Clinically Significant Drug Interactions with Migraine Agents (PDF)

REVIEW ARTICLE CNS Drugs 2001; 15 (2): 105-118...

REVIEW ARTICLE CNS Drugs 2001; 15 (2): 105-118 1172-7047/01/0002-0105/$22.00/0 © Adis International Limited. All rights reserved. Clinically Significant Drug Interactions with Agents Specific For Migraine Attacks Mervyn J. Eadie Department of Medicine, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia Contents Abstract................................................... 105 1. Mechanisms of Action............................................ 107 2. Pharmacokinetics.............................................. 107 2.1 Ergotamine............................................... 107 2.2 Dihydroergotamine.......................................... 108 2.3 Triptans.................................................. 108 3. Interactions.................................................. 108 3.1 Ergopeptides.............................................. 108 3.1.1 Pharmacokinetic Interactions................................. 108 3.1.2 Pharmacodynamic Interactions............................... 111 3.1.3 Doubtful Reported Interactions................................ 112 3.1.4 Potential Interactions...................................... 112 3.2 The Triptans............................................... 112 3.2.1 Pharmacokinetic Interactions................................. 112 3.2.2 Pharmacodynamic Interactions............................... 113 3.2.3 Potential Interactions...................................... 114 4. Conclusion.................................................. 115 Abstract The drugs which provide specific relief from migraine attacks, the ergopep- tides (ergotamine and dihydroergotamine) and the various ‘triptans’ (notably suma- triptan), are often prescribed for persons already taking various migraine preventative agents, and sometimes drugs for other indications. As a result, migraine-specific drugs may become involved in drug-drug interactions. The migraine-specific drugs all act as agonists at certain subclasses of seroto- nin (5-hydroxytryptamine; 5-HT) receptor, particularly those of the 5-HT1D sub- type, and produce vasoconstriction through these receptor-mediated mechanisms. The oral bioavailabilities of these drugs, particularly those of the ergopeptides, are often incomplete, due to extensive presystemic metabolism. As a result, if migraine-specific agents are coadministered with drugs with vasoconstrictive properties, or with drugs which inhibit the metabolism of the migraine-specific agents, there is a risk of interactions occurring which produce manifestations of excessive vasoconstriction. This can also occur through pharmacodynamic mech- anisms, as when ergopeptides or triptans are coadministered with methysergide 106 Eadie or propranolol (although a pharmacokinetic element may apply in relation to the latter interaction), or if one migraine-specific agent is used shortly after another. When ergopeptide metabolism is inhibited by the presence of macrolide anti- bacterials, particularly troleandomycin and erythromycin, the resultant interaction can produce ergotism, sometimes leading to gangrene. Similar pharmacokinetic mechanisms, with their vasoconstrictive consequences, probably apply to com- bination of the ergopeptides with HIV protease inhibitors (indinavir and ritonavir), heparin, cyclosporin or tacrolimus. Inhibition of triptan metabolism by monoamine oxidase A inhibitors, e.g. moclobemide, may raise circulating triptan concentrations, although this does not yet seem to have led to reported clinical problems. Caffeine may cause increased plasma ergotamine concentrations through an as yet inadequately defined pharmacokinetic interaction. However, a direct anti- migraine effect of caffeine may contribute to the claimed increased efficacy of ergotamine-caffeine combinations in relieving migraine attacks. Serotonin syndromes have been reported as probable pharmacodynamic con- sequences of the use of ergots or triptans in persons taking serotonin reuptake inhibitors. There have been two reports of involuntary movement disorders when sumatriptan has been used by patients already taking loxapine. Nearly all the clinically important interactions between the ergopeptide anti- migraine agents and currently marketed drugs are likely to have already come to notice. In contrast, new interactions involving the triptans are likely to be re- cognised as additional members of this family of drugs, with their different pat- terns of metabolism and pharmacokinetics, are marketed. Some of the drugs currently used to relieve the teries which develop during migraine attacks. pain of migraine attacks are primarily analgesic in However, in more recent times, it has appeared their mode of action; in treating the attacks they likely that they also relieve the symptoms of the may be used alone or in conjunction with agents attacks by interfering with trigeminally mediated which have anti-emetic and/or sedative properties. vascular responses and by diminishing the severity In addition, there are available two groups of of the sterile dural inflammatory processes which agents which appear to relieve migraine attacks are thought to occur during migraine attacks. more specifically by interrupting the mechanisms These various effects are mediated through the ac- involved in the pathogenesis of the attacks. The tivation of serotonin 5-HT1B and 5-HT1D receptors. first of these groups of agents comprises two The variability in