ZOLAN 2.5

Indications

• Acute treatment of migraine attacks
• Management of migraine with or without aura

Mechanism of action

Zolmitriptan primarily acts as an agonist at the 5-HT1B and 5-HT1D receptor subtypes. By binding to these receptors, it modulates nociceptive nerve signaling in the central nervous system, particularly within the trigeminocervical complex (TCC). This modulation inhibits the release of pro-inflammatory neuropeptides, such as calcitonin gene-related peptide (CGRP), leading to cranial vasoconstriction and alleviation of headache symptoms. Additionally, zolmitriptan's action reduces the activation of the trigeminal nerve and the associated vasodilation that contributes to migraine pain.

Pharmacodynamics

Zolmitriptan, being a triptan, exhibits properties that enhance its effectiveness in treating migraines. It is a potent agonist of the serotonin receptors, particularly 5-HT1B and 5-HT1D. This agonistic activity leads to vasoconstriction of cerebral blood vessels and inhibition of neurogenic inflammation. The drug's efficacy is attributed to its ability to rapidly alleviate headache symptoms and reduce the associated discomfort, such as photophobia and nausea. However, it may also cause adverse cardiovascular effects, including vasospasm and elevated blood pressure.

Pharmacokinetics

Zolmitriptan is absorbed rapidly after administration, with peak plasma concentrations occurring within 1.5 to 2 hours when taken orally. It undergoes extensive first-pass metabolism in the liver, leading to a bioavailability of approximately 40%. The drug is mainly metabolized by cytochrome P450 enzymes, particularly CYP1A2. It has a half-life of approximately 3 hours, allowing for quick alleviation of migraine symptoms. Excretion primarily occurs through the kidneys, with a majority of the metabolites being eliminated in urine.

Contra-indications

• Coronary heart disease
• Coronary vasospasm (Prinzmetal's angina)
• Ischemic heart disease
• Moderate to severe uncontrolled hypertension
• History of seizures
• Conditions predisposing to coronary artery disease
• Elderly patients

Adverse effects

• Asthenia
• Dizziness
• Drowsiness
• Dyspnea
• Flushing
• Myalgia
• Nausea
• Abnormal pain sensation
• Abnormal skin reactions
• Temperature sensation altered
• Vomiting
• Epistaxis
• Nasal irritation
• Altered taste
• Throat irritation
• Haemorrhage
• Swelling

Interactions

• Cimetidine may increase exposure to zolmitriptan
• MAOIs (irreversible) may increase exposure
• Mexiletine may increase exposure
• Moclobemide may increase exposure
• Osilodrostat may increase exposure
• Ciprofloxacin may increase exposure
• Rucaparib may increase exposure
• Fluvoxamine may increase exposure
• Zolmitriptan and ergotamine may increase the risk of vasoconstriction
• SSRIs may increase exposure

Precautions

• Caution in patients with mild, controlled hypertension
• Caution in patients with history of seizures
• Use with caution in hepatic impairment
• Caution in patients with risk factors for seizures
• Consider potential benefits versus risks when prescribing to pregnant women

Pregnancy

Limited experience with 5-HT1 receptor agonists during pregnancy; manufacturers advise caution.

Breast-feeding

Zolmitriptan is present in milk but in small amounts; it is advisable to withhold breastfeeding for 12 hours after administration.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Intranasal spray: 5 mg
• Tablets: 2.5 mg, 5 mg

Mechanism of action

Migraines are complex physiological events characterized by unilateral throbbing headaches combined with photophobia and other aversions to sensory input. Migraine attacks are generally divided into phases: the premonitory phase, which typically involves irritability, fatigue, yawning, and stiff neck; the headache phase, which lasts for between four and 72 hours; and the postdrome phase, which lasts for up to a day following resolution of pain and whose symptoms are similar to those of the premonitory phase. In addition, neurological deficits, collectively termed migraine aura, may precede the headache phase. The underlying pathophysiology of migraines is a matter of active research but involves both neurological and vascular components. The head pain associated with migraine is thought to be a consequence of activation of the nociceptive nerves comprising the trigeminocervical complex (TCC). Terminals of nociceptive nerves that innervate the dura matter release vasoactive peptides, such as calcitonin gene-related peptide (CGRP), resulting in cranial vasodilation. Finally, when present, migraine aura appears to correlate with a transient wave(s) of cortical depolarization, termed cortical spreading depression (CSD). Triptans, including zolmitriptan, are proposed to act in three ways. The main mechanism is through modulation of nociceptive nerve signalling in the central nervous system through 5-HT_1B/1D receptors throughout the TCC and associated areas of the brain. In addition, triptans can enhance vasoconstriction, both through direct 5-HT_1B-mediated dilation of cranial blood vessels, as well as through 5-HT_1D-mediated suppression of CGRP release. Although triptans are classically described solely in terms of their effects on 5-HT_1B/1D receptors, they also act as 5-HT_1F agonists as well. This 5-HT subtype is also found throughout the TCC, but is not present appreciably in cerebral vasculature; the significance of triptan-mediated 5-HT_1F activation is currently not well described. Additionally, CSD that initiates in the ipsilateral parietal region may exert its effects in a manner that relies on 5-HT_1B/1D receptor activation, suggesting that triptans may have some effect on CSD-mediated symptoms.

Pharmacodynamics

Zolmitriptan, like other triptans, is a serotonin (5-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT_1B and 5-HT_1D receptor subtypes. It is through the downstream effects of 5-HT_1B/1D activation that triptans are proposed to provide acute relief of migraines. Zolmitriptan is also a vasoconstrictor, leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions. In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome. Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine.