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5-Hydroxytryptamine, Migraine.pptx

The document discusses serotonin (5-HT), its receptors, pharmacological actions, and role in conditions like migraine. It describes various drugs that act on the 5-HT system including 5-HT precursors, reuptake inhibitors, antagonists, and 5-HT1D/1B agonists that are used to treat migraine like sumatriptan. It provides details on the pathogenesis, types, and treatment of migraine with medications and discusses drug side effects and contraindications.

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5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine Dr. Anubhuti Khare Asst. Prof. Dept. of Pharmacology
5-HYDROXYTRYPTAMINE (5-HT, Serotonin) • 90% of body’s content of 5-HT- intestines (enterochromaffin cells) • Rest- platelets and brain • Also found- wasp, and scorpion sting; widely distributed in invertebrates and plants (banana, pear, pineapple, tomato, stinging nettle, cowhage).
SYNTHESIS, STORAGE AND DESTRUCTION
SEROTONERGIC (5-HT) RECEPTORS
Pharmacological actions • 1. CVS • In intact animals- coronary chemoreflex (Bezold Jarisch reflex) through action on vagal afferent nerve endings in the coronary bed: bradycardia, hypotension and apnoea • BP: a triphasic response (i.v. injection of 5-HT in animals) • • Early sharp fall in BP—due to coronary chemoreflex. • • Brief rise in BP—due to vasoconstriction and increased cardiac output. • • Prolonged fall in BP—due to arteriolar dilatation and extravasation of fluid.
• 2. Visceral smooth muscles – GI- Peristalsis is increased & diarrhoea – Constricts bronchi • 3. Glands – Inhibits gastric secretion (both acid and pepsin), but increases mucus production – ulcer protective property • 4. Nerve endings and adrenal medulla – Afferent nerve endings- tingling, pricking sensation, pain. – Visceral afferents- respiratory & cardiovascular reflexes, nausea & vomiting. – Adrenal medulla- release CAs • 5. Respiration – A brief stimulation of respiration & hyperventilation – Large doses -transient apnoea • 6. Platelets – change in shape of platelets; weak aggregator • 7. CNS – poor entry across BBB – serves as a transmitter, primarily inhibitory – Direct injection in the brain- sleepiness, changes in body temperature, hunger and a variety of behavioural effects
PATHOPHYSIOLOGICAL ROLES • Neurotransmitter • Precursor of melatonin • Neuroendocrine function • Nausea and vomiting • Migraine • Haemostasis • Raynaud’s phenomenon • Variant angina • Hypertension • Intestinal motility • Carcinoid syndrome • Use • Due to widespread and variable actions, 5-HT has no therapeutic use.
DRUGS AFFECTING 5-HT SYSTEM • Tryptophan 5-HT precursor • p-Chlorophenylalanine (PCPA) inhibits tryptophan hydroxylase (rate limiting step) Synthesis inhibitor • TCAs • SSRIs Uptake inhibitor • Reserpine- inhibits VMAT-2 • Fenfluramine- release causing depletion Storage inhibitor • Nonselective MAO inhibitor(tranylcypromine) • selective MAO-A inhibitor (clorgyline) Degradation inhibitor • 5, 6 dihydroxytryptamine selectively destroys 5-HT neurones. Neuronal degeneration
• D-Lysergic acid diethyl amide (LSD)- nonselective 5-HT agonist; hallucinogenic • Azapirones (buspirone, gepirone ,ipsapirone)- antianxiety drugs. PA 5-HT1A receptors • Sumatriptan and other triptans - selective 5- HT1D/1B agonists; T/t of MIGRAINE • Cisapride Renzapride - prokinetic drugs; selective 5- HT4 agonist. 5-HT receptor agonists
5-HT ANTAGONISTS • Cyproheptadine – Blocks 5-HT2A receptors :controlling intestinal manifestations of carcinoid & postgastrectomy dumping syndromes and antagonize priapism/ orgasmic delay caused fluoxetine & trazodone – additional H1 antihistaminic, anticholinergic and sedative properties :antipruritic, increases appetite & has been used in children and poor eaters to promote weight gain. • Methysergide – antagonizes 5-HT action on vascular & visceral smooth muscles – 5-HT2A/2C antagonist – Not used- abdominal, pulmonary & endocardial fibrosis
• Ketanserin – 5-HT2 antagonist – Opposes 5-HT induced vasoconstriction, platelet aggregation & contraction of airway smooth muscle – additional weak α1, H1 and dopaminergic blocking activities. – Ritanserin- relatively more selective 5-HT2A antagonist • Clozapine – atypical antipsychotic - resistant cases of schizophrenia – 5-HT2A/2C antagonist; inverse agonist at 5-HT2A/2C receptors • Risperidone, olanzapine and quetiapine – 5-HT2A + D2 antagonist – Atypical antipsychotics • Ondansetron, Granisetron and Tropisetron – 5-HT3 antagonists – Control anticancer & radiotherapy induced N& V
