1. Serotonin ( 5- hydroxy tryptamine; 5HT )

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

3. Synthesis: Synthesis: * Trp l – a. a * Trp l – a. a Hydroxylase Decarboxylase Hydroxylase Decarboxylase Trp 5-OH Trp 5-HT Trp 5-OH Trp 5-HT l a.a methylation Dec. Tryptamine CH 3 – tryptamine ( hallucinogen ) Tryptamine CH 3 – tryptamine ( hallucinogen )

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

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

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

9. Serotonin receptors: Serotonin receptors: 5 – 7 different receptors 3 well defined 5 – 7 different receptors 3 well defined - 5-HT 1 in CNS: mediate synaptic inhibition - 5-HT 1 in CNS: mediate synaptic inhibition mechanism: ↓cAMP, ↑ K + conductance mechanism: ↓cAMP, ↑ K + conductance in periphery: mediate excitatory & inhibitory effects in various smooth muscles in periphery: mediate excitatory & inhibitory effects in various smooth muscles

10. - 5-HT 2 mediate synaptic excitation in CNS and smooth muscle contraction ( gut, bronchi, blood vessels ) or dilatation of some blood vessels Mechanism: ↓cAMP; ↓ K + conductance; ↑ IP 3 Mechanism: ↓cAMP; ↓ K + conductance; ↑ IP 3 - 5-HT 3 mainly present in CNS particularly in the CTZ and vomiting center ( stimulation → vomiting ) - 5-HT 3 mainly present in CNS particularly in the CTZ and vomiting center ( stimulation → vomiting )

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

12. Serotonin pharmacological effects: Serotonin pharmacological effects: - Blood vessels Arteries → constriction Arteries → constriction Veins → constriction Veins → constriction Skeletal muscles → dilatation 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 Clinical pharmacology * Serotonin agonists: - Dexfenfluramine - Dexfenfluramine ↑ serotonin release, inhibits serotonin uptake and stimulates serotonin receptors ↑ serotonin release, inhibits serotonin uptake and stimulates serotonin receptors Use: appetite suppressant (withdrawn by FDA in USA due to high risk of CV events) Use: appetite suppressant (withdrawn by FDA in USA due to high risk of CV events) - Somatriptan - Somatriptan 5-HT 1 agonist mainly used in migraine 5-HT 1 agonist mainly used in migraine Given orally, S.C, intranasally Given orally, S.C, intranasally Major side effects: Chest pain ( coronary artery disease ) Major side effects: Chest pain ( coronary artery disease )

15. - Buspirone - Buspirone 5-HT 1 agonist used in cases of anxiety 5-HT 1 agonist used in cases of anxiety - Cisapride - Cisapride 5-HT 4 agonist and has parasympathomimetic effect ( GIT motility) used in gastroesophygeal reflux (withdrawn from USA because it leads to long QT syndrome) 5-HT 4 agonist and has parasympathomimetic effect ( GIT motility) used in gastroesophygeal reflux (withdrawn from USA because it leads to long QT syndrome) - Ergot alkaloids (Ergotamine) - Ergot alkaloids (Ergotamine) Have partial 5-HT receptor agonistic activity Have partial 5-HT receptor agonistic activity

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

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

18. Carcinoid syndrome Serotonin producing tumor Manifestations: - Diarrhea - Diarrhea - Cutaneous flushing - Cutaneous flushing - Bronchoconstriction - Bronchoconstriction - Pellagra (niacin=vitamin B 3 deficiency) - Pellagra (niacin=vitamin B 3 deficiency)Management Serotonin release inhibitors (octreotide) and antagonists Serotonin release inhibitors (octreotide) and antagonists

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

20. - Ketanserin - Ketanserin Antiserotonin + α – adrenoreceptor blocking effects Antiserotonin + α – adrenoreceptor blocking effects - Phenothiazines Have α – adrenergic blocking activity and partial Have α – adrenergic blocking activity and partial serotonin antagonistic effects serotonin antagonistic effects - 5-HT 3 antagonists Ondansetron, Granisetron, Tropisetron Ondansetron, Granisetron, Tropisetron Highly effective in the management of Highly effective in the management of anticancerous – induced nausea and vomiting anticancerous – induced nausea and vomiting Effective orally, I.V, I.V infusion Effective orally, I.V, I.V infusion