DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

action is as early as 15 minutes with the nasal spray. The
recommended oral dose of sumatriptan is 25-100 mg, which may be
repeated after 2 hours up to a total dose of 200 mg over a 24-hour
period. When administered by nasal spray, from 5-20 mg of
sumatriptan is recommended, repeatable after 2 hours up to a
maximum dose of 40 mg over a 24-hour period. Zolmitriptan is
given orally in a dose of 1.25-2.5 mg, which can be repeated after
2 hours, up to a maximum dose of 10 mg over 24 hours if the
migraine attack persists. Naratriptan is given orally in a dose of 1-2.5 mg,
which should not be repeated until 4 hours after the previous dose.
The maximum dose over a 24-hour period should not exceed 5 mg.
The recommended oral dose of rizatriptan is 5-10 mg. The dose can
be repeated after 2 hours up to a maximum dose of 30 mg over a
24-hour period. The safety of treating more than 3 or 4 headaches
over a 30-day period with triptans has not been established. No
triptan should be used concurrently with (or within 24 hours of) an
ergot derivative (described later) or another triptan.
Ergot and the Ergot Alkaloids. The elucidation of the
constituents of ergot and their complex actions was an
important chapter in the evolution of modern pharmacology,
even though the very complexity of their actions
limits their therapeutic uses. The pharmacological effects
of the ergot alkaloids are varied and complex; in general,
the effects result from their actions as partial agonists or
antagonists at serotonergic, dopaminergic, and adrenergic
receptors. The spectrum of effects depends on the agent,
dosage, species, tissue, physiological and endocrinological
state, and experimental conditions.
History. Ergot is the product of a fungus (Claviceps purpurea) that
grows on rye and other grains. The contamination of an edible grain
by a poisonous, parasitic fungus spread death for centuries. As early
as 600 B.C., an Assyrian tablet alluded to a “noxious pustule in the
ear of grain.” Written descriptions of ergot poisoning first appeared
in the Middle Ages, describing strange epidemics in which the characteristic
symptom was gangrene of the feet, legs, hands, and arms.
In severe cases, extremities became dry and black, and mummified
limbs separated off without loss of blood. Limbs were said to be consumed
by the holy fire, blackened like charcoal with agonizing burning
sensations, the disease was called holy fire or St. Anthony’s fire
in honor of the saint at whose shrine relief was said to be obtained.
The relief that followed migration to the shrine of St. Anthony was
probably real, for the sufferers received a diet free of contaminated
grain during their sojourn at the shrine. The symptoms of ergot poisoning
were not restricted to limbs. A frequent complication of it
was a dramatic abortive effect of ergot ingested during pregnancy.
The active principles of ergot were isolated and chemically identified
in the early 20th century.
Chemistry. The ergot alkaloids can all be considered to be derivatives
of the tetracyclic compound 6-methylergoline (Table 13–6).
The naturally occurring alkaloids contain a substituent in the beta
configurations at position 8 and a double bond in ring D. The natural
alkaloids of therapeutic interest are amide derivatives of d-lysergic
acid. The first pure ergot alkaloid, ergotamine, was obtained in 1920,
followed by the isolation of ergonovine in 1932. Numerous semisynthetic
derivatives of the ergot alkaloids have been prepared by
catalytic hydrogenation of the natural alkaloids (e.g., dihydroergotamine).
Another synthetic derivative, bromocriptine (2-bromo-αergocryptine),
is used to control the secretion of prolactin, a property
derived from its DA agonist effect. Other products of this series
include lysergic acid diethylamide (LSD), a potent hallucinogen, and
methysergide, a serotonin antagonist.
Absorption, Fate, and Excretion. The oral administration of ergotamine
by itself generally results in low or undetectable systemic
drug concentrations, because of extensive first-pass metabolism.
The bioavailability after administration of rectal suppositories is
greater. Ergotamine is metabolized in the liver by largely undefined
pathways, and 90% of the metabolites are excreted in the bile.
Despite a plasma t 1/2
of ~2 hours, ergotamine produces vasoconstriction
that lasts for 24 hours or longer. Dihydroergotamine is
eliminated more rapidly than ergotamine, presumably due to its
rapid hepatic clearance.
Ergonovine and methylergonovine are rapidly absorbed after
oral administration and reach peak concentrations in plasma within
60-90 minutes that are more than 10-fold those achieved with an
equivalent dose of ergotamine. Although often given IV, an uterotonic
effect in postpartum women can be observed within 10 minutes
after oral administration of 0.2 mg of ergonovine. The t 1/2
of methylergonovine
in plasma ranges between 0.5 and 2 hours.
Use in the Treatment of Migraine. The multiple pharmacological
effects of ergot alkaloids have complicated the determination of their
precise mechanism of action in the acute treatment of migraine.
Based on the mechanism of action of sumatriptan and other
5-HT 1B/1D
receptor agonists, the actions of ergot alkaloids at 5-HT 1B/1D
receptors likely mediate their acute anti-migraine effects.
The use of ergot alkaloids for migraine should be restricted
to patients having frequent, moderate migraine or infrequent, severe
migraine attacks. As with other medications used to abort an attack,
ergot preparations should be administered as soon as possible after
the onset of a headache. GI absorption of ergot alkaloids is erratic,
perhaps contributing to the large variation in patient response to
these drugs. Available preparations currently in the United States
include sublingual tablets of ergotamine tartrate (ERGOMAR) and a
nasal spray and solution for injection of dihydroergotamine mesylate
(MIGRANAL, D.H.E. 45, respectively). Ergotamine in fixed-dose
combinations with caffeine is also marketed under the brand names
of CAFERGOT (oral tablets) and MIGERGOT (rectal suppositories) and
as generic formulations (oral tablets). The recommended dose for
ergotamine tartrate is 2 mg sublingually, which can be repeated
at 30-minute intervals if necessary up to a total dose of 6 mg in a
24-hour period or 10 mg a week. Dihydroergotamine mesylate
injections can be given intravenously, subcutaneously, or intramuscularly.
The recommended dose is 1 mg, which can be repeated after
1 hour if necessary up to a total dose of 2 mg (intravenously) or 3 mg
(subcutaneously or intramuscularly) in a 24-hour period or 6 mg in
a week. The dose of dihydroergotamine mesylate administered as
a nasal spray is 0.5 mg (one spray) in each nostril, repeated after
15 minutes for a total dose of 2 mg (4 sprays). The safety of > 3 mg
over 24 hours or 4 mg over 7 days has not been established.
Adverse Effects and Contraindications of Ergot Alkaloids. Nausea
and vomiting, due to a direct effect on CNS emetic centers, occur in
~10% of patients after oral administration of ergotamine, and in
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CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE