Triptans
Triptans are vasoconstricting, anti-inflammatory and analgesic agents that are used as medicinal substances for the acute treatment of migraines and cluster headaches .
They act as agonists on the serotonin receptor of type 5-HT 1 , subtypes B, D and F.
Drugs and Chemistry
All triptans used therapeutically are structurally derived from serotonin (5-HT) and from 5-carboxamidotryptamine .
| Surname | Half-life | Defined daily dose | Market launch in D |
|---|---|---|---|
| Almotriptan | 3-4 h | 12.5 mg (oral) | 2001 ( Almogran ) |
| Eletriptan | 4-5 h | 40 mg (oral) | 2002 ( Relpax ) |
| Frovatriptan | approx. 25 h | 2.5 mg (oral) | 2002 ( Allegro ) |
| Naratriptan | 6 h | 2.5 mg (oral) | 1997 ( Naramig ) |
| Rizatriptan | 2-3 h | 10 mg (oral) | 1998 ( Maxalt ) |
| Sumatriptan | 2 h |
20 mg (nasal) |
1992 ( Imigran ) |
| Zolmitriptan | 3 h |
2.5 mg (oral) |
1997 ( Ascotop ) |
First modifications based on the nonselectively active serotonin resulted in the introduction of a sulfonamide structure, the selective 5-HT 1B / 1D / 1F receptor agonist sumatriptan . This structural feature was also retained in numerous newer triptans ("2nd generation triptans"). By varying the substituents and lipophilicity , mainly pharmacokinetic parameters, such as e.g. B. bioavailability and half-life changed, while the action profile remained largely unaffected.
Other triptans, such as B. Avitriptan and Donitriptan , were in clinical trials, but did not make it to the market. The selective 5-HT 1D and 5-HT 1F receptor agonists that are currently in clinical trials , such as e.g. B. LY 334370 and LY 344864, given as possible successors of the triptans.
pharmacology
application areas
Triptans are used to treat acute migraine attacks with and without aura . In addition, they show clinical effectiveness in the treatment of cluster headache. In contrast to classic painkillers such as acetylsalicylic acid or paracetamol , triptans (with the exception of naratriptan since April 2006) require a prescription . In Germany, naratriptan in units containing 2 tablets of 2.5 mg naratriptan each and almotriptan as a single dose of 12.5 mg in a pack size of 25 mg maximum are exempt from the requirement for a medical prescription.
Mechanism of action
The mechanism of action of the triptans is based on a selective stimulation of serotonin receptors of the subtypes 5-HT 1B and 5-HT 1D (summarized as 5-HT 1B / 1D receptors). Three mechanisms are discussed for the effectiveness of triptans, which are associated with activation of these receptors:
- Triptans lead to a narrowing of the cerebral blood vessels that are enlarged during a migraine attack.
- Triptans inhibit the release of inflammatory peptides such as B. Substance P and calcitonin gene-related peptides (CGRP), from neurons in the central nervous system .
- Triptans inhibit the spread of pain stimuli through the cerebral cortex.
In addition, most triptans show an agonistic activity at 5-HT 1F receptors. Activation of these receptors also leads to an inhibition of the release of inflammatory peptides, but not to narrowing of the cerebral blood vessels. The 5-HT 1F receptor is thus possibly also involved in the migraine effectiveness of the triptans.
Each of the seven prescription triptans has been shown to help in more than half of people with migraines. The triptans differ in their duration of action. Some triptans work faster than others, while others last longer. Triptans with a longer half-life tend to have slightly lower recurrence rates than those with a short half-life. If one triptan is ineffective, another triptan may produce the desired effect in the same patient. People with migraines should therefore try different triptans to find the drug that is most effective and tolerable for them.
Side effects
General and typical side effects of the triptans are: slight feeling of weakness, dizziness, paresthesia / tingling, sensation of warmth or heat, slight nausea. In addition, temporary increases in blood pressure and, more rarely, angina pectoris- like symptoms can be observed. These adverse drug effects are attributed to stimulation of 5-HT 1B / 1D receptors within the cardiovascular system. Cardiac arrhythmias , circulatory disorders and disorders of the skeletal muscles occurred very rarely with the use of triptans .
Interactions
With simultaneous use of triptans with the ergot alkaloids also used in migraine therapy , such as. B. ergotamine , there is an increased risk of spasm of the coronary arteries . Therefore, ergot alkaloids should not be taken at the same time as triptans.
