Benzimidazole Derivatives Proton Pump Inhibitors

ch2 ,c-no2

h nhch3

Ranitidine

chain) and 6.8 (dimethylamino). Nizatidine's mechanism of action is similar to other H2-antagonists, as is its receptor selectivity. It is more potent than cimetidine.

Nizatidine has excellent oral bioavailability (>90%). The effects of antacids or food on its bioavailability are not clinically significant.66 The elimination half-life is 1 to 2 hours. It is excreted primarily in the urine (90%) and mostly as unchanged drug (60%). Metabolites include nizatidine sulfoxide (6%), N-desmethylnizatidine (7%), and nizatidine N-oxide (dimethylaminomethyl function).66 Nizatidine has no demonstrable antiandrogenic action, effects on other hormones, or inhibitory effects on cytochrome isozymes involved in the metabolism of other drugs.

Dosage forms: Tablets (75 mg), capsules (150 and

300 mg), oral solution (15 mg/mL) Usual adult oral dose:

• Benign gastric ulcer: 150 mg twice a day or 300 mg once daily at bedtime.

• Duodenal ulcer: Treatment, 300 mg once to twice a day; maintenance, 150 mg once daily

• Heartburn (OTC products only): 1 tablet with a full glass of water, up to 2 tablets in 24 hours.

• Hypersecretory condition: 150 mg twice a day

Other Antiulcer and Gastric Acid Hypersecretory Disease Therapies: Proton Pump Inhibitors

The final step in acid secretion in the parietal cell is the extrusion or "pumping" of protons into the lumen of stomach by the membrane H+, K+-ATPase pump as described previously (Fig. 23.14). Thus, inhibition of this proton pump acts beyond the site of action of second messengers (e.g., calcium and cAMP) and is independent of the action of se-cretogogues histamine, gastrin, and acetyicholine. Thus, acid pump inhibitors block both basal and stimulated acid secretion.

In 1972, a group of Swedish medicinal chemists discovered that certain pyridylmethyl benzimidazole sulfides were capable of functioning as H+, K+-ATPase or PPIs.67,68 These compounds were subsequently converted to sulfoxide derivatives, which exhibited highly potent, irreversible inhibition of the proton pump. The benzimidazole PPIs are prodrugs that are rapidly converted to a sulfenamide inter-medate in the highly acidic environment of gastric parietal cells. The weakly basic benzimidazole PPIs accumulate in these acidic compartments on the luminal side of the tubu-vesicular and canalicular structures of the parietal cells. The benzimidazole PPIs are then chemically converted by acid to a sulfenamide intermediate that inhibits the proton pump via covalent interaction with sulfhydryl groups with cysteine residues of the H+, K+-ATPase pump (Fig. 23.15).67,68 All of the PPIs have been shown to react with cysteine 813 of pump, but some bind to additional pump sulfhydryl residues as well.69 For example, omeprazole and esomeprazole also react with cysteine 892, and pantoprazole with cysteine 822 and lansoprazole to cysteine 321.69,70 Cysteines 321, 813, and 822 are all in the proton-transport domain of the H+, K+-ATPase system, whereas cysteine 892 is on the external luminal surface and does not affect pump transport ability.69,70 The bioaccumulation and activation of the PPIs within the acidic environment of the parietal cell also ensures specificity of pharmacologic action. The acid lability of the benzimidazole PPIs dictates that these drugs must be formulated as delayed-release, enteric-coated granular dosage forms.

To date, five structually related benzimidazole sulfoxide PPIs have been approved for use in the United States to treat various gastric acid hypersecretory disorders. These include omeprazole, esomeprazole (the active enantiomers of omeprazole), lansoprazole, patoprazole, and rabeprazole. The PPIs differ only in the nature and degree and pyridine and imidazole ring substituents, which has an impact on pKa values and pharmacokinetic properties. The extent of initial PPI protonation and, thereby, parietal cell accumulation is governed by the pKa of the pyridine ring nitrogen that ranges from 3.8 for lansoprazole and pantoprazole to 4.5 for rabeprazole (Table 23.6).71 Thus, all drugs are believed to be concentrated at their physiologic site of action to a similar extent. The rate of conversion of PPIs to their active sulfenamides, however, is determined largely by the pKa of the benzimidazole group (pKa2). Omeprazole, lansoprazole, and rabeprazole with higher pKa2s (0.62-0.79) undergo

Figure 23.15 • Mechanism of action of PPIs.

TABLE 23.6 pKas of the Proton Pump Inhibitors r

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