Mechanism of Action

Dihydroergotamine binds with high affinity to 5-HT_1Da and 5-HT_1Db receptors. It also binds with high affinity to serotonin 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors, noradrenaline a2A, a2B and a receptors, and dopamine D_2L and D₃ receptors.

The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT_1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT_1D receptor agonists in migraine. One theory suggests that activation of 5-HT_1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT_1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

In addition, dihydroergotamine possesses oxytocic properties. (See CONTRAINDICATIONS)

Pharmacokinetics

Absorption: Absolute bioavailability for the subcutaneous and intramuscular route have not been determined however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses. Dihydroergotamine mesylate is poorly bioavailable following oral administration.

Distribution: Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.

Metabolism: Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite 8'-b-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-30% of plasma AUC. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.

Excretion: The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6%-7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours.

Subpopulations: No studies have been conducted on the effect of renal or hepatic impairment, gender race, or ethnicity on dihydroergotamine pharmacokinetics. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with severely impaired hepatic or renal function. (See CONTRAINDICATIONS)

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