In Brief Polypharmacy: Boon or Bane? / From Research to Practice

This article focuses on common prescription drug interactions in the treat- ment of diabetes, dyslipidemia, hypertension, and erectile dysfunction. Mechanisms of the drug interactions and recommendations for clinical prac- tice 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 diabetes. dispense, or administer the interact- decrease renal function.7 HDL cholesterol increased by 29%, ing drugs. If the outcome were possi- In a recently published retrospec- LDL cholesterol decreased by 8–9%, ble death, the risk would likely out- tive chart review of 100 patients who and triglycerides decreased by weigh the benefit. If the outcome received two or more prescriptions for 23–28%. Niacin only modestly were increased drowsiness, the bene- metformin during a 9-month period,8 increased glucose levels 8.7 and 6.3 fit would appear to outweigh the 22 patients had either renal insuffi- mg/dl in patients with and without risk. ciency or congestive heart failure. diabetes, respectively. A small but sta- 250 Diabetes Spectrum Volume 15, Number 4, 2002 tistically significant increase in A1C of placebo group and 9.2 mg/dl in the benefits in patients with diabetes and Polypharmacy: Boon or Bane? / From Research to Practice 0.3% occurred in niacin-treated chlorthalidone group. myocardial infarction. They have also patients with diabetes. There were no In summary, diuretics should be been used safely and with good out- significant differences in niacin dis- used more frequently in the manage- comes in the treatment of concomitant continuation, niacin dosage, or antidi- ment of hypertension because changes hypertension in patients with diabetes. abetic therapy in patients with dia- in glucose and cholesterol concentra- Patients should be counseled regarding betes assigned to niacin versus those tions are minor, especially with the hypoglycemia unawareness, especially assigned to placebo. The average dose lower doses of diuretics prescribed if they use insulin. Cardioselective - of niacin was ~2,500 mg, and the today.23 Also, cardiovascular morbidi- blockers are preferred over noncar- study duration was 60 weeks. The ty and mortality have been reduced in dioselective -blockers in patients authors concluded that niacin can be patients with hypertension when with diabetes. safely used in patients with diabetes diuretics are prescribed, including It is important to control blood and should be considered an alterna- patients with dyslipidemia or pressure in patients with diabetes tive to statins or fibrates. diabetes.23 regardless of the antihypertensive cho- This trial provides evidence that sen. In clinical trials, intensive blood niacin can be used with careful moni- -Blockers pressure control decreased cardiovas- toring in patients with diabetes, espe- -Blockers are another antihyperten- cular morbidity and mortality in cially those in whom glycemia is fair- sive drug class that many providers patients with diabetes. This held true ly well controlled. The American avoid in patients with diabetes regardless of whether patients received Diabetes Association (ADA) considers because of concerns that -blockers low-dose diuretics, -blockers, ACE statins as first-line therapy for lower- could mask symptoms of hypo- inhibitors, or CCBs as initial drug ing LDL cholesterol. However, its glycemia, such as palpitations, tremor, therapy.27 guidelines acknowledge that niacin is and hunger and could prolong recov- the best drug for raising HDL choles- ery from hypoglycemia. Inhibition of Atypical Antipsychotics terol and that glycemic control can be hypoglycemia-induced sweating is not Case reports, chart reviews, and results maintained with adjustments in the affected because it is not under sym- from clinical trials have shown a rela- antidiabetic regimen with niacin pathetic control. tionship between increased glucose lev- doses ≤3 g/day.19 The nonselective beta-blockers (e.g., els and treatment with the atypical propranolol [Inderal] and nadolol antipsychotics clozapine (Clozaril) and Diuretics [Corgard]) are more likely to blunt the olanzapine.28 A few cases of hyper- Diuretics are recommended as add-on counterregulatory effects of epineph- glycemia have also been reported with treatment for hypertension if they rine compared to cardioselective - risperidone (Risperdal) and quetiapine were not chosen as initial drug thera- blockers (e.g., atenolol [Tenormin] (Seroquel).28 The