CHAPTER

AUTACOIDS AND THEIR

ANTAGONISTS

LEARNING OBJECTIVES
After the completion of this chapter, you should be able to explain the
following concepts:
Synthesis, metabolism and pharmacolgical effects of histamines

Classification of antihistamines 5-HT

receptors and
pharmacological actions of serotonin Drug acting on
5-HT system Biosynthesis of prostaglandins,
thromboxanes and leukotrienes Pathophysiological
role and pharmacological effects of PAF.
8

0092

SAS
WASS

1. INTRODUCTION
The term autacoid or autocoid is derived from Greek
words autos meaning self and akos meaning remedy or
self healing substance.
Autacoids are a group of diverse substances which are produced by
a wide variety of cells in the body. They are 'involved in a wide
variety of physiological as well as pathological processes and also
serve as neurotransmitters.
Autacoids are also called as local hormones. However, unlike
hormones which are secreted by the glands, autacoids are secreted
from special cells (endothelial cells or tissues) and are transported
through the circulatory system to act either locally (at the site of
synthesis or release) or on distant target tissues.'
Autacoids can be broadly divided into three categories.
Amine Autacoids: E.gs: Histamine, and 5-hydroxytryptamine
(serotonin).
Peptide Autacoids: E.gs: Angiotensin, plasma kinins (like bradykinin
and kallidin), somatostatin, and pentagastrin. 3. Phospholipid Derived
Autacoids: E.gs: Eicosanoids (prostaglandins, leukotrienes,
thromboxanes), and platelet
activating factor.
Autacoids like histamine, 5-HT or bradykinin do not have any major
therapeutic use, but their numerous agonists and antagonists act by
modifying the actions of autacoids and hence find abundant clinical applications.
.
ni mi

.
2. HISTAMINES AND ANTIHISTAMINES e Histamine is a tissue
amine. Chemically, it is ß-imidazolyl ethylamine, a derivative of imidazole. It is
one occurring compound and plays many important
pathophysiological roles,
bvenly throughout the body. It is mostly concentrated in the granules
of the mast cells Histamine is distributed unevenly throughout the
body. It is mostly concentrated in
in hasophils. Skin, gastric and intestinal mucosa, lungs, placenta and
hepatic system (in the form of inactive complex) and in basophils.
Skin, gastric and intestinal mucosa, lun
e fluids such as blood, plasma, body secretions and pathological
fluids also contain have reserved stores of histamine. Tissue fluids such as
blood, plasma, body secretions and pathologic -histamine but in minor
quantities.
Synthesis and Metabolism
esived in the body from histidine upon decarboxylation by histidine
decarboxylase, Histamine is a natural amine synthesized in the body
from histidi Which is abundant throughout the body including CNS, gastric
mucosa, parietal ce
gastric mucosa, parietal cells, mast cells, basophils etc,

366
Pharmacology-I

(CH2)2NH2
N-7
COOH
Histidine -CH-NH, decarboxylase

-CO, (Decarboxylation)
Η

Histidine
Histamine

Metabolism
Histamine undergoes rapid degradation either through methylation in
the presence of N-methyl transferase leading to the formation of
N-methylhistamine or through oxidation in the presence of diamine oxidase
leading to the formation of imidazole acetic acid. Histaminic Receptors
Histamine elicits its pharmacological response by interacting with receptors
termed as histaminic receptors. These receptors are classified into four
types as H,, H, H, and H, which are located on the cell membranes of
brain, smooth muscles, mucosa etc. Their activity is similar to that of
muscarinic and nicotinic receptors of acetylcholine.
Table: Histaminic Receptors
Histamine receptor
H , receptor G-protein coupled receptor
- H, receptor G-protein coupled receptor
H, receptor G-protein coupled receptor
He receptor G-protein coupled receptor
Receptor type

Location
On intestinal, bronchial and - On parietal cells of uterine smooth muscles, |
gastrointestinal tract.: endothelial cells, CNS and . On blood vessels, heart sensory nerve endings.
and brain.
On brain, lungs, spleen,
skin, gastric mucosa and | certain blood vesses:
On thymus gland, small intestine, spleen and colon. It is also present on the surface of basophils and
in bone marrow.

Specific agonist
Dimaprit, impromidine, 4-methy lhistamine
| a-methylhistamine
Imetit, clozapine

Phar
Specific antagonist
Ranitidine, cimetidine
:
Thioperamide
1.

Mechanism of action
2-methylhistamine, 2-thiazolyl ethylamine, 2-pyridylethylamine Chlorpheniramine,
mepyramine - Hydrolysis of PIP,
increases IP, and DAG
levels. - Release of intracellular
Ca+2 ions. - Activation of protein
kinase C.
Thioperamide, clobenpropit burimamide.
- Decrease in the levels of
CAMP and Ca+influx. - Causes the opening of
K+ channels.
- Increase in CAMP

levels. .- Phosphorylation of
proteins.
Decrease in the levels of CAMP and Ca*? influx.

Pharmacological effect
Causes chemotaxis of WBC.
- Contraction of smooth
muscles. - Vasodilation of blood
vessels. - Increase in capillary
permeability. - Pain and itching through
sensory nerve endings.
- Increases gastric acid
secretion from gastric
glands - Vasodilation of blood
vessels. - Relaxation of uterine
smooth muscles. - Positive inotropic and
chronotropic effects on heart.
- Decreases the levels of neurotransmitters such as histamine, Ach and norepinephrine. -
Decreases gastric acid
secretions. - Causes vasodilation of
blood vessels.

Pathophysiological Role 1. In Hypersensitivity Reactions

Hypersensitivity is regarded as the most primary physiological
effect of histamine. Histamine produced during antigen-antibody
reactions (IgE type) leads to certain hypersensitivity reactions
especially immediate type of hypersensitivities. Histamine is
responsible for urticaria (skin rashes), angioedema (swelling of
tongue, lips and eyes), bronchoconstriction, anaphylactic shock etc. .
w
NA NOUS
AVADA

(Chapter-7) Autacoids and their Antagonists

367

ding
tion

cese oth

5.
6.

