Potential mechanisms of prospective antimigraine drugs: A focus on vascular (side) effects

Abstract

Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate-at least a part of-their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT(1F) receptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the previously mentioned compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects.

PET Tracers for Serotonin Receptors and Their Applications

“…5-HT 1D R agonists are used for migraine treatment except PNU-142633, a specific 5-HT 1D R agonist that proved ineffective for the treatment of migraine [184, 185]. The 5-HT 1E R has ~ 60% homology with 5HT 1B R. It is concentrated in caudate putamen and hippocampus with lower levels in amygdala, frontal cortex and globus pallidus.…”

Effect of Telcagepant on Spontaneous Ischemia in Cardiovascular Patients in a Randomized Study

“…Further studies are necessary to evaluate the cardiovascular effects of longer‐term intermittent use or long‐term chronic daily use (eg, for migraine prophylaxis). Theoretically, CGRP could have a cardioprotective effect in some patients, which could be attenuated by CGRP receptor antagonists 9 . Third, this study was intended to provide safety data during activities of daily living, including pre‐specified minimum exercise tasks (walking and step‐climbing), prior to the conduct of a more strenuous treadmill study.…”

“…Calcitonin gene‐related peptide (CGRP) receptor antagonists such as olcegepant 4 and telcagepant 5‐8 are being investigated for the acute treatment of migraine. Since CGRP is a highly potent vasodilator and is active in the coronary vasculature, there has been interest in its role in cardiac ischemia and in the possible effects of CGRP antagonists 9 . Although CGRP receptor antagonists block the vasodilatory response to CGRP, there is no evidence to suggest they have direct vasoconstrictive activity.…”

Headache, Cerebral Aneurysms, and the Use of Triptans and Ergot Derivatives

“…The triptans cause vasoconstriction in human blood vessels both in vitro and in vivo , although they have significantly more selective action in the cranial vasculature compared with the periphery and coronary arteries . Notably, the triptan doses are much higher (up to 1000 or 3‐log units) than the doses required to trigger the same vascular effects in vitro or in vivo , and it is suspected that the higher doses are necessary to reach brain targets . Transcranial Doppler studies have shown an increase in middle cerebral artery cross‐sectional lumen with an associated decrease in blood flow velocity on the affected side during unilateral migraine attacks due to vasodilatation, with one study estimating a mean diameter increase of 20% .…”