Zolmitriptan

Abstract

Zolmitriptan is a selective serotonin 5-HT_1b/id receptor agonist (‘triptan’). Its efficacy and tolerability have been assessed in a number of randomised, placebo-controlled, double-blind trials in large numbers of adults with moderate to severe migraine attacks. Oral zolmitriptan 2.5 and 5mg has a rapid onset of action (significant headache relief is observed at 45 minutes) and efficacy is sustained in most patients who respond at 2 hours. The drug is significantly more effective than placebo as measured by a number of parameters including 2-hour headache response rates and pain-free response rates. Other symptoms of migraine, including nausea, photophobia and phonophobia are also alleviated with zolmitriptan. Zolmitriptan is effective in the treatment of migraine associated with menses and migraine with aura. There is some evidence to support the use of zolmitriptan in patients with migraine who have had a poor response to previous therapy. The efficacy of zolmitriptan appears to be maintained, with no tachyphylaxis, following repeated administration for multiple attacks of migraine over a prolonged period of time, with high headache response rates reported over all attacks. In comparison with placebo, the incidence of persistent migraine headache is reduced by zolmitriptan and recurrent migraine headache occurs less frequently with the active treatment. Zolmitriptan has also demonstrated efficacy in the treatment of persistent and/or recurrent migraine headache. For relief of migraine headache, zolmitriptan 5mg had similar efficacy to sumatriptan 100mg for a single attack, but generally was more effective than sumatriptan 25 and 50mg for multiple attacks, in single trials. The incidence of recurrent headache with zolmitriptan was similar to that with sumatriptan. Zolmitriptan is generally well tolerated with most adverse events being mild to moderate, transient and resolving without intervention or the need for treatment withdrawal. The most common adverse events with zolmitriptan therapy are asthenia, heaviness other than that of the chest or neck, dry mouth, nausea, dizziness, somnolence, paraesthesia, warm sensation, tightness, vasodilation and chest pain. Conclusion: Zolmitriptan is effective across a wide range of migraine subtypes, maintains efficacy when used in the long term and is generally well tolerated. Further clinical experience is necessary to define the position of zolmitriptan among other currently or soon to be available selective 5-HT_1b/id receptor agonists. However, on the basis of available data, zolmitriptan should emerge as a useful treatment option in the management of patients with moderate to severe migraine. Zolmitriptan has high affinity for serotonin 5-HT_1b/id receptors with modest selectivity for the 5-HT_1d subtype over the 5-HT_1b subtype. The drug has moderate affinity for 5-HT_1a and 5-HT_1f receptors, but negligible or no affinity for a wide range of other receptors. Zolmitriptan has 1 active major metabolite that is expected to contribute to the therapeutic efficacy of the drug. The 2 remaining major metabolites are not active. Drugs used in the acute treatment of migraine are well known to cause constriction of cranial blood vessels and a redistribution of blood flow in the cranial circulation. Indeed, zolmitriptan induces constriction of various isolated vascular preparations known to contain 5-HT_1B/1Dreceptors; maximal contraction of isolated human coronary arteries with zolmitriptan is similar to that with naratriptan, rizatriptan and sumatriptan. Reductions in carotid arterial conductance with zolmitriptan are almost exclusively caused by constriction of cranial arteriovenous anastomotic shunts. Importantly, zolmitriptan produces no change in intracranial cerebral blood flow. Various animal models have demonstrated that zolmitriptan has the ability to inhibit trigeminovascular activation both peripherally and centrally, actions which may be relevant to its therapeutic efficacy. Although single doses of zolmitriptan 1 to 50mg produce increases in blood pressure in healthy volunteers, changes are generally not considered to be clinically significant and individual data often showed high variability. Zolmitriptan 20mg does not significantly alter cardiac output or heart rate in healthy volunteers. Although data from volunteers and patients with migraine shows that zolmitriptan acts centrally (on serotonergic pathways), available data indicate that the drug does not induce cognitive or psychomotor impairment in healthy volunteers. Orally administered zolmitriptan is rapidly absorbed in healthy volunteers [75% of the maximum plasma concentration (C_max) is achieved within 1 hour]. However, there is limited evidence to indicate that, like all serotonin 5-HT_1b/id receptor agonists (‘triptans’), the absorption of zolmitriptan 10mg is slowed during migraine associated with severe headache, nausea and photophobia. Area under the plasma concentration versus time curve (AUC) and C_max values showed approximate dose proportionality over the range zolmitriptan 2.5 to 50mg. However, there is considerable interindividual variation in plasma zolmitriptan concentrations. Food has no significant effect on the oral absorption of a 5mg dose of zolmitriptan. The mean absolute bioavailability of oral zolmitriptan 2.5mg in healthy volunteers is 39%. Binding to plasma proteins is not extensive (≈25%) and the mean volume of distribution following oral 2.5 and 5mg doses of zolmitriptan is 8.3 L/kg. Zolmitriptan is cleared principally by hepatic metabolism followed by urinary excretion of its metabolites. It has 3 major metabolites: an active N-desmethyl (183C91), an N-oxide and an indole acetic acid metabolite. Zolmitriptan is metabolised by the cytochrome P450 isoenzyme (CYP) 1A2 and by monoamine oxidase A and...