Gastric Secretion
On Heart Histamine causes potent stimulation of gastric glands Histamine
shows positive chronotropic and inotropic leading to increased secretion of
gastric acid. Apart
effect on heart through H,-receptors. It decreases AV from mast cells, it is also present in
histaminocytes
conduction through H,-receptors. It also increases located close to the parietal cells of
the gastric
coronary blood flow. mucosa. It is released from these cells in response 2
On Smooth Muscles to stimuli such as during feeding, stimulation of
Histamine has a direct stimulant effect on the vagus nerve, in presence of
cholinergic drugs etc., and causes potent secretion of gastric acid (HCI)
smooth muscles of the intestine, bronchi and uterus from these parietal cells.
through H,-receptors. It leads to contraction of the
visceral and nonvascular smooth muscles causing 3. Neuronal Transmission
bronchoconstriction and increased motility of the Histamine acts as a neurotransmitter
and causes
intestinal mucosa. stimulation of sensory nerve endings leading to
On Gastric Glands itching and pain. Its presence in brain (hypothalamus) is
responsible for maintaining alertness among
Histamine via H, -receptors (located in the gastric individuals. It is also involved in
the regulation of
parietal cells) causes an increase in the cyclic AMP body heat, natural responses
such as thirst, hormone
production which in turn has a direct effect on gastric release and has minor
effects on cardiovascular
glands leading to an increase in the secretion of system.
gastric acid. Inflammation
On Afferent Nerve Endings Histamine due to its vasodilatory effect causes
Histamine induces itching and pain by stimulating inflammation. It expresses adhesion
of molecule
the afferent nerve endings, when given by i.v or s.c p-selectin on the surface of the
endothelial cells and
route. thus promotes adhesion of leucocytes' to vascular endothelium.
On Central Nervous System

5. Tissue Growth and Repair Blindheid

Histamine has no direct effect on CNS upon Histamine being a tissue amine,
plays an important
intravenous administration as it cannot pass role in the growth and
regeneration of tissues.
through the blood-brain barrier, but upon
intracerebroventricular administration it causes Pharmacological Effects
stimulation of nerve cells leading to behavioural On Blood Vessels
disturbances, stimulation of cardiac centre, increased Histamine dilates
pulmonary vessels and produces blood pressure, vomiting etc. a fall in
pulmonary artery pressure. It also causes
On Ganglionic Cells dilatation of cerebral blood vessels leading to throbbing
headache, increase in CSF pressure
Histamine causes direct stimulation of ganglionic and palpable temporal
pulsation. It induces rapid
cells thereby inducing the release of adrenaline that and short-lived vasodilatation
by activating
increases blood pressure. H-receptors. By stimulating H, -receptors in vascular
Therapeutic Uses smooth muscles, slower but prolonged vasodilation
Histamine is used only for diagnostic purposes and is caused. It
produces a sharp fall in blood pressures
is not used therapeutically. by its vasodilatory effect on smooth muscles of 4
capillaries and venules.
1. It is used as a positive control injection in skin
hyper-reactivity testing. Smaller blood vessels such as terminal arterioles,
venules and capillaries are dilated by histamine
It is used to test acid secreting capacity of stomach, resulting in a sharp fall in
blood pressure. Intradermal
It is also used in clinical diagnosis of phaeochromocytoma. injection of histamine
causes triple response which
SEU However, all these applications have now become is characterized by,
obsolete. Flush/Red Reaction: It is immediate reddening of
Antihistaminic Drugs the skin. This occurs due to intense dilatation of capillaries and
venules. It develops within 10 sec.
Drugs that antagonize the actions or effects of
histamine are known as antihistaminic drugs. They nullity Wheal: It is the
formation of oedematous patch due
13 almost all the pathophysiological effects of histamine and to extravasation of fluid from
capillaries and venules, It lasts for about 90 sec.
ted site due to Flare: It is the reddening of the affected site due to
Antihistaminic drugs are mainly of two types i.e.. e mediated by axon reflex. dilatation
of arterioles mediated by axon reflex..310! H, -antihistamines an
30 H -antihistamines and H,-antihistamines.
7.

. 2..
3.

carry out the reverse action.

BRONIONS

368 Pharmacology-1 2.1 H,-ANTIHISTAMINES

Drugs that antagonize the actions or effects of histamine on H,
-receptors are known as H, -antihistamines. Classification w Based
on Chemical Structure
Hy-antihistaminics

Ethanolamines Ethylenediainines Alkylamines Piperazines Phenothiazines.

Piperidines
Dibenzoxepines E.gs:Diphenhydramine, E.gs:Tripelennamine, E.gs:Chlorpheniramine,
E.gs:Hydroxyzine, E.gs: Promethazine, E.gs:Cyproheptadine, E.g: Doxepine.
Doxylamine. Mepyramine, Triprolidine.
Cinnarizine, Trimeprazine. Loratadine, Antazoline,
Cetirizine,
Ketotifen. Pyrilamine.
Buclizine, Meclizine, Cyclizine.

Based on Sedative Property

On the basis of sedative property, H,-antihistaminics are classified as follows,
H -antihistaminics

Statistiche
First generation
Second generation (Sedative)
(Non-sedative) Highly sedative E.gs:Fexofenadine, Eigs: Diphenhydramine.
Loratadine,
Dimenhydrinate,
Desloratadine, : Promethazine,
Cetirizine, Hydroxyzine. ::
Astemezole.

=> Moderately sedative

E.gs:Pheniramine,
Cyproheptadine, Cinnarizine,
Meclizine, Buclizine.

> Mild sedative

E.gs: Chlorpheniramine,
Dexchlorpheniramine, Dimethindene, Triprolidine, Cyclizine, Clemastine.

First Generation (Sedative) Antihistamines General Mechanism of

Action USH -receptor antagonists selectively and competitively blocks the H,
-receptors and thus effectively antagonizes the actions of histamine on
gastrointestinal, uterine and bronchial smooth muscles, capillaries and afferent
nerve endings. Pharmacological Effects .: Antihistaminic Actions in
They effectively inhibit the histamine-induced bronchoconstriction, salivary
secretion, enhanced gastric motility, triple response, itching, oedema, urticaria
and adrenaline release. They also prevent hypotension produced in response to
histamine but to a lesser extent.
They prevent allergic and inflammatory actions of histamine by suppressing the release of
mediators from mast cells and basophils and by down regulation of H -receptors.
WBA

(d)
(Chapter-7) Autacoids and their Antagonists 369

2. Other Actions
Adverse Effects (a) Sedation and Hypnosis: CNS depression is a 1. CNS
Manifestations: Most common adverse effects
common side effect with older antihistaminic
seen with these drugs may be sedation, impairment drugs. They produce
variable degree of sedation,
of motor activity, drowsiness, dizziness, light drowsiness and sleep. Sedation is
useful in treating
headedness, blurred vision etc. In these conditions,

allergic conditions. It is commonly seen with

the patient is advised not to do any work that requires
diphenhydramine and promethazine and is negligible
great skill and attention.

