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

Table 13–5
Serotonergic Drugs: Primary Actions and Clinical Indications
RECEPTOR ACTION DRUG EXAMPLES CLINICAL DISORDER
5-HT 1A
Partial agonist Buspirone, ipsaperone Anxiety, depression
5-HT 1D
Agonist Sumatriptan Migraine
5-HT 2A/2C
Antagonist Methysergide, risperidone, Migraine, depression, schizophrenia
ketanserin
5-HT 3
Antagonist Ondansetron Chemotherapy-induced emesis
5-HT 4
Agonist Cisapride GI disorders
SERT Inhibitor Fluoxetine, sertraline Depression, obsessive-compulsive disorder,
(5-HT transporter)
panic disorder, social phobia, post-traumatic
stress disorder
photophobia, hyperacusis, polyuria, and diarrhea, and
by disturbances of mood and appetite. A migraine
attack may last for hours or days and be followed by
prolonged pain-free intervals. The frequency of
migraine attacks is extremely variable. Therapy of
migraine headaches is complicated by the variable
responses among and within individual patients and by
the lack of a firm understanding of the pathophysiology
of the syndrome. The efficacy of anti-migraine
drugs varies with the absence or presence of aura, duration
of the headache, its severity and intensity, and as
yet undefined environmental and genetic factors
(Silberstein, 2008).
The pathogenesis of migraine headache is complex, involving
both neural and vascular elements (Mehrotra et al., 2008).
Evidence suggesting that 5-HT is a key mediator in the pathogenesis
of migraine includes:
• plasma and platelet concentrations of 5-HT vary with the different
phases of the migraine attack
• urinary concentrations of 5-HT and its metabolites are elevated
during most migraine attacks
• migraine may be precipitated by agents (e.g., reserpine and fenfluramine)
that release 5-HT from intracellular storage sites
Consistent with the 5-HT hypothesis, 5-HT receptor agonists
have become a mainstay for acute treatment of migraine headaches.
Treatments for the prevention of migraines, such as β adrenergic
antagonists and newer anti-epileptic drugs, have mechanisms of
action that are, presumably, unrelated to 5-HT (Mehrotra et al., 2008).
5-HT 1
Receptor Agonists
The Triptans. The triptans are effective, acute anti-migraine agents.
Their ability to decrease, rather than exacerbate, the nausea and vomiting
of migraine is an important advance in the treatment of the condition.
The selective pharmacological effects of the triptans at 5-HT 1
receptors has provided insights into the pathophysiology of
migraine. Available compounds include almotriptan (AXERT), eletriptan
(RELPAX), frovatriptan (FROVA), naratriptan (AMERGE), rizatriptan
(MAXALT, others), sumatriptan (IMITREX, others), and zolmitriptan
(ZOMIG). Sumatriptan for migraine headaches is also marketed in a
fixed-dose combination with naproxen (TREXIMET).
History. Sumatriptan emerged from the first experimentally based
approach to identify and develop a novel therapy for migraine. In
1972, Humphrey and colleagues initiated a project aimed at identifying
novel therapeutic agents in the treatment of migraine with the
goal of developing selective vasoconstrictors of the extracranial circulation,
based on the theories of the etiology of migraine prevalent
in the early 1970s (Humphrey et al., 1990). Sumatriptan, first synthesized
in 1984, became available for clinical use in the United
States in 1992; since then, several other triptans have been FDAapproved
for clinical use. The second generation triptans have higher
oral bioavailabilty.
Chemistry. The triptans are indole derivatives. Representative structures
are given in Figure 13–5.
Pharmacological Properties. In contrast to ergot alkaloids (described
later), the pharmacological effects of the triptans appear to be limited
to the 5-HT 1
family of receptors, providing evidence that this receptor
subclass plays an important role in the acute relief of a migraine
attack. The triptans interact potently with 5-HT 1B
and 5-HT 1D
receptors
and have a low or no affinity for other subtypes of 5-HT receptors,
as well as α 1
and α 2
adrenergic, β adrenergic, dopaminergic, muscarinic
cholinergic, and benzodiazepine receptors. Clinically effective
doses of the triptans correlate well with their affinities for both 5-HT 1B
and 5-HT 1D
receptors, supporting the hypothesis that 5-HT 1B
and/or 5-
HT 1D
receptors are the most likely receptors involved in the mechanism
of action of acute anti-migraine drugs.
Mechanism of Action. There remains a controversy about the relative
importance of vascular versus neurological dysfunction in migraine;
thus the mechanism of the efficacy of 5-HT 1B/1D
agonists in migraine
is not resolved. One hypothesis implicates the capacity of these
receptors to cause constriction of intracranial blood vessels
including arteriovenous anastomoses. According to a prominent
pathophysiological model of migraine, unknown events lead to the
abnormal dilation of carotid arteriovenous anastomoses in the head
and shunting of carotid arterial blood flow, producing cerebral ischemia
and hypoxia. Based on this model, an effective anti-migraine agent
would close the shunts and restore blood flow to the brain. Indeed,