Autacoid (II) 2008 Hsiao G <ul><li>Serotonin & Histamine </li></ul><ul><li>Biosynthesis </li></ul><ul><li>Pharmacological Effects </li></ul><ul><li>Action Mechanisms </li></ul><ul><li>Adverse Effects </li></ul>
<ul><li>“ Noxious pustule in the ear of grain” Assyrian Tablet, 600 B.C. </li></ul><ul><li>Vomiting, diarrhea, burning sensation, limbs gangrenous and rotted off, hallucination and manic excitement </li></ul>Serotonin
5-Hydroxytryptamine (5-HT), serotonin (Page, 1976) 1. endogenous monoamine 2. central neurotransmitter 3. local (autacoid) action in various tissues Occurrence and distribution Mammalian: (1) about 90% of serotonin produced by enterochromaffin cells in intestine (Erspamer, 1930s) (2) 8% in platelet (uptake system, transporter) (3) 2% in CNS (serotonergic neurons, rostral raphe nuclei), pineal gland, hypothalamus
Serotonin GI Psycho. CV Haemo. & Thromb. (Carcinoid tumor)
<ul><li>Biosynthesis and metabolism </li></ul><ul><li>Serotonin is synthesized in neuron and enterochromaffin cells by hydroxylation and decarboxylation of the amino acid tryptophan. (melatonin) </li></ul><ul><li>5-hydroxyindoleacetic acid (5-HIAA) is major serotonin metabolite. </li></ul>
Pharmacological effects Cardiovascular system 1. Vasoconstraction (5-HT2A R.), arteriolar dilation (5-HT1 R.), peripheral adrenergic neurotransmission 2. Triphasic change in blood pressure (1) a transient decrease (reflex stimulation of chemoreceptors within the coronary arteries) (Bezold- Jarisch reflex) (2) a period of hypertension that lasts several minutes (direct constraction of blood vessels of splanchnic and renal vascular beds) (3) a prolonged period of lowered pressure (vasodilation of vessels in specific vascular beds) (ex. Skeletsl muscle) 3. heart: positive inotropic and chronotropic effect (5-HT1)
Platelet 1. 5-HT2A produces a weak platelet aggregation, but with adhesive factor (collagen) -> 5-HT can amplify the platelet aggregation reaction and speed clot formation GI tract 1. direct stimulation of intestinal muscle 2. indirect stimulation through excitation of ganalion cells within the intestinal wall -> diarrhea and abdominal pain 3. Cisapride (5-HT4 receptor agonist) -> propulsive motor activity of stomach and small, large intestine -> treatment of motility disorder Airway bronchial smooth muscle cell constriction
CNS 1. stimulate afferent nerve ending, ganalion cells -> pain perception, behavior, body temperature 2. synaptic transmission -> antidepressant drugs 3. 5-HT1 receptors on adrenergic nerve terminal -> NE release 4. 5-HT3 receptor located on sensory neuron mediate a depolarizing response -> pain and itching
Mechanism of action ketanserin Receptor mechanism Response agonist antagonist 5-HT1A -AC Presynaptic autoreceptor which inhibt neurotransmitter release in doral raphe, hippocampus and cerebral cortex. Postsynaptic receptors at several sites including hippocampus Ergotamine Buspirone 5-HT1C PI turnover Central neuronal depolarizing -- Mianserin Ketanserine 5-HT1D - AC Vasoconstriction in some cranial vascular beds, e.g. carotid artery, pial and dural vessels. Inhibitory presynaptic autoreceptors (which reduce 5-HT release) Sumatriptan 5-HT2 PI turnover Platelet aggregation, vasoconstriction, bronchoconstriction, poatsynaptic receptors mediate central and peripheral neuronal depolarization -- Methysergide Pizotifen mianserin 5-HT3 Ion channel Central and peripheral neuronal depolarization, vomiting via sensory nerve terminals of the vagus -- ondansetron
Methysergide 1. a congener of methylergonovine and LSD 2. vasoconstrictor and inhibit 5-HT2 receptor and - adrnergic block 3. prevent migraine headache, but not effective in treatment of established migraine 4. rebound headaches may occur when the drug is withdraw 5. side effect: nausea, dizziness, insomnia, behavioral changes Cyproheptadine 1. H1, 5-HT2A receptor antagonist 2. used to relieve itiching of skin, intestinal hypermotility of carcinoid syndrom 3. side effect: antihistamine-like effect
Side effects <ul><li>Cimetidine: </li></ul><ul><li>renal and hepatic damage (high dose) </li></ul><ul><li>dizzine, confusion (elderly pt), leukopenia, rashes or myalgias </li></ul><ul><li>interfere with metabolism of the drug inhibit hepatic cytochrome p 450 ( warfarin, phenytoin, benzodiazepine, propranolol metabolism) </li></ul><ul><li>antiandrogenic action binding to testosterone receptor in man (gynecomastia, tenderness, impotence) </li></ul><ul><li>Other new drugs did not interfere with metabolism of the drug and antiandrogenic action </li></ul>
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