Biosynthesis and Metabolism

Tryptophan-5-hydroxylase X p-chlorophenilalanine
5-Hydroxy tryptophan

Dopa decarboxylase
5-HT N-acetylase
MAOA-B N-acethyl-5-HT

5-hydroxyindole acetaldehyde
Aldehyde dehydrogenase Aldehyde reductase
5-HIAA 5-Hydroxytryptophol
Distribution and Storage
• Found in plant (eg. bananas), animal tissues, • Enterochromaffin cells in the gastrointestinal tract • Serotonergic neurons in the enteric nervous system • Raphe nuclei of the brain stem, brain serotonergic neurons (involved in deppression, anxiety, migraine, mood, sleep, appetite, temperature regulation, pain, blood pressure and vomiting) • Pineal gland (Serotonin → Melatonin) • Carcinoid tumor
Pharmacological Effects


Distribution Postreceptor
Partially selective Partially selective
5-HT5A,B Brain Unknown

Cardiovascular System
• A powerful vasoconstrictor except in skeletal muscle
• Dimetoxyiodophenylaminopropan → 5-HT ↑→ • Sumatriptan → 5-HT1D → vasoconstraction • Ergot alkaloids → 5-HT1 → vasoconstraction • Serotonin → Angiotensin II, norepinephrine, PGF2α↑→ 1. Bezold-Jarich reflex → blood pressure ↓ 2. Vasoconstraction → blood pressure ↑ 3. Vasodilation in vessels in skeletal muscle, NO ↑→ Airways
bronchial sensory nerve ending → hyperventilation • Bronchospasm in asthmatic patients
Gastrointestinal tract
• The stimulatory response
→ direct effects of 5-HT in smooth muscle cells (5-
in intestine and 5-HT2B in stomach fundus) → stimulation of enteric ganglia (5-HT ↑ → stimulation of nevre endings on longitudinal and • Relaxation or contraction in esophagus (5-HT ↑ • Enteric 5-HT → intraluminal pressure↑, pH ↓, intraluminal pressure↑, pH ↓, peristaltic contraction ↑ (5-HT ↑
Nervous System
• present in raphe nuclei of the brain stem, brain
in vomiting center and GI tract → vomiting reflex X Ondansetron, granisetron. • A potent stimulant pain and itch sensory nerve ending chemoreceptor reflex (Bezold-Jarich reflex) → bradycardia and hypotention
Pathophysiologic effects
Carcinoid tumors

Enterochromaffin cell tumors → secretion of 5-HT↑→
serotonin crysis X octreotide
• Plasma and platelet 5-HT concentrations vary with the
• Urinary concentrasions of 5-HT and its metabolites↑
Dumping sendrome
Postgastrectomy sendrome (flushing, dizziness,
weakness, vasomotor collapse, pain and headache)
Pulmonary embolism
Thromboemboli → Serotonin ve TXA ↑→
(5-HT2 X Ketanserin)
Anxiety and depression
Serotonin→5-HT →

Serotonin Agonists

• Acute treatment of migraine attacks with or without
Cont: Ischemic heart disease, peripheral and cerebral
vascular syndromes, uncontrolled hypertension, use within 24 hours of ergotamine derivatives, another 5-HT1 agonists; use within 72 hrs CYP3A4 inhibitors, hemiplegic or basilar migraine, prophylactic treatment of migraine, severe hepatic impairment, in patients <18 years of age • Adverse reactions: Chest pain, palpitation, dizziness,
headache, chills, pain, vertigo, nausea, vomiting, dyspepsia, abdominal pain/discomfort, weakness, paresthesia, back pain, hypertonia, pharyngitis • Pregnancy Risk Factor C

• It is the latest addition to this group
• Ketoconazole, erytromycin, fluconazole & verapamik
• Is the one of the most potent 5-HT agonist
• The active metabolite, N-desmethyl rizatriptan has
(Maxalt RPD)
• Absorption and elimination are rapid
• Metabolise by MAO-A to inactive metabolites • Competitive inhibitor of CYP2D6

(Imigran, Sumatran)
• 5-HT1B and 5-HT1D ↑→ Acute migraine and Cluster
• Contraindicated in coronary artery disease and angina • Naratriptan is contraindicated in severe hepatic or renal impairment, peripheral vascular syndromes
• The dose should be reduced in moderate to severe

(Avmigran, Cafergot, Ergafein),
dihydroergotamine (Neomigran)
• Some of their properties are similar to those of
Additional effects: adrenergic receptors block, vasoconstriction directly
(Buspon), gepirone, ipsapirone
• 5-HT ↑

Fenfluramine, deksfenfluramine

• 5-HT res↑, serotonin release↑, serotonin re-uptake↓

Sibudramin (Reductil)
• serotonin re-uptake↓ →anorexigenic


• 5-HT ↑→

Serotonin- selective reuptake inhibitors

Fluoxetine, paroxetine, sertraline
• Antidepressants
• +MAO inhibitors → Serotonin syndromes
Serotonin antagonists

Methysergide (5-HT1 and 5-HT2 block)
strong competitive serotonin antagonist, partial serotonin agonist (vasoconstrictor) • used in the prophylaxis of migraine and Horton • antidiaretic in carcinoid syndrome and Dumping • contraindicates in peripheral vascular diseases and
(5-HT2A ve H1 block)
• Antidiaretic in carcinoid syndrome and Dumping • side effects: weight gain, drowsiness and increased
(5-HT1C, 5-HT2 and α1 block)
• used in the treatment of hypertension, vasospastic conditions and Raynaud syndrome
(5-HT2 block)
• platelet agregation ↓, vasoconstriction↓,
Granisetron >Ondansetron
(5-HT3 block)
• used in the prevention of nausea and vomiting
(5-HT3 block)
• used in the prevention of nausea and vomiting
(Antiserotonerjik, antihistaminik)
• used in the prophylaxis of migraine



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