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Triptans

Triptans are drugs for acute treatment of migraine and cluster headache. Their mechanism of action is based on a selective stimulation of serotonin receptor subtype 5-HT1B/1D.

All triptans currently on the market are structurally derived from the serotonin, 5-HT and 5-carboxamidotryptamine. Currently being used Triptanstherapeutically in Germany are the following triptans, Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan and Zolmitriptan

The Initial modifications from the non-selective serotonin supplied are by contributing Sulfonamidstruktur to selective 5-HT1B/1D-Rezeptoragonisten sumatriptan.

This structural feature was retained in many of the newer triptans or “2nd generation triptans” by varying the constituents and the lipophilicity pharmacokinetic parameters like the bioavailability and product half-life, were altered, leaving the activity profile largely unaffected.

Currently the most potent triptan frovatriptan, is regarded as a closed ring 5-carboxamidotryptamine, while other triptans, like Avitriptan and Donitriptan are in clinical trials, but as yet have not reached the market. There is growing emphasis currently placed in the clinical testing of selective 5-HT1D and 5-HT1F receptor agonists, such as paid LY 334,370 and LY 344,864, as a possible successor to the triptans.

Pharmacology

Applications
Triptans are used for the treatment of acute migraine attacks and in the treatement of cluster headaches, where they show clinical efficacy, and unlike traditional painkillers such as aspirin or paracetamol which are available across the counter, triptans, in preparations of tablets of 2.5 mg are only available by prescription.

How it works
Triptans are agonists like serotonin 5-HT1B and 5-HT 1D receptors, summarized as 5-HT1B/1D-Rezeptoren, for their effectiveness three mechanisms are discussed that are associated with activation of these receptors.

1] Triptans lead to a narrowing of the cerebral blood vessels enlarged by a migraine attack.
2] Triptans inhibit the release of inflammatory peptides such as substance P and calcitonin gene-related peptide CGRP, from neurons in the central nervous system.
3] Triptans inhibit the propagation of pain stimuli on the cerebral cortex.

In addition to the above most of the triptans show an agonistic activity at 5-HT1F receptors. An activation of these receptors also leads to an inhibition of the release of inflammatory peptides, but not the tightening of the cerebral blood vessels. The 5-HT1F receptor thus may also be involved in migraine efficacy of triptans.

Side-effects
Terms and typical side effects of triptans are: slight weakness, dizziness, abnormal sensations, tingling, warmth or flushing, mild nausea, and in addition, transient increases in blood pressure and mild angina like symptoms can be observed.

These adverse effects are attributed to a stimulation of 5-HT1B/1D-Rezeptoren within the cardiovascular system, and very rarely arrhythmia, circulatory disorders and disorders of the skeletal muscles occur under the controlled administration of triptans

Interactions
Other chemicals used for the treatment of migraine therapy like ergot alkaloids such as ergotamine should not be taken simultaneously with triptans to avoid spasms of the coronary arteries.

MAO inhibitors can cause a slow degradation of triptans. And some triptans such as rizatriptan, are in turn themselves inhibitors of the drug metabolising cytochrome P450 enzyme system.

The American Health Organization warns of the potentially life-threatening interaction of serotonin syndrome where the body accumulates too much serotonin in the nervous system, while taking a triptan in conjunction with an antidepressant from the group of SSRIs or Selective Serotonin Reuptake Inhibitors or SNRIs, selective serotonin and norepinephrine reuptake inhibitors.

When triptans are taken with an SSRI or a SNRI, the symptoms of serotonin syndrome may be restlessness, hallucinations, loss of coordination, fast heart beat, blood pressure changes, including increased body temperature, increased reflexes, nausea, vomiting and diarrhoea.

Formulations

A Triptans dose is available, depending on the type of triptan prescribed as a syringe, tablet, melting tablet, nasal spray or suppository.

History

Since the 19th Century it was commonly knowledge that a migraine headache is linked to an enlargement of the cerebral and cranial blood vessels. Traditional medicines such as ergotamine, which led to the contraction of these blood vessels, were the effective migraine treatments.

The history of the development of triptans began with the observation that serotonin also led to a pathological, constriction and dilation of blood vessels during a migraine attack.

Serotonin was then considered for study, and its affect on the entire cardiovascular system and the gastrointestinal side effects, however, the intention in terms of the study of migraine therapy was to was to develop a drug derivative of serotonin, that would contract the selective cerebral blood vessels, but be free of systemic side effects.

In the 1980s, there was a 5-carboxamidotryptamine drug identified, which selectively stimulates the 5-HT1 receptors, but the substance, demonstrated in preclinical studies, systemic cardiovascular side effects from hypotension to tachycardia and was dispensed ending the clinical development of this compound.

A short time later however GlaxoSmithKline found and developed a Sumatriptan Codename GR43175, a 5-HT1B/1D-Rezeptoragonist, that contracted the selective cerebral blood vessels.

Approval was given for sumatriptan on 28 December 1992 by the U.S. FDA’s for treatment of acute migraine. Sumatriptan had a poor oral bioavailability and low penetration abilities for the blood-brain barrier poorly penetrated, so furth research was done to create “2nd generation triptans” with much improved pharmacokinetic properties.

By the late 1990s, saw the launch of many more products from zolmitriptan, naratriptan and rizatriptan, followed a little later by almotriptan, eletriptan and frovatriptan, while triptans, like Donitriptan and Avitriptan, have still to reach market maturity.

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