in case of fexofenadine and desloratadine.lt

2. GI Manifestations: Loss of appetite, nausea, vomiting,
diarrhoea, epigastric distress and constipation. Restlessness, Tremors and
Insomnia: CNS
3. On Blood: Leucopenia (decrease in leucocyte stimulation is less with antihistaminics.
Drugs
count), agranulocytosis (deficiency of neutrophils), like phenindamine has been
reported to produce
haemolytic anemia (rarely) etc. restlessness and insomnia at conventional doses.
4.
On Skin: Topical application of antihistamines Anticholinergic Actions: Most of
the first generation
produces hypersensitivity reactions leading to antihistamines block cholinergic actions of
ACh.. .. allergic dermatitis. Dryness of mouth is a common side effect. 5. ANS
Manifestations: Anticholinergic activity Anticholinergic activity is graded as,
of these drugs may lead to dryness of mouth, High: Diphenhydramine,
dimenhydrinate,
dysuria (difficulty in urination), alteration in bowel promethazine, pheniramine and
cyproheptadine.
movement and blurred vision.
Therapeutic Uses Low: Chlorpheniramine, hydroxyzine, triprolidine and
cyclizine.
1. Treatment of Allergic Disorders: H, -antihistaminics
effectively treat seasonal hay fever, itching, urticaria, Minimal/Absent: Fexofenadine,
loratadine,
allergic conjunctivitis, angioedema etc. They are less cetirizine, astemizole.
effective in the treatment of perennial vasomotor
rhinitis, chronic urticaria and atopic dermatitis. Antiemetic Action: Antiemetic drugs
inhibit
Type-I hypersensitivity reactions induced by some histaminergic signals from the
vestibular nucleus
drugs also respond to H, -antihistaminics. They are to the vomiting centre and hence
are useful in
ineffective in bronchial asthma and other types of preventing emesis.
cell mediated and humoral allergies. (e) Antimotion Sickness Effects: Certain
antihistamines 2. Treatment of Pruritus: Pruritus is a type of itching
like promethazine, diphenhydramine, dimenhydrinate
caused due to excessive production of histamine. and piperazine derivatives prevent
motion sickness
Though they are less effective, conventional caused due to vestibular
disturbances.
antihistamines are regarded as the first line drugs in
the treatment of idiopathic pruritus. Anti-parkinsonian Effects: Promethazine and
Treatment of Common Cold: Antihistaminics, few other antihistaminics are useful in
reducing
especially cetirizine is commonly used to provide tremors, rigidity and sialorrhoea
associated with
symptomatic relief from common cold. These parkinsonism.
drugs are known to reduce rhinorrhoea (continuous
discharge of mucilaginous fluid through nose) by : Local Anaesthetic Action: Drugs like
promethazine,
their anticholinergic and sedative properties pheniramine and diphenhydramine
show local
4. In Motion Sickness; Although scopolamine is anaesthetic effect by blocking
Nat channels in
regarded as a potent drug in controlling motion excitable membranes. However, they
are not
sickness, antihistamines are beneficial due to their clinically useful.
lesser side effects, Drugs such as promethazine and

Pharmacokinetics
diphenhydramine are commonly used in controlling
milder types of motion sickness, These drugs are well absorbed orally and
parenterally
Treatment of Vertigo; Most preferred H, -antagonist and easily pass through the
gastrointestinal mucosa. The
in the treatment of vertigo is cinnarizine. This drug reduces the flow of Cat? ions into
the vestibular sensory neuronal cells, thus reducing the post rotatory labyrinthine
reflexes. Besides inhibiting the actions of histamine, this drug also has vasodilatory and
sedative properties which are required for the treatment of vertigo,
3.

Set of action is within 2-3 hrs of oral administration and

uration of action may range from 3-6 hrs.
These drugs undergo relatively rapid first pass iclabolism in children than in adults. They may
also
go self-metabolism by inducing the cytochrome P450 wines. The metabolites are excreted
in urine.
enzymes. The

6.
8.

370 Pharmacology-1
Treatment of Cough: H, antagonists such as? 3. Alkylamines chlorpheniramine,
diphenhydramine and
Chlorpheniramine promethazine are used as adjuvants along with other
antitussives and expectorants in cough formulations.
It is the most prominent and potent H, antihistamine, These drugs are also known to
reduce bronchial
available in salt form i.e., chlorpheniramine maleate.

secretions.
It inhibits the reuptake of serotonin. It competitively
blocks H,-receptor sites on effector cells in the GIT, Treatment of Parkinsonism:
Promethazine (due to
blood vessels and respiratory tract. its anticholinergic and sedative action) is used in the
treatment of early cases of parkinsonism.
It is used in the prevention of symptoms of allergic
conditions such as urticaria and rhinitis. It is also Treatment of Acute Muscle Dystonia:
Parenteral
used in the management of motion sickness, postural administration of
antihistamines such as promethazine
hypotension and in attaining symptomatic relief from and hydroxyzine provides relief
from acute muscular
cough. dystonia.
4.
Piperazines
Enter The various classes of H, antihistaminic drugs belonging to first
generation are discussed below..
Cyclizine
1. Ethanolamines
The drug may show its direct effect on the labyrinthine
reflexes and stimulate the chemoreceptor trigger Diphenhydramine
zone. It exerts anticholinergic action. It is a long It is the prototype member of this class
and is
acting drug with an elimination half-life of about commonly used in controlling motion
sickness. It
20 hrs.

blocks the actions of histamine, mediated through

Most common adverse effects may be dizziness, histaminic and muscarinic
receptors and also inhibits
drowsiness, sedation and dry mouth. Less common serotonin reuptake.
effects are headache, impairment of motor activity,
urinary retention etc. Hypersensitivity reactions Oral bioavailability is about 80%. It is a long
acting
may occur rarely. It is used in motion sickness and drug with a t,, of 2-8 hrs and
undergoes extensive
to attain relief from cough. first pass metabolism. Sedation, dizziness, tiredness,
5. Phenothiazines drowsiness and disturbed motor coordination are commonly seen.
Hypertension occurs in sensitive
Promethazine individuals.
It possesses antihistaminic, antiemetic, anticholinergic It is popularly used in the
treatment of symptoms
and sedative properties. of allergic rhinitis, itching, rhinorrhoea and
Oral absorption of the drug is about 88% but motion sickness. It is also used in the
treatment of
only 25% reaches the systemic circulation as it extrapyramidal side effects caused by
antipsychotics.
undergoes extensive first pass metabolism. It is
a long acting drug with a ty of about 16-19 hrs. Ethylenediamine :
Adverse effects include blurred vision, drowsiness, Pyrilamine that .
dizziness, fatigue, dry mouth, neuroleptic malignant It is the oldest member of this class
and had led to the
syndrome, respiratory depression etc. It is used development of several newer
compounds. It blocks
to treat the primary effects of parkinsonism, to the activity of histamine by competitively
binding to
treat hypersensitivity reactions, to combat motion
sickness and for drug-induced and post-operative H,-receptors. It also causes moderate
sedation due
vomiting. to its anticholinergic activity.
Piperidines It is a short acting drug and has a duration of action of about 4-6 hrs. Serious
undesirable effects caused
Cyproheptadine by pyrilamine are swelling of lips, tongue and face.
It is used in the treatment of allergies especially The other less common side effects are dryness
caused due to hay fever. It is a short acting drug of eyes, mouth and nose, dizziness,
drowsiness,
with a t of about 1-4 hrs. It undergoes both renal blurred vision, urticaria etc. It is used to
treat nasal
and hepatic metabolism. Common side effects of the congestion and sinusitis associated
with allergies,
drug are sedation, epigastric distress, loss of appetite, hay fever and common cold.
nausea, vomiting etc.
1998
IN
NA
SAN
SON

6.

