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Mechanisms of Action of the 5-HT1B/1D Receptor Agonists
Stewart J. Tepper, MD;
Alan M. Rapoport, MD;
Fred D. Sheftell, MD
Arch Neurol. 2002;59:1084-1088.
ABSTRACT
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Recent studies of the pathophysiology of migraine provide evidence that
the headache phase is associated with multiple physiologic actions. These
actions include the release of vasoactive neuropeptides by the trigeminovascular
system, vasodilation of intracranial extracerebral vessels, and increased
nociceptive neurotransmission within the central trigeminocervical complex.
The 5-HT1B/1D receptor agonists, collectively known as triptans,
are a major advance in the treatment of migraine. The beneficial effects of
the triptans in patients with migraine are related to their multiple mechanisms
of action at sites implicated in the pathophysiology of migraine. These mechanisms
are mediated by 5-HT1B/1D receptors and include vasoconstriction
of painfully dilated cerebral blood vessels, inhibition of the release of
vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive
neurotransmission. The high affinity of the triptans for 5-HT1B/1D
receptors and their favorable pharmacologic properties contribute to the beneficial
effects of these drugs, including rapid onset of action, effective relief
of headache and associated symptoms, and low incidence of adverse effects.
INTRODUCTION
The pathophysiology of migraine is fairly well understood, and evidence
supports contributory roles of both neural and vascular mechanisms. The manifestation
of headache in migraineurs is probably associated with activation of the trigeminovascular
system, followed by the release of vasodilatory neuropeptides. Changes in
circulating levels of the neurotransmitter serotonin (5-HT) are characteristic
of migraine and may contribute to the pathogenesis of the disorder. Recent
progress in understanding the pathophysiology of migraine includes the identification
of the physiologic roles of vasoactive neuropeptides associated with migraine
and the characterization of 5-HT receptor subtypes.
Increased understanding of the pathophysiology of migraine has led to
the development of improved migraine treatments such as the 5-HT1B/1D receptor agonists, collectively known as triptans. The emergence of
the triptans has revolutionalized the management of migraine by providing
options for the highly selective stimulation of 5-HT1B/1D receptors,
while reducing or eliminating unwanted activity at other receptor subtypes,
thus improving therapeutic tolerability. This article focuses on the mechanisms
of action of the triptans in relation to current concepts of the pathophysiology
of migraine and the clinical role of these drugs in the management of patients
with migraine.
PATHOPHYSIOLOGY OF MIGRAINE
The manifestation of headache in migraineurs has been attributed to
activation of the sensory trigeminovascular system and the subsequent release
of vasoactive neuropeptides.1 In the genetically
susceptible patient, activation of the trigeminovascular system can be initiated
by a variety of triggers, including stress, certain foods or drugs, odors,
trauma, and changes in sleep habits. The release of vasoactive substances
from trigeminal nerve terminals in patients with migraine induces inflammatory
reactions in meningeal blood vessels, characterized by vasodilation, plasma
protein extravasation, and activation of trigeminovascular afferents.2 Studies in animals support the observation that pain-producing
intracranial extracerebral vessels in the dura mater (peripherally), not the
brain, are responsible for the generation of headache in patients with migraine.3
Vasoactive neuropeptides found within the trigeminal neurons that innervate
intracranial blood vessels and contribute to the manifestation of head pain
in migraineurs include calcitonin gene-related peptide (CGRP), substance P,
and neurokinin A. Calcitonin gene-related peptide is the most potent vasodilator
neurotransmitter mapped to the trigeminal system, and its action is endothelium
independent.4 Substance P, a nondecapeptide
involved in nociceptive transmission, has endothelium-dependent vasodilatory
effects on the cerebrovascular bed.5 Neurokinin
A is a decapeptide with a profile of action and localization in the trigeminal
system that is similar to that of substance P but with less potent vasodilatory
effects and longer-lasting effects on blood vessel permeability.6
The critical neuropeptide in the generation of migraine seems to be CGRP rather
than substance P or neurokinin A.
Neurogenic inflammation within the meninges has been suggested as a
potential model to explain the source of head pain in patients with migraine,
but it has been unclear whether neurogenic inflammation occurs during an acute
migraine attack. Studies in animals demonstrate increased endothelial permeability
and leakage of albumin into the dura and the retina after high-intensity electrical
stimulation of the trigeminal ganglion, but no increased endothelial permeability
or protein extravasation has been documented in human retinal or choroidal
vessels during migraine attacks or the headache-free interval in migraineurs.7 These findings suggest that other fundamental processes,
probably in the central nervous system, are key to the pathophysiology of
a migraine attack.
