The drugs dealt with in this section are ergot derivatives and triptans (or more properly serotonin 5-HT1 agonists), whose main use is in treatment of migraine. table 1 below, (below) lists some of drugs commonly used in migraine. Drugs such as propranolol, which are more commonly used in other conditions, are discussed elsewhere in publication.
The main problem with use of ergot derivatives is that of ergotism. Drug interactions may result in additive effects or cause raised levels of ergot derivatives, which may result in symptoms of ergot poisoning. This may include severe circulatory problems e.g. the extremities may become numb,cold to the touch, tingle, and muscle pain may result. In extreme cases there may be no palpable pulse. Ultimately gangrene may develop,and amputation may be required. Chest pain can also occur,and in some cases myocardial infarction has been reported. Since ergotamine and dihydroergotamine are metabolised in liver by CYP3A4, drugs which inhibit this isoenzyme, particularly potent inhibitors, such as protease inhibitors, , should generally be avoided due to risk of precipitating ergotism.
Although triptans would be expected to share a number of pharmacodynamic drug interactions, due to their differing metabolic pathways they will not all necessarily share same pharmacokinetic interactions. For example, sumatriptan, which is metabolised mainly by monoamine oxidase A, is unlikely to interact with macrolide antibacterials, which are inhibitors of cytochrome P450 isoenzyme CYP3A4. However,eletriptan, which is metabolised by CYP3A4 and possibly CYP2D6 could potentially interact (see Triptans + Macrolides interaction, for full details). Frovatriptan and zolmitriptan are substrates for CYP1A2,and are affected by CYP1A2 inhibitors such as fluvoxamine, but zolmitriptan also inhibits CYP1A2 and may therefore be expected to have additional interactions. The picture with zolmitriptan becomes more complicated since it is also metabolised by monoamine oxidase A. Naratriptan appears unlikely to undergo significant pharmacokinetic interactions since half dose is excreted unchanged and rest metabolised by a variety of isoenzymes. A summary of metabolic pathways of triptans can be found in table 2 below,(below).
Early in development of triptans it was theorised that they might possibly add to increased levels of serotonin caused by other serotonergic drugs, leading to excess serotonergic activity and increasing risk of the serotonin syndrome, . Therefore sumatriptan was contraindicated in patients taking SSRIs,MAOIs, and lithium, but note, there is little evidence that this occurs in practice. However,there is also a pharmacokinetic interaction between some triptans and MAOIs, see or SSRIs, .
Flunarizine,Pizotifen
Atenolol,Metoprolol, Nadolol, Propranolol, Timolol
Codergocrine,Ergotamine, Dihydroergotamine, Methysergide
Almotriptan,Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan
2 Interactions between drug metabolising enzymes and triptans†
†Other isoenzymes have been implicated, but not at clinically relevant concentrations of triptans
| Table 1 Antimigraine drugs | |
| Group | Drugs |
| Antihistamines | Flunarizine, Pizotifen |
| Beta blockers | Atenolol, Metoprolol, Nadolol, Propranolol, Timolol |
| Ergot derivatives | Codergocrine, Ergotamine, Dihydroergotamine, Methysergide |
| Triptans (Serotonin (5-HT1) agonists) | Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan |
| Table 2 Interactions between drug metabolising enzymes and the triptans† | ||||||
|---|---|---|---|---|---|---|
| MAO-A | CYP1A2 | CYP2C9 | CYP2C19 | CYP2D6 | CYP3A4 | |
| Almotriptan | Substrate | Substrate | Substrate | |||
| Eletriptan | Substrate | |||||
| Frovatriptan | Substrate | Possible substrate | ||||
| Naratriptan | Substrate (minor) | Substrate (minor) | Substrate (minor) | Substrate (minor) | Substrate (minor) | |
| Rizatriptan | Substrate | Substrate (minor) | ||||
| Sumatriptan | Substrate | |||||
| Zolmitriptan | Substrate | Substrate | Substrate | |||