(Chapter-7) Autacoids and their Antagonists 371

Second Generation (Non-Sedative) Antihistamines
It has about 80% oral bioavailability and attains peak These drugs do not possess
any sedative effect when
plasma concentration in about 1.5 hrs. It is about 97% compared to first
generation antihistamines, hence they are
plasma protein bound and undergoes extensive first pass also called as
non-sedative antihistamines. Their actions are
metabolism. It is a long acting drug with an elimination mediated mainly through H,
-receptor blockade. These drugs
half-life of 7-10 hrs. Adverse effects include dizziness, are found to have certain
beneficial effects when compared
drowsiness, headache, gastric distress etc. to first generation antihistamines
such as,
It is used in the treatment of allergic conditions such
n as upper respiratory allergies, urticaria, pollinosis, atopic 1. They possess
greater selectivity towards H, -receptors. dermatitis and in seasonal asthma. 2.
They do not produce anticholinergic side effects Terfenadine
such as blurred vision, dryness of mouth, alteration in bowel movement etc.
It was the most widely used and first discovered
non-sedative antihistaminic drug. It was used for the They are effective against
effects mediated via treatment of allergic symptoms such as sneezing, runny
leukotrienes and platelet activating factor (PAF). nose, urticaria, itchy eyes etc.,
but has been withdrawn from
the market as its drug interactions has led to life-threatening They do not produce
sedation, drowsiness or dizziness.
Torsades de pointes a very dangerous form of tachycardiac They do not
enhance the sedative effect of alcohol by blocking K* channels in the heart.
and other sedatives like the first generation
Astemizole antihistamines.
The effects of this drug are also similar to that of They do not impair
motor coordination.
terfenadine and was used to provide an effective treatment . However,
these drugs have limited spectrum of
against allergic reactions. However, its use has been banned action and are
effective only in those cases where histamine . because of its to is the main
cause of the diseased condition. All other. Fexofenadine properties are similar
to first generation antihistaminics.
It is an active metabolite of terfenadine with low Therapeutic Uses :
arrhythmogenic potential. However, it is not safe in patients
with pre-existing long QT-interval. It does not cause These drugs find their
main use in the treatment
sedation, motor incoordination and atropinic side effects. of immediate
hypersensitivities such as rhinitis,
It is rapidly absorbed, metabolized in liver and excreted in conjunctivitis
and pollinosis (allergy due to pollen bile. It has a half-life of 11-12 hours
and its action persists grains).
for only 24 hours: 2. These drugs are used to control extensive sneezing
 Loratadine
and prevent the itching of eyes.
It is a rapid and long acting selective peripheral They are used in the
treatment of urticaria, local H-antagonist which is devoid of CNS depressant
effects. irritation of skin and in cases where there is a It gets metabolized to an
active metabolite with a . of hereditary or constitutional tendency to develop 17
hours. It is effective in urticaria and atopic dermatitis hypersensitivity reactions.
2.2 H,-ANTIHISTAMINES They are not used in acute allergic reactions to
drugs
P These are the drugs that effectively block the actions and foods.
of histamine mediated through H, -receptors. They compete
with histamine for binding with Hz-receptors and hence The various
classes of H -antihistaminic drugs
antagonizes its activity, H, receptors are mainly located belonging to second
generation are discussed below,
on the basolateral membrane of the parietal cells of the Cetirizine
gastrointestinal tract and are responsible for increasing the
gastric acid secretion. It is a potent anti-allergic and most common
Drugs included under H,-antihistamines include alternative for the treatment of
common cold. It has greater Sensitivity towards H.-receptors. Beside inhibiting the
cimetidine, ranitidine, famotidine, roxatidine etc. These latelets and drugs are
found to be highly effective in the treatment of ndary allergenic response.
peptic ulcer diseases a
peptic ulcer diseases as they reduce gastric acid secretion. cosinophils Thus it
inhibits secondary allergenic response.
activity of histamine, it also inhibits the release of other Cytotoxic mediators
such as leukotrienes from platelets and
372 Pharmacology-I

i Cimetidine, ranitidine and roxatidine competitively

bind to H -receptors a
ana roxatidine competitively bind to H-receptors and reduce the basal acid
secretion, which determines their activity in reducing nocturnal acid secretion in treating duodenal
ul
reducing nocturnal acid secretion in treating duodenal ulcers. They are regarded
as the first line drugs in the treatment of gastroesophageal disorders. Cimetidine
 It is the prototype drug
of H,-antihistamines. Mechanism
of Action
Cimetidine causes potent inhibition of gastric acid secretion by selectively and competitively binding
0.2776ceptors and antagonizing the actions of histamine. However, it does not interfere with the formation and
release of endogenous histamine.

Pharmacologic
al Effects
Antihistaminic Action: Cimetidine blocks all the actions of histamine, mediated through
Hz-receptors. It blocks histamine-induced cardiac stimulation, gastric secretion, relaxation of uterine and
bronchial smooth muscles. It also inhibits hypotension caused due to histamine. Gastric
Secretion: Cimetidine causes marked reduction in the secretion of gastric acid by blocking
the effect of histamine on parietal cells via H,-receptors. It suppresses all phases of gastric
secretion but shows predominant effect on the basal acid secretion. This effect is beneficial
for the healing of duodenal ulcers. Cimetidine also suppresses secretory responses to
other stimuli such as ACh, gastrin, food etc. It also reduces the volume of gastric acid,
pepsin content and intrinsic factor secretion. However, it does not show any effect on
gastrointesti
nal motility.
Pharmacokinetics
: Cimetidine is well absorbed orally and reaches peak plasma concentration within 1-3
hrs of oral administration. Only small amounts of the drug undergoes first pass metabolism while
remaining 60-80% reaches systemic circulation. It exhibits a t, of 2-3 hrs. It is generally taken
after meals, as the presence of food increases its absorption. Adverse Effects 1. Less severe
effects of cimetidine are dizziness, headache, fatigue, diarrhoea, constipation, dry mouth
and rashes.
Intravenous administration of cimetidine produces certain adverse effects on CNS
such as slurred speech, restlessness, confusion, convulsions and coma.
Prolonged usage of cimetidine leads to certain antiandrogenic effects by which it may inhibit
the binding of dihydrotestosterone to its cytoplasmic receptors and also inhibits the
hydroxylation of estradiol. These effects may lead to galactorrhoea in women and loss of
sexual potency, temporary reduction in sperm count and gynaecomastia
in men. 4.
Cimetidine rarely causes blood dyscrasias
such as thrombocytopenia, neutropenia etc. Drug Interactions 1.
Antacids decrease the bioavailability of all H, antagonists
including cimetidine.
Cimetidine also interferes with the hepatic metabolism of various drugs such as phenytoin,
nifedipine, warfarin, metronidazole, phenobarbitone, lignocaine by inhibiting the metabolic
enzymes such as cytochrome P450, P206
etc. This results in systemic
accumulation of these drugs. Ranitidine