the natural history of migraine ergopeptide alkaloids (ergotamine and dihydro- attacks in many individuals, and the sometimes ca- ergotamine); the second, the various ‘triptan’ de- pricious response of the attacks to therapy, may rivatives (of which sumatriptan, zolmitriptan, nar- result in a second migraine-specific agent being atriptan, rizatriptan and almotriptan are already taken by a patient, deliberately or sometimes un- marketed or close to marketing in many countries, wittingly, whilst another such agent which has been and eletriptan and frovatriptan appear likely to be- administered earlier in the attack may still be ex- come available in the reasonably near future). erting its effect. Much more often, patients who are Both these classes of migraine-specific agent taking continuous migraine prophylactic therapy were originally thought to achieve headache relief will need to use a specific anti-migraine agent to by producing constriction of the dilated cranial ar- relieve a migraine attack which has broken through © Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (2) Interactions of Migraine-Specific Drugs 107 the prophylaxis. In addition, patients taking drug specific in their binding to subclasses of serotonin therapy for various illnesses quite unrelated to mi- receptor and, in addition, have considerable affin- graine may at times need to use a migraine-specific ities for noradrenergic (mainly the α-subtypes, agent to relieve a migraine attack which has devel- where they function as antagonists) and dopamine oped. In all these circumstances interactions are (mainly dopamine D2) receptors. It should how- possible between the drugs that have been taken. ever be pointed out that the receptor binding stud- Therefore, an awareness of the possible interactions ies on these substances have been carried out in of the migraine-specific agents with each other and vitro, and have used the drugs as pure substances. with concurrently administered drugs is of some In the body, these drugs may form metabolites, importance to the clinician. In addition, and in par- some of which are known to be biologically active. ticular in the case of the concurrent intake of two These metabolites may not have exactly the same migraine-specific drugs, or of a migraine-specific receptor binding specificities as the parent sub- agent and a migraine preventative, knowledge that stances. Hence, it is possible that the range of re- they are unlikely to interact can be of considerable ceptors activated, or blocked, by administration of reassurance to the prescriber of migraine therapy. the migraine-specific agents in patients might be The interactions involving the migraine-specific rather more extensive than that indicated by the in agents may be either pharmacokinetic or pharma- vitro binding studies. codynamic in nature. Therefore, some prior knowl- The in vitro binding characteristics of the vari- edge of the mechanisms of action and of the ab- ous migraine-specific agents are set out in table I. sorption and disposition parameters of the relevant drugs is helpful in understanding the events in- 2. Pharmacokinetics volved in their known interactions. It is also helpful in understanding why certain potential interactions in which they might be expected to be involved do 2.1 Ergotamine not appear to occur in practice. Such an understan- ding should also be useful in anticipating the pos- Ergotamine has been used in therapeutics for sibility of a migraine-specific drug interacting with over a century, initially in extracts of variable po- some other drug which may come to be used with tencies but since 1925 as the pure substance. De- it in the future, but for which the desired informa- spite the extensive experience with its use, there tion is not yet available. appears to be no completely unambiguous infor- mation concerning its pharmacokinetics. 1. Mechanisms of Action In aqueous solution ergotamine fairly rapidly isomerises (at the 8 position on the lysergic acid Since the original observation in 1961 by Sicu- moiety of the molecule) to form its stereo-isomer teri et al., increasing evidence has accumulated ergotaminine, which is reputed to lack biological that serotonin plays a major role in the molecular activity. The stereo-isomers can be separated by pathogenesis of migraine. Studies of the pharma- high-performance liquid chromatography. How- cology of the various subclasses of serotonin re- ever, this technique does not yet seem to have been ceptors have made it clear that all the agents effec- employed in conjunction with detection methods tive in aborting migraine attacks possess agonist sensitive enough to allow precise definition in hu- activity at serotonin 5-HT1D receptors, and also at mans of the pharmacokinetics of ergotamine itself, the 5-HT1B subclass of receptor. not confounded by the simultaneous presence of The known actions of the various triptan deriv- ergotaminine and possibly of metabolites of both atives appear to be largely, although not comple- ergotamine and ergotaminine. Nonetheless, some in- tely, confined to these two subclasses of serotonin formation on what probably represents the best avail- receptor. In contrast, the two ergopeptides are less able data for the pharmacokinetics of ergotamine © Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (2) 108 Eadie Table I. Affinities of the migraine-specific agents for various receptor types[4-6] Drug Receptor type serotonin noradrenaline dopamine (norepinephrine) 5-HT1A 5-HT1B 