Note: KD Tripathi's "Essentials of Medical Pharmacology" is not available in the library, but the content below is drawn from Katzung's Basic & Clinical Pharmacology, Goodman & Gilman's, and Lippincott Illustrated Reviews - all of which cover migraine pharmacology in the same structured format that Tripathi uses, and contain the same drug classes and mechanisms.

Migraine Pharmacology

Pathophysiology (Basis for Drug Targets)

• Cortical spreading depression (CSD): A wave of neuronal depolarization followed by suppression spreads from occipital to frontal cortex - responsible for the aura in classic migraine.
• Trigeminovascular activation: Trigeminal nerve endings around intracranial vessels release vasoactive neuropeptides - calcitonin gene-related peptide (CGRP), substance P, and neurokinin A - causing neurogenic inflammation and vasodilation.
• CGRP: A potent vasodilatory and proinflammatory neuropeptide; plasma levels rise during acute attacks and fall with effective treatment.
• Serotonin (5-HT): Platelet 5-HT decreases and urinary 5-HIAA rises during attacks. Drugs that release 5-HT (reserpine, fenfluramine) can precipitate migraine. 5-HT1B/1D receptors are key therapeutic targets.
• Pain generation: Perivascular edema from neuropeptide extravasation causes mechanical stretching of dural pain endings, perceived as pulsating headache.

Classification of Antimigraine Drugs

A. DRUGS FOR ACUTE MIGRAINE

1. Triptans (5-HT1B/1D Agonists) - First-line

• Selectively agonize 5-HT1B receptors on intracranial blood vessels → vasoconstriction, opposing neurogenic vasodilation.
• Agonize 5-HT1D receptors (presynaptic autoreceptors) on trigeminal nerve terminals → inhibit release of CGRP, substance P, and other proinflammatory neuropeptides.
• No significant activity at adrenergic, dopaminergic, muscarinic, or benzodiazepine receptors.

• Effective in ~70% of patients for acute migraine (with or without aura).
• Initiate as early as possible after headache onset.
• Parenteral/nasal routes preferred when nausea/vomiting is present.
• Do NOT use for prophylaxis.
• Eletriptan has the best 2-hour and 24-hour outcomes in meta-analyses.

• "Triptan sensations": tingling, warmth, flushing, heaviness, chest tightness/pressure (1-5%).
• Dizziness, drowsiness, neck stiffness, nausea.
• Coronary vasospasm - the main serious concern.

• Coronary artery disease, angina, uncontrolled hypertension.
• Concurrent ergot alkaloid use (within 24 h) - risk of severe vasospasm.
• Severe hepatic/renal impairment (naratriptan, eletriptan).
• Wolff-Parkinson-White syndrome (zolmitriptan).

2. Ergot Alkaloids

• Ergotamine: oral tablet (with caffeine), sublingual, suppository. Most effective in early stages of migraine. Caffeine enhances absorption.
• DHE: IV or intranasal. Efficacy similar to sumatriptan for severe migraine. Causes less arterial vasoconstriction than ergotamine.

• Second-line, reserved for moderate to severe migraine not responding to triptans.
• Daily and weekly dose limits strictly imposed to prevent dependence and medication-overuse headache (rebound headaches).

• Nausea and vomiting (dopamine agonism - use with metoclopramide).
• Peripheral vasoconstriction - cold extremities.
• Ergotism: severe vasospasm, gangrene with overuse.
• Rebound headache with chronic use.

• Peripheral vascular disease, CAD, angina.
• Pregnancy (oxytocic effect).
• Within 24 h of triptans.
• Concomitant potent CYP3A4 inhibitors (risk of life-threatening peripheral ischemia).

3. Ditans (5-HT1F Agonists) - Newer class

4. CGRP Receptor Antagonists (Gepants)

5. Non-Specific Symptomatic Drugs

• NSAIDs (aspirin, ibuprofen, naproxen): Useful for mild-moderate migraine. Sumatriptan + naproxen is an approved combination.
• Antiemetics (prochlorperazine, metoclopramide): Control vomiting; metoclopramide also aids gastric motility (enhances oral drug absorption).
• Opioids (tramadol, codeine): Rarely, for refractory cases only - risk of medication-overuse headache is high.

B. PROPHYLACTIC DRUGS (Preventive Therapy)

1. Beta-Blockers - First-line

• Drugs: Propranolol, metoprolol.
• Mechanism: Not fully understood; possibly reduce cortical excitability and stabilize cerebrovascular tone. Inhibit trigeminovascular activation.
• Propranolol is most studied; non-selective beta-blockers preferred.

2. Antiepileptics - First-line

• Valproic acid / Sodium valproate: Enhances GABAergic inhibition, reduces neuronal hyperexcitability.
• Topiramate: Multiple mechanisms - Na+ channel blockade, GABA enhancement, AMPA/kainate glutamate receptor blockade. Also causes weight loss (useful if obesity is a comorbidity).

3. Antidepressants

• Amitriptyline (TCA): First-line prophylaxis, especially if comorbid depression or sleep disturbance. Blocks 5-HT and noradrenaline reuptake.
• Venlafaxine (SNRI): Second-line.
• SSRIs are less effective than TCAs for migraine prophylaxis.

4. Calcium Channel Blockers

• Flunarizine: Used extensively in India and Europe. Effective both for prevention and reducing severity of acute attacks. Not approved in the USA.
• Verapamil: Modest prophylactic efficacy; more commonly used for cluster headache.

5. Anti-CGRP Monoclonal Antibodies - Newer, Second-line

• Erenumab: Binds CGRP receptor.
• Fremanezumab, Galcanezumab, Eptinezumab: Bind CGRP itself.
• Given subcutaneously once monthly (or quarterly for fremanezumab).
• Reserved for patients not controlled by oral agents - expensive.
• Adverse effects: injection-site reactions, constipation.

6. Botulinum Toxin A (OnabotulinumtoxinA)

• Approved for chronic migraine (≥15 headache days/month).
• Injected into pericranial muscles every 12 weeks.
• Mechanism: blocks release of proinflammatory neuropeptides from trigeminal terminals.

Summary Table

Important note: KD Tripathi's Essentials of Medical Pharmacology is not in the available textbook library. The content above is drawn from comparable standard pharmacology references and covers the same drug classes, mechanisms, and clinical points that Tripathi covers. The classification structure, drug groupings, and emphasis on mechanism-based learning mirror Tripathi's approach closely.