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Triptans are a family of antimigraine drugs used to abort and . While effective at treating individual headaches, they do not provide prophylaxis treatment and are not cure. They are not effective for the treatment of tension headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain. They are taken orally and by other routes.
The drugs of this class act as agonists for serotonin 5-HT1B and 5-HT1D receptors at blood vessels and nerve endings in the brain. Some also activate the 5-HT1F receptor. Structurally, triptans are substituted tryptamines or closely related to tryptamines, for instance the psychedelic drug dimethyltryptamine (DMT).
The first clinically available triptan was sumatriptan, which has been marketed since 1991. Subsequently, a variety of other triptans have also been marketed, including zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. Triptans have largely replaced ergoline drugs like ergotamine and dihydroergotamine, an older class of medications used to relieve migraine and cluster headaches.
Triptans are highly effective, reducing the symptoms or aborting the attack within 30 to 90 minutes in 70–80% of patients. A 2024 systematic review and Meta-analysis compared the effectiveness of medications for acute migraine attacks in adults. It found that triptans were the most effective class of drugs followed by non-steroidal anti-inflammatories.
A test measuring a person's skin Allodynia during a migraine may indicate whether the individual will respond to treatment with triptans. Triptans are most effective in those with no skin sensitivity; with skin sensitivity, it is best to take triptans within twenty minutes of the headache's onset.
Oral rizatriptan and nasal zolmitriptan are the most used triptans for migraines in children.
| + Formulations ! Tablet ! Oral disintegrating tablets ! Nasal spray ! Subcutaneous injection ! Rectal suppository | ||||
| all triptans | rizatriptan | sumatriptan | sumatriptan | sumatriptan |
| zolmitriptan | zolmitriptan |
At least two triptans (sumatriptan and rizatriptan) have been listed under the unacceptable medication by the Canadian Blood Services as a potential risk to the recipient; hence, donors are required not to have taken the medication for the last 72 hours.
There is a theoretical risk of coronary spasm in patients with established heart disease, and cardiac events after taking triptans may rarely occur.
In a study from Harvard Medical School and the University of Florida College of Medicine involving 47,968 patients and published on 26 February 2018, concomitant use of a selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor for depression with a triptan for migraine did not demonstrate an increased risk of the serotonin syndrome.
Pharmacokinetic interactions (for example, mediated by CYP liver enzymes or transporter proteins) are different for the individual substances; for most triptans, they are mild to absent. Eletriptan blood plasma levels are increased by strong inhibitors of CYP3A4, and frovatriptan levels by CYP1A2 inhibitors such as fluvoxamine.
5-HT receptors are classified into seven different families named 5-HT1 to 5-HT7. All receptors are G protein coupled receptors with seven transmembrane domains with the one exception of 5-HT3 receptor which is a ligand gated ion channel. There is a high homology in the amino acid sequence within each family. Each family couples to the same second messenger systems. Subtypes of 5-HT1 are the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F receptors. All 5-HT1D receptors are coupled to inhibition of adenylate cyclase. 5-HT1B and 5-HT1D receptors have been difficult to distinguish on a pharmacological basis. After cloning two distinct genes for 5-HT1B and 5-HT1D receptors, a better insight into distribution and expression in different tissues was gained, except in brain tissue where they are overlapping in several areas.
Most mammalian species, including humans, have 5-HT1D binding sites widely distributed throughout the central nervous system. 5-HT1D receptors are found in all areas of the brain but they differ in quantity at each area. An important initiator of head pain is suggested to be the activation of trigeminovascular afferent nerves which upon activation releases neuropeptides such as CGRP, substance P and neurokinin A. Also they are thought to promote neurogenic inflammatory response important for sensitization of sensory neuron afferents, and also transmission and generation of head pain centrally. 5-HT1D has been found responsible for inhibition of neurogenic inflammation upon administration with sumatriptan and other related compounds that act on prejunctional 5-HT1D receptors.
