Serotonin-Receptor Antagonists

SEROTONIN-RECEPTOR ANTAGONISTS

A wide variety of drugs with actions at other receptors (eg, α adrenoceptors, H₁-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine  has a long-lasting blocking action at 5-HT₂ receptors.

Cyproheptadine resembles the phenothiazine antihistaminicagents in chemical structure and has potent H₁-receptor–blocking as well as 5-HT₂–blocking actions. The actions of cyproheptadine are predictable from its H₁ histamine and 5-HT receptor affini-ties. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It also has significant antimuscarinic effects and causes sedation.

The major clinical applications of cyproheptadine are in the treat-ment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. The usual dosage in adults is 12–16 mg/d in three or four divided doses. It is of some value in serotonin syndrome, but because it is available only in tablet form, cyproheptadine must be crushed and administered by stomach tube in unconscious patients.

Ketanserin blocks 5-HT₂receptors on smooth muscle and othertissues and has little or no reported antagonist activity at other 5-HT or H₁ receptors. However, this drug potently blocks vascular α₁ adrenoceptors. The drug blocks 5-HT₂ receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mecha-nism involved in ketanserin’s hypotensive action probably involves α₁adrenoceptor blockade more than 5-HT₂receptor blockade.Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. Ritanserin, another 5-HT₂antagonist, has little or noα-blocking action. It has been reported to alter bleeding time and to reduce thromboxane formation, presumably by altering platelet function.

Ondansetron is the prototypical 5-HT₃antagonist. This drugand its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy.

Considering the diverse effects attributed to serotonin and the heterogeneous nature of 5-HT receptors, other selective 5-HT antagonists may prove to be clinically useful.

Ergot Poisoning: Not Just an Ancient Disease

As noted in the text, epidemics of ergotism, or poisoning by ergot-contaminated grain, are known to have occurred sporadi-cally in ancient times and through the Middle Ages. It is easy to imagine the social chaos that might result if fiery pain, gangrene, hallucinations, convulsions, and abortions occurred simultane-ously throughout a community in which all or most of the people believed in witchcraft, demonic possession, and the visitation of supernatural punishments upon humans for their misdeeds. Fortunately, such beliefs are uncommon today. However, ergot-ism has not disappeared. A most convincing demonstration of ergotism occurred in the small French village of Pont-Saint-Esprit in 1951. It was described in the British Medical Journal in 1951 (Gabbai et al, 1951) and in a later book-length narrative account (Fuller, 1968). Several hundred individuals suffered symptoms of hallucinations, convulsions, and ischemia—and several died— after eating bread made from contaminated flour. Similar events have occurred even more recently when poverty, famine, or incompetence resulted in the consumption of contaminated grain. Ergot toxicity caused by excessive self-medication with pharmaceutical ergot preparations is still occasionally reported.