SN4 SHORT NOTE 5M ★ High-yield

Describe 5-hydroxytryptamine, its receptors and the drugs acting on them. Add a note on serotonin syndrome.

Pharmacology · 2nd Professional — Para-Clinical

Serotonin — Synthesis and Distribution

5-hydroxytryptamine (5-HT, serotonin) is an autacoid and neurotransmitter formed from the amino acid tryptophan.

Tryptophan → 5-hydroxytryptophan (by tryptophan hydroxylase, the rate-limiting step) → 5-HT (by decarboxylase)
Degraded by monoamine oxidase to 5-HIAA, measured in urine as the marker of carcinoid tumours
Distribution — 90% in enterochromaffin cells of the gut; about 8% in platelets (which take it up but cannot synthesise it); the remainder in the CNS raphe nuclei

Receptors and Their Drugs

Receptor	Type	Effects	Drugs
5-HT1A	GPCR (Gi)	Anxiolysis; presynaptic autoreceptor	Buspirone (partial agonist)
5-HT1B/1D	GPCR	Cranial vasoconstriction; inhibits neuropeptide release	Triptans — sumatriptan
5-HT2A	GPCR (Gq)	Vasoconstriction, platelet aggregation, bronchoconstriction; hallucinations	Ketanserin; atypical antipsychotics; cyproheptadine; LSD is an agonist
5-HT3	Ligand-gated ion channel — the only one	Vomiting (area postrema and vagal afferents); pain	Ondansetron, granisetron, palonosetron
5-HT4	GPCR (Gs)	Increased gut motility	Prucalopride (agonist); cisapride was withdrawn for QT prolongation

CLINICAL PEARL

5-HT3 is the exception that makes ondansetron work so quickly. Every other serotonin receptor is G-protein coupled and acts over seconds; 5-HT3 is a ligand-gated ion channel acting in milliseconds. Blocking it interrupts the vomiting reflex almost at once, which is why these drugs are so effective in chemotherapy-induced and post-operative vomiting.

Actions of 5-HT

Cardiovascular — a triphasic response: initial fall (reflex bradycardia), then a rise (vasoconstriction), then a fall (vasodilatation in skeletal muscle)
Gastrointestinal — increased motility and secretion; excess causes diarrhoea and cramps
Platelets — aggregation and vasoconstriction at sites of injury
CNS — regulation of mood, sleep, appetite, temperature, pain perception and vomiting
Respiratory — bronchoconstriction, marked in asthmatics

Clinical Syndromes and Uses

Carcinoid syndrome — a serotonin-secreting tumour causing flushing, diarrhoea, bronchospasm and right-sided valvular fibrosis; diagnosed by urinary 5-HIAA and treated with octreotide
Serotonin syndrome — excess serotonergic activity, usually from combining drugs: an SSRI with an MAO inhibitor, tramadol, linezolid, triptans or St John wort. The triad is (1) altered mental state, (2) autonomic instability with fever, sweating and tachycardia, and (3) neuromuscular hyperactivity with clonus, hyperreflexia and rigidity — clonus is the most useful sign. Treated by stopping the drugs, cooling, benzodiazepines and, in severe cases, cyproheptadine
Therapeutic uses of serotonergic drugs — SSRIs in depression and anxiety; triptans in migraine; ondansetron for vomiting; buspirone for anxiety; cyproheptadine as an appetite stimulant and antipruritic

Applied Aspects

Serotonin syndrome is distinguished from neuroleptic malignant syndrome by its rapid onset (hours rather than days), clonus and hyperreflexia; neuroleptic malignant syndrome causes lead-pipe rigidity with hyporeflexia and evolves over days
Allow a washout of at least 2 weeks between an SSRI and an MAO inhibitor, and 5 weeks after fluoxetine because of its long half-life
Tramadol is a frequently overlooked serotonergic drug, and is commonly prescribed alongside antidepressants without the interaction being considered
Ondansetron prolongs the QT interval, and should be used cautiously with other QT-prolonging drugs and in electrolyte disturbance
Ask about herbal preparations, particularly St John wort, which is serotonergic and an enzyme inducer, and which patients do not regard as a drug

All questions in Autacoids, Nsaids & Antigout

Every Pharmacology chapter →