Mechanism of action Their action is attributed to their agonist effects on serotonin 5-HT1B and 5-HT1D receptors in blood vessels (causing their constriction) and nerve endings in the brain, and subsequent inhibition of pro-inflammatory neuropeptide release, including CGRP and substance P.<unk> s are selective agents for 5-HT1B and 5-HT1D and have low or even no affinity for other types of 5-HT receptors. 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 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<unk> s, 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.<unk> s have at least three modes of action. These antimigraine mechanisms are: # vasoconstriction of pain producing intra cranial extracerebral vessels by a direct effect on vascular smooth muscle. Sumatriptan and rizatriptan have been shown to cause vasoconstriction in the human middle meningeal arteries. # inhibition of vasoactive neuropeptide release by trigeminal terminals innervating intracranial vessels and the dura mater. The trigeminocervical complex has 5-HT1D receptors that bind dihydroergotamine and<unk> s in humans. Rizatriptan has been shown to block dural vasodilation and plasma protein extravation by inhibiting the release of CGRP via activation of receptors on preganglionic trigeminal sensory nerver terminals. Sumatriptan is shown to inhibit potassium stimulated CGRP secretion from cultured trigeminal neurons in dose dependant manner and may also inhibit the release of substance P. # inhibition of nociceptive neurotransmission within the trigeminocervical complex in the brainstem and upper cervical spinal column. Rizatriptan has central trigeminal antinociceptive activity. Other possibilities of<unk> s in antimigraine effects are modulation of nitric oxide dependent signal transduction pathways, nitric oxide scavenging in the brain, and sodium dependent cell metabolic activity. Pharmacokinetics<unk> s have a wide variety of pharmacokinetic properties. Bioavailability is between 14% and 70%, biological half-life (T1/2) is between 2 and 26 hours. Their good ability to cross the blood-brain barrier and the rather long half life of some<unk> s may result in lower frequencies of migraine recurrence. Comparison + Comparative pharmacology of<unk> s, oral formulations Drug Brand Company Receptor agonist 5-HT1D affinity(pKI in nM) Bioavail­ability (%) log DpH 7.4 Tmax (h) T1/2 (h) Metab­olism Dose (mg) Sumatriptan Imitrex Glaxo Smith Kline 5-HT1B/D 7.9–8.5 14–17 –1.3 2–2.5 2.5 MAO-A 25, 50, 100 Zolmitriptan Zomig Grünenthal 5-HT1B/D 9.2 40 –0.7 1.5–2 2–3 MAO-A CYP1A2 2.5, 5 Naratriptan Amerge Glaxo Smith Kline 5-HT1B/D 8.3 70 –0.2 2–3 6 many CYPs MAO-A 1, 2.5 Rizatriptan Maxalt Merck 5-HT1B/D 7.7 45 –0.7 1–1.5 2–2.5 MAO-A 5, 10 Almotriptan Axert Almirall-Prodesfarma 5-HT1B/D 5-HT1F 7.8 70 +0.35 2.5 3.6 CYP2D6 CYP3A4 MAO-A 6.25, 12.5 Eletriptan Relpax Pfizer 5-HT1B/D 5-HT1F 8.9 50 +0.5 1–2 3.6–5.5 CYP3A4 20, 40, 80 Frovatriptan Frova Vernalis 5-HT1B/D 8.4 24–30 2–4 26 CYP1A2 2.5 Zolmitriptan is different from the other<unk> s because it is converted to an active N-desmethyl metabolite which has higher affinity for the 5-HT1D and 5-HT1B receptors; both substances have a biological half-life of 2 to 3 hours. In studies, newer<unk> s 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. History The history of<unk> s began with the proposed existence of then unknown serotonin (5-hydroxytryptamine, 5-HT). In the late 1940s two groups of investigators, one in Italy and the other in the United States, identified a substance that was called serotonin in the US and enteramine in Italy. In the early 1950s it was confirmed that both substances were the same. In the mid-1950s it was proposed that serotonin had a role as a neurotransmitter in the central nervous system (CNS) of animals. Investigations of the mechanism of action were not very successful as experimental techniques were lacking. 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 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<unk> s that have been developed for improved selectivity for the 5-HT1D/B receptors.
Triptan
Sumatriptan
Frovatriptan
Rizatriptan
Eletriptan
Almotriptan
Zolmitriptan
Naratriptan