are
effective against moderately emetogenic chemotherapy.
7. Substance P/neurokinin-1 receptor blocker: Aprepitant belongs to a new family
of antiemetic agents. Constipation and fatigue appear are major side effects.
ANTIDIARRHEALS
1. Antimotility agents
Two drugs that are widely used to control diarrhea are diphenoxylate and loperamide.
They have opioid-like actions on the gut inhibit acetylcholine release and decrease
peristalsis. Side effects include drowsiness, abdominal cramps, and dizziness.
Because these drugs can contribute to toxic megacolon, they should not be used in
young children or in patients with severe colitis.
2. Adsorbents
Adsorbent agents, such as kaolin and pectin that appear to act as absorbents of
bacteria, toxins, and fluid, thereby decreasing stool liquidity and number.
3. Agents that modify fluid and electrolyte transport
Bismuth subsalicylate, used for traveler's diarrhea, decreases fluid secretion in the
bowel.
Bile Salt Binding Resins
The bile salt binding resins cholestyramine or colestipol may decrease diarrhea
caused by excess fecal bile acids. Side effects include flatulence, constipation and
exacerbation of fat malabsorption.
LAXATIVES
They are medicines that promote defecation and are classified as follows:
A. Irritants (stimulants) laxative
 Senna is a widely used stimulant laxative. Taken orally, it causes evacuation of
the bowels within 8 to 10 hours.
 Bisacodyl, available as suppositories and enteric-coated tablets, is a potent
stimulant of the colon. It acts directly on nerve fibers in the mucosa of the colon.
 Sodium picosulphate is similar and is also used to evacuate the bowel for
investigative procedures and surgery.

49
 Castor oil is broken down in the small intestine to ricinoleic acid, which is very
irritating to the gut, and promptly increases peristalsis.
Adverse effects include abdominal cramps and the potential for atonic colon with
prolonged use. These drugs should used only with caution in pregnancy, and never
where intestinal obstruction is suspected.
B. Stool softeners
These include docusate sodium, docusate calcium, and docusate potassium. They
soften faeces and allow more water to remain in the faeces.
C. Osmotic laxatives
 Saline laxatives, such as magnesium citrate, magnesium sulfate, sodium
phosphate, and magnesium hydroxide.
 Lactulose is a semisynthetic disaccharide sugar that also acts as an osmotic
laxative. Oral doses are degraded in the colon by colonic bacteria into lactic,
formic, and acetic acids. This increases osmotic pressure, thereby accumulating
fluid, distending the colon and causing defecation.
 Electrolyte solutions containing polyethylene glycol (PEG) are used as colonic
lavage solutions to prepare the gut for radiologic or endoscopic procedures.
D. Bulk laxatives
The bulk laxatives include hydrophilic colloids (from indigestible parts of fruits
and vegetables). They form gels in the large intestine, causing water retention and
intestinal distension, thereby increasing peristaltic activity. Similar actions are
produced by methylcellulose, psyllium seeds, and bran.
They should be used cautiously in patients who are bed-bound, due to the
potential for intestinal obstruction.
E. Lubricant laxatives
 Mineral oil and glycerin suppositories are considered to be lubricants. They
facilitate the passage of hard stools.

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