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Chemistry; Mechanism of Action; Pharmacology. The most potent suppressors of gastric acid secretion are inhibitors of the gastric H+, K+-ATPase (proton pump) (Figure 45–2). In typical doses, these drugs diminish the daily production of acid (basal and stimulated) by 80-95%. Six proton pump inhibitors are available for clinical use: omeprazole (prilosec, others) and its S-isomer, esomeprazole (nexium), lansoprazole (prevacid) and its R-enantiomer, dexlansoprazole (kapidex), rabeprazole (aciphex), and pantoprazole (protonix, others). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties (Appendix II). Omeprazole is a racemic mixture of R- and S-isomers; the S-isomer, esomeprazole (S-omeprazole), is eliminated less rapidly than R-omeprazole, which theoretically provides a therapeutic advantage because of the increased t1/2. Despite claims to the contrary, all proton pump inhibitors have equivalent efficacy at comparable doses.

Figure 45–2.

Proton pump inhibitors. A. Inhibitors of gastric H+, K+-ATPase (proton pump). B. Conversion of omeprazole to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfenamide interacts covalently with sulfhydryl groups in the proton pump, thereby irreversibly inhibiting its activity. The other three proton pump inhibitors undergo analogous conversions.

Proton pump inhibitors (PPIs) are prodrugs that require activation in an acid environment. After absorption into the systemic circulation, the prodrug diffuses into the parietal cells of the stomach and accumulates in the acidic secretory canaliculi. Here, it is activated by proton-catalyzed formation of a tetracyclic sulfenamide (Figure 45–2), trapping the drug so that it cannot diffuse back across the canalicular membrane. The activated form then binds covalently with sulfhydryl groups of cysteines in the H+, K+-ATPase, irreversibly inactivating the pump molecule. Acid secretion resumes only after new pump molecules are synthesized and inserted into the luminal membrane, providing a prolonged (up to 24- to 48-hour) suppression of acid secretion, despite the much shorter plasma half-lives (0.5-2 hours) of the parent compounds. Because they block the final step in acid production, the proton pump inhibitors are effective in acid suppression regardless of other stimulating factors.

To prevent degradation of proton pump inhibitors by acid in the gastric lumen, oral dosage forms are supplied in different formulations:

The delayed-release and enteric-coated tablets dissolve only at alkaline pH, whereas admixture of omeprazole with sodium bicarbonate simply neutralizes stomach acid; both strategies substantially improve the oral bioavailability of these acid-labile drugs. Until recently, the requirement for enteric coating posed a challenge to the administration of proton pump inhibitors in patients for whom the oral route of administration is not available (Freston et al., 2003). These patients and those requiring immediate acid suppression now can be treated parenterally with esomeprazole, pantoprazole, or lansoprazole, which are approved for intravenous administration in the U.S. A single intravenous bolus of 80 mg of pantoprazole inhibits acid production by 80-90% within an hour, and this inhibition persists for up to 21 hours, permitting once-daily dosing to achieve the desired degree of hypochlorhydria. The FDA-approved dose of intravenous pantoprazole for gastroesophageal reflux disease is 40 mg daily for up to 10 days. Higher doses (e.g., 160-240 mg in divided doses) are used to manage hypersecretory conditions such as the Zollinger-Ellison syndrome.

Pharmacokinetics. Because an acidic pH in the parietal cell acid canaliculi is required for drug activation and food stimulates acid production, these drugs ideally should be given ~30 minutes before meals. Concurrent administration of food may reduce somewhat the rate of absorption of proton pump inhibitors, but this effect is not thought to be clinically significant. Concomitant use of other drugs that inhibit acid secretion, such as H2 receptor antagonists, might be predicted to lessen the effectiveness of the proton pump inhibitors, but the clinical relevance of this potential interaction is unknown.

Once in the small bowel, proton pump inhibitors are rapidly absorbed, highly protein bound, and extensively metabolized by hepatic CYPs, particularly CYP2C19 and CYP3A4. Several variants of CYP2C19 have been identified. Asians are more likely than whites or African Americans to have the CYP2C19 genotype that correlates with slow metabolism of proton pump inhibitors (23% vs. 3%, respectively), which has been suggested to contribute to heightened efficacy and/or toxicity in this ethnic group (Dickson and Stuart, 2003). Although the CYP2C19 genotype is correlated with the magnitude of gastric acid suppression by proton pump inhibitors in patients with gastroesophageal reflux disease, there is no evidence that the CYP2C19 genotype predicts clinical efficacy of these drugs (Chong and Ensom, 2003).