MAO inhibitors can lead to a slower breakdown of the triptans. Some triptans, such as B. rizatriptan, are themselves inhibitors of the drug-metabolizing cytochrome P450 enzyme system.
The American health authority warns of the potentially life-threatening interaction of the serotonin syndrome (the body accumulates too much serotonin in the nervous system) when taking a triptan and an antidepressant from the group of SSRIs (selective serotonin reuptake inhibitors) or SSNRIs (selective serotonin and noradrenaline) at the same time. Reuptake inhibitors). Symptoms of serotonin syndrome can include restlessness, hallucinations, loss of coordination, rapid heartbeat, fluctuations in blood pressure, increased body temperature, increased reflexes, nausea, vomiting, and diarrhea.
Contraindications
Because of their vasoconstrictive effect, triptans are contraindicated in coronary heart disease , hypertension and vascular diseases.
Dosage forms
Depending on the type of triptan, triptans are available as needle-free injectors , pre-filled syringes, tablets , orodispersible tablets , nasal sprays or suppositories .
history
It has been known since the 19th century that a migraine attack is linked to an expansion of cerebral and cranial blood vessels. Classic drugs such as B. Ergotamines , which cause these blood vessels to contract, are effective therapeutics for migraine. The history of the development of the triptans began with the observation that serotonin also led to a constriction of the blood vessels that were pathologically dilated during a migraine attack. Serotonin was far from being considered as a migraine therapy due to its side effects affecting the entire cardiovascular system and the gastrointestinal tract. The aim of drug development was therefore to find a serotonin derivative that selectively contracts cerebral blood vessels but is free from systemic side effects.
In the 1980s, 5-carboxamidotryptamine was identified as an active ingredient which selectively stimulates 5-HT 1 receptors. However, since this substance has already shown systemic cardiovascular side effects (hypotension, tachycardia) in preclinical studies, clinical development of this substance was dispensed with. A little later, the sumatriptan developed by GlaxoSmithKline (code name GR43175) was found to be a 5-HT 1B / 1D receptor agonist that selectively contracts cerebral blood vessels. Sumatriptan was approved by the US FDA on December 28, 1992 for the treatment of acute migraines.
Since sumatriptan has poor oral bioavailability and can only pass the blood-brain barrier inadequately, numerous so-called "2nd generation triptans" with improved pharmacokinetic properties have been developed. Zolmitriptan, Naratriptan and Rizatriptan were launched on the market as early as the late 1990s. A little later, almotriptan, eletriptan and frovatriptan followed. Other triptans, such as B. Donitriptan and Avitriptan, have not yet reached the market.
literature
- Hartmut Göbel : Headaches and Migraines . Springer-Verlag, 2nd edition 1998, pp. 209-224
Web links
- Eletriptan and Frovatriptan for Migraine Therapy, Pharmazeutische Zeitung, issue 48/2003
- Evers S, May A, Fritsche G, Kropp P, Lampl C, Limmroth V, Malzacher V, Sandor S, Straube A, Diener HC: Acute therapy and prophylaxis of migraines - guidelines of the German Migraine and Headache Society and the German Society for Neurology . In: Neurology . 27, No. 10, 2008, pp. 933-949.
- Institute for Quality and Efficiency in Health Care : Migraine Drugs: Are there differences between the triptans?
- Stefanie Kempt: Triptan treatment of migraines - a comparative study on response rates, effectiveness, dosages and application forms. Dissertation, Münster 2011. DNB 1017896321/34
- CK knowledge: information on the fixed price group of triptans
Individual evidence
- ↑ Limmroth V: mechanism of action of triptans . In: Pharmacy in our time . 31, No. 5, 2002, pp. 458-461. doi : 10.1002 / 1615-1003 (200209) 31: 5 <458 :: AID-PAUZ458> 3.0.CO; 2-G . PMID 12369163 .
- ^ Institute for Quality and Efficiency in Health Care (IQWiG): Drugs for the treatment of migraine in adults ( Memento from April 21, 2010 in the Internet Archive ), January 21, 2009, accessed on September 11, 2011.
- ↑ Evers S, May A, Fritsche G, Kropp P, Lampl C, Limmroth V, Malzacher V, Sandor S, Straube A, Diener HC: Acute therapy and prophylaxis of migraines - guideline of the German Migraine and Headache Society and the German Society for Neurology . In: Neurology . 27, No. 10, 2008, pp. 933-949.
- ↑ Steiner TJ, Martelletti P: Aids for management of common headache disorders in primary care . In: J Headache Pain . 8 Suppl 1, October 2007, p. S2. PMID 18700249 .
