Common Drug Pathways and Interactions

In Brief to Practice Research From / Boon or Bane? Polypharmacy: This article focuses on common prescription drug interactions in the treatment of diabetes, dyslipidemia, hypertension, and erectile dysfunction. Mechanisms of the drug interactions and recommendations for clinical practice are highlighted. Because of concerns about potentially negative effects some prescription medications may have on glycemic control in people with diabetes, some of these drug-disease interactions are also addressed. Common Drug Pathways and Interactions The Food and Drug Administration events in hospitalized patients can be approves about 25 new drug entities attributed to preventable drug interac- each year, and new interactions are tions.4 These account for half of the Beverly A. Kroner, PharmD, BCPS also reported for drugs already in use. total costs of adverse outcomes from Only recently have serious drug inter- drug therapy. actions been responsible for the with- Quite simply, a drug-drug interac- drawal of drugs from the market- tion occurs when the effects of one place. Terfenadine (Seldane), astemi- drug are changed by the presence of zole (Hismanal), mibefradil (Posicor), another drug. Drug-drug interactions and cerivastatin (Baycol) are exam- can be categorized as pharmacokinetic ples. Cisaparide (Propulsid), used to or pharmacodynamic. Pharmacokinetic treat diabetic gastroparesis, is only drug interactions occur when one drug available through a special process enhances or interferes with the absorp- involving strict criteria because of tion, distribution, metabolism, or clinically significant drug interactions excretion of another drug resulting in a that resulted in patient deaths. change in drug concentration in the Knowing about every drug interac- body. The ability of phenobarbital to tion is impractical, and not all drug decrease the effect of warfarin interactions have adverse clinical conse- (Coumadin) by increasing its metabo- quences. Computer screening programs lism through hepatic enzyme induction are available in pharmacies, but they do is an example of a pharmacokinetic not always contain the most recent drug interaction.1,2 Pharmacodynamic information. In addition, many screen- drug interactions occur when one drug ing programs are too inclusive and enhances or decreases the effect of sometimes numb users to clinically another drug at its site of action with- important drug interactions. Drug out altering the drug’s concentration in Interaction Facts1 and Drug Interactions the body. The interaction between pro- Analysis and Management: A Clinical pranolol (Inderal) and albuterol Perspective and Analysis of Current (Proventil, Ventolin) is a pharmacody- Developments2 are two good resources namic drug interaction in which pro- commonly used by pharmacists for pranolol (a ␤-blocker) diminishes the information on drug interactions. effect of albuterol (a ␤-agonist) Significant drug interactions and through antagonism at the ␤2 receptor patient harm that results from them site in the lungs.1,2 are common concerns in clinical prac- Because most drugs are detoxified tice. One study showed that although by the liver, the most important of the drug interactions account for only pharmacokinetic drug interactions 3.8% of emergency room visits, the involve drug metabolism. This is patients affected by them usually have influenced by genetics, which explains to be admitted to the hospital.3 why some patients suffer adverse con- Another study demonstrated that sequences from some drug combina- about one-third of all adverse drug tions and others do not. 249 Diabetes Spectrum Volume 15, Number 4, 2002 The cytochrome P450 (CYP450) The availability of alternative med- Two charts contained documentation enzyme system is responsible for the ications and the ease of monitoring the that the prescriber had considered the oxidative-reductive metabolism of drug interaction are secondary consid- contraindications to metformin. The medications. These enzymes are pri- erations. In today’s managed care researchers did not mention whether marily concentrated in the liver and environment, drug formularies may any of the patients developed lactic small intestines. More than 30 human limit alternatives or make them cost- acidosis. CYP450 enzymes have been identi- prohibitive. This is not necessarily bad fied; however, only four isoenzymes because drugs can be costly, and drug Corticosteroids (CYP3A4, CYP2C9, CYP1A2, and interactions are not generally regarded Corticosteroids are commonly used as CYP2D6) are responsible for the as contraindications unless the out- anti-inflammatory and immunosup- majority of drug metabolism.5 come is extremely serious. pressive agents. They are administered CYP3A4 metabolizes the greatest by oral, parenteral, topical, intra-artic- number of medications and endoge- DRUG INTERACTIONS ular, and inhaled routes. It is widely nous substances in the body, account- IN DIABETES accepted that corticosteroids can ing for most CYP450 enzymes in the Pharmacokinetic drug interactions increase plasma glucose levels in liver and small intestines (60 and among medications used to treat dia- patients with diabetes. Hyperglycemia 70%, respectively).6 betes are not very common because can occur with any route of adminis- Many substrates, inhibitors, and antidiabetic agents are generally not tration.9–14 The degree of hyper- inducers of CYP450 isoenzymes have substrates, inducers, or inhibitors of the glycemia depends on the dose, route, been identified. A substrate is the med- major CYP450 enzymes. Repaglinide duration, and patient-specific charac- ication being metabolized by the (Prandin) is an exception because it is teristics. enzyme system. Warfarin, statins (e.g. metabolized by CYP3A4 and is there- Corticosteroids affect glucose con- lovastatin [Mevacor] and simvastatin fore a substrate; however, clinically sig- trol by decreasing glucose utilization [Zocor]), and theophylline are exam- nificant drug interactions with repagli- and increasing gluconeogenesis.13 The ples of substrates. An inhibitor is a nide are not common.1,2 The more addition of corticosteroids, especially medication that decreases enzyme common clinically relevant drug inter- high-dose systemic steroids, necessi- activity and leads to increased concen- actions in the treatment of diabetes are tates an adjustment of the dosage for trations of the substrate. Some drug-disease interactions. diabetes medication or, in some cases, macrolide antibiotics (e.g., ery- initiation of insulin. All patients on thromycin and clarithromycin [Bi- Drug-Disease Interactions corticosteroids should routinely moni- axin]), cimetidine (Tagamet), and azole tor their blood glucose levels and have antifungals (e.g., fluconazole [Diflu- Metformin (Glucophage) instructions on what to do to address can], itraconazole [Sporanox], and Since its approval in 1995, metformin increasing glucose levels. ketoconazole [Nizoral]) are known has been widely prescribed to treat inhibitors of CYP450. An inducer is a type 2 diabetes. Although it has many Niacin medication that increases the number beneficial effects, it is not the drug of Niacin, an antilipemic agent, is avail- of enzymes and leads to decreased con- choice for all patients because of the able as a prescription in a sustained- centrations of the substrate. Notorious risk of lactic acidosis, which can occur release form and in combination with enzyme inducers are rifampin (Rifadin, with inappropriate use. Metformin is lovastatin. Published reports discour- Rimactane), carbamazepine (Tegretol), absolutely contraindicated in patients age the use of niacin in patients with phenytoin (Dilantin), and phenobarbi- with renal dysfunction (defined as a diabetes because of resultant deterio- tal. Thus, enzyme inhibitors can pre- serum creatinine >1.5 mg/dl for males ration in glycemic control.15–17 dispose to drug toxicity, whereas and >1.4 mg/dl for females) and in However, these are uncontrolled stud- enzyme inducers have the potential to those with congestive heart failure ies or case reports. decrease the effectiveness of a medica- requiring pharmacological treatment.7 The ADMIT study18 prospectively tion. Of the two processes, an interac- It should not be prescribed for randomized patients with and without tion that leads to inhibition has a more patients >80 years of age unless mea- diabetes who had peripheral arterial rapid onset. surement of creatinine clearance disease to treatment with immediate- The optimal management of a shows that renal function is not release niacin or placebo. The patients drug interaction involves recognition reduced.7 Patients with conditions with diabetes had glycemia well con- of the interaction; decision regarding predisposing them to lactic acidosis trolled at baseline. The mean glucose whether to prescribe, dispense, or (e.g., dehydration, hepatic disease, level was 168 mg/dl, the mean hemo- administer the interacting combina- sepsis) should not use metformin.7 globin A1c (A1C) was 7.8%, and only tion; follow-up monitoring; and Additionally, metformin should be 59% of patients received drug therapy appropriate patient counseling. Once temporarily discontinued in patients for their diabetes. the interaction is recognized, one undergoing procedures involving There were statistically significant must consider the possible outcome administration of intravenous iodinat- improvements in the lipid profiles of before deciding whether to prescribe, ed contrast materials, which can patients with and without

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