Migrane

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Migrane

  1. 1. Serotonin or 5-hydroxytryptamine <ul><li>Widely distributed amine (animals + plants) </li></ul><ul><li>In humans, present in GI enterochromaffin cells (90%), platelets and brain. </li></ul><ul><li>Synthesized from tryptophan (in diet) in two steps. </li></ul><ul><li>Platelets do not synthesize but take up from blood (active uptake process in platelets and nerve terminals). </li></ul><ul><li>Cell storage in granules similar to catecholamines. </li></ul>www.freelivedoctor.com
  2. 2. N C N C NH 2 COOH COOH NH 2 OH N C NH 2 OH H Tryptophan 5-Hydroxytryptophan 5-Hydroxytryptamine N C COOH 5-OH Indole Acetaldehyde 5-Hydroxy Indole Acetic Acid Tryptophan hydroxylase 5-OH Tryptophan decarboxylase MAO Aldehyde dehydrogenase (Rate limiting) In diet. Active CNS transport www.freelivedoctor.com
  3. 3. Synthesis and Metabolism <ul><li>Competition at the level of brain and neuronal uptake </li></ul><ul><li>Rate limiting enzyme not saturated usually </li></ul><ul><li>No end-product negative feedback </li></ul><ul><li>5-OHTr decarboxylase same as DOPA decarboxylase </li></ul><ul><li>5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine. </li></ul>www.freelivedoctor.com
  4. 4. Interference with the system <ul><li>Inhibit uptake into CNS (other AA’s) </li></ul><ul><li>Inhibit synthesis : p-chlorophenylalanine (irreversible) </li></ul><ul><li>Inhibit neuronal re-uptake : cocaine, SSRA (e.g. fluoxetine), TCA (e.g. imipramine) </li></ul><ul><li>Inhibit storage-deplete : reserpine </li></ul><ul><li>Inhibit metabolism : MAO inhibitors </li></ul><ul><li>Promote release : p-chloroamphetamine - then depletes (e.g. fenfluramine to ↓ appetite) </li></ul>Non-selective www.freelivedoctor.com
  5. 5. Serotonin Receptors <ul><li>At least 15 types and subtypes </li></ul><ul><li>Multiple transduction mechanisms </li></ul><ul><li>5HT-1A: role in anxiety/depression </li></ul><ul><li>5HT-1D: role in migraine </li></ul><ul><li>5HT-2: role in CNS various behaviors, and in cardiovascular system </li></ul><ul><li>5-HT3: role in nausea and vomiting esp. due to Chemotherapy. </li></ul>www.freelivedoctor.com
  6. 6. Endogenous Function <ul><li>Central neurotransmitter </li></ul><ul><li>Precursor of melatonin </li></ul><ul><li>GI tract: uncertain; motility? </li></ul><ul><li>In carcinoid tumors: large amounts released leading to diarrhea, bronchoconstriction and edema </li></ul><ul><li>Platelets: 5-HT2 receptors -> aggregation and vasoconstriction </li></ul>www.freelivedoctor.com
  7. 7. Serotonin Pharmacological Effects <ul><li>Respiratory system: bronchoconstriction if asthmatic; stimulation of aortic and carotid chemoreceptors -> ↑ RR and minute vol. </li></ul><ul><li>GI tract: small intestine very sensitive to serotonin -> intense rhythmic contractions due to direct and indirect (ganglia in wall) effects. </li></ul><ul><li>Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally). </li></ul>www.freelivedoctor.com
  8. 8. <ul><li>Cardiovascular system: Multiple direct and indirect effects: </li></ul><ul><li>Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI 2 – mediated) </li></ul><ul><li>Heart: direct inotropic and chronotropic effects </li></ul><ul><li>Reflex mechanisms due to change in BP </li></ul><ul><li>Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) -> bradycardia and hypotension </li></ul>Serotonin Pharmacological Effects -2 www.freelivedoctor.com
  9. 9. <ul><li>Pain perception </li></ul><ul><li>Sleep/Wakefulness </li></ul><ul><li>Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior, etc. </li></ul><ul><li>Neuroendocrine regulation – controls hypothalamic cells involved in release of several anterior pituitary hormones. </li></ul>Serotonin in the Central Nervous System www.freelivedoctor.com
