DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

D.h.e. 45 (Dihydroergotamine Mesylate) - Description and Clinical Pharmacology

 
 



D.H.E. 45®
(dihydroergotamine mesylate)
Injection, USP
Rx only
Prescribing Information

DESCRIPTION

D.H.E. 45® is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. D.H.E. 45® is known chemically as ergotaman-3´,6´,18-trione,9,10-dihydro-12´-hydroxy-2´-methyl-5´-(phenylmethyl)-,(5´α)-, monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is C33H37N5O5·CH4O3S.

The chemical structure is

C<sub>33</sub>H<sub>37</sub>N<sub>5</sub>O<sub>5</sub>·CH<sub>4</sub>O<sub>3</sub>S                Mol. wt. 679.80

C33H37N5O5·CH4O3S                Mol. wt. 679.80

D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is a clear, colorless solution supplied in sterile ampuls for I.V., I.M., or subcutaneous administration containing per mL:

dihydroergotamine mesylate, USP………………………………………………………1 mg

ethanol, 94% w/w………………………………………………………………………6.2% by vol.

glycerin…………………………………………………………………………………15% by wt.

water for injection, qs to………………………………………………………………..1 mL

CLINICAL PHARMACOLOGY

Mechanism of Action

Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α, receptors, and dopamine D2L and D3 receptors.

The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D 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-HT1D 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´-β-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 .)

Interactions

Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See CONTRAINDICATIONS ).

No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017