Peter De Vries

Triptans in migraine : A comparative review of pharmacology, pharmacokinetics and efficacy

Triptans are a new class of compounds developed for the treatment of migraine attacks. The first of the class, sumatriptan, and the newer triptans (zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan) display high agonist activity at mainly the serotonin 5-HT1b and 5-HT1d receptor subtypes. As expected for a class of compounds developed for affinity at a specific receptor, there are minor pharmacodynamic differences between the triptans.Sumatriptan has a low oral bioavailability (14%) and all the newer triptans have an improved oral bioavailability and for one, risatriptan, the rate of absorption is faster. The half-lives of naratriptan, eletriptan and, in particular, frovatriptan (26 to 30h) are longer than that of sumatriptan (2h). These pharmacokinetic improvements of the newer triptans so far seem to have only resulted in minor differences in their efficacy in migraine.Double-blind, randomised clinical trials (RCTs) comparing the different triptans and triptans with other medication should ideally be the basis for judging their place in migraine therapy. In only 15 of the 83 reported RCTs were 2 triptans compared, and in 11 trials triptans were compared with other drugs. Therefore, in all placebo-controlled randomised clinical trials, the relative efficacy of the triptans was also judged by calculating the therapeutic gain (i.e. percentage response for active minus percentage response for placebo). The mean therapeutic gain with subcutaneous sumatriptan 6mg (51%) was more than that for all other dosage forms of triptans (oral sumatriptan 100mg 32%; oral sumatriptan 50mg 29%; intranasal sumatriptan 20mg 30%; rectal sumatriptan 25mg 31%; oral zolmitriptan 2.5mg 32%; oral rizatriptan 10mg 37%; oral eletriptan 40mg 37%; oral almotriptan 12.5mg 26%). Compared with oral sumatriptan 100mg (32%), the mean therapeutic gain was higher with oral eletriptan 80mg (42%) but lower with oral naratriptan 2.5mg (22%) or oral frovatriptan 2.5mg (16%). The few direct comparative randomised clinical trials with oral triptans reveal the same picture. Recurrence of headache within 24 hours after an initial successful response occurs in 30 to 40% of sumatriptan-treated patients. Apart from naratriptan, which has a tendency towards less recurrence, there appears to be no consistent difference in recurrence rates between the newer triptans and sumatriptan. Rizatriptan with its shorter time to maximum concentration (tmax) tended to produce a quicker onset of headache relief than sumatriptan and zolmitriptan.The place of triptans compared with non-triptan drugs in migraine therapy remains to be established and further RCTs are required.

Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy

The last decade has witnessed a tremendous progress in the acute therapy of migraine, with sumatriptan, belonging to a new class of drugs, now known as 5-HT(1B/1D/1F) receptor agonists, leading the way. The undoubted success of sumatriptan stimulated the development of new triptans as well as other suitable pharmacological tools and experimental models to probe into complex migraine mechanisms. In this review, we discuss the main experimental models for migraine, against the background of the disease pathophysiology and 5-HT receptors considered most important for migraine therapy. We believe that the use of these migraine models will provide even better treatment for migraine patients in the next millennium.

Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends

Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, the 5-HT1B/1D/1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D/5-ht1F receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side effects.

Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: role of 5-HT1B/1D receptors and α2-adrenoceptors

The antimigraine drugs methysergide, ergotamine and dihydroergotamine (DHE) produce selective vasoconstriction in the external carotid bed of vagosympathectomized dogs anaesthetized with pentobarbital and artificially respired, but the receptors involved have not yet been completely characterized. Since the above drugs display affinity for several binding sites, including α‐adrenoceptors and several 5‐HT1 and 5‐HT2 receptor subtypes, this study has analysed the mechanisms involved in the above responses. Intracarotid (i.c.) infusions during 1 min of methysergide (31–310 μg min−1), ergotamine (0.56–5.6 μg min−1) or DHE (5.6–31 μg min−1) dose‐dependently reduced external carotid blood flow (ECBF) by up to 46±4, 37±4 and 49±5%, respectively. Blood pressure and heart rate remained unchanged. The reductions in ECBF by methysergide were abolished and even reversed to increases in animals pre‐treated with GR127935 (10 μg kg−1, i.v.). The reductions in ECBF by ergotamine and DHE remained unchanged in animals pre‐treated (i.v.) with prazosin (300 μg kg−1), but were partly antagonized in animals pre‐treated with either GR127935 (10 or 30 μg kg−1) or yohimbine (1000 μg kg−1). Pre‐treatment with a combination of GR127935 (30 μg kg−1) and yohimbine (1000 μg kg−1) abolished the responses to both ergotamine and DHE. The above doses of antagonists were shown to produce selective antagonism at their respective receptors. These results suggest that the external carotid vasoconstrictor responses to methysergide primarily involve 5‐HT1B/1D receptors, whereas those to ergotamine and DHE are mediated by 5‐HT1B/1D receptors as well as α2‐adrenoceptors.

