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Serotonin & migraine

For Medical Students

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Serotonin & migraine

  1. 1. Ashfaq SEROTONIN (5-Hydroxytryptamine)
  2. 2. • Substances in tissues (In response to stimulus …… Released ) Red Skin, Itch, Pain, Bronchospasm. [ autocoids ] Histamine & SEROTONIN ( Bioactive amines ) • Vasoconstrictor released from clot. Tonic Substance …. SEROTONIN • SM stimulant in intestine ( ENTERAMINE ) Synthesis 5-Hydroxytryptamine (5-T) ALL … same metabolite of 5-Hydroxytyptaphan
  3. 3. Serotonin acts as • Neurotransmitter • Local Hormone • Component of platelet clotting process • Role in migraine (Headache) • Mediator of Signs & Symptoms of Carcinoid syndrome ( carcinoid Tumor) ( serotonin antagonists as TREATMENT)
  4. 4.  Plants, Animals,Venoms & Stings (Red skin, Itch, Pain, Bronchospasm)  L- tryptaphan  Hydroxylation of indole ring at C 5 (Rate limiting ) [fenclonine(PSPA), p-chloramphetamine]  Decarboxylation SEROTONIN
  5. 5.  Storage by VAT (vesicle associated transporter)  Metabolism By MAOs ◦ 5-hydroxyindoleacetaldehyde ◦ 5-hydroxyindoleacetic acid ( 5-HIAA ) ◦ Excretion in urine (24 hrs HIAA in Urine DIAGNOSTIC)  90% of total in Enterochromaffin cells in GIT  In Plaetlets …. Blood …. SERT (active serotonin Transporter)  Membranes of serotonergic Nerve Endings  Cell bodies of of serotonergic neurons Raphe N.
  6. 6. Mechanism of Action( Subtype, location, G protein ) Through Specific Receptors ( 5-HT Receptors) – 7 Sub Types ( 5-HT1 ……..5-HT3 ………..5-HT7 ) • Further sub Types – 5-HT1 A. 5-HT1B, 5-HT1D, 5-HT1E. 5-HT1F … Gi, cAMP – 5-HT2A. 5HT2B, 5-HT2C ………………….Gq, IP3 – 5-HT3 ….. Ion Channel – 5-HT4 …. Gs, cAMP – 5-HT5A,B … , cAMP – 5-HT6,7 …Gs, cAMP – 5-HT1P … GO . Slow EPSP …. Enteric Nervous system • 6 are G-Protein Linked Membrane Receptors • 1 i.e. 5-HT3 Is Ligand gated Ion Channel ( Member of nicoitinic/GABAA family of Na/K Channel Protein )
  7. 7.  CNS ◦ Neurotransmitter ◦ Precursor of Melatonin  PNS ◦ Chemoreceptor reflex ( Bezold-Jarisch reflex ) ◦ 5H3 receptors in coronary vasculature when stimulated , there is bradycardia (vagal outflow) & hypotension (decreased heart rate)
  8. 8. • CVS – B.P. • Triphasic B.P. Response – Dec. B.P. (5HT3 … Chemoreceptor ref.) – Inc. B.P. ( 5HT2 …. Vasocostriction.) – Dec. B.P. ( Vasodilation of Sk.Ms. Vessels – Vessels • Vasocostriction (5HT2) • Dilation --- Sk.Ms.& Heart ( Intact Endothelium ) • Pulmonary & Renal vassels Constriction • Veins also constrict ….. Capillary filling ….. Flush • Prolonged B.P. ……… subendocardial fibroplasia. – Heart • Direct +chronotropic & Ionotropic Effect (small) • 5-HT1A, 5-HT2, 5-HT4 ……. Development of Heart in Fetus • 5HT2B Agonists …. Ch. Exposure …. Valvulopathy • 5HT2B Antagonists can prevent Pulmonary hypertension
  9. 9.  GIT  Secretions Little effect …. Generally Inhibitory  Motility  Powerful Stimulant (5-HT2, & Stimulation of Ganglion cells in ENS) . (also 5-HT1A & 5-HT7 ) Inc. Tone & Facilitate Peristalsis  Prokinetic Effect ( 5-HT4 in ENS)  Increse Ach. Release ….. Cisapride
  10. 10.  Skeletal Muscle  5-HT2 Role not understood  Serotonin Syndrome  Hyperthermia  Hyprtension  Tremour  Clonus  Hyper reflexia  Hyperactive Bowel Sounds …. Diarrhea  Mydriasis  Agitation  Coma  Onset in Hrs  D/D Malignant Hyperthermia (MH) & Neuroleptic malignant Syndrome (NMS)
  11. 11.  Eye  5-HT2A Agonists Reduce IOP  5-HT2 Antagonists & Ketanserin Block this action
  12. 12. Therapeutic Uses Not Clinically used • Some 5-HT agonists are in use – Triptans 5-HT1D/1B (Migraine) – Ergot Alkaloids 5-HT1D/1B (Migraine) Partial agonist – CISAPRIDE 5-HT4 (Prokinetic, GERD) – TEGASEROD 5-HT4 Partial agonist(IBS) – FLUOXETINE SSRI (antidepressant)
  13. 13. Serotonin Antagonists Synthesis Inhibitors p-chloroampetamine, TOXIC p-chlorophenylalanin TOXIC Storage Inhibitors Reserpine Symptholytic effects. High circulting Serotonin Antagonism at RECEPTORS is desirable in Carcinoid Tumor • 5HT2 Blockers – Phenoxybenzamine (alpha1 Blockers) – Cyproheptidine (Phenothiazine H1 Blocker) – Ketanserine alpha1 Block Antagonise Platelet aggregation – Ritanserine No alpha block Alter BT., Thrmboxane, Alter Platelet • 5HT3 Blockers – Ondansetron Antiemetic in Cancer Chemotherapy
