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  1. 1. 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>
  2. 2. <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
  3. 4. 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
  4. 5. Serotonin GI Psycho. CV Haemo. & Thromb. (Carcinoid tumor)
  5. 6. <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>
  6. 7. 5-HT4 + -CNS- -GI- Prokinetic (fast) -CNS- Serotonin (5-HT) MAO
  7. 8. Hybrid-like, multiple actions
  8. 9. 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)
  9. 11. 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
  10. 12. 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
  11. 13. 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
  12. 15. Migraine (headache attack) <ul><li>Premonitory aura: flashing lights, throbbing unilateral headache, photophobia, hemianopia, vomiting, polyurea, etc. </li></ul><ul><li>Prodromal phase: vasoconstriction </li></ul><ul><li>Headache phase: vasodilation (1950) </li></ul><ul><li>Inflammatory mediators: substance P & calcitonin gene-related peptide (1990) </li></ul><ul><li>Tx: ergot alkaloids or sumatriptan </li></ul>
  13. 16. 5-HT agonists and antagonists Ergot alkaloids (Ergotamine, dihydroergotamine, bromociptine, ergonovine, methylergonovine, methysergide ) (1) from Secale cornutum (ergot), the sclerotium of fungus ( Claviceps purpurea ) parasitizing rye (2) contain lysergic acid (3) partial 5-HT, dopaminergic and  -adrenergic receptor agonists (St Anthony’s fire) (4) uterus and vascular smooth contraction (5) prevent migraine headache
  14. 19. CNS
  15. 21. 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
  16. 22. Ketanserin 1.(selective) 5-HT2 antagonist 2. Vasodilation (  1-antagonist), antihypertension   Fluoxetine 1. second-line antidepressant (atypical) 2. Block 5-HT reuptake in serotonergic neuron   Buspirone 1. anxiolytic drug 2. A partial central 5-HT1A agonist   Ondansetron 1. chemotherapy-induced emesis/vomiting 2. Block 5-HT3 receptor 3. 5-HT -> 5-HT3 receptor (chemoreceptor trizzer zone) -> vomting center -> vomting
  17. 24. , H4
  18. 33. Mechanism of histamine H1 receptor: phosphoinositol-phospholipase C (PI-PLC)->↑Ca 2+ , DAG H2 receptor: activate adenylyl cyclase->↑cAMP H3 receptor: inhibit adenylyl cyclase->↓cAMP
  19. 35. H1 antagonists   Pharmacology properties 1. Antiallergic action (perennial allergic rhinitis, conjunctivitis, itching) 2. Sediation (drug pass BBB and inhibit central H1) 3. Antimotion sickness (antimuscarinic action) 4. Antiemetic action (inhibit dopamine D2) 5. Antiparkinsonism (antimuscarinic action) 6. Local anesthetic action (inhibit sodium channel in excitable membrane)
  20. 40. 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>