A wide variety of drugs with actions at other receptors (eg, α adrenoceptors, H1-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine (see Chapter 10) has a long-lasting blocking action at 5-HT2 receptors. In addition, the ergot alkaloids discussed in the last portion of this chapter are partial agonists at serotonin receptors.
Cyproheptadine resembles the phenothiazine antihistaminic agents 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 affinities. 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 treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. The usual dosage in adults is 12–16 mg/d orally 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. The drug also appears to reduce muscle spasms following spinal cord injury, in which constitutive activity of 5-HT2C receptors is associated with increases in Ca2+ currents leading to spasms. Anecdotal evidence suggests some efficacy as an appetite stimulant in cancer patients, but controlled trials have yielded mixed results.
Ketanserin blocks 5-HT2 receptors on smooth muscle and other tissues 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 mechanism involved in ketanserin’s hypotensive action probably involves α1 adrenoceptor blockade more than 5-HT2 receptor 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-HT2 antagonist, has little or no α-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-HT3 antagonist. This drug and its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy. They are discussed in Chapter 62.
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 alkaloids are produced by Claviceps purpurea, a fungus that infects grasses and grains—especially rye—under damp growing or storage conditions. This fungus synthesizes histamine, acetylcholine, tyramine, and other biologically active products in addition to a score or more of unique ergot alkaloids. These alkaloids affect α adrenoceptors, dopamine receptors, 5-HT receptors, and perhaps other receptor types. Similar alkaloids are produced by fungi parasitic to a number of other grass-like plants.