Anne M. Baciewicz

Update on rifampin, rifabutin, and rifapentine drug interactions.

Abstract Background: Rifampin is a potent inducer of both cytochrome P-450 oxidative enzymes and the P-glycoprotein transport system. Among numerous well documented, clinically significant interactions, examples include warfarin, oral contraceptives, itraconazole, digoxin, verapamil, simvastatin, and human immunodeficiency virus-related protease inhibitors. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. Rifapentine is also an inducer of drug metabolism. Methods: A literature search of English language journals from 2008 to March 2012 was completed using several databases, including PubMed, EMBASE, and SCOPUS. Search terms included rifampin, rifabutin, rifapentine AND drug interactions. Findings: Examples of clinically relevant interactions with rifampin demonstrated by recent reports include posaconazole, voriconazole, oxycodone, risperidone, mirodenafil, and ebastine. Conclusions: To avoid a reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin, rifabutin, or rifapentine are added to or discontinued from medication regimens, clinicians need to be aware of these interactions. Recent studies have indicated that other transporter systems play a role in these drug interactions. As reports of rifampin drug interactions continue to grow, this review is a reminder to clinicians to be vigilant.

Isoniazid Drug and Food Interactions

Isoniazid inhibits the metabolism of several drugs, resulting in clinically significant interactions in some patients. Clinical trials and case reports have documented that isoniazid can cause increased phenytoin and carbamazepine serum concentrations and toxicity. In relatively high doses, isoniazid can also cause increased effect of theophylline and warfarin. Isoniazid inhibits metabolism of selected benzodiazepines and vitamin D. Inhibition of monoamine oxidase and histaminase by isoniazid can cause significant drug-food interactions. Food greatly decreases isoniazid bioavailability. Although probably best recognized as an inhibitor of drug metabolism, isoniazid has a biphasic effect of inhibition-induction on one cytochrome P450 isozyme, CYP2E1, which partially explains the interaction with acetaminophen and increased risk of hepatotoxicity. Continued investigations will likely result in discovery of new isoniazid interactions.

Effect of cimetidine and ranitidine on cardiovascular drugs.

A compilation of drug interactions between H2 antagonists and cardiovascular drugs is found in Table I. Cimetidines potency, lipophilicity, and affinity for binding to the P-450 cytochrome system can probably be attributed to the drug interactions that have been identified with the H2 antagonists. The mechanism for most cimetidine drug interactions is inhibition of hepatic metabolism. There is conflicting evidence regarding significance of altered liver blood flow for both cimetidine and ranitidine and their influence on other agents. Cimetidine may increase propranolols blood concentrations and potentiate beta blocking effects through inhibition of hepatic microsomal enzymes and possibly through reduction of hepatic blood flow. Ranitidine has no effect on propranolol. Cimetidine, when administered concurrently with metoprolol, could possibly cause an increase in plasma metoprolol concentrations or bioavailability through inhibition of hepatic P-450 metabolizing enzymes. No effect of cimetidine on metoprolol pharmacodynamics was evident. Ranitidine has no effect on metoprolol pharmacokinetics or pharmacodynamics. Neither H2 antagonist altered the kinetics or physiologic effects of atenolol. Atenolol is the drug of choice in patients receiving H2 antagonists, since no interaction has been observed. Metoprolol could probably be used safely in most patients, as no change in pharmacodynamics has been evident. Concurrent administration of cimetidine and nifedipine may result in alterations in heart rate and blood pressure. The mechanism is inhibition of oxidative liver metabolism. Ranitidine has no effect on nifedipine. Studies are needed to investigate the interaction between the H2 antagonists and diltiazem or verapamil. Cimetidine, given concomitantly with lidocaine, may increase lidocaine concentrations and clinical symptoms of lidocaine toxicity. The mechanism involved is probably a reduction in oxidative drug metabolism or liver blood flow. Ranitidine has no significant effects on lidocaine pharmacokinetics. Cimetidine may increase quinidine levels and symptoms of quinidine toxicity. Additionally, enhanced arrhythmic effects may be observed. The interaction probably caused by an inhibition of hepatic drug metabolism of quinidine by cimetidine would be most significant in patients with liver disease and in the elderly. Ranitidine may enhance quinidines arrhythmic effect. Cimetidine can possibly increase procainamide and NAPA serum concentrations, especially in the elderly and in patients with renal dysfunction, predisposing them to adverse side effects. The interaction is mediated by a reduction of tubular secretion of procainamide and NAPA.

Cholestyramine Resin in the Treatment of Digitoxin Toxicity

Cholestyramine, an ion-exchange resin, has been used in the treatment of digitoxin toxicity. A case report describing the use of a therapeutic regimen of this resin in a toxic patient is presented. Although cholestyramine aided in binding digitoxin in the intestine, its effect was not so pronounced as in past studies. Further investigation of this agent as adjunctive therapy in digitoxin toxicity is warranted.

Hypoglycemia Induced by the Interaction of Chlorpropamide and Co-Trimoxazole:

Sulfonylureas hypoglycemic action may be potentiated by sulfonamides. This case report describes a 69-year-old female with a hypoglycemic episode suggestive of an interaction between chlorpropamide and sulfamethoxazole (co-trimoxazole). The patient had no renal or liver dysfunction. This interaction is rare but one should be aware of it, especially with combination products.

Conversion of Intravenous Ranitidine to Oral Therapy

A two-phase drug program concentrating on inappropriate use of intravenous ranitidine is described at a 612-bed university teaching hospital. Phase 1 of the study was a retrospective audit of 50 randomly selected adult patients receiving iv ranitidine. The chart was reviewed for indications for therapy, rationale for iv ranitidine, median length of iv therapy, and appropriateness of iv use. Phase 2 consisted of concurrent monitoring of iv ranitidine soley to assess the appropriateness of the iv dosage form at our hospital. Staff pharmacists reviewed the patients medication profile from the central pharmacy to determine if the patient had standing orders for any oral or nasogastric medications while concomitantly receiving iv ranitidine. An educational memo was placed in the patients chart if the patient was concurrently receiving oral or nasogastric medications and iv ranitidine. In phase 1, iv ranitidine was inappropriate either partially or totally in 51 percent of the cases. The median length of inappropriate iv therapy was five days. During the second phase, the pharmacy staff reviewed 4301 profiles of patients receiving iv ranitidine over eight months. Educational memos were placed in 451 patient charts (11 percent) where conversion from iv to oral therapy was feasible; a favorable follow-up occurred in 275 cases (61 percent). This would result in an estimated annual cost savings of

Aminoglycoside-Associated Nephrotoxicity in the Elderly

4685. Based on our ranitidine use review, extrapolating the median length of inappropriate iv therapy to five days would result in a yearly cost savings of

Rifampin and Rifabutin Drug Interactions

23425. This project demonstrated that staff pharmacists can impact on physician education and cost savings by routinely screening patients medication profiles from the central pharmacy. A TWO-PHASE DRUG PROGRAM concentrating on inappropriate use of intravenous ranitidine was undertaken at a 612-bed university teaching hospital to demonstrate how pharmacists can make an impact on drug therapy both financially and clinically. Intravenous ranitidine was selected based on cost, frequent use, and potential for inappropriate use. Parenteral ranitidine offers no therapeutic advantage over oral therapy if the gastrointestinal tract is intact and functioning.1 At our hospital, the cost of daily iv ranitidine (50 mg iv q8h) is

Acute pancreatitis associated with celecoxib.

14.50, approximately eight times that of daily oral tablets (150 mg po q12h) which cost

Clozapine-associated neuroleptic malignant syndrome

1.75.