Adverse Effects of Proton Pump Inhibitor Drugs: Clues and Conclusions

Denis M. McCarthy


Curr Opin Gastroenterol. 2010;26(6):624-631. 

In This Article

Effects on other Medications

Rises in pH and lack of gastric acid have been shown to impair the absorption of various drugs in common use, including ketoconazole, indinavir, midazolam, didanosine and methadone. Following absorption, some but not all PPIs inhibit various components of the cytochrome P-450 (CYP) enzyme system in liver and intestine, notably CYP 2C19 and CYP 3A4. This has varying effects, most of them subclinical, on many other drugs in common use, but the effects have not risen to the level of posing clinically significant problems. PPIs also variably affect the hepatic catabolism of thyroxine by UDP-glucuronyl transferase, increasing TSH slightly and in some cases requiring an increase in the dose of thyroxine.[35] Another interaction, currently causing a flurry of attention because of its possible linkage to adverse clinical outcomes, is the effect of PPI therapy in patients also using clopidogrel.

Clopidogrel is a prodrug used to inhibit platelet aggregation in patients at increased cardiovascular risk. After absorption, it requires activation by CYP 2C19, before becoming active against platelets. Some PPIs, notably omeprazole and esomeprazole, are metabolized to various extents by CYP 2C19 and this diminishes the activation of clopidogrel, but this is not believed to be a class effect of all PPIs. What is at the heart of current controversy is whether or not this effect on platelet activation translates into increased risks of myocardial infarction, arterial stent occlusion or other related thrombotic risks including death. There have been several large studies, all potentially flawed in various ways, which have yielded conflicting and contradictory conclusions. Even among those observational studies that claim that risk is increased, the ORs or hazard ratios are generally low (under 2.0) and not enough to confidently exclude residual confounding by comorbidity, cotherapy, population genetic heterogeneity and other factors. The studies are especially problematic in their lack of accounting for genetic polymorphisms in CYP 2C19. These affect the metabolism of clopidogrel, contributing to clopidogrel resistance in approximately 30% of the patients.[36•] There are also 21 polymorphisms of CYP 2C19, giving rise to the existence of two main PPI patient groups, extensive metabolizers and poor metabolizers, variously responding to different PPIs.[37,38•] The frequencies of occurrence of such polymorphisms are also different in different races and geographical areas, but, so far, not addressed in resolving problems with clopidogrel activation.

Cotherapy with clopidogrel and low-dose PPI therapy is widely used to minimize the risk of serious gastrointestinal bleeding, particularly in high-risk patients, so a balancing of risks in the individual patient is appropriate. Although the FDA has recently promulgated some cautionary statements,[39] these remain controversial, and many feel that the risk of cotherapy with low-dose omeprazole (20 mg per day) may be acceptable, especially in those at high risk of gastrointestinal bleeding, and particularly if the daily doses are given 12 h apart. The agency's acknowledgement that H2RAs like famotidine, ranitidine or nizatidine (but not cimetidine) can be used instead of PPIs in cotherapy until the issue is resolved also seems prudent. Several studies have shown reductions in hospitalization for gastrointestinal bleeding in patients taking both clopidogrel and PPI compared with those taking clopidogrel alone (COGENT trial results at[40] With pending emergence of newer antiplatelet agents that do not require activation by CYP 2C19 or interact with PPIs, the whole issue may prove short-lived.