It is similar to cimetidine in all aspects, except

for the following advantages. 1. It is a highly potent drug
being 5 times more effective than cimetidine,
It has a greater duration of
action.
It is devoid of antiandrogenic action and hence unlike cimetidine it does not cause loss of libido,
gynaecomastia etc.
WW
SAS

(Chapter-7) Autacoids
and their Antagonists
3
7
3
4
.
It does not penetrate into the CNS, therefore
lacks CNS effects.
5
.
It does not interfere with the metabolism of other drugs and thus very few drug interactions have
been reported.
6
.
It has low propensity to cause side effects like headache,
dizziness, confusion etc.
Famoti
dine
 It is a thiazolidine derivative and is very specific towards H,-receptors. It is more
potent than ranitidine.
It is more preferred in Zollinger-Ellison syndrome and to prevent aspiration
pneumonia as it possesses longer duration of action and greater potency than other drugs.
Pharmacokinetics
It is a long acting drug and has an elimination half- life of 2.5-3.5 hrs. It possesses
good oral bioavailability ranging upto 50%. It undergoes less first pass metabolism and about
70% of the drug is excreted unchanged in urine. Adverse Effects 1. It causes relatively lesser
adverse effects than ranitidine which include dizziness, mild headache, bowel upset etc. 2.
Hypersensitivity reactions such as rashes are seen rarely. 3. It does
not possess antiandrogenic effect. Drug Interactions
It does not affect the metabolism of other drugs as it
possesses low affinity towards cytochrome P450 enzymes. However, minor
interactions may be seen with other gastrointestinal drugs. Therapeutic Uses of
H.-Antihistamines
H,-antihistamines are regarded as highly effective class of gastrointestinal drugs.
They are widely used in the treatment of gastric and peptic ulcers.
1
.
Treatment of Duodenal Ulcers: All H,-antagonists provide symptomatic relief from pain due
to duodenal ulcers. They heal upto 85% of duodenal ulcers by the end of 4 weeks. If
the dose is continued further up to 8 weeks, then upto 95% of the ulcers can be healed.
They reduce gastric acid secretion at night and a single bed time dose is found to be
highly effective. However, patients become dependable after prolong usage and the
conditions relapse after its withdrawal. Hence, maintenance therapy is generally
required to reduce such relapse. Treatment of Gastric Ulcers: H -blockers are less effective
than proton pump inhibitors in the treatment of gastric ulcers. They are frequently
administered in bleeding peptic ulcers. A full term therapy for 8 weeks can heal up to
75% of the ulcer but the condition relapses after withdrawal of the drug. Hence,
maintenance therapy is required.. Treatment of Stress Induced Ulcers: Ulcers may be
induced in the gastrointestinal tract due to intense stressful conditions such as renal failure,
asphyxia (suffocation), traumatic stress, hepatic insufficiency etc. Intravenous infusion of
H-antagonists effectively reduces gastric erosions and bleeding. Treatment of Zollinger-Ellison
Syndrome: This disease is characterized by hypersecretion of gastric acid due to excessive
production of gastrin hormone. Though proton pump inhibitors are used as the first line drugs
in this condition, higher doses of H, -antagonists helps in attaining relief from
symptoms and hyperacidic conditions in certain patients. , Treatment of
GERD (Gastroesophageal Reflux Disease): HZ-antagonists reduce gastric
secretions and thus etfectively heal oesophageal and gastric lesions, but are less
efficacious than proton pump inhibitors in the treatment of GERD, Hence, they are
preferred only in the initial stages. To Prevent Aspiration of Gastric Fluids:
H-antihistamines are administered before major gastrointestinal surgeries to
prevent the aspiration of gastric fluids. Miscellaneous Use: H.-antagonists are used as an
adjunct in the treatment of urticaria, if H.-antihistamines alone are found to be ineffective.
w
NO
DOR
AM
SAN

376 Pharmacology-1 3. 5-HYDROXYTRYPTAMINE

AGONISTS AND ANTAGONISTS
plamine or simply 5-HT is a monoamine neurotransmitter which is synthesized in the
serotonergic neurons present in the CNS, CVS and GIT (intestines). It is also
found in mast cells and pr
vw and GIT (intestines). It is also found in mast cells and platelets. About 90% of 5-HT;.
distributed in the enterochromaffin cells and myenteric plexus of GIT, where it
acts as a prok motility by regulating smooth muscle function) and as a
neurotransmitter.
ounts for 1% of the total body 5-HT content. It is present in pineal gland in the brain
where it serves as a precursor of melatonin. The remaining is distributed in lungs,
bone marrow, mast cells and platelets, un Dives as an important neurotransmitter. It
plays an important role in migraine and headache. Synthesis and
Metabolism
In the body, serotonin is synthesized from the essential amino acid,
tryptophan obtained from diet. Metabolism of 5-HT occurs through oxidative
deamination by an enzyme called monoamine oxidase (MAO) to 5-hydroxyindole
acetic acid (5-HIAA). This metabolite is excreted in urine and acts as an indicator of
tumours i.e., increased levels of J-HIAA in urine indicates carcinoid tumours.

-CH2-CH-0-OH
CH2-CH-0
NH2
Tryptophan hydroxylase
'

NH2
N
N

a-tryptophan
H 5-hydroxy-1-tryptophan
5-hydroxy-1-tryptophan
decarboxylase

Dubai
Monoamine oxidase
(Metabolism)
'N

5-hydroxy indole acetic acid

(5-HIAA)
5-hydroxytryptamine
(5-HT)

Figure: Biogenesis and Metabolism of Serotonin (5-HT) 5-HT

(Serotonergic) Receptors
Presently about seven main types of 5-HT receptors i.e.,
5-HT, to 5-HT, and their subtypes have been identified. Out of
these 5-HT,, 5-HT, and 5-HT are G-protein coupled receptors
(GPCR) while 5-HT, is ligand operated ion channel receptor.
Table: 5-HT Receptors

Receptor
Location
Functions
Antagonists
Agonists Buspirone
5-HTJA
Raphe cell bodies, hippocampus, dendrites
Spiperone, Ergotamine,
pus,

