Serotonin & Their antagonists

SEROTONIN
&
THEIR ANTAGONISTS
By
Rajneesh Kumar Singh
M.Pharm. (Pharmacology)

SEROTONIN
Serotonin is a naturally occurring amine synthesized from the
tryptophan & commonly found in plants ,some fruits ,animal
tissues & insect venoms. In human being , it is found in
enterochromaffin cells in g.i.t & CNS .
Serotonin containing neurons are mainly found in limbic
system, raphae nucleus, cortex, hypothalamus, amygdala,
caudal nucleus , mid –brain, vomiting centre & spinal cord .
These regulate sleep, body temperature & mood .
A hormone melatonin is derived from serotonin .

PHARMACOLOGICAL ACTIONS
OF SEROTONIN (5-HT)
• Action on GIT
 5-HT act as a local hormone & to
regulate peristelsis movement.
• Action on CNS
 It act as neurotransmitter in CNS
• Action on CVS
 5-HT produces positive ionotropic
EFFECT & chromotropic effect in
myocardium .
• Action on smooth muscles
 5-HT constrict the smooth muscles of
bronchia and GIT .

PHARMACOLOGICAL
ACTIONS
Action on blood vessels
 5-HT dilate the blood vessels of skeletal muscles,
coronary arteries & capillary of skin .
Action on platelets
 It enhance the aggregation of platelets &
haemostatis.

DEPRESSION
 Possible problems include low brain cell
production of serotonin, a lack of
receptor sites able to receive the
serotonin that is made, inability of
serotonin to reach the receptor sites, or a
shortage in tryptophan, the chemical
from which serotonin is made.
 If any of these biochemical glitches
occur, researchers believe it can lead to
depression, as well as obsessive-
compulsive disorder, anxiety, panic, and

5-HT RECEPTORS
 The 5-HT receptors are the receptors for
serotonin. They are located on the cell
membrane of nerve cells and other cell
types in animals, and mediate the effects
of serotonin as the endogenous ligand.
 With the exception of the 5-HT3
receptor, a ligand-gated ion channel, all
other 5-HT receptors are G protein-
coupled, seven transmembrane(or
heptahelical) receptors that activate an
intracellular second messenger cascade.

5-HT Receptors
 5-HT1-receptors occur mainly in CNS
(all subtypes) and some blood vessels
(5-HT1D subtype).
 Effects are neural inhibition and
vasoconstriction. Act by inhibiting
adenylate cyclase.

 5-HT2-receptors occur in CNS and many peripheral
sites (especially blood vessels, platelets, autonomic
neurons). Neuronal and smooth muscle effects are
excitatory. Some blood vessels dilated as a result of
nitric oxide release from endothelial cells. 5-HT2-
receptors acts through phospholipase C/inositol
trisphosphate pathway.
 5-HT3-receptors occur in peripheral nervous
system, especially nociceptive afferent neurons and
enteric neurons, and in CNS. Effects are excitatory,
mediated via direct receptor-coupled ion channel.

 5-HT4-receptors occur mainly in the
enteric nervous system (also in CNS).
Effects are excitatory, causing
increased gastrointestinal motility. Act
by stimulating adenylate cyclase.
 Little is known so far about the
function and pharmacology of 5-HT5-7-
receptors.

MECHANISM OF ACTION
 5-HT1A receptor-induced membrane
hyperpolarization and reduction in input
resistance results from an increase in K+
conductance.
 Slow depolarization induced by 5-HT2A-
receptor activation in areas such as the
prefrontal cortex, nucleus accumbens, and
facial motor nucleus involves a decrease in
K+ conductance.
 A second, distinct mechanism involving Ca2+-
activated membrane currents enhances
neuronal excitability and potentiates the
response to excitatory signals such as
glutamate.

 The fast depolarization elicited by 5-
HT3 receptors reflects direct gating of
an ion channel intrinsic to the receptor
structure itself.
 The 5-HT3 receptor-induced inward
current has the characteristics of a
cation-selective, ligand-operated
channel. Membrane depolarization is
mediated by simultaneous increases
in Na+ and K+ conductance.

PATHOPHYSIOLOGICAL
ROLES
 Neurotransmitter
 Precursor of melatonin
 Neuroendocrine functions
 Nausea and vomiting
 Migraine
 Haemostasis
 Hypertension
 Intestinal motility etc.

DRUGS AFFECTING
5-HT SYSTEM
 5-HT PRECURSORS:
Tryptophan increase brain 5-HT & produce behavioral
effects.
 SYNTHESIS INHIBITORS
p-Chlorophenylalanin selectively inhibit tryptophan
hydroxylase & reduce 5-HT level in tissue .
 UPTAKE INHIBITORS
Tricyclic antidepressants inhibit 5-HT uptake along with
NA .Some like fluoxetine ,sertraline are selective
serotonin reuptake inhibitors.

 STORAGE INHIBITORS
Reserpine block 5-HT uptake into storage
granules & cause depletion of all cell monoamines .
 DEGRADATION INHIBITORAS
Non-selective MAO inhibitors (tranylcypromine)
&selective MAO –A inhibitors (chlorgyline) increase 5-HT
content by preventing its degradation.
 NEURONAL DEGENRATION
5,6 Dihydroxytryptamine selectively destroys 5-HT
neurons .

5-HT RECEPTIR AGONISTS
1. D-Lysergic acid diethyl amide(LSD)
 Non selective 5-HT agonist
 Activates subtypes of 5-HT receptors including 5-HT1A,
5HT2A/2C ,5HT5-7 .
 Antagonize 5HT2A receptor in ileum .
AZAPIRONES
 Like buspirons ,gepirone act as partial agonist of 5HT1A
Receptor in brain.
8 HYDROXYDIPROPYLAMINO TETRALINE
 Selective 5HT1A agonist
 Used as experimental tool

 SUMATRIPTAN AND OTHER TRIPTAN
Selective 5HT1B/1D agonists,
Most effective in treatment of acute migraine attack
 CISAPRIDE
Prokinetic drug
increase g.i.t motility
Selective 5HT4 agonist.
 M-Cholorophenylpiperazine
Active metabolite of antidepressant drug
TRAZODONE.
found to be agonist of 5HT1B 5HT2A/2C Receptor in
brain.

5-HT RECEPTOR
ANTAGONISTS
 Cyproheptadine
 Methysergide
 Ketanserin
 Clozapine
 Risperidone
 Ondansetron

CYPROHEPTADINE
Block 5HT2A receptor
Utilized in controlling intestinal
manifestations of carcinoid &
postgastrectomy dumping syndrome
Antagonize priapism caused by 5HT
uptake inhibitor like fluoxetine.
Side effects: drowsiness,dry mouth
,ataxia confusion.

METHYSERGIDE
Antagonize action of 5HT on smooth
muscles including that of blood
vessels
Potent 5HT2A/2C ANTAGONIST & Non
selectively act on 5HT1 receptors .
Used for migraine prophylaxis

RISPERIDONE
5HT2A antagonist
Ameliorates negative symptoms of
schipherenia
Produce extrapyramidal side effects
on slightly higher doses

ONDANSETRON
Selectively 5HT3 Antagonist
Remarkable efficacy in controlling
nausea & vomiting following
administration of highly emetic
anticancer drugs & radiotherapy .

KETANSERIN
Selective 5HT2 receptor blocking
property with action on 5HT1,5HT3 &
5HT4 receptors .
5HT induced vasoconstriction
,platelets aggregation & contraction of
airway smooth muscles are
antagonized but not contraction of
guinea pig ileum or rat stomach .

CLOZAPINE
5HT2A/2C blocker
Inverse agonist activity at cerebral
5HT2A/2C Receptors
Efficacy in resistant cases of
schizophrenia

 Goodman & Gilman’s “The Pharmacological basis of
Therapeutics” Eleventh Edition, 2001. Published By McGraw-
Hill Publishing Company.
 “Tripathi K D”; “Essential of Medical Pharmacology”; Fifth
edition 2003, Published by Jaypee Brothers .
 “Rang H P”, “Dale M M”, “Ritter J M”, “Flower R J”; “Rang
and Dale’s Pharmacology”; Sixth edition, Published by
Churchchill Livingstone.
REFRENCES

 GOODMAN & GILMAN'S “THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS”, Eleventh Edition, 2001. Published By McGraw-Hill
Publishing Company
 Tripathi K..D , ”Essentials of Medical Pharmacology”, 6th Edition 2010,
Published By : Jaypee Medical Publishers
 RANG H.P, DALE M.M, RITTER.J, FLOWER.R,” Rang & Dales
Pharmacology, Sixth Edition 2010. Published By : Churchill Livingstone.

Serotonin & Their antagonists

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