Serotonin ( 5- hydroxy tryptamine ; 5HT )

1. Serotonin ( 5- hydroxytryptamine; 5HT )

2. Serotonin ( 5- hydroxy tryptamine; 5HT ) • Locations: - Gut enterochromaffin cells ( 90% ) - CNS ( Raphe nucleus, hypothalamic – limbic system, pituitary gland, pineal gland → melatonin, role as a neurotransmitter ) - Platelets ( scavengers )

3. Synthesis: *Trpl – a . a HydroxylaseDecarboxylase Trp 5-OH Trp 5-HT la.amethylation Dec. Tryptamine CH3– tryptamine ( hallucinogen )

6. Serotonin synthesis inhibitors: ** p – chlorophenylalanin irreversible Trp hydroxylase inhibitor ** Methyl dopa a.a decarboxylase inhibitor

7. Serotonin metabolism & excretion: Occurs wherever serotonin is present. Major sites of metabolism the lungs, liver, and brain. Major site of excretion is the kidneys. Ald. MAO Dehydrogenase 5-HT → 5-OH indoleacetyldehyde →5-OH indole acetic acid ( 5-HIAA )

8. MAO inhibitors: Pargyline, Tranylcyprmine • Another pathway to serotonin occurs in the pineal gland: 5-HT N-acetyl Hydroxy-o-methyl transferasetransferase 5-HT N-acetyl 5-HT melatonin

9. Serotonin receptors: 5 – 7 different receptors 3 well defined - 5-HT1 in CNS: mediate synaptic inhibition mechanism: ↓cAMP, ↑ K+ conductance in periphery: mediate excitatory & inhibitory effects in various smooth muscles

10. - 5-HT2 mediate synaptic excitation in CNS and smooth muscle contraction ( gut, bronchi, blood vessels ) or dilatation of some blood vessels Mechanism: ↓cAMP; ↓ K+ conductance; ↑ IP3 - 5-HT3 mainly present in CNS particularly in the CTZ and vomiting center ( stimulation → vomiting )

11. General effects: Serotonin physiologic effects: * Regulation of many aspects of behavior e.g sleep, pain perception, depression, sexual activity, aggressiveness…etc * Hypothalamic – pituitary function ↑ ACTH; GH; PRL release ↓ LH; FSH; TSH release

12. Serotonin pharmacological effects: - Blood vessels Arteries → constriction Veins → constriction Skeletal muscles → dilatation - B.P ↓ ↑ ↓ (overall effect ↑ B.P) - Heart ↑ Ht rate and contractility - Small intestine ↑ motility → diarrhea

13. - Stomach ↓ acid secretion ↑ mucus production - Bronchospasm - ↑ platelet aggregation - ↑ catecholamine release

14. Clinical pharmacology * Serotonin agonists: - Dexfenfluramine ↑ serotonin release, inhibits serotonin uptake and stimulates serotonin receptors Use: appetite suppressant (withdrawn by FDA in USA due to high risk of CV events) - Somatriptan 5-HT1 agonist mainly used in migraine Given orally, S.C, intranasally Major side effects: Chest pain ( coronary artery disease )

15. - Buspirone 5-HT1 agonist used in cases of anxiety - Cisapride 5-HT4 agonist and has parasympathomimetic effect ( GIT motility) used in gastroesophygeal reflux (withdrawn from USA because it leads to long QT syndrome) - Ergot alkaloids (Ergotamine) Have partial 5-HT receptor agonistic activity

16. Serotonin reuptake inhibitors Mainly used in the management of depression Selective Fluoxetine, Sertraline, Fluvoxamine… Nonselective TCA’s

17. Inhibitors of serotonin release: Octreotide, Lanreotide ( synthetic somatostatin-like drugs ) Mainly used in the management of Carcinoid syndrome and intractable diarrhea

18. Carcinoid syndrome Serotonin producing tumor Manifestations: - Diarrhea - Cutaneous flushing - Bronchoconstriction - Pellagra (niacin=vitamin B3 deficiency) Management Serotonin release inhibitors (octreotide) and antagonists

19. * Serotonin antagonists - Ergot alkaloids LSD (Lysergic acid diethylamide), Methysergide Use: Carcinoid syndrome; migraine - Cyproheptadine Antiserotonin and antihistamine effects Use: Allergic reactions, Carcinoid syndrome, Cushing’s syndrome

20. - Ketanserin Antiserotonin + α– adrenoreceptor blocking effects - Phenothiazines Have α– adrenergic blocking activity and partial serotonin antagonistic effects - 5-HT3 antagonists Ondansetron, Granisetron, Tropisetron Highly effective in the management of anticancerous – induced nausea and vomiting Effective orally, I.V, I.V infusion