Migraine is a syndrome with characteristic features composed of aura symptoms followed by headache associated with nausea, vomiting, photophobia, and photophobia
(
140). Based on the pharmacology of triptans (see above), triptans can abort migraine attack by four different mechanisms (
Fig. 51-4): (i) a direct contraction of dilated cranial extracerebral blood vessels (
62,
296), (ii) suppression of neuropeptide (mainly CGRP) release from peripheral nerve endings around blood vessels (
118,
121), (iii) inhibition of impulse transmission centrally in the trigeminal nucleus caudalis (
118,
121), and (iv) presynaptic blockade of synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts (
172). Although the case for the involvement of neurogenic mechanisms is compelling, in our view, however, the main action of triptans in migraine is the constriction of dilated cranial extracerebral blood vessels via 5-HT
1B receptors (
97,
150,
151,
244,
262). First, the possible contribution of the neuronal effects of triptans mediated via 5-HT
1D receptor, which are abundantly present in the trigeminal system (
239), has been put in doubt because PNU142633, a selective 5-HT
1D receptor agonist, was found ineffective in the treatment of migraine (
132). The intrinsic activity of PNU-142633 (70% of 5-HT) at the human 5-HT
1D receptor is only a little less than that of sumatriptan (84% of 5-HT), but it is equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation and can reduce increases in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion; importantly, in contrast to sumatriptan it does not reduce carotid blood flow (
200). Moreover, besides PNU-142633, there are many other selective 5-HT
1D receptor agonists lacking vasoconstrictor activity (
179,
202), but none has been described as effective in migraine. Another reason that speaks against the involvement of a central action is that sumatriptan (despite a report to the contrary where an extremely high intravenous dose of 3.2 mg/kg was used [
159]), does not easily cross the blood-brain barrier (
152,
162), is comparable in therapeutic effectiveness to centrally penetrative triptans (e.g., rizatriptan and eletriptan); see below. Accordingly, Pascual and Muñoz (
229) found no correlation between lipophilicity coefficients and therapeutic efficacy; interestingly there was a significant correlation between lipophilicity and central nervous system (CNS) adverse events. Thus, we submit that the central
mechanisms of triptans may not be necessary for therapeutic efficacy.
It is sometimes suggested (
87) that because of the efflux of eletriptan by p-glycoprotein from the brain, one needs a relatively “high” therapeutic dose negating the dose “advantage” by virtue of its high potency at the 5-HT
1B receptor (see
Table 51-1). However, it must be pointed out that about 85% of eletriptan is bound to plasma proteins (see
Table 51-2), thus reducing its pharmacologically effective (protein-unbound) fraction. The protein-bound fraction of eletriptan may serve as a “reservoir” to prolong its pharmacologic action.