Inhibits the release of

adenylyl cyclase,
• Activates K+ channels
causing hyperpolarization
· and inhibits Cat2 channels.
• Anxiety
Thermoregulation Behavioural effects Behavioural effects Pulmonary
vasoconstriction Presynaptic inhibition.
5-HT
Sumatriptan
Methiothepin
CNS and vascular smooth muscles
RU
CASA

(Chapter-7) Autacoids and their Antagonists

377

Function
Location
Receptor
Antagonists
Agonists

so
Sumatriptan
Methiothepin
5-HTD
Throughout CNS and cranial blood vessels
Behavioural effects , Cerebral vasoconstriction

5-HT2A
Cerebral cortex, smooth muscles, platelets and autonomic neurons Gastric fundus
Choroid plexus
Ketanserin, Cyproheptadine, Methysergide.
A-methyl-5-hydroxy tryptamine, lysergic acid diethylamide (LSD) Same as above
Neuronal excitation Platelet aggregation Contraction of GI and
bronchial smooth muscles Contraction
SB-204741
5-HT2B

5-HT2c
Same as above

5-HT2
Secretion of cerebrospinal fluid (CSF)
Emetic reflex (vomiting)
Augments peristalsis * Behavioural effects
Mesulergine, Methysergide. Ondansetron, Granisetron, Tropisetron.
|
Cholinergic terminals of GIT, area postrema, hippocampus and nucleus tractus
solitarus.
2-methyl-5-hydroxy tryptamine, m-chloro-phenyl biguanide
(pain) and autonomic neurons.
5-HT.
Cisapride, Renzapride, Metoclopramide.
GR-113808, SB-207266.
Hippocampus, superior and inferior calculi of brain, smooth muscles of gut and
oesophagus Secretory cells.
Neuronal excitation Contraction of smooth muscles of gut.
Stimulates intestinal - secretion.

2.
Pathophysiological Role 1. Neurotransmitter: 5-HT acts as a neurotransmitter
and is widely distributed in the brain. It is involved in the regulation
of consciousness, sleep, behaviour, mood, thought, cognitive function, appetite,
vomiting and pain perception. Melatonin Precursor: 5-HT acts as a precursor of
melatonin in pineal gland where it regulates biological clock and circadian rhythm. .
Neuroendocrine Role: 5-HT regulates the hypothalamic neurons that are
responsible for the secretion of anterior pituitary hormones. Raynaud's Disease:
5-HT released from the platelets promote occlusion and constriction of larger arteries.
Migraine: Migraine is an episodic headache commonly restricted to one side and
is exacerbated by physical activity: It is characterized by nausea, vomiting,
diarrhoea, vertigo, sensitivity to light and sound etc. Its exact mechanism is still
unclear. It is believed to occur as a result of abnormal 5-HT transmission in CNS,
leading to pulsatile dilatations of large cranial vessels (especially the arterio-venous
shunts in the carotid artery) which reduces the blood flow to the brain and causes
pain. According to vascular theory, 5-HT is said to cause vasoconstriction which produces
cerebral ischaemia and initiates the attack. 6. Nausea and vomiting: Efficacy of 5HT,
antagonists in preventing the emesis induced by anticancer drugs and
radiotherapy suggests the role of 5-HT in nausea and vomiting. 7. Haemostasis: 5-HT by
its vasoconstrictory effect promotes retraction of injured vessel. It also augments the
aggregation
of platelets and clot formation. These effects helps to maintain haemostasis. Variant
Angina: 5-HT released from platelets along with TXA, causes coronary
spasm and variant angina. Carcinoid Syndrome: Overproduction of 5-HT by
enterochromaffin cells of GIT causes carcinoid tumour.
8.

Hypertension: Increased 5-HT levels causes hypertension. Ketanserin is used as a prophylactic

drug in hypertension.

5-HT sy widely u

5-HT agon
5-H
E.g: 5-H) E.g:
5-HT
E.gs:
378 Pharmacology-I Pharmacological Effects
0722.7TOOR2012 113.
· 1. On Cardiovascular System
(a) Heart: 5-HT shows weak positive inotropic and chronotropic effects on healt. (b)
Blood Vessels: It causes contraction of the peripheral blood vessels including
splanchnic arteries. It also constricts the veins and venules. However, blood capa
arteries are dilated. Administration of 5-HT causes cutaneous vasodilation and more
site of injection which later turns blue due to peripheral pooling of blood. (C) Blood
Pressure: Intravenous administration of 5-HT produces a typical triphasic response as
follows,
(i) Initial fall in blood pressure for a short period due to stimulation of chemoreceptors
located in coronary
and carotid arteries. ; (ii) Immediate elevation due to constriction of peripheral
blood vessels. . (iii) Sustained hypotension due to dilation of the skeletal blood
vessels. On Central Nervous System Appreciable amounts of 5-HT is found in the
brain. 5-HT receptors located in the brain control mood, emotions and
memory. 5-HT administered exogenously cannot cross the blood-brain barrier and
hence produces no CNS effects. 3.
On Platelets Platelets do not synthesize 5-HT but obtain it from the circulation and
store it. Upon injury they release the stored 5-HT which stimulates 5-HT,, receptors
and induces platelet aggregation along with other mediators of injury. Thus platelet
derived 5-HT plays an important role in promoting vasoconstriction and vascular
occlusion. On Sleep Decreased levels of 5-HT in brain causes insomnia (lack
of sleep), as it controls the sleep-wakefulness cycle. On Respiratory
System 5-HT exerts stimulant effect on bronchial smooth muscles. Elevated
levels of 5-HT causes bronchoconstriction and
hyperventilation due to the stimulation of bronchial sensory nerve endings. 6.
Miscellaneous Effects
(a) It shows nociceptive effect (perception of pain) by activating the 5-HT,
receptors located on the afferent nerve
endings. (b) 5-HT plays a significant role in appetite control. It shows anorexiant
effect and decreases food intake. Drugs Acting on 5-HT System
Parti E.g: 1

5 Non
E.gs:
3.1 1.
5-4 5-H
Bus
It is
con
for
use

Me
Ite
Depending upon the type of activity exerted on the 5-HT receptors, drugs are
broadly classified as follows.
5-HT agonists E.gs:Sumatriptan, Buspirone,
Cisapride, Ergot alkaloids. 5-HT antagonists E.gs: Methysergide,
Cyproheptadine, Ketanserin, Pizotifen, Clozapine, Ondansetron.
5-HT precursor
· E.g: Tryptophan
Drugs acting on
5-HT system
5-HT synthesis inhibitor E.g: p-Chlorophenylalanine (PCPA) 5-HT storage inhibitor E.g:
Reserpinel
i
5-HT reuptake inhibitor E.gs: Fluoxetine, Sertraline.
N
E.g: Chlorgyline
Selective MAO inhibitors
5-HT degradation inhibitor

