Mechanism of Action

Almotriptan binds with high affinity to 5-HT_1D, 5-HT_1B, and 5-HT_1F receptors.Almotriptan has weak affinity for 5-HT_1A and 5-HT₇ receptors, but has no significant affinity or pharmacological activity at 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆; alpha or beta adrenergic; adenosine (A₁, A₂); angiotensin (AT₁, AT₂); dopamine (D₁, D₂); endothelin (ET_A, ET_B); or tachykinin (NK₁, NK₂, NK₃) binding sites.

Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system.The therapeutic activity of almotriptan in migraine can most likely be attributed to agonist effects at 5-HT_1B/1D receptors on the extra cerebral, intracranial blood vessels that become dilated during a migraine attack, and on nerve terminals in the trigeminal system.Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathways.

Pharmacokinetics

General

Almotriptan is well absorbed after oral administration (absolute bio availability about 70%) with peak plasma levels 1 to 3 hours after administration; food does not affect pharmacokinetics.Almotriptan has a mean half-life of 3 to 4 hours.It is eliminated primarily by renal excretion (about 75% of the oral dose). Almotriptan is minimally protein bound (approximately 35%) and the mean apparent volume of distribution is approximately 180to 200 liters.

Metabolism and Excretion

Almotriptan is metabolized by one minor and two major pathways. Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and cytochrome P450-mediated oxidation (approximately 12% of the dose) are the major routes of metabolism, while flavin mono oxygenase is the minor route. MAO-A is responsible for the formation of the indoleacetic acid metabolite, whereas cytochrome P450 (3A4 and 2D6) catalyzes the hydroxylation of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde dehydrogenase to the gamma-amino butyric acid derivative. Both metabolites are inactive.

Approximately 40% of an administered dose is excreted unchanged in urine. Renal clearance exceeds the glomerular filtration rate by approximately 3-fold, indicating an active mechanism. Approximately 13% of the administered dose is excreted via feces, both unchanged and metabolized.

Special Populations

Geriatric

Renal and total clearance, and amount of drug excreted in the urine were lower in elderly healthy volunteers (age 65 to 76 years) than in younger healthy volunteers (age 19 to 34 years), resulting in longer terminal half-life (3.7 h vs. 3.2 h) and a 25% higher area under the plasma concentration-time curve in the elderly subjects.The differences, however, do not appear to be clinically significant.

Pediatric

The pharmacokinetics of almotriptan in pediatric patients have not been evaluated.

Gender

No significant gender differences have been observed in pharmacokinetic parameters.

Race

No significant differences have been observed in pharmacokinetic parameters between Caucasian and African-American volunteers.

Hepatic Impairment

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