To describe the roles of histamine and serotonin receptor
subtypes
Histamine
• Naturally occurring, low-molecular weight, hydrophilic
endogenous amine found in large amount in circulating
mast cell and circulating basophil. The bound form of
histamine is biologically inactive.
• Non-mast cell histamine is found in several tissues,
including the brain, where it functions as a
neurotransmitter.
• Synthesis: in tissue by decarboxylation of histidine and
stored in vesicle. It is released in response to antigen-
antibody reaction or in response to certain drug
(Tubocurarine, succinylcholine, morphine, some
antibiotics).
• Metabolism: important pathway is methylation by
histamine-N-methyltransferase and further degraded by
MOA. The other pathway is oxidative deamination by
histaminase. Metabolites of both pathways are inactive.
• 4 subtypes of histamine receptor H1 (Gq coupled), H2 (Gs
coupled), H3 and 4 (Gi coupled)
Histamine 1 receptor (SM, endothelium, brain)
• Primarily cause most of SM contraction in respiratory and
GI tract except blood vessel
• Cause pruritis and sneezing by sensory nerve stimulation
• Slow HR by decreasing AV node conduction. Coronary
vasoconstrictor.
• In CNS concentrated in hypothelamus, increase
wakefulness
• They are also involved in the signalling at the vestibular
apparatus and vomit centre, and involved in motion
sickness.
Histamine 2 receptor (gastric mucosa, cardiac muscle, mast
cell, brain)
• Stimulation of gastric H ion secretion
• Increase cardiac contractility and HR. coronary vasodilator.
Effect mediated by both H1 and H2 receptor
• Peripheral vascular smooth muscle relaxation (by NO
release)
• Increased capillary permeability
Histamine 3 (presynaptic, brain, myenteric plexus)
• When stimulated, cause inhibition and release of
histamine. Also inhibit the release of a variety of
neurotransmitters.
Histamine 4
• Seem to be important in immune reaction, act to mediate
mast cell chemotaxis.
To describe the roles of histamine and serotonin receptor
subtypes
Serotonin (5-hydroxytryptophan )
• Widely distributed endogenous vasoactive substance
present predominantly in enterochromaffin cell of
gastrointestinal tract, and the remaining in CNS and
platelet.
• It causes widespread vasoconstriction (cerebral, coronary,
pulmonary) and important neurotransmitter in emesis
and pain modulation. Also has implication in
pathogenesis of carcinoid syndrome (too much 5HT),
mood disorder (too little serotonin).
• Synthesis: precursor is tryptphan, dietary source.
Conversion happen by tryptophan hydroxylase enzyme
rich in enterochromaffin cell
• Metabolism: Mainly by MAO. Principal metabolite is 5
hydroxyindoleacetic acid. (5-HIAA) Urinary excreted.
Serotonin receptor subtypes
Serotonin 1 receptor (Gi coupled)
• Function mainly as inhibitory presynaptic receptors.
Found mainly in brain.
• The 5-HT1A subtype is particularly important in the brain,
in relation to mood and behaviour
• The 5-HT1D subtype, which is expressed in cerebral blood
vessels, is believed to be important in migraine. (Cerebral
vessel’s vasoconstriction is mediated by 5HT1 while in
other vessels, 5HT2 is responsible.)
Serotonin 2 receptor (Gq coupled)
• 5HT2A most important. Particularly important in
periphery, mediate smooth muscle constriction in
coronary, pulmonary vessel, gut, bronchi. Platelet
aggregation
• Important in pathogenesis of carinoid tumor
Serotonin 3 receptor (Ligand-gated cation channel)
• Occur mainly peripheral nervous system, autonomic and
enteric neuron.
• 5-HT3 receptors also occur in the brain, particularly in the
area postrema, a region of the medulla involved in the
vomiting reflex,
Serotonin 4 receptor (Gs coupled)
• Their main physiological role appears to be in the
gastrointestinal tract, where they produce neuronal
excitation and mediate the effect of 5-HT in stimulating
peristalsis. (prokinetic). Occur in brain, peripheral organs,
GIT, bladder, heart.
Serotonin 5-7
• Function not well known
To outline the pharmacology of histamine antagonists
H1 antagonist (dirty drug)
• H1 antagonist is highly selective for histamine 1 receptor
(competitive antagonist but no effect on histamine
release) and has little effect on H2 or H3 receptor
• It may also block (cholinergic) muscuranic receptor,
(adrenergic) alpha receptor, serotonin receptor (e.g.
cyproheptadine), sodium channel in excitable tissue. (LA
like activity), also antiparkinson effect
• First generation H1 antagonist has more complete
distribution in CNS so block more autonomic receptor
compared to second generation H1 antagonist.
Especially first generation.
• Adverse effect in CNS common – somnolence,
impairment of cognitive function, diminished alertness.
• Antimuscarinic effect: dry mouth, urinary retention,
blurred vision, impotence, tachycardia. Prolonged QTc,
dysrrhythmia can happen.
• Antihistamine OD resemble anticholinergic OD. Maybe
associated with seizure, cardiac conduction abnormality
resembling TCA.

Clinical use
• Allergic reaction including anaphylaxis, allergic
rhinoconjunctivitis, motion sickness and post op N+V.

Pharmacokinetic
• Well absorbed in oral administration. PPB high fro, 78-
99%. Most H1 antagonist is metabolized by hepatic mixed
function oxidase.

Side effects
To outline the pharmacology of drugs acting via effects on
serotonin or serotonin receptors
Drug affecting serotonin system may be classified as
Drug increase effect of serotonin
• Drug of agonist at serotonin receptor (e.g. sumitriptan
5HT1D agonist for migrane. Cisapride 5HT4 agonist for
GORD and motility disorder)
• Drug enhance release of serotonin (e.g. tramadol)
• Drug inhibit reuptake of serotonin (e.g. antidepressant
TCA, SSRI)
• Drug inhibit metabolism of serotonin (e.g. MAOI)
Drug reduce effect of serotonin
• Drug of antagonist at serotonin receptor. (e.g.
ondansetron 5HT3 antagonist. Lysergic acid derivative.
Cyproheptadine for carcinoid syndrome, serotonergic
syndrome known to block 5HT2A, ketanserin also block
5HT2A and alpha 1 adrenoreceptor so used for
hypertension and some vasospastic condition.)