Pompa Proton Inhibitor (PPI): Mekanisme, Farmakokinetik, Efek samping, dan Interaksi Obat
Mechanism and Site of Action of Proton Pump Inhibitors (PPI)
The PPIs are a class of drugs that decrease gastric acid secretion through inhibition of H+,K+-ATPase, the proton pump of the parietal cell. Currently, five PPIs are used widely as antisecretory agents:
- esomeprazole (the S optical isomer of omeprazole),
- pantoprazole, and
These compounds, all substituted benzimidazoles, are weak bases, with a pKa of approximately 4.0 for omeprazole, lansoprazole, and pantoprazole, and approximately 5.0 for rabeprazole. These agents are prodrugs that must be activated by acid to effect inhibition of H+,K+-ATPase. However, the prodrugs are acid-labile compounds that must be protected from degradation by stomach acid during oral administration.
Pharmacokinetics of Proton Pump Inhibitors (PPI)
The PPIs are well absorbed after oral dosing, and the simultaneous administration of antacids does not appear to affect their bioavailability. Food may delay the absorption of lansoprazole, pantoprazole, and rabeprazole, but this delay does not alter the area under the plasma concentration–time curve, which is a key factor in achieving clinical efficacy for these agents. Absorption of the enteric-coated agents may be erratic, and peak serum concentrations are not achieved until 2 to 5 hours after oral administration. Although the plasma half-life of the PPIs is short (<2 hours), the duration of acid inhibition is long (>24 hours) as a result of covalent binding to the H+,K+-ATPase.
Newer PPIs inhibit H+,K+-ATPase more rapidly than omeprazole, and emerging clinical data support potential clinical benefits resulting from this pharmacologic property. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, dose adjustments are not required even in patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the CYP isoenzymes involved in PPI metabolism, CYP2C19. Approximately 3% of white persons and 15% of Asians are deficient in CYP2C19. This polymorphism has been shown to substantially raise plasma levels of omeprazole, lansoprazole, and pantoprazole but not those of rabeprazole.
As a result of their requirement for concentration and activation in acidic compartments, the PPIs bind predominantly to those proton pumps that are actively secreting acid. Thus, the efficacy of the PPIs for inhibiting acid secretion is limited if they are administered during the fasting state, when only approximately 5% of the stomach's proton pumps are active. With meal stimulation, in contrast, 60% to 70% of the proton pumps actively secrete acid. Thus, the PPIs are most effective if they are administered immediately before meals. For once-daily dosing, it is recommended that the PPIs be taken immediately before breakfast. Eradication of H. pylori infection has been found to render PPIs somewhat less effective in elevating the gastric pH in patients with duodenal ulcer. The mechanism by which H. pylori infection augments the pH-elevating effect of the PPIs is not clear. Conceivably, this phenomenon might be a consequence either of alkaline ammonia produced from urea by the organism or, more likely, of the greater gastric bicarbonate secretion and lesser gastric acid secretion associated with ongoing infection.
Adverse Effects of Proton Pump Inhibitors (PPI)
The PPIs are a remarkably safe and well-tolerated group of agents. The most commonly reported side effects are headache and diarrhea, yet the rate at which patients experience these symptoms does not differ significantly from that for patients treated with placebo.
Drug Interactions of Proton Pump Inhibitors (PPI)
The elevation of gastric pH induced by the PPIs can affect the absorption of a number of medications. However, this antisecretory action rarely has clinically important effects on drug pharmacokinetics, except when the PPIs are given with ketoconazole or digoxin. Ketoconazole requires stomach acid for absorption, and this drug may not be absorbed effectively after PPIs have inhibited gastric acid secretion. Conversely, an elevated gastric pH facilitates the absorption of digoxin, resulting in higher plasma levels of this agent. If a patient requires both PPI and antifungal therapy, it is recommended that an agent other than ketoconazole be chosen. For patients treated concomitantly with PPIs and digoxin, clinicians should consider monitoring plasma digoxin levels.
Because the PPIs are metabolized by the CYP system, there is potential for them to alter the metabolism of other drugs that are eliminated by CYP enzymes. Among the available PPIs, omeprazole appears to have the greatest potential for such drug interactions and has been shown to delay the clearance of warfarin, diazepam, and phenytoin. Lansoprazole, pantoprazole, and rabeprazole do not appear to interact significantly with drugs metabolized by the CYP system. Even with omeprazole, however, clinically important drug interactions are uncommon.
Sleisenger and Fordtran's Gastrointestinal and Liver Disease 8th Edition (Saunders) 2006