  10. 10. Migraine <ul><li>Clinical Presentations: </li></ul><ul><ul><li>Often accompanied by brief aura (visual scotomas, hemianopia) </li></ul></ul><ul><ul><li>Severe, throbbing, usually unilateral headache (few hours to a few days in duration) </li></ul></ul><ul><li>Migraine Pathophysiology: </li></ul><ul><ul><li>  Vasomotor mechanism -- inferred from: </li></ul></ul><ul><ul><ul><li>increased temporal artery pulsation magnitude </li></ul></ul></ul><ul><ul><ul><li>pain relief (by ergotamine) occurs with decreased artery pulsations </li></ul></ul></ul><ul><ul><li>Migraine attack associated with (based on histological studies): </li></ul></ul><ul><ul><ul><li>sterile neurogenic perivascular edema </li></ul></ul></ul><ul><ul><ul><li>inflammation (clinically effective antimigraine medication reduce perivascular inflammation) </li></ul></ul></ul>www.freelivedoctor.com
  11. 11. Migraine: Drug Treatment <ul><ul><li>Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses </li></ul></ul><ul><ul><ul><li>combined with caffeine: better absorption </li></ul></ul></ul><ul><ul><ul><li>potentially severe long-lasting Vasoconstriction. </li></ul></ul></ul><ul><ul><li>Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine </li></ul></ul><ul><ul><li>Nonsteroidal antiinflammatory drugs (NSAIDs) </li></ul></ul><ul><ul><li>Sumatriptan : alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk. </li></ul></ul><ul><ul><ul><li>formulations: subcutaneous injection, oral, nasal spray </li></ul></ul></ul><ul><ul><ul><li>selective serotonin-receptor agonist (short duration of action) </li></ul></ul></ul><ul><ul><ul><li>probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray) </li></ul></ul></ul>www.freelivedoctor.com
  12. 12. Migraine: Prophylaxis <ul><ul><li>  Methysergide </li></ul></ul><ul><ul><ul><li>effective in about 60% of patients </li></ul></ul></ul><ul><ul><ul><li>NOT effective in treating an active migraine attack or even preventing an impending attack. </li></ul></ul></ul><ul><ul><ul><li>Methysergide toxicity: retroperitoneal fibroplasia, subendocardial fibrosis. Recommend 3-4 week drug holiday every six months </li></ul></ul></ul><ul><ul><li>  Propranolol - Most common for continuous prophylaxis </li></ul></ul><ul><ul><ul><li>best established drug for migraine attack prevention. </li></ul></ul></ul><ul><ul><li>  Amitriptyline (TCA) </li></ul></ul><ul><ul><ul><li>most frequently used among the tricyclic antidepressants </li></ul></ul></ul><ul><ul><li>  Valproic acid (Antiepileptic) </li></ul></ul><ul><ul><ul><li>effective in decreasing migraine frequency. </li></ul></ul></ul><ul><ul><li>  Nonsteroidal antiinflammatory drugs (NSAIDs) </li></ul></ul><ul><ul><ul><li>used for attack prevention and aborting acute attack </li></ul></ul></ul>www.freelivedoctor.com
  13. 13. Serotonin in Migraine <ul><li>Neurogenic vs. Vascular theories </li></ul><ul><li>Several drugs that modulate the serotonin system are effective in migraine: </li></ul><ul><li>Cyproheptadine/methysergide - prophylaxis </li></ul><ul><li>Sumatriptan, ergotamine - acute </li></ul><ul><li>MAO inhibitors and TCA – both </li></ul><ul><li>Caffeine (↑ cAMP?) </li></ul><ul><li>Reserpine worsens migraine </li></ul>www.freelivedoctor.com
  14. 14. Unknown Trigger Activation antidromic Orthodromic conduction Trigeminal neuron Inhibitory receptor (5-HT1D) Mast cell PAIN Cortex Thalamus Trigem. Nucleus caudalis Blood Vessel nausea autonomic www.freelivedoctor.com
  15. 15. Serotonin Agonists <ul><li>Sumatriptan : 5-HT1D agonist; contraindicated in patients with angina </li></ul><ul><li>Fluoxetine : Selective serotonin uptake inhibitors for depression and other indications </li></ul><ul><li>Buspirone : 5-HT1A agonist for anxiety </li></ul><ul><li>Cisapride : 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market due to fatal arrhythmias) </li></ul><ul><li>LSD : 5HT1A – hallucinogen </li></ul><ul><li>Ergot alkaloids : 5-HT1 and 2 and other receptors </li></ul>www.freelivedoctor.com
  16. 16. Serotonin Antagonists <ul><li>Methysergide and Cyproheptadine . 5HT2 antagonists. In carcinoid, migraine. </li></ul><ul><li>Ketanserin : 5HT2 and Alpha antagonist – used as antihypertensive. </li></ul><ul><li>Ondansetron : 5-HT3 antagonist for chemotherapy induced nausea and vomiting </li></ul><ul><li>Clozapine : 5HT2A/2C antagonist: for schizophrenia. </li></ul>www.freelivedoctor.com

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