The autonomic nervous system may contribute to the pathophysiology of
migraine. Hyperfunctioning of both the sympathetic and parasympathetic nervous
systems has been suspected in patients with migraine, based on vasomotor reactions
to temperature changes, cardiovascular responses, and other investigations.
The normal responses of cranial arteries during increased sympathetic activity
cast doubt on a major role of sympathetic dysfunction in the pathophysiology
of migraine, but mild parasympathetic hypofunction with denervation hypersensitivity
could be a contributing factor.8
The role of nitric oxide in the pathophysiology of migraine and other
vascular headaches is supported by the observations that both glyceryl trinitrate
(a nitric oxide donor) and histamine (an activator of endothelial nitric oxide
formation) cause dose-dependent headaches with several migrainous characteristics.9 Patients with migraine respond to nitric oxide delivered
by nitroglycerin by developing an early nonmigraine headache and then a delayed,
migraine-like headache several hours after dosing—a headache not seen
when healthy control patients are given nitroglycerin, which suggests an increased
vulnerability in migraineurs to one or more of the toxic effects of nitric
oxide, including enzyme inhibition and the formation of peroxynitrate with
lipid peroxidation.9
5-HT RECEPTORS
The role of 5-HT in migraine is supported by the observations that urinary
and platelet 5-HT levels decrease, and that circulating levels of 5-hydroxyindoleacetic
acid (5-HIAA), the major metabolite of 5-HT, increase during migraine.10 The ability of 5-HT–depleting and 5-HT–releasing
agents such as reserpine and fenfluramine to induce migraine-like symptoms
provides further evidence of the role of serotonin in the pathophysiology
of migraine.11 Intravenous infusion of 5-HT
aborts both reserpine-induced and spontaneous headache, but the clinical use
of 5-HT in migraine is precluded by significant untoward effects.11
The 5-HT receptors are highly heterogeneous, broadly distributed, and
classified into 7 different families on the basis of their amino acid sequences
and other properties.12 The 5-HT1
receptors are the largest subfamily of 5-HT receptors and typically demonstrate
a high affinity for 5-HT. The 5-HT1 receptors are further subdivided
according to their physiologic functions, binding affinity, and other features.
The cloning of 5-HT1 receptors and the development of 5-HT
receptor agonists with specific affinity for 5-HT1 receptor subtypes
provided evidence for substantial populations of 5-HT1B receptors
on vascular endothelium and human meningeal blood vessels.6
The messenger RNA for the 5-HT1B receptor is abundantly expressed
on neuronal tissues and vascular smooth muscle cells, and evidence suggests
that this receptor mediates contraction of vascular smooth muscle.13 Both the 5-HT1B and 5-HT1D
receptors have been localized in human trigeminal ganglia and trigeminal nerves,
but only 5-HT1D receptors have been detected in trigeminal nerves
projecting peripherally to the dural vasculature and centrally to the brainstem
trigeminal nuclei.6, 13 The 5-HT1D receptors are thus localized peripherally to inhibit activated trigeminal
nerves and prevent vasoactive neuropeptide release, and centrally to interrupt
pain signal transmission from the blood vessels to sensory neurons located
in the brainstem.6
Local application of 5-HT1B/1D receptor agonists inhibits
firing activity by second-order trigeminal neurons, and this activity is shared
by ergonovine, a nonspecific 5-HT1 receptor agonist.14
These observations support the presence of inhibitory receptors on these neurons
that are capable of decreasing trigeminal neuronal traffic and thus pain transmission
in migraine and other primary headaches.
MECHANISMS OF ACTION OF THE 5-HT1B/1D RECEPTOR AGONISTS
Studies of the mechanisms of action of 5-HT1B/1D receptor
agonists, or triptans, provide important insights into the pathophysiology
of migraine. The triptans have at least 3 distinct modes of action, all of
which may be additive in their antimigraine effects (Table 1). 6, 15 These
effects include vasoconstriction of painfully distended intracranial extracerebral
vessels by a direct effect on vascular smooth muscle, inhibition of the release
of vasoactive neuropeptides by trigeminal terminals innervating the intracranial
vessels and dura mater, and inhibition of nociceptive neurotransmission within
the trigeminocervical complex in the brainstem and upper spinal cord.15 Other possible antimigraine effects of the triptans
include modulation of nitric oxide–dependent signal transduction pathways,
nitric oxide scavenging in the brain, and sodium-dependent cell metabolic
activity.16-18
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Table 1. Antimigraine Mechanisms of the 5-HT1B/1D Receptor
Agonists*
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Sumatriptan and rizatriptan have been shown to act selectively to cause
vasoconstriction in isolated human middle meningeal arteries and are 10 times
more potent in these arteries than in human coronary arteries.19
The maximal response evoked by both agents is less than that of 5-HT.20 These observations and those of Maassen VanDenBrink
et al21 suggest that therapeutic plasma concentrations
of the triptans do not reach levels likely to cause myocardial ischemia in
patients with normal coronary circulation. However, given that there are some
5-HT1B receptors in coronary arteries, triptans are contraindicated
in patients with cerebrovascular or cardiovascular disease.