5-HT neuron degenerators E.g: 5, 6-dihydroxytryptamine

Non-selective MAO inhibitors E.g: Tranylcypromine
Among the different classes of drugs affecting the 5-HT system, 5-HT receptor
agonists and antagonists are widely used for therapeutic purpose.
Drugs acting on 5-HT system
Pl
5-HT agonists skolen
5-HT antagonists
- noi.

|
→ 5-HT a agonists
E.g: Buspirone F> 5-HT18 and 5-HTid agonists
E.g: Sumatriptan 5-HT, agonists E.gs: Cisapride, .. Mosapride. Partial agonists E.g: Ergot
preparations
(Ergotamine tartarate,
Dihydroxyergotamine) Non-selective 5-HT agonists E.gs: Lysergic acid
diethylamide (LSD), Dexfenfluramine.
5-HT2A and 5-HT2c antagonists E.gs:Methysergide,
Pizotifen,
Clozapine 5-HT2A antagonists E.gs:Cyproheptadinc,
Ketanserin 5-HT antagonists E.gs:Ondansetron,
Granisetron, Dolasetron.
L
.

2.
· Contraindications . It is contraindicated in severe renal and hepatic
insufficiency, angle-closure glaucoma, myasthenia gravis, patients on MAO inhibitors
and pre-existing heart disease. T Limitations 1. Slow onset of action. 2.
Weaker anxiolytic effect than benzodiazepines.
Not useful in severe anxiety associated with : alcohol withdrawal and panic
states. Therapeutic Uses 1. It is used as an anxiolytic drug. 2. It can be used as a
synergistic agent for
depression when used along with selective serotonin reuptake inhibitors like fluoxetine,
paroxetine etc. 3. It is used to treat phobic neurosis.. 5-HT, and 5-HT, Agonists
5-HT Sumatriptan It is an indole derivative which selectively acts on 5-HT,, and
5-HT, receptors. At higher concentrations, it activates 5-HT, receptors.
Mechanism of Action It is the first line drug for the treatment of migraine. Its
anti-migraine activity is attributed to constriction of the dilated cranial blood vessels
especially the arterio-venous shunts in the carotid artery which increases the blood
flow to the brain. Pharmacological Effects Sumatriptan when administered at the
onset of migraine proves to be effective. It control the nausea and vomiting associated
with migraine. It suppresses the inflammation of cranial nerves and impulse
transmission through the trigeminal nerve. It also control the release of neurokinin A
which causes inflammation of the cranial blood vessels as well as prevents the
extravasation (escape) of plasma proteins across the meningeal vessels.
Pharmacokinetics Sumatriptan when injected subcutaneously is completely and
rapidly absorbed. It is metabolized by MAO-A isoenzyme in liver and excreted
through urine. Adverse Effects Adverse effects of sumatriptan are mild. It causes
dizziness, muscle weakness, tingling in hands, flushing at the site of injection, neck pain
and a slight rise in blood pressure, which is not clinically relevant. It also causes
myocardial ischaemia and hence is contraindicated in cardiovascular disorders.
3.1 5-HT Agonists 1. 5-HT2A Agonists
Buspirone It is mostly used for the treatment of mild to moderate conditions of
generalized anxiety but cannot be used for obssessive compulsive disorders. It can also
be used to treat phobic neurosis. Mechanism of Action It exerts its anxiolytic effect
by acting as a partial agonist mainly on brain 5-HT, receptors. It also has some weak
blocking action on dopamine (D) receptors. It thus reduces the activity of serotonergic
neurons. It does not produce any extrapyramidal side effects. Pharmacokinetics It is
rapidly absorbed orally but is prone to high first pass metabolism through hydroxylation
and dealkylation to give many active metabolites like l-pyramidyl piperazine, which is
also a 5-HT. partial agonist. Its elimination half-life is about 2-4 hours. Excretion is
through urine (29-63%) and faeces (18-38%). Adverse Effects Common adverse
effects include headache, nausea, dizziness, nervousness, agitation, light
headedness, confusion and tachycardia.

Drug Interactions 1. It increases the plasma levels of haloperidol. 2.

When given along with monoamine oxidase
(MAO) inhibitors, severe hypertension may occur.
.
380

ed with migraine,
3.

Pharmacology-I
Drug Interactions :
Adverse Effects
1. Nausea, vomiting and vasoconstriction. The Sumatriptan interacts with ergotamine,
ifadministered
aggravate the nausea associated with migra; concomitantly within 24 hrs. It interacts with 5-HT
hence an antiemetic is also prescribed. uptake inhibitors, MAO inhibitors, lithium and
2. Anginal pain due to coronary vasoconstriction vasoconstrictor drugs.
Prolong administration induces paraesthesia
3. Therapeutic Uses
(tingling), numbness in the limbs. 1. Sumatriptan is the drug of choice in the
treatment of acute attacks of migraine.
4. Ergotamine causes headache, confusion.
depression, drowsiness, diarrhoea and cerebral 2. It is also indicated in cluster headache
attacks.
haemorrhage. 5-HT, Agonists
Therapeutic Uses Cisapride
Ergot preparations are effective in the treatment of * Mechanism of Action
acute migraine attacks when given in combination It is a selective 5-HT, receptor
agonist. It promotes
with caffeine (which aids in their absorption). They the release of acetylcholine from the
myenteric
cause vasoconstriction of the dilated cranial nerves. plexus, thereby inducing gastric
motility. It
These drugs should be discontinued once the attack facilitates gastric motility and
hastens gastric
subsides. Over treatment with ergot preparations emptying. It improves the tone of lower
oesophageal
may cause cumulative effects leading to ergot sphincter (LES) and oesophageal peristalsis.
Oral
poisoning. bioavailability is approximately 33%. It undergoes 5. Non-Selective, 5-HT
Receptor Agonist? hepatic metabolism and has a t,, of approximately
Lysergic Acid Diethylamide (LSD) 10 hrs.
It is a non-selective, 5-HT agonist which acts on Adverse Effects
· 5-HT4, 5-HT2A: 5-HT2C, 5-HT, and 5-HT,receptors. It has been found that
cisapride prolongs the QT interval and causes ventricular fibrillation at higher
Dexfenfiuramine doses. Hence, due to its cardiac toxicity, it is
It is also a non-selective, 5-HT receptor agonist which presently not used.
was used as an anorexiant (appetite suppressant).
It acts by two mechanisms, release of 5-HT and Partial Agonists
inhibition of its reuptake. It has been withdrawn due Ergot Preparations
to its reported toxicity. Ergotalkaloids like ergotamine and dihydroergotamine 3.2 5-HT
ANTAGONISTS are important drugs used in the treatment of acute attacks of migraine.
Ergotamine is a natural ergot
1. 5-HT2A and 5-HT2c Antagonists with alkaloid while dihydroergotamine is a
synthetic
Methysergide dehydrogenated alkaloid.,
Methysergide is an oral, synthetic congener of ergot Mechanism of Action
alkaloids which is structurally related to LSD. It is Ergot alkaloids act by constricting the
dilated
a potent and selective 5-HT,, and 5-HT, receptor cranial blood vessels as they are
partial agonists of
antagonist. It does not interact with adrenergic or 5-HT and 5-HT, receptors located in and
around
dopamine receptors. the cranial nerves. They also act by constricting
2 It is used only as a prophylactic agent in migrainous the AV shunt channels in the carotid
artery so that
headaches, The effect of the drug is evident within considerable amount of blood flows
to the brain.
1-2 days of starting the therapy and persists even Pharmacological Effects
after its withdrawal. Abrupt withdrawal of the drug
may lead to rebound headaches. Therefore, dose Ergot alkaloids reduce the
inflammation of the
should be tapered gradually 2-3 weeks before its cranial nerves and also prevent the
extravasation
cessation. (leakage) of plasma proteins in the dura mater.
Adverse Effects Pharmacokinetics
Irritation of the GI tract leading to nausea, CNS They are poorly absorbed on 'oral
 administration.
effects like vertigo, drowsiness and insomnia, CVS Most of the parenterally administered
dose is
effects like postural hypotension and bradycardia, metabolized in the body and excreted
through urine... oedema, paraesthesia, restlessness,
Seriou: and pr effects, damage fibrosis patients it has go Pizotifen It is also which
i antidepres anticholin retention agent in almost of Clozapine It is a t dopamin of
5-HT for its ef schizoph 5-HT TE risperid 5-HT, Ketanse It is the blockin recepto
affinity recepte Ritans selecti ვures thereb effect lower It cau and ti Rayn: Cypro It is of an
i
aunthetic

