Coronary side-effect potential of current and prospective antimigraine drugs.
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).


RESULTS
Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/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 (Emax <25% of K+-induced contraction). The Cmax 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.
Department of Pharmacology, Erasmus University Rotterdam, The Netherlands.
A
A
MaassenVanDenBrink
M
M
Reekers
W A
WA
Bax
M D
MD
Ferrari
P R
PR
Saxena
D000293:Adolescent; D000328:Adult; D000368:Aged; D000787:Angina Pectoris / Q000139:chemically induced; D002648:Child; D003331:Coronary Vessels / Q000187:drug effects*; D004087:Dihydroergotamine / Q000009:adverse effects*; D004878:Ergotamine / Q000009:adverse effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000009:adverse effects; D008297:Male; D008784:Methysergide / Q000009:adverse effects*; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy*; D010880:Piperidines / Q000009:adverse effects; D013449:Sulfonamides / Q000009:adverse effects; D018170:Sumatriptan / Q000009:adverse effects*; D014230:Triazoles / Q000009:adverse effects; D014363:Tryptamines; D014662:Vasoconstrictor Agents / Q000009:adverse effects*
D007211:Indoles; D010880:Piperidines; D013449:Sulfonamides; D014230:Triazoles; D014363:Tryptamines; D014662:Vasoconstrictor Agents; D004087:Dihydroergotamine; C093622:rizatriptan; C103231:avitriptan; D018170:Sumatriptan; D004878:Ergotamine; C106783:naratriptan; D008784:Methysergide