  14. 14.  “Classic”  “aura” nausea,Vomiting,Visual Disturbances (Scotomas, Hemiaopia)Speech abnormalities  Severe Throbbing Unilateral Headache  “Common”  No “aura”  Headache is similar
  15. 15.  Still not Understood ◦ Involves Trigeminal N. distribution to intracranial/Extracranial arteries ◦ Temporal Artery Pulsation ◦ CGRP ( Calcitonin gene-related peptide), powerful vasodilator ◦ Substance P ◦ Neurokinin A - Extravasation of plasma & plasma proteins - Mechanical stretch of PAIN NERVE ENDINGS by this perivascular edema
  16. 16.  Acute Attack ◦ Triptans Sumatryptan ◦ Ergot Alkaloids ◦ Antidepressants  Stimulate Presynaptic 5-HT1D/1B receptors on Trigeminal Nerve Endings (Inhibit Rlease of Vasoactive Peptide)  Ergot alkaloids & Triptans have VASOCONSTROCTOR Effect ◦ Antiseizures  Suppress Excessive firing of neurons.
  17. 17. • Others – NSAIDS • Paracetamol, • Aspirin, • Ibuprofen – Antiemetics • Metoclopramide I/V – Rarely Parenteral Opioid
  18. 18.  Prophylaxis  Propranolol, Nadolol  Amitriptyline  Topiramate  Verapamil
  19. 19. Triptans • Naratiptan Eletriptan • Zolmitiptan Frovatriptan • Almotriptan Rizatriptan – All are 5HT1 agonists – Equal in efficacy – Greater efficacy than Other Drugs • e.g. Oral, Parentral, Rectal, Ergot Alkaloids – Differ Pharmacokinetically
  20. 20. Side Effects Of Triptans • Mild – Altered Sensations ( Tinggling, Warmth ) – Dizziness – Muscle Weakness – Neck Pain – Injection Site Reaction ( if Parenral ) – Chest Pain 1 – 5% • Duration of Action Shorter Than duration of Headache ( should be repeated )
  21. 21. • Severe – Risk of Coronary artery disease – Naratriptan & Eletriptan C/I Hepatic &Renal impairment Or Peripheral vascular Synd. – Frovotiptan C/I in peripheral vascular disease. – Zolmitriptan C/I in Wolff-Parkinson-White Synd. Brand name Expensive USE Generic Sumatriptan
  22. 22.  Tetracyclic Ergoline ring  AMINE ALKALOIDS ▪ 6-Methylergoline ▪ Lysergic acid diethylamide (LSD) ▪ Ergonovine ( Ergometrine )  PEPTIDE ALKALOIDS ▪ Ergotamine ▪ Alpha- Ergocryptine ▪ Bromocriptine ▪ Cabergoline
  23. 23.  Oral …. Invariable absorption (Increase with Caffeine)  Amine alkaloids can be given  RECTALLY,  Buccal Cavity,  Aerosole (Bromocriptine, Cabergoline can be given ORALLY)  I/M slow absorption, RELIABLE  METABOLISM …. Extensive … Hydroxylation of Ring (1st step)
  24. 24. Pharmacodynamics • Mechanism of Action – Act on several Receptors (Agonist, Partial agonist, Antagonist) – Antagonist at Alpha Adrenoceptor – Antagonist at 5HT1A, 5HT1D; Less 5HT2,3 – Agonist &Partial agnist at Dopamine Recetors in CNS – High affinity at Presynaptic/Prejunctional Receptors • Powerful Stimulant effect on Uterus (Gravid/Full Term) …..Ergometrine (5-HT2 Agonistic/Partial agonistic Effect)
  25. 25. Organ System Effect • CNS – Ergotism – Hallucinogens (LSD) 5-HT2 Antagonist. – Behavioural Effects , (LSD) • (Prejunctional or Post junctional 5HT2 in CNS (agonist Effect) – Suppress prolactin • (direct effect through D regulatory receptors – Bromocriptine, Cabergoline, Pergolide
  26. 26. Vascular Smooth Muscle  Constriction (even in nanomolar conc.)  ProlongedVasospasm (alpha Blocker dec. it)  Phenomenon of Epineph. Reversal ( P. agonist)  P.agonist at 5HT2 vascular receptors  ACTION ON PREJUNCTIONAL NEURONAL 5-HT RECEPTORS  INTOXICITY vascular spasm is not reversed by alpha antagonists, serotonin antagonists or combination of both.
  27. 27. • Uterine smooth muscle – During pregnancy the SM is dramatically sensitized – Constriction/spasm (alpha1, serotonin effect) – In very small dose INITIATE rhythmic contractions & relaxations ERGONOVINE more selective for Uterine SM
  28. 28. Other Smooth Muscles - No significant effect on bronchiolar & urinary SMs - GIT Ms. are quite sensitive Nausea, vomiting, diarrhea with low dose (Emetic centre, GIT serotonin receptors)
  29. 29. Clinical Uses • Migraine • Hyperprolactinemia • Postpartum hemorrahage • Diagnosis of variant angina • Senile cerebral insufficiency (Alzimer’s Disease)
  30. 30. Toxicity & C/I • GIT DISTURBANCES • Overdosage …. – Vasospasm (nitroprusside) – Cardiac toxicity • Valve damage, (Fibrotic changes) • Ureter obstrucion (spasm) ….. Hydronephrosis • C/I – Obstructive vascular disease – Pregnancy
  31. 31. Thanks

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