All triptans, like the older drug dihydroergotamine, have agonistic effects on the 5-HT1D receptor. Comparison of sumatriptan and dihydroergotamine showed that dihydroergotamine has high affinity and sumatriptan has medium affinity for 5-HT1D. Triptans have at least three modes of action. These antimigraine mechanisms are:
Most of the triptans, for instance sumatriptan, zolmitriptan, and others, are inactive as serotonin 5-HT2A receptor . However, a few triptans, including donitriptan, avitriptan, and eletriptan, have been found to act as serotonin 5-HT2A receptor agonists, albeit with one to three orders of magnitude lower activational potency than at the serotonin 5-HT1B and 5-HT1D receptors.
| + Comparative pharmacology of marketed triptans in their oral formulations | |||||||||||
| Sumatriptan | Imitrex | 5-HT1B/D | 3.2–13nM | 14–17% | 0.8 | –1.3 | 2–2.5h | 2.5h | MAO-A | 25, 50, 100mg | |
| Zolmitriptan | Zomig | Grünenthal | 5-HT1B/D | 0.63nM | 40% | 1.6 | –0.7 | 1.5–2h | 2–3h | MAO-A CYP1A2 | 2.5, 5mg |
| Naratriptan | Amerge | 5-HT1B/D | 5.0nM | 70% | 2.2 | –0.2 | 2–3h | 6h | Many CYPs MAO-A | 1, 2.5mg | |
| Rizatriptan | Maxalt | Merck | 5-HT1B/D | 20nM | 45% | 1.4 | –0.7 | 1–1.5h | 2–2.5h | MAO-A | 5, 10mg |
| Almotriptan | Axert | Almirall- Prodesfarma | 5-HT1B/D 5-HT1F | 16nM | 70% | 1.6 | +0.35 | 2.5h | 3.6h | CYP2D6 CYP3A4 MAO-A | 6.25, 12.5mg |
| Eletriptan | Relpax | Pfizer | 5-HT1B/D 5-HT1F | 1.3nM | 50% | 3.9 | +0.5 | 1–2h | 3.6–5.5h | CYP3A4 | 20, 40, 80mg |
| Frovatriptan | Frova | Vernalis | 5-HT1B/D | 4.0nM | 24–30% | 0.9 | –1.53 | 2–4h | 26h | CYP1A2 | 2.5mg |
Zolmitriptan is different from the other triptans because it is converted to an active N-desmethyl metabolite which has higher affinity for the serotonin 5-HT1D and 5-HT1B receptors; both substances have a biological half-life of 2 to 3 hours. In studies, newer triptans are mostly compared to sumatriptan. They are better than sumatriptan for their longer half-life in plasma and higher oral bioavailability, but have a higher potential for central nervous side effects.
Donitriptan and avitriptan were never marketed.
| + Chemical structures of triptans | ||
sumatriptan | rizatriptan | naratriptan |
eletriptan | donitriptan | almotriptan |
frovatriptan | avitriptan | zolmitriptan |
LY-334370 | LY-344864 | L-694247 |
Triptans are either tryptamines or closely related compounds. Most triptans are simple tryptamines. These include sumatriptan, rizatriptan, donitriptan, almotriptan, zolmitriptan, and L-694247. Certain triptans, including eletriptan, frovatriptan, and LY-344864, are cyclized tryptamines. Other triptans, including naratriptan, LY-334370, and avitriptan, are not technically tryptamines, although they are still closely related to tryptamines. Naratriptan and LY-334370 are piperidinylindoles rather than tryptamines, while avitriptan features a cyclic compound propyl groupamine side chain instead of the ethyl group side chain present in tryptamines. A number of triptans, including sumatriptan, rizatriptan, eletriptan, almotriptan, zolmitriptan, contain the psychedelic drug dimethyltryptamine (DMT) within their chemical structures and hence are derivatives of DMT. Triptans may be thought of as synthetic analogues of the monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT).
Later in the 1960s, studies showed that vasoconstriction caused by 5-HT, noradrenaline and ergotamine could reduce migraine attacks. Patrick P.A. Humphrey among others at Glaxo started researching the 5-HT receptor to discover a more direct 5-HT agonist with fewer side effects.
They continued developing and working on a desirable action on 5-HT by 5-HT1 receptor activation for an anti-migraine drug. Continued work led to the Drug development of sumatriptan, now known as the first 5-HT1 agonist, selective for the 5-HT1D/B receptors and also the 5-HT1F receptor with less affinity. By 1991 sumatriptan became available in clinical use in the Netherlands and in the US in 1993. However, there was always a debate about its mechanism of action, and it still remains unclear today. Later, Mike Moskowitz proposed a theory about "neuronal extravasation", and this was the first clue that sumatriptan might have a direct neuronal effect in migraine attacks.
Sumatriptan became a prototype for other triptans that have been developed for improved selectivity for the 5-HT1D/B receptors.
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