The normalization of vessel diameter in cerebral arteries in migraineurs
can be achieved without frank vasoconstriction through inhibition of CGRP
release, and this mechanism may contribute to the relief of headache in patients
treated with triptans. Studies in anesthetized rats demonstrate that rizatriptan
has no direct vasoconstrictor effects, and blocks electrically stimulated
dural vasodilation and plasma protein extravasation by inhibiting the release
of CGRP via activation of prejunctional receptors located on trigeminal sensory
nerve terminals.22 Sumatriptan inhibits potassium-stimulated
CGRP secretion from cultured trigeminal neurons in a dose-dependent manner
and may also inhibit the release of substance P.23
These observations support the concept that sumatriptan and other triptans
may block a deleterious feedback loop in migraine whereby neurogenic inflammatory
agents sensitize the trigeminal ganglia neurons to sustain elevated levels
of CGRP.
The dilation of meningeal blood vessels may evoke a sensitization of
central trigeminal neurons that may underlie the symptoms of headache and
allodynia in migraineurs.24 The inhibition
of evoked trigeminal nucleus firing by 5-HT, and the blockade of this activity
by a 5-HT1B/1D agonist with central nervous system penetration
suggest that triptans inhibit trigeminal activity centrally.25
Rizatriptan has been shown to have central trigeminal antinociceptive activity
in addition to peripheral vasoconstriction and inhibitory effects on the trigeminovasculature,26 and these effects may be mediated by the 5-HT1D receptor.
CLINICAL EFFICACY OF THE 5-HT1B/1D RECEPTOR AGONISTS
The 5-HT1B/1D receptor agonists are remarkably effective
in the treatment of migraine pain (Table
2),27-43
considerably decreasing the need for rescue medications. The triptans are
also effective for migraine-associated symptoms, such as nausea, vomiting,
photophobia, andphonophobia. A primary shortcoming of most triptans is headache
recurrence.
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Table 2. Comparison of Efficacy of Approved and Investigational Oral
Triptans at Most Commonly Used Doses*
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Significant differences in safety among the triptans have not been demonstrated,
although the clinically used doses of naratriptan and almotriptan yield few
adverse effects, producing a tolerability similar to that seen with placebo.
Typical adverse effects of the triptans are fatigue, dizziness, paresthesias,
warm sensations, and neck, chest, and throat tightness. The tolerability of
individual triptans is relative and cannot be predicted on the basis of lipophilicity,
bioavailability, absolute dose size, or any combination of these variables.44 Because all triptans are 5-HT1B/1D agonists
in the low nanomolar range, differences in their adverse effects profiles
are unlikely to be mediated through 5-HT1B/1D receptors.44
The first triptan to be developed and approved for clinical use in patients
with migraine was sumatriptan, which is available in injectable, intranasal,
and oral formulations. The limitations of sumatriptan include low bioavailability,
short plasma half-life, and low liposolubility. These and other drawbacks
prompted the development of triptans with improved pharmacokinetic properties.
Zolmitriptan has a significantly higher oral bioavailability than sumatriptan
(40% vs 14%).45 Zolmitriptan has efficacy similar
to that of sumatriptan for the relief of a single migraine attack, and a high
consistency of response in open-label extension studies longer than 1 year,
with 95% of attacks aborted by 4 hours with 1 to 2 doses of 2.5 mg or 5 mg.46 Zolmitriptan is generally well tolerated, with mild,
brief adverse effects typical of all triptans.
