then a series of drugs with progressive increases in the acid secretion-blocking action and reduction in irrelevant effects. This development led to renewed interest in possible physiologic roles for histamine and to a classification of effects of both agonists and antagonists based upon histamine receptor subtypes. The high incidence of peptic ulcer disease and related gastrointestinal complaints created great interest in the therapeutic potential of Hp receptor antagonists. Because of the ability of this class of drugs to reduce gastric acid secretion and their low toxicity, they are now among the ‘most frequently used drugs in the USA and have become OTC items. These drugs are discussed in Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. Katzung PHARMACOLOGY, 9¢ > Section IV. Drugs with Important Actions on Smooth, Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Serotonin (5-Hydroxy-Tryptamine) Before the identification of 5-hydroxytryptamine (5-117), it was known that when blood is allowed to clot, a vasoconstrictor (tonic) substance is released from the clot into the serum; this substance was called serotonin. Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa; this was called enteramine. The synthesis of S-hydroxyiryptamine in 1951 permitted the identification of serotonin and enteramine as the same metabolite of 5~ hydroxytryptophan, Serotonin is thought to play a role in migraine headache. Serotonin is also one of the mediators of the signs and symptoms of carcinoid syndrome, an unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. In patients whose tumor is not operable, serotonin antagonists may constitute the best treatment. Basic Pharmacology of Serotonin Chemistry & Pharmacokinetics Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, ‘venoms, and stings. It is an indoleethylamine formed in biologic systems from the amino acid L~ tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16-3). Hydroxylation at C5 is the rate-limiting step and can be blocked by p- chlorophenylalanine (PCPA; fenclonine) and by p-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome. Figure 16-3.