A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
D H E 45 Pharmacology, Pharmacokinetics, Studies, Metabolism - Dihydroergotamine
D H E 45 Pharmacology, Pharmacokinetics, Studies, Metabolism - Dihydroergotamine
CLINICAL PHARMACOLOGY
Mechanism of Action
Dihydroergotamine binds with high affinity
to 5-HT1Da and 5-HT1Db
receptors. It also binds with high affinity
to serotonin 5-HT1A,
5-HT2A, and 5-HT2C receptors, noradrenaline
a2A, a2B and
a 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'-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)
Interactions: Pharmacokinetic interactions (increased
blood levels) have been reported in patients treated orally with
dihydroergotamine and macrolide
antibiotics, principally troleandomycin, presumably due to inhibition
of cytochrome P450
3A metabolism of
dihydroergotamine by troleandomycin. Dihydroergotamine has also
been shown to be an inhibitor
of cytochrome P450 3A catalyzed reactions. No
pharmacokinetic interactions involving other cytochrome
P450 isoenzymes are known.
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