ERGOT ALKALOIDS • Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other grains • Epidemics of ergot poisoning (ergotism), due to consumption of contaminated grains • Natural ergot alkaloids – (a) Amine alkaloid - Ergometrine (Ergonovine): oxytocic – (b) Amino acid alkaloids- Ergotamine, Ergotoxine : emetic, vasoconstrictor & α adrenergic blocker/PA; migraine
• Other semisynthetic derivatives – (a)Dihydroergotamine (DHE), Dihydroergotoxine (Codergocrine): antiadrenergic, cerebroactive- t/t of dementia – (b)2-Bromo-α-ergocryptine (Bromocriptine): D2 agonist (antiparkinsonian), inhibit prolactin release, emetic – (c)Methysergide: mainly anti 5-HT • Adverse effects • Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesias, coronary and other vascular spasm, chest pain (due to coronary vasoconstriction)
Selective 5-HT1D/1B agonists (Triptans) • Currently, first line drugs for patients who fail to respond to analgesics [sumatriptan, riza., frova., nara., zolmi.] • MOA – 5-HT1D/1B receptor mediated constriction of dilated cranial blood vessels (in AV shunts in the carotid artery) – 5-HT1D/1B are presynaptic autoreceptors: triptans reduce 5-HT release at these blood vessels – inhibit inflammatory neuropeptide release around the affected vessels as well as extravasation of plasma proteins across dural vessels – suppress neurogenic inflammation of cranial vessels • All triptans: significant pharmacokinetic differences
• Sumatriptan- lowest BA; absorbed rapidly and completely after s.c. injection; intranasal spray • Naratriptan & Frovatriptan- longer t½; fewer headache recurrences; slow in affording initial pain relief. • Side effects- – Tightness in head & chest, feeling of heat & other paresthesias in limbs, dizziness, weakness – Slight rise in BP; bradycardia, coronary vasospasm & risk of MI- rare but serious • Contraindications: – Ischaemic heart disease, hypertension, epilepsy, hepatic or renal impairment & pregnancy ; cautioned not to drive. • Sumatriptan and ergotamine should not be administered within 24 hours of each other. • Interaction with 5-HT reuptake inhibitors, MAO inhibitors & lithium
MIGRAINE • Pulsating headache • usually restricted to one side • attacks lasting 4–48 hours • often associated with nausea, vomiting, sensitivity to light and sound, flashes of light, vertigo, loose motions and other symptoms • Two major types – —migraine with aura (classical migraine) – —migraine without aura (common migraine)
• Pathogenesis – Vascular theory – Neurogenic theory • Mild migraine – fewer than one attack per month – lasts upto 8 hours – does not incapacitate the individual – Drug therapy - Simple analgesics/NSAIDs or their combinations (± antiemetic) – Paracetamol, aspirin, ibuprofen, naproxen, diclofenac either alone or combined with paracetamol/codeine/ diazepam or another sedative/diphenhydramine or another antihistaminic/caffeine
• Moderate migraine – One or more attacks per month – lasts for 6–24 hours – Throbbing headache more intense, nausea/vomiting & other features more prominent – Patient is functionally impaired – Drug therapy- NSAIDs combinations/a triptan/ ergot alkaloids (+ antiemetic) – Prophylactic therapy advised: attacks more frequent than 2–3 per month • Severe migraine – 2–3 or more attacks per month of – lasts 12–48 hours – severe throbbing headache, vertigo, vomiting and other symptoms – Pt. grossly incapacitated during the attack – Drug therapy- a Triptan/ergot alkaloids (+ antiemetic) + Prophylaxis
PROPHYLAXIS OF MIGRAINE • (i) β-Adrenergic blockers- Propranolol • (ii) Tricyclic antidepressants- Amitriptyline • (iii) Calcium channel blockers- Verapamil – Flunarizine- cerebro-selective CCB, also inhibits Na+ channels • (iv)Anticonvulsants - Valproic acid, gabapentin, topiramate • (v) CGRP antagonist- monoclonal antibody Erenumab (s.c. once a month)
• Q. Serotonin can be synthesized from: – a) Tryptophan – b) Tyrosine – c) Dopa – d) Epinephrine • Q. Drug which blocks both H1 & 5HT2 receptor: – a) Phenoxybenzamine – b) Cyprohepatidine – c) Ritanserin – d) Ondansetron
• Q. After taking some drug for acute attack of migraine, a patient developed nausea & vomiting. He also developed tingling & numbness in the tip of the finger that also turned blue. Which of the following is the most likely drug implicated in causing the above findings? – a) Dihydroergotamine – b) Sumatriptan – c) Aspirin – d) Butorphanol