Blockade of porcine carotid vascular responses to sumatriptan by GR127935, a selective 5-HT1D receptor antagonist

1 . It has previously been shown that the antimigraine drug, sumatriptan, a putative 5‐HT1D receptor agonist, decreases porcine common carotid and arteriovenous anastomotic blood flows, but slightly increases the arteriolar (capillary) blood flow to the skin and ears. Interestingly, such responses, being mediated by 5‐HT1‐like receptors, are resistant to blockade by metergoline, which, in addition to displaying a very high affinity for (and occasionally intrinsic efficacy at) the 5‐HT1D receptor subtypes, blocks (with lower potency than methiothepin) some 5‐HT1D receptor‐mediated vascular responses. These findings raise doubts whether sumatriptan‐sensitive 5‐HT1‐like receptors mediating changes in the distribution of porcine carotid blood flow are identical to cloned 5‐HT1D receptors. With the recent advent of the potent and selective 5‐HT1D receptor antagonist, GR127935, we have examined in the present study whether the carotid vascular effects of sumatriptan in the pig are amenable to blockade by GR127935. 2 . In animals pretreated with saline, sumatriptan (30, 100 and 300 μm kg−1, i.v.) reduced the total carotid and arteriovenous anastomotic blood flows in a dose dependent manner. In contrast, sumatriptan increased blood flow to the skin, ears and fat, although the total capillary fraction was not significantly affected. 3 . While GR127935 pretreatment (0.25 and 0.5 mg kg−1) itself slightly reduced the total carotid and arteriovenous anastomotic blood flows, carotid vasoconstrictor responses to sumatriptan were either partly (0.25 mg kg−1) or completely (0.5 mg kg−1) blocked by the compound. In GR127935 pretreated animals, the sumatriptan‐induced increases in blood flow to the skin, ears and fat were also attenuated. 4 . Taken together, the results suggest that arteriovenous anastomotic constriction and, possibly, arteriolar dilatation in the skin, ears and fat by sumatriptan are mediated by 5‐HT1D receptors. Therefore, vascular 5‐HT1‐like receptors in the porcine carotid bed appear to be identical to 5‐HT1D receptors.

Characterization of 5-HT receptors mediating constriction of porcine carotid arteriovenous anastomoses; involvement of 5-HT1B/1D and novel receptors

It was previously shown that porcine cranial arteriovenous anastomoses (AVAs) constrict to 5‐hydroxytryptamine (5‐HT), ergotamine, dihydroergotamine, as well as sumatriptan and that sumatriptan acts exclusively via 5‐HT1B/1D receptors. The present study was devoted to establish the contribution of 5‐HT1B/1D receptors in the constriction of AVAs elicited by 5‐HT (in presence of 0.5 mg kg−1 ketanserin), ergotamine and dihydroergotamine in anaesthetized pigs. Intracarotid infusion of 5‐HT (2 μg kg−1 min−1) and intravenous doses of ergotamine (2.5–20 μg kg−1) and dihydroergotamine (3–100 μg kg−1) reduced AVA and increased nutrient blood flows and vascular conductances. The vasodilator response to 5‐HT, observed mainly in the skin and ear, was much more prominent than that of the ergot alkaloids. Treatment with the 5‐HT1B/1D receptor antagonist GR127935 (0.5 mg kg−1, i.v.) significantly attenuated both ergot‐induced AVA constriction and arteriolar dilatation, whereas GR127935 only slightly affected the carotid vascular effects of 5‐HT. The results suggest that 5‐HT constricts carotid AVAs primarily via receptors, which seem to differ from those (5‐HT1B/1D) stimulated by sumatriptan. The ergot alkaloids produce AVA constriction for a substantial part via 5‐HT1B/1D receptors, but also stimulate unidentified receptors. Both these non‐5‐HT1B/1D receptors may be targets for the development of novel antimigraine drugs. The moderate vasodilator response to the ergot derivatives seems to be mediated, at least in part, by 5‐HT1B/1D receptors, whereas the arteriolar dilatation caused by 5‐HT may be mediated by other, possibly 5‐HT7 receptors.

Investigation of the role of 5-HT1B and 5-HT1D receptors in the sumatriptan-induced constriction of porcine carotid arteriovenous anastomoses.