antag antic activ

Phar
1.
(Chapter-7) Autacoids and their
Antagonists** 381
Serious toxic effects include arterial
insufficiency and precipitation of angina due
to vasoconstrictor effects, exacerbation of
peptic ulcer, cardiac valves damage,
blockade of urinary tract and pulmonary
fibrosis. These effects are seen in almost
40% patients on long term therapy. Due to
these effects, it has gone into disrepute.
Pizotifen leveringstide
r

It is also a 5-HT2, and 5-HT2

receptor antagonist which is structurally related to
tricyclic antidepressants. It also shows
antihistaminic (H,) and anticholinergic action. It
causes drowsiness, urine retention and
weight gain. It is used as a prophylactic
agent in migraine and vascular headaches but is
almost obsolete now. Clozapine It is a typical
antipsychotic agent which is a dopaminergic (D2)
antagonist as well as a blocker of 5-HT,, and 5-HT,
receptors, which accounts for its efficacy in the
treatment of resistant cases of schizophrenia. Other
antipsychotic agents possessing 5-HT receptor
blocking action are olanzapine, risperidone and
quetiapine. 5-HT2A Antagonists Ketanserin It
is the prototype for drugs having 5-HT, receptor
blocking activity. It selectively blocks
5-HT2A receptors with little effect on 5-HT2r. It also
shows affinity towards a, (adrenergic) and H,
(histaminic) receptors. Ritanserin is a congener of
ketanserin and is a more selective 5-HT, antagonist.
It inhibits platelet aggregation by reducing
thromboxane formation thereby increases bleeding
time and is therefore effective in Raynaud's
disease. It also causes lowering of blood pressure
and bronchoconstriction. It causes nausea, dryness of
mouth, dizziness and tiredness. It is used as a
prophylactic drug in : Raynaud's disease.
Cyproheptadine It is structurally related to
phenothiazine, a classi of antihistaminics. It is
a potent 5-HT2A receptor 3. antagonist with
additional antihistaminic (H.), anticholinergic and
calcium channel blocking activities.
Pharmacological Effects 1. On Central
Neryous System: It shows mild
CNS depressant activity and causes
sedation due to H, blocking activity. It
also shows anti-tremor and antiepileptic
activities.
2. On Endocrine System: 5-HT controls the
 secretion of adrenocorticotropic
hormone (ACTH) by stimulating the
corticotropin releasing factor (CRF) from
the hypothalamus. Cyproheptadine
blocks the release of hydrocortisone,
therefore is used in the treatment of
Cushing's syndrome. It also suppresses
aldosterone production in idiopathic
aldosteronism. 3. On Appetite: It improves appetite by acting
on the hypothalamus. Its appetite stimulant relo
activity is not justifiable and may even prove to be dangerous, hence it is not used clinically
for this purpose. 4. In Hypersensitivity:-Due to its antihistaminic
activity, it is useful in controlling skin
allergies
like urticaria and hay fever. Pharmacokinetics It is absorbed from the GI tract. Plasma
protein binding is 96-99% and it undergoes
renal and hepatic metabolism. Its half-life is
1-4 hours and it gets
excreted through urine and
faeces.
· Adverse Effects Adverse effects of
cyproheptadine are mild. These include
drowsiness, dizziness, headache, weight
gain and dryness of mouth. Occasionally,
it causes mental confusion, visual
hallucinations and ataxia (incoordination
of muscle movements).
Therapeutic
Uses
· 1. It is used for prophylaxis in migraine. 2. Treatment of postgastrectomy
dumping
syndrome, carcinoid syndrome, Cushing's disease and allergies (hay fever, urticaria,
pruritus, dermatitis, and neurodermatitis). It
is also used to combat sexual
dysfunction caused by selective
serotonin reuptake inhibitors (SSRIs). It
is a useful alternative to
 benzodiazepines in the treatment of
insomnia because it enhances
the quality and quantity of sleep. 5-HT, Antagonists

Ondansetron Mechanism of action The antiemetic action of ondansetron is partly central

and partly peripheral. It acts by blocking the
depolarizing action of 5-HT on the 5-HT,
receptors located in the area postrema of
the brain as well as in the gut.
382 Pharmacology-1
Pharmacokinetics Oral bioavailability of ondansetron is
60-70%. It undergoes first pass metabolism. Its t, is 3-5
hrs and duration of action is 4-12 hours. It is excreted
through urine and faeces. Adverse Effects It is well tolerated
with mild adverse effects like headache, constipation, chest
pain. Intravenous administration rarely causes skin rashes
and allergic reactions. Therapeutic Uses It is useful in the
management of vomiting and nausea associated with cancer
chemotherapy and radiotherapy and also in prophylaxis and
treatment of post-operative nausea and vomiting.
Granisetron It is 10-15 times more potent than
ondansetron. It is similar to ondansetron in all the aspects,
except that its t, is 6-8 hrs (i.e., longer than ondansetron).
It causes headache, fever, dizziness and anxiety.