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Chapter: Basic & Clinical Pharmacology : Histamine, Serotonin, & the Ergot Alkaloids

Clinical Pharmacology of Serotonin

Serotonin has no clinical applications as a drug.


Serotonin Agonists

Serotonin has no clinical applications as a drug. However, several receptor subtype-selective agonists have proved to be of value. Buspirone, a 5-HT1Aagonist, has received wide attention for itsusefulness as an effective nonbenzodiazepine anxiolytic . Dexfenfluramine, another selective 5-HT agonist, was widely used as an appetite suppressant but was withdrawn because of cardiac valve toxicity. Appetite suppression appears to be associated with agonist action at 5-HT2C receptors in the cen-tral nervous system.

5-HT1D/1B Agonists & Migraine Headache

The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost exclusively for migraine headache. Migraine in its “classic” form is characterized by an aura of variable duration that may involve nausea, vomiting, visual scotomas or even hemianopsia, and speech abnormalities; the aura is followed by a severe throb-bing unilateral headache that lasts for a few hours to 1–2 days. “Common” migraine lacks the aura phase, but the headache is similar. After a century of intense study, the pathophysiology of migraine is still poorly understood and controversial. Although the symptom pattern and duration of prodrome and headache vary markedly among patients, the severity of migraine headache justifies vigorous therapy in the great majority of cases.

Migraine involves the trigeminal nerve distribution to intracra-nial (and possibly extracranial) arteries. These nerves release pep-tide neurotransmitters, especially calcitonin gene-related peptide (CGRP;), an extremely powerful vasodilator. Substance P and neurokinin A may also be involved. Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and is found in biopsy specimens from migraine patients. This effect probably reflects the action of the neuropeptides on the vessels. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache is sometimes associated with a marked increase in amplitude of temporal artery pulsations, and relief of pain by administration of effective therapy is sometimes accompanied by diminution of the arterial pulsations.

The mechanisms of action of drugs used in migraine are poorly understood, in part because they include such a wide variety of drug groups and actions. In addition to the triptans, these include ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents, β-adrenoceptor blockers, calcium channel blockers, tricyclic anti-depressants and SSRIs, and several antiseizure agents. Furthermore, some of these drug groups are effective only for prophylaxis and not for the acute attack.

Two primary hypotheses have been proposed to explain the actions of these drugs. First, the triptans, the ergot alkaloids, and antidepressants may activate 5-HT1D/1B receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating pep-tides, and antiseizure agents may suppress excessive firing of these nerve endings. Second, the vasoconstrictor actions of direct 5-HT agonists (the triptans and ergot) may prevent vasodilation and stretching of the pain endings. It is possible that both mechanisms contribute in the case of some drugs. Sumatriptan and its conge-ners are currently first-line therapy for acute severe migraine attacks in most patients (Figure 16–3). However, they should not be used in patients at risk for coronary artery disease. Anti-inflammatory analgesics such as aspirin and ibuprofen are often helpful in controlling the pain of migraine. Rarely, parenteral opioids may be needed in refractory cases. For patients with very severe nausea and vomiting, parenteral metoclopramide may be helpful.

Propranolol, amitriptyline, and some calcium channel block-ers have been found to be effective for the prophylaxis of migraine in some patients. They are of no value in the treatment of acute migraine. The anticonvulsants valproic acid and topiramate  have also been found to have prophylactic efficacy in many migraine patients. Flunarizine, a calcium channel blocker used in Europe, has been reported in clinical trials to effectively reduce the severity of the acute attack and to prevent recurrences. Verapamil appears to have modest efficacy as prophylaxis againstmigraine.

Sumatriptan and the other triptans are selective agonists for 5-HT 1D and 5-HT1B receptors; the similarity of the triptan struc-ture to that of the 5-HT nucleus can be seen in the structure below. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neu-rons and probably function as presynaptic inhibitory receptors.

The efficacies of all the triptan 5-HT1 agonists in migraine are equal to each other and equivalent to or greater than those of other acute drug treatments, eg, parenteral, oral, and rectal ergot alka-loids. The pharmacokinetics of the triptans differ significantly and are set forth in Table 16–5. Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and for parenteral sumatriptan, injection site reactions. Chest discomfort occurs in 1–5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindi-cated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan, Table 16–5) is often shorter than the duration of the headache. As a result, several doses may be required during a pro-longed migraine attack, but their adverse effects limit the maxi-mum safe daily dosage. In addition, these drugs are expensive. Naratriptan and eletriptan are contraindicated in patients with severe hepatic or renal impairment or peripheral vascular syn-dromes; frovatriptan in patients with peripheral vascular disease; and zolmitriptan in patients with Wolff-Parkinson-White syn-drome. The brand name triptans are extremely expensive; thus generic sumatriptan should be used whenever possible.

Other Serotonin Agonists in Clinical Use

Cisapride,a 5-HT4agonist, was used in the treatment of gastro-esophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation.

Compounds such as fluoxetine and other SSRIs, which modu-late serotonergic transmission by blocking reuptake of the trans-mitter, are among the most widely prescribed drugs for the management of depression and similar disorders.


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