It has previously been shown that the antimigraine drug sumatriptan constricts porcine carotid arteriovenous anastomoses via 5‐HT1‐like receptors, identical to 5‐HT1B/1D receptors. The recent availability of silent antagonists selective for the 5‐HT1B (SB224289) and 5‐HT1D (BRL15572) receptor led us to further analyse the nature of receptors involved. In pentobarbitone‐anaesthetized, bilaterally vagosympathectomized pigs, sumatriptan (30, 100 and 300 μg kg−1, i.v.) dose‐dependently decreased carotid arteriovenous anastomotic conductance by up to 70±5%. The dose‐related decreases in carotid arteriovenous anastomotic conductance by sumatriptan (30, 100 and 300 μg kg−1, i.v.) remained unchanged in animals treated (i.v.) with 1 mg kg−1 of BRL15572 (maximum decrease: 72±3%), but were significantly attenuated by 1 mg kg−1 (maximum decrease: 30±11%) and abolished by 3 mg kg−1 (maximum decrease: 3±7%) of SB224289. The highest dose of SB224289 did not attenuate the hypertension, tachycardia or increases in carotid blood flow induced by bolus injections of noradrenaline (0.1–3 μg kg−1, i.v.). The results indicate that sumatriptan constricts porcine carotid arteriovenous anastomoses primarily via 5‐HT1B, but not via 5‐HT1D receptors.

Serotonin receptors as cardiovascular targets

Serotonin exerts complex effects in the cardiovascular system, including hypotension or hypertension, vasodilatation or vasoconstriction, and/or bradycardia or tachycardia; the eventual response depends primarily on the nature of the 5-HT receptors involved. In the light of current 5-HT receptor classification, the authors reanalyse the cardiovascular responses mediated by 5-HT receptors and discuss the established and potential therapeutic applications of 5-HT ligands in the treatment of some cardiovascular pathologies.

Characterization of putative 5-HT7 receptors mediating tachycardia in the cat

It has been suggested that the tachycardic response to 5‐hydroxytryptamine (5‐HT) in the spinal‐transected cat is mediated by ‘5‐HT1‐like’ receptors since this effect, being mimicked by 5‐carboxamidotryptamine (5‐CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5‐HT receptor classification schemes proposed in 1994 and 1996. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5‐CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30μgkg−1), 5‐HT (3, 10 and 30μgkg−1) and 5‐methoxytryptamine (3, 10 and 30μgkg−1) as well as the atypical antipsychotic drug, clozapine (1000 and 3000μgkg−1) resulted in dose‐dependent increases in heart rate, with a rank order of agonist potency of 5‐CT >>5‐HT >5‐methoxytryptamine >>clozapine. The tachycardic effects of 5‐HT and 5‐methoxytryptamine were dose‐dependently antagonized by i.v. administration of lisuride (30 and 100μgkg−1), ergotamine (100 and 300μgkg−1) or mesulergine (100, 300 and 1000μgkg−1); the highest doses of these antagonists used also blocked the tachycardic effects of 5‐CT. Clozapine (1000 and 3000μgkg−1) did not affect the 5‐HT‐induced tachycardia, but attenuated, with its highest dose, the responses to 5‐methoxytryptamine and 5‐CT. However, these doses of clozapine as well as the high doses of ergotamine (300μgkg−1) and mesulergine (300 and 1000μgkg−1) also attenuated the tachycardic effects of isoprenaline. In contrast, 5‐HT‐, 5‐methoxytryptamine‐ and 5‐CT‐induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3mlkg−1), the 5‐HT1B/1D receptor antagonist, GR127935 (500μgkg−1) or the 5‐HT3/4 receptor antagonist, tropisetron (3000μgkg−1). Intravenous injections of the 5‐HT1 receptor agonists, sumatriptan (30, 100 and 300μgkg−1) and indorenate (300 and 1000μgkg−1) or the 5‐HT4 receptor (partial) agonist cisapride (300 and 1000μgkg−1) were devoid of effects on feline heart rate per se and failed to modify significantly 5‐HT‐induced tachycardic responses. Based upon the above rank order of agonist potency, the failure of sumatriptan, indorenate or cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned 5‐ht7 receptor, the present results indicate that the 5‐HT receptor mediating tachycardia in the cat is operationally similar to other putative 5‐HT7 receptors mediating vascular and non‐vascular responses (e.g. relaxation of the rabbit femoral vein, canine external carotid and coronary arteries, rat systemic vasculature and guinea‐pig ileum). Since these responses represent functional correlates of the 5‐ht7 gene product, the 5‐HT7 receptor appellation is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other 5‐HT receptors, can be utilized to characterize and develop new drugs with potential agonist and antagonist properties at functional 5‐HT7 receptors.

Pharmacological evidence that α1- and α2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs

Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting antimigraine agents, including the triptans and ergot alkaloids. While 5‐HT1B/1D receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with α‐adrenoceptors. In the present study, we investigated the potential role of α1‐ and α2‐adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 μg kg−1 min−1) or BHT 933 (3, 10 and 30 μg kg−1 min−1) produced dose‐dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 μg kg−1, i.v.) and rauwolscine (300 μg kg−1, i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5‐HT1B/1D receptor antagonist GR127935 (500 μg kg−1, i.v.). These results show that both α1‐ and α2‐adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti‐migraine activity, an agonist activity at particularly the α2‐adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current anti‐migraine agents and may eventually be helpful in the development of future treatment in migraine.