Newman Osafo, BPharm, PhD.

Department of Pharmacology, FPPS, CoHS, KNUST

nosafo.pharm@knust.edu.gh
§ 5-HT synthesis involves the rate limiting
enzyme, tryptophan hydroxylase and is
mainly degraded by the action of
monoamine oxidases.

§ 5-HT is best known as a neurotransmitter

in the brain, but about 95% of it is
synthesized, stored and released by
enterochromaffin cells in the intestinal
mucosa.

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§ 5-HT signaling may modulate the peripheral immune
system

§ different immune cells can generate, store, respond to

and/or transport serotonin

§ many different immune cell types, including T cells,

macrophages, mast cells, dendritic cells and platelets have
one or more of these capacities.

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§ In monocytes/macrophages, serotonin modulates
cytokine secretion.

§ Serotonin can also suppress the release of TNF-α

and IL-1β by activating serotonin receptors (5-HT2A)

§ Neutrophil recruitment and T-cell activation can

both be mediated by serotonin.
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§ Serotonin can affect food intake via activation of the
anorexigenic melanocortin system involving 5-HT2c
receptors

§ It also inhibits the orexigenic NPYergic system

§ reduction of brain serotonin by reducing availability of its

precursor tryptophan has been shown to be beneficial in
the treatment in anorexia during cancer.

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§ Receptors of the CTZ that have been identified to induce emesis
include opioid µ, κ, D2, NK-1 and 5-HT3.

§ Ondansetron and Granisetron are a selective serotonin

antagonist, used for treating chemotherapy-induced nausea and
vomiting.

§ binds to the serotonin receptors located on the vagal neurons

lining the gastrointestinal tract, and block signaling to the
vomiting center in the brain
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§ The 5-HT receptors occur on other neurons in the ENS,
where they can be stimulatory (5-HT3 and 5-HT4)
§ The availability of serotonergic prokinetic drugs has in
recent years been restricted because of serious adverse
cardiac events
§ Prucalopride is a specific 5-HT4R agonist that facilitates
cholinergic neurotransmission.
§ It acts throughout the length of the intestine, increasing
oral-cecal transit and colonic transit without affecting
gastric emptying.

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§ Cisapride is a 5-HT4 agonist that stimulates adenylyl
cyclase activity in neurons. It also has weak 5-HT3
antagonistic properties and may directly stimulate smooth
muscle.

§ Withdrawn due to the potential to induce serious and

occasionally fatal cardiac arrhythmias.

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§ Recurrent unilateral headache which may be accompanied by
GI and visual disorders
§ More prevalent in females than males with a ratio of 3:1

§ Complex neurovascular disorder marked by vasodilation of

intracranial and extracerebral vessels

§ Involves stimulation of surrounding trigeminal sensory nervous

pain pathway that results in headache

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§ Out of the 7 receptor types, 5-HT1, 5-HT2 and 5-HT3
are identified to be responsible for migraine

§ 5-HT receptors may have different roles in

migraine.

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§ CGRP is released via activation of the trigeminovascular
system

§ There is also marked decreased levels of 5-HT in migraineurs

§ Serotonin principally acts on serotonin receptors in the

trigeminovascular system to lower levels of key molecules
such as CGRP

§ The interplay of the levels of these peptides gives the

nociceptive information to the central neurons in the brain 11
stem that in turn relay the pain signals
§ Levels of serotonin and CGRP are affected by
physiological hormonal intervention.

§ A fluctuation in estrogen decreases serotonin by

affecting its metabolism which can bring on
migraine

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§ Molecules that act as agonist/antagonist of 5-HT receptors in
trigeminovascular system are used in migraine management.

§ CGRP receptor antagonist

§ Currently, CGRP receptor antagonists such as Rimegepant and
ubrogepant are used as antimigraine therapy.

§ Selectively block CGRP receptor without the vasoconstrictive effect

§ Monoclonal antibodies targeting CGRP or its receptors:

Eptinezumab, galcanezumab, erenumab.
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§ Lysergic acid diethylamide (LSD), methysergide

§ They bind to multiple 5-HT receptors

§ Methysergide has antagonist activity on 5-HT2B to selectively

decrease carotid blood flow by constricting arteriovenous
anastomoses providing migraine prophylaxis. Also blocks 5-
HT2A and 5-HT2C in its antimigraine action.

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§ Triptans
Sumatriptan, zolmitriptan, rizatriptan, frovatriptan
§ Have fewer side effects than the ergot derivatives
§ Potent cranial vasoconstrictor with neural antimigraine
activity.
§ Are selectively agonist on 5-HT1B/1D receptor
§ Vascular complications due to vasoconstriction

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§ Ditans
Lasmiditan
§ A serotonin receptor agonist which binds to 5-HT1F receptor
subtype.
§ Possesses fewer side effects than triptans possibly due to its
lack of activity on 5-HT1D and 5-HT1B receptor subtypes.
Devoid of vascular complications.
§ Drug causes CNS depression resulting in dizziness and
sedation.
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