Directly acting serotoninomimetics
Serotoninomimetics can be divided into directly and indirectly acting molecules.
Directly acting serotoninomimetics activate serotonin receptors: they are agonists of its receptors, the main being 5-HT1 and 5- HT4 receptor agonists.
5-HT1 Agonists
5-HT1D Agonists: the triptans
The 5-HT1D agonists currently used in therapeutics for curative treatment of migraine attacks have been called triptans. These drugs are sumatriptan, zolmitriptan, naratriptan, eletriptan, almotriptan and rizatriptan.
Sumatriptan , agonist of 5-HT1, 5-HT1D receptors, and to a lesser degree of 5-HT1B , causes a vasoconstriction of cerebral vessels, in particular of carotid arteriovenous anastomoses, but this vasoconstriction can touch other vessels such as coronary. Another explanation is that sumatriptan activates presynaptic 5-HT1D receptors whichleads to an inhibition of the release of pro-inflammatory transmitters, including substance P, CGRP (calcitonin gene-regulated peptide) and serotonin itself.
Sumatriptan is indicated for treatment of migraine and cluster headache attacks but not for their long- term prevention.
Because of its low bioavailability by oral route, the amount of sumatriptan in a tablet is much more important than that of an injectable formulation. The use of sumatripan is disadvised in patients with angina pectoris or having had myocardial infarction or stroke. Cases of seizures were observed after its injection. It should not be combined with other vasoconstrictive drugs such as dihydroergotamine and especially ergotamine.
Zolmitriptan, naratriptan,eletriptan, almotriptan and rizatriptan are other agonists of 5-HT1D and 5-HT1B receptors, active as antimigraine agents at lower dose than sumatriptan. They have properties similar to those of sumatripan but a better bioavailability by oral route and are presented in the form of tablets. Their therapeutic use is also the treatment of migraine attacks.
5-HT1A agonists: buspirone
5-HT1A agonists such as buspirone have anxiolytic and perhaps antidepressant and anti-obsessive effects. However their mechanism of action is not clearly specified. It is known that buspirone does not interfere with GABAA nor benzodiazepines receptors. It is thought that it acts as a partial agonist of 5-HT1A presynaptic limbic receptors, what would decrease serotonin release. In addition, its principal metabolite is an antagonist of alpha- 2 adrenergic presynaptic receptors, in the same way as mianserin, explaining why it can exert an antidepressant action. It does not have, in theory, sedative or muscle relaxant effect.
In high doses, buspirone has a D2 antidopamine effect, but the rise in prolactin which it can induce is more the consequence of its serotonergic than of its antidopaminergic effect, because this rise is blocked by metergoline, an antagonist of serotonin receptors.
Buspirone is the first drug of a new anxiolytic group in which advantages in clinical practise over benzodiazepines are not demonstrated because they have probably more frequent adverse effects and possible pharmacokinetic drug interactions. Other compounds of the same group are gepirone and ipsapirone.
5-HT2 agonists
Lysergide or lysergic acid diethylamide or LSD is an agonist of 5-HT2A and 5 - HT2C receptors. It is not a drug but an hallucinogenic compound.
5-HT4 agonists: tegaserod
5-HT4 agonists increase intestinal motility and could be used in the treatment of gastroesophageal reflux, intestinal paresis (constipation), irritable bowel syndrome. The first drug of this group is tegaserod. A frequent adverse effect of tegaserod is diarrhea and a rare more severe effect is ischemic colitis.
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