What is the mechanism of action of different antimigraine drugs, including triptans (e.g. sumatriptan) and ergotamines (e.g. ergotamine), in patients with and without a history of cardiovascular disease?

Mechanism of Action of Antimigraine Drugs

Triptans (5-HT₁B/1D Receptor Agonists)

Triptans work through selective agonism at serotonin 5-HT₁B/1D receptors, producing both cranial vasoconstriction and inhibition of trigeminovascular inflammation. 1

Dual Mechanism of Action

• Vascular effects: Triptans activate 5-HT₁B receptors on cranial blood vessels, causing selective vasoconstriction of dilated intracranial and extracranial arteries, particularly in the carotid circulation, without significantly affecting cerebral blood flow 2, 3

• Neurogenic effects: Through 5-HT₁D receptor activation on trigeminal nerve terminals, triptans inhibit the release of vasoactive neuropeptides including calcitonin gene-related peptide (CGRP) and substance P, thereby blocking neurogenic inflammation 3, 4

• Additional mechanism: Triptans also inhibit plasma protein extravasation into the dura mater in response to trigeminal ganglion stimulation, though this effect may be secondary to their selective vasoconstriction 2

Cardiovascular Contraindications

• Triptans are absolutely contraindicated in patients with ischemic vascular conditions, vasospastic coronary disease, uncontrolled hypertension, or other significant cardiovascular disease because their 5-HT₁B receptor-mediated vasoconstriction can cause coronary artery vasospasm (Prinzmetal's angina), myocardial infarction, and arrhythmias 1, 5, 6

• Patients with multiple cardiovascular risk factors (increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) require cardiovascular evaluation before receiving triptans, and first-dose administration should occur in a medically supervised setting with immediate post-dose ECG 5, 6

• Life-threatening cardiac arrhythmias including ventricular tachycardia and ventricular fibrillation have been reported within hours of triptan administration 5, 6

Ergotamine and Dihydroergotamine (Non-Selective 5-HT Agonists)

Ergotamines function as non-selective 5-hydroxytryptamine (5-HT) agonists, producing potent vasoconstriction of extracranial arteries and arteriovenous anastomoses in scalp and dural regions. 1

Mechanism and Limitations

• Ergotamine acts as a non-selective 5-HT₁ receptor agonist with additional activity at multiple receptor subtypes, producing less selective vasoconstriction compared to triptans 1

• Dihydroergotamine (DHE) is a semisynthetic ergot alkaloid and non-selective 5-HT₁ receptor agonist considered more appropriate for severe migraines than ergotamine 1

• Ergotamines have largely fallen out of favor due to their potential for causing medication-overuse headaches, increasing headache frequency, ergot poisoning, negative effects on prophylactic medications, and peripheral vasoconstriction with chronic use 1

Critical Safety Concerns in Cardiovascular Disease

• Ergot alkaloids cause peripheral vasoconstriction and should not be used chronically or in patients with peripheral vascular disease 1

• They possess oxytocic properties, absolutely contraindicated in pregnancy 1

• Ergotamines cannot be used within 24 hours of triptans due to additive vasoconstrictive effects that can produce myocardial infarction, vasospastic ischemia, and other serious cardiovascular events 7

• When ergotamine metabolism is inhibited by macrolide antibiotics (particularly troleandomycin and erythromycin), HIV protease inhibitors (indinavir, ritonavir), or other CYP3A4 inhibitors, the resulting interaction can produce ergotism and gangrene 7

NSAIDs (Non-Specific Anti-Inflammatory Mechanism)

• NSAIDs work through inhibition of COX-1 and COX-2 enzymes, reducing prostaglandin synthesis and other inflammatory mediators involved in migraine pathophysiology 4

• NSAIDs provide first-line therapy for mild-to-moderate migraine without the cardiovascular contraindications of triptans or ergotamines 8

Combination Therapy: Sumatriptan + Naproxen

• The combination of sumatriptan (85mg) plus naproxen sodium (500mg) produces pharmacological synergy superior to either agent alone by targeting both the 5-HT₁B/1D receptor pathway (sumatriptan) and the COX-mediated inflammatory pathway (naproxen) simultaneously 4

• This combination provides rapid pain relief (primarily from sumatriptan's mechanism) with sustained response (primarily from naproxen's mechanism), addressing the 40% of patients who experience symptom recurrence within 48 hours of triptan monotherapy 4

Newer CGRP-Targeted Therapies

• Gepants (ubrogepant, rimegepant) and monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) directly block CGRP signaling without vasoconstriction, making them safe alternatives for patients with cardiovascular disease where triptans are contraindicated 9

• Lasmiditan is a highly selective 5-HT₁F receptor agonist that inhibits CGRP release from trigeminovascular nerves without vasoconstrictive properties, allowing use in patients with cardiovascular risk 9