Pharmaceutical Chemistry Of H2 Antagonist Drug

Ketotifen Fumarate

The recommended dose of ketotifen solution is 1 drop instilled into each affected eye every 8 to 12 hours. The most frequently reported adverse reactions are conjunctival infection, headaches, and rhinitis. This drug product is for ocular administration only and not for injection or oral use. Ketotifen solution should be used with caution during pregnancy or while nursing, because its safety has not been studied under these circumstances.58


Drugs whose pharmacological action primarily involves antagonism of the action of histamine at its H2-receptors find therapeutic application in the treatment of acid-peptic disorders including heartburn, gastroesophageal reflux disease (GERD), erosive esophagitis, gastric and duodenal ulcers, and gastric acid pathologic hypersecretory diseases such as Zollinger-Ellison syndrome. They are also useful in combination with Hi-antihistamines for the treatment of chronic urticaria and for the itching of anaphylaxis and pruritis.59-62

Gastric Acid Secretion

A characteristic feature of the mammalian stomach is its ability to secrete acid as part of its processes to digest food for absorption later in the intestine. The presence of acid and proteolytic pepsin enzymes, whose formation is facilitated by the low gastric pH, is generally assumed to be required for the hydrolysis of proteins and other food constiuents. The acid secretory unit of the gastric mucosa is the parietal (oxyntic) cell. Parietal cells contain an H+, K+-ATPase or hydrogen ion pump that secretes proton (H+) in exchange for the uptake of K+ ion (Fig, 23.14).61,62 Secretion of acid by gastric parietal cells is stimulated by various mediators at receptors located on the basolateral membrane, including histamine agonism of H2-receptors (cellular), gastrin activity at G receptors (blood), and acetylcholine (ACh) at M2 muscarinic receptors (neuronal). Gastric and muscarinic receptors modulate acid secretion through calcium-dependent processes, while the H2-receptor is coupled to adenylate cy-

clase (Fig. 23.14). The adenylate cyclase pathway, and therefore acid secretion, is inhibited by intracellular prostaglandins of the E series. These prostaglandins also stimulate other GI epithelial cells to secrete mucous and bicarbonate, and enhance blood flow through gastric tissues. All of these prostaglandin-mediated actions have acid-neutralizing and gastric tissue protective properties referred to generally as "cytoprotection." When there is hypersecretion of gastric acid or breakdown of muscosal cell defenses, including bacterial infection, gastric tissues and contiguous structures (esophagus, intestines) may become compromised and ulcerated.61,62

Peptic Ulcer Disease

Peptide ulcer disease (PUD) is a group of upper GI tract disorders characterized by mucosal erosions equal to or greater than 0.5 cm that result from the erosive action of acid and pepsin.63 Duodenal ulcer and gastric ulcer are the most common forms, although PUD may occur in the esophagus or small intestine. Factors involved in the pathogenesis and recurrence of PUD include hypersecretion of acid and pepsin and GI infection by Helicobacter pylori, a Gram-negative spiral bacterium. H. pylori have been found in virtually all patients with duodenal ulcers and approximately 75% of patients with gastric ulcers. Some risk factors associated with recurrence of PUD include cigarette smoking, chronic use of ulcerogenic drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]), male gender, age, alcohol consumption, emotional stress, and family history. About 4% of gastric ulcers are caused by a malignancy, whereas duodenal ulcers are generally benign.

The goals of PUD therapy are to promote healing, relieve pain, and prevent ulcer complications and recurrences. Medications used to heal or reduce ulcer recurrence include antacids, histamine H2-antagonists, protective mucosal barriers, proton pump inhibitors (PPIs), prostaglandins, and bismuth salt and combinations of these drugs with antibiotics to eradicate H. pylori infection.

Structural Derivation of the "^-Antagonists"

The H2-antagonists are used to treat acid indigestion (an OTC application), GERD, peptic ulcers, and pathologic hy-persecretory disorders, as well as some of the symptoms of urticaria and anaphylaxis. Cimetidine, the original member of this drug class, was developed by a classical structure-activity study beginning with the endogenous agonist, hista-mine as shown in Table 23.4.64 Methylation of the 5-position of the imidazole heterocycle of histamine produced a selective agonist at atrial histamine receptors (H2). The guanidino analog of histamine was then found to possess weak antagonist activity to the acid-secretory actions of histamine. Increasing the length of the side chain from two to four carbons, coupled with replacement of the strongly basic guanidino group by a neutral methyl thiourea function, led to development of burimamide, the first full H2-receptor antagonist, albeit one of low potency. The low potency of buri-mamide was postulated to be related to its nonbasic, electron-releasing side chain, which favors the nonpharma-cophoric N^—H imidazole tautomer over the basic, electron-withdrawing side chain in histamine, which predominantly presents the higher-affinity NT—H imidazole tautomer to the

Figure 23.14 • Hormonal regulation of acid secretion by parietal cells.

receptor. Insertion of an electronegative thioether function in the side chain in place of a methylene group favors the NT—H tautomer, and introduction of the 5-methyl group favors H2 selectivity and led to metiamide, an H2-blocker of higher potency and oral bioavailability than burimamide. Unfortunately, drug-related toxicities including agranulocy-tosis prevented further development of this compound. However, replacement of the thiourea moiety of metiamide with a cyano-imino function produced cimetidine, the first clinically effective and relatively safe member of this therapeutic class (Table 23.4).64

Introduction of cimetidine into medicine revealed an effective gastric antisecretory agent that promotes the healing of duodenal ulcers. Cimetidine is not without several limitations, however. Because it is short acting, it requires a frequent-dosing schedule. Also, cimetidine was found to possess an-tiandrogenic activity, which can lead to gynecomastia, and to cause confusional states in some elderly patients and decreased renal function. Also, cimetidine inhibits CYP isozymes and renal tubular secretion, resulting in clinically significant drug interactions.65 The drug interaction potential and several adverse effects (gynecomastia) of cimetidine appear to be directly related to the presence of the imidazole group. These limitations prompted additional drug design and development efforts, which revealed that the imidazole ring was not required for H2-antagonist activity (discussed next). In fact, replacement of the imidazole ring with a furan (rani-ditine) or a thiazole (famotidine, nizatidine) heterocycle with a basic ring substitutent (guanidine or dimethylaminomethyl) not only enhances both potency and selectivity of H2-antago-nism, but also reduces cytochrome and renal secretory drug interactions.64

The pharmacokinetic properties of the H2-antagonists are summarized in Table 23.5.66 Cimetidine, ranitidine, and

TABLE 23.4 Development of H2-Antagonists

Structure-Activity Relationship

Histamine: Nonselective histamine receptor agonist (H-i = H2)


5-Methylhistamine: Selective H2-agonist (H2 > Ht)

W"-Guanylhistamine: Partial H2-receptor agonist (weak antagonist)

Burimamide: Full H2-receptor antagonist; but low potency and poor oral bioavailability

Metiamide: Full H2-receptor antagonist with higher potency and improved oral bioavailability; but toxicity resulting from the thiourea

Cimetidine: Full H2-receptor antagonist with higher potency and improved oral bioavailability and low systemic toxicity

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