Because not all pumps or all parietal cells are active simultaneously, maximal suppression of acid secretion requires several doses of the proton pump inhibitors. For example, it may take 2-5 days of therapy with once-daily dosing to achieve the 70% inhibition of proton pumps that is seen at steady state (Wang and Hunt, 2008). More frequent initial dosing (e.g., twice daily) will reduce the time to achieve full inhibition but is not proven to improve patient outcome. Because the proton pump inhibition is irreversible, acid secretion will be suppressed for 24-48 hours, or more, until new proton pumps are synthesized and incorporated into the luminal membrane of parietal cells.

Chronic renal failure does not lead to drug accumulation with once-a-day dosing of the proton pump inhibitors. Hepatic disease substantially reduces the clearance of esomeprazole and lansoprazole. Thus, in patients with severe hepatic disease, dose reduction is recommended for esomeprazole and should be considered for lansoprazole.

Adverse Effects and Drug Interactions. Proton pump inhibitors generally cause remarkably few adverse effects. The most common side effects are nausea, abdominal pain, constipation, flatulence, and diarrhea. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. As noted earlier, proton pump inhibitors are metabolized by hepatic CYPs and therefore may interfere with the elimination of other drugs cleared by this route. Proton pump inhibitors have been observed to interact with warfarin (esomeprazole, lansoprazole, omeprazole, and rabeprazole), diazepam (esomeprazole and omeprazole), and cyclosporine (omeprazole and rabeprazole). Among the proton pump inhibitors, only omeprazole inhibits CYP2C19 (thereby decreasing the clearance of disulfiram, phenytoin, and other drugs) and induces the expression of CYP1A2 (thereby increasing the clearance of imipramine, several antipsychotic drugs, tacrine, and theophylline). There is emerging evidence that omeprazole can interact adversely with the anticlotting agent, clopidogrel, at the level of CYP2C19, for which both are substrates; thus, omeprazole can inhibit conversion of clopidogrel to the active anticoagulating form. Pantoprazole is less likely to result in this interaction (Ferreiro and Angiolillo, 2009; Norgard et al., 2009); concurrent use of clopidogrellarry and PPIs (mainly pantoprazole) significantly reduced GI bleeding without increasing adverse cardiac events (Ray et al., 2010). For the pharmacological issues involved in the concurrent use of dual antiplatelet therapy and proton pump inhibitors, see Chapter 30, "Regulation of Blood Coagulation."

Chronic treatment with omeprazole decreases the absorption of vitamin B12, but the clinical relevance of this effect is not clear. Loss of gastric acidity also may affect the bioavailability of such drugs as ketoconazole, ampicillin esters, and iron salts. Chronic use of proton pump inhibitors has been reported to be associated with an increased risk of bone fracture and with increased susceptibility to certain infections (e.g., hospital-acquired pneumonia, community-acquired Clostridium difficile) (Coté and Howden, 2008). Hypergastrinemia is more frequent and more severe with proton pump inhibitors than with H2 receptor antagonists, and gastrin levels of >500 ng/L occur in ~5-10% of users with chronic omeprazole administration. This hypergastrinemia may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and also may promote the growth of gastrointestinal (GI) tumors. In rats, long-term administration of proton pump inhibitors causes hyperplasia of enterochromaffin-like cells and the development of gastric carcinoid tumors. Although the gastrin levels observed in rats are ~10-fold higher than those seen in human beings, this finding has raised concerns about the possibility of similar complications of proton pump inhibitors in humans, for which there is no unequivocal evidence.

Therapeutic Uses. Prescription proton pump inhibitors are used to promote healing of gastric and duodenal ulcers and to treat gastroesophageal reflux disease (GERD), including erosive esophagitis, which is either complicated or unresponsive to treatment with H2 receptor antagonists. Over-the-counter omeprazole is approved for the self-treatment of heartburn. Proton pump inhibitors also are the mainstay in the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Lansoprazole and esomeprazole are FDA approved for treatment and prevention of recurrence of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use. It is not clear if proton pump inhibitors affect the susceptibility to NSAID-induced damage and bleeding in the small and large intestine. In addition, all proton pump inhibitors are approved for reducing the risk of duodenal ulcer recurrence associated with H. pylori infections. Therapeutic applications of proton pump inhibitors are further discussed later under "Specific Acid-Peptic Disorders and Therapeutic Strategies."

Use in Children. In children, omeprazole is safe and effective for treatment of erosive esophagitis and GERD. Younger patients generally have increased metabolic capacity, which may explain the need for higher dosages of omeprazole per kilogram in children compared with adults.

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