Naratriptan, compared with sumatriptan, has greater bioavailability
(about 60%); a longer elimination half-life (5.0-5.5 hours); better lipophilicity,
and thus, better central nervous system penetration; and less reversibility
in 5-HT receptor binding.32 Comparative trials
have shown that 2.5 mg of naratriptan is less effective than 100 mg of sumatriptan
in terms of the likelihood of achieving headache relief, but has almost no
adverse effects.45 Naratriptan has a lower
headache recurrence rate than sumatriptan and rizatriptan when directly compared,
but the time to recurrence is not longer with naratriptan.29
Rizatriptan has a rapid onset of action, high bioavailability, and a
favorable adverse effects profile. In direct comparisons of oral sumatriptan
and rizatriptan in patients with migraine, 10 mg of rizatriptan had a slightly
quicker time to headache relief in hazards ratio analysis against both the
50-mg and 100-mg doses of sumatriptan and better effects on several other
secondary measures of efficacy, including reduction of functional disability
and the proportion of patients who were pain free at 2 hours.47
As with sumatriptan, rizatriptan is not affected by concurrent use of oral
contraceptives or medications metabolized by the hepatic cytochrome P 450
3A4 system. Doses of rizatriptan must be halved when administered concomitantly
with propranolol, but not with other ß-blockers.
Almotriptan is structurally related to sumatriptan, but its potency
at the 5-HT1D receptor is lower than that of sumatriptan, though
its potency at the 5-HT1B receptor is similar to that of sumatriptan
and rizatriptan.30 Results from a randomized,
double-blind, placebo-controlled trial indicate that almotriptan is effective
across multiple attacks, with 2 of 3 attacks relieved in 75% of patients treated
with 12.5 mg of almotriptan.48
Frovatriptan has one of the highest affinities for the 5-HT1B receptor and a long elimination half-life (as long as 25 hours).30
Frovatriptan seems to have a slower onset of action than most other triptans.
About one third of patients in open-label extension studies longer than 1
year reported pain relief in less than 2 hours after dosing, with headache
recurrence rates of less than 10%.49
Eletriptan has affinity for 5-HT1B/1D receptors that is 4
to 8 times higher than that of sumatriptan.50
Eletriptan is a substrate for P-glycoprotein, an important efflux transporter
at the blood-brain barrier. This finding suggests that eletriptan has the
potential for increased central nervous system concentrations and drug-drug
interactions when coadministered with medications that are substrates or inhibitors
of P-glycoprotein. In addition, eletriptan is metabolized by the cytochrome
P 450 3A4 system, and dose reduction may be mandated in the prescribing information
when eletriptan is administered with medications that also are degraded by
cytochrome P 450 3A4, such as macrolide antibiotics and antifungal medications.
CONCLUSIONS
Triptans are a major clinical advance in the treatment of migraine.
The clinical efficacy of these drugs in migraine is related in part to their
multiple mechanisms of action at vascular, neural, and central physiologic
sites implicated in the pathophysiology of migraine. In combination with their
highly selective affinity for 5-HT1B/1D receptors, the triptans
have favorable pharmacologic properties, characterized by high oral bioavailability,
rapid onset of action, and low incidence of adverse effects. These features
underlie the beneficial effects of the triptans in patients with migraine,
including rapid relief of headache and associated symptoms and improvements
in productivity and health-related quality of life. Future studies may identify
additional mechanisms of action of the triptans and the optimal role of these
agents in the management of patients with migraine.
AUTHOR INFORMATION
Accepted for publication October 8, 2001.
Author contributions: Study concept and design (Drs Tepper, Rapoport, and Sheftell); acquisition of data (Drs Tepper, Rapoport, and Sheftell); analysis and interpretation
of data (Drs Tepper, Rapoport, and Sheftell); drafting
of the manuscript (Drs Tepper, Rapoport, and Sheftell); critical revision of the manuscript for important intellectual content (Drs Tepper, Rapoport, and Sheftell); statistical expertise (Drs Tepper, Rapoport, and Sheftell).
Corresponding author and reprints: Stewart J. Tepper, MD, the New
England Center for Headache, 778 Long Ridge Rd, Stamford, CT 06902-1251 (e-mail: SJTepper{at}aol.com).
From the New England Center for Headache, Stamford, Conn (Drs Tepper,
Rapoport, and Sheftell); the Department of Neurology, Yale University School
of Medicine, New Haven, Conn (Drs Tepper and Rapoport); and the Department
of Psychiatry, New York Medical College, Valhalla (Dr Sheftell). Drs Tepper,
Rapoport, and Sheftell are consultants for GlaxoSmithKline, Merck, AstraZeneca,
and Pharmacia; conduct research for GlaxoSmithKline, Merck, AstraZeneca, Pharmacia,
Allergan, Elan, and OrthoMcNeill; and are on the speakers bureau for GlaxoSmithKline,
Merck, and AstraZeneca. Dr Rapoport is also a consultant for Abbott, Pfizer,
Forest Laboratories, Elan, and Bristol-Myers Squibb. Dr Sheftell is also a
consultant for Pfizer.
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SECTION EDITOR: DAVID E. PLEASURE, MD
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