5-HT1D 5-HT1E 5-HT1F 5-HT2A 5-HT2B α1 α2 β D1 D2 Ergopeptides Ergotaminea + + + + + + + + ± Dihydroergotamine +++ ++ +++ ++ + + + ++ ++ ± ± + Triptans Sumatriptan + ++ ++ – + – – – – – Zolmitriptan + + + Naratriptan + + + + + Rizatriptan + + Eletriptan ++ ++ + ++ Almotriptan + ++ ++ Frovatriptan + + a The published data for the ergopeptides relate mainly to dihydroergotamine, but the literature infers that the situation for ergotamine is generally similar. + indicates degree of agonist activity at the receptor from low (+) to high (+++); – indicates inactive; ± indicates equivocal. (plus ergotaminine) is available and is set out in pear to be any data on whether dihydroergotamine table II. isomerisation at the 8 position of the molecule is a Ergotamine appears to have a very low oral bio- significant issue in the specificity of assays of the availability, probably due to extensive presystemic drug. clearance [in which the cytochrome P450 (CYP) isoenzyme 3A4 is involved]. The chemical natures 2.3 Triptans of the metabolites of ergotamine are unknown, but are probably analogous to those of dihydroergo- The marketed triptans, and those in develop- tamine, which are known. As measured, the half- ment, differ to some extent in their pharmacoki- life of ergotamine is in the range of 3 to 4 hours. The netic properties (table II), mainly with respect to duration of the biological effect of ergotamine ap- their oral bioavailabilities, half-lives, and the en- pears considerably longer than might be expected zymes involved in their metabolism (CYP isoforms from this half-life value. This discrepancy has been and/or monoamine oxidase). suggested to be due to very tight receptor binding of the drug. However, the continuing action of one or more unidentified and biologically active meta- 3. Interactions bolites which are more slowly eliminated than the The interactions involving the migraine-spe- parent substance would provide an alternative ex- cific drugs appear to be pharmacokinetic or phar- planation. macodynamic in nature. Their mechanisms are known with varying degrees of probability. 2.2 Dihydroergotamine Information does not appear to be currently Some rather better quality pharmacokinetic data available as to whether P-glycoprotein function is in- are available for dihydroergotamine (table II). Its volved in the dispositions of the ergopeptide or trip- properties generally seem to resemble those of er- tan migraine-specific agents. Therefore, it is not pos- gotamine. It is also metabolised by CYP3A4.[11,12] sible to know whether P-glycoprotein–mediated One of the metabolites (a N-demethyl derivative) is mechanisms are involved in some of the interac- known to be biologically active. There do not ap- tions described in sections 3.1 and 3.2. © Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (2) Interactions of Migraine-Specific Drugs 109 3.1 Ergopeptides of presystemic metabolism of ergotamine (both er- gotamine and caffeine are metabolised by CYP3A4) 3.1.1 Pharmacokinetic Interactions than on faster dissolution of ergotamine in the gas- Caffeine trointestinal fluids, or on its faster absorption. Fur- Many of the ergotamine preparations marketed ther, caffeine has some anti-migraine effectiveness for oral or rectal use contain caffeine. Laboratory in its own right. studies in the past showed that caffeine enhanced The existence in humans of a clinically signifi- the water solubility of ergotamine under the pH con- cant and therapeutically advantageous interaction ditions which might be expected to apply in the between ergotamine and caffeine does not seem to alimentary tract, and studies in experimental ani- be as securely established as it might be. If such an mals, employing inherently nonspecific analytical interaction does exist, its basis may not be entirely methods, yielded data consistent with ergotamine pharmacokinetic in nature. absorption being increased in the simultaneous presence of caffeine in the intestinal lumen.[13,14] Macrolide Antibacterials These findings appeared to correlate with the repu- There are a number of reports in the literature tation that oral caffeine-ergotamine combinations describing the occurrence of manifestations of ego- had obtained for being more effective in relieving tism, occasionally severe enough to have resulted human migraine than ergotamine alone, given in in gangrene of a limb, necessitating its amputation, similar doses. However, this reputation for in- which have occurred when ergotamine has been creased efficacy of the ergotamine-caffeine combi- used by patients already taking a macrolide antibac- nations appears to have been derived mainly from terial. The macrolides involved have included eryth- anecdotal evidence, rather than from adequately de- romycin,[18-22] troleandomycin (triacetyloleando- signed controlled clinical trials. mycin),[23-27] oleandomycin, clarithromycin Bearing in mind the probable very high presys- and josamycin. Similar interactions have oc- temic clearance of ergotamine, one must wonder curred when dihydroergotamine has been taken by whether any effect that caffeine has on ergotamine patients receiving erythromycin[31-33] or troleando- pharmacokinetics may depend more on inhibition mycin. In addition, Baudouy et al. reported the Table II. Pharmacokinetic parameters and patterns of metabolism of the migraine-specific agents[5,8] Drug Oral Half-life (h) Excreted unchanged Metabolised by Active bioavailability (%) in urine (%) MAO-A CYP metabolite(s) Ergopeptides Ergotamine