Coronary Side-Effect Potential of Current and Prospective Antimigraine Drugs

From the Department of Pharmacology, Erasmus University Rotterdam, and Department of Neurology (M.D.F.), Leiden University Medical Centre, the Netherlands. Dr Bax is now with the Department of Cardiology and Internal Medicine, Eemland Hospital, Amersfoort, the Netherlands.

Correspondence to P.R. Saxena, MD, PhD, Department of Pharmacology, Erasmus University Rotterdam, Dr Molewaterplein 50, PO Box 1738, 3000 DR Rotterdam, Netherlands. E-mail saxena{at}farma.fgg.eur.nl

Background—The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan).

Methods and Results—Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (E_max) and the concentration eliciting 50% of E_max (EC₅₀). The EC₅₀ values were related to maximum plasma concentrations (C_max) reported in patients, obtaining C_max/EC₅₀ ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC₅₀ values) in contracting the coronary artery but had similar efficacies (E_max <25% of K⁺-induced contraction). The C_max of avitriptan was 7- to 11-fold higher than its EC₅₀ value, whereas those of the other drugs were <40% of their respective EC₅₀ values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing.

Conclusions—All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.

Key Words: coronary disease • vasoconstriction • migraine • pharmacology • antimigraine drugs

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