hyperglycemia is not py because they have additive effects and metoprolol [Lopressor]).1,2 This dose dependent, is reversible with drug with other antihypertensive classes.20 action inhibits glycogenolysis, especial- discontinuation, and reappears with Many clinicians are hesitant to use ly in patients who take insulin. In this rechallenge.28 Postulated mechanisms diuretics, particularly thiazide diuret- way, nonselective beta-blockers may for the hyperglycemia include antago- ics, in patients with diabetes because delay recovery from hypoglycemia; nism of several neurotransmitters and of the possibility of increased glucose however, the clinical importance of insulin resistance. concentrations. Thiazide diuretics this is unknown. (e.g., hydrochlorothiazide [HCTZ, The United Kingdom Prospective DRUG INTERACTIONS Hydrodiuril]) have a greater effect on Diabetes Study24 did not demonstrate IN DYSLIPIDEMIA blood glucose than loop diuretics an increased incidence of hypo- Compared to medications used to (e.g., furosemide [Lasix]), and the glycemia in the group treated with treat diabetes or hypertension, drugs effect is dose-related, with an beta-blockers. In addition, Shorr et used to treat dyslipidemia are associ- increased likelihood at HCTZ doses al.25 concluded that specific antihyper- ated with more clinically significant ≥25 mg or its equivalent.10–13 The tensives had little impact on the risk pharmacokinetic drug interactions. mechanism for diuretic-induced of hypoglycemia in older patients with Also, drug interactions may be com- hyperglycemia may be related to drug- diabetes. Angiotensin-converting mon in clinical practice because ator- induced hypokalemia leading to enzyme (ACE) inhibitors, -blockers vastatin (Lipitor), simvastatin, and decreased insulin secretion; however, (cardioselective and nonselective), thi- pravastatin (Pravachol) were the No. this has been debated. azide diuretics, and calcium-channel 1, No. 17, and No. 37 most pre- A retrospective study suggested that blockers (CCBs) were included in the scribed medications by sales volume patients with diabetes who received study. in 2000, respectively.29 Given the diuretics had increased cardiovascular -Blockers have shown relative risk recent results of the Heart Protection mortality.21 However, in the prospec- reductions in mortality of ~25% in Study,30 sales of these medications are tive, randomized SHEP trial, low-dose patients with myocardial infarction.26 likely to increase further. chlorthalidone (Hygroton) 12.5–25 Because diabetic patients with myocar- The management of dyslipidemia mg/day, reduced the cardiovascular dial infarction have a higher mortality in patients with diabetes needs to be event rate 34% compared with place- than nondiabetic patients with aggressive. Diabetes is considered a bo, and the absolute risk reduction myocardial infarction, the absolute coronary heart disease (CHD) risk was twice as much for patients with benefit of a given relative reduction equivalent because diabetes itself diabetes as for those without dia- may be greater in patients with dia- poses a high risk of new CHD within betes.22 At 3 years, serum glucose lev- betes.26 10 years.31 Also, patients with dia- els were increased by 5.6 mg/dl in the In summary, -blockers have clear betes who experience a myocardial 251 Diabetes Spectrum Volume 15, Number 4, 2002 infarction have an unusually high An appreciation of the metabolism als, the incidence of myalgia was death rate.26,31 Ideally, goals should be of these drugs is important in predict- 2–7% compared to 0.1–0.2% for LDL cholesterol <100 mg/dl, HDL ing drug interactions. (See Case Study myopathy in patients treated with cholesterol >40 mg/dl, and triglyc- 1.) Lovastatin, simvastatin, and ator- statin monotherapy.33 erides (TGs) <150 mg/dl.19,31 Patients vastatin are primarily metabolized by By definition, myopathy must be with diabetes may be at increased risk CYP3A4.5,6,32 Fluvastatin is mainly muscle aches or weakness with eleva- for drug interactions because they metabolized by CYP2C9, and pravas- tions in creatine kinase (CK) levels often have mixed dyslipidemias and tatin does not undergo substantial more than 10 times the upper limit of thus may require one medication to metabolism by CYP450 enzymes.5,32 It normal. The risk of myopathy is decrease LDL cholesterol and another makes sense that drugs that affect increased by 1) high-dose statin use; medication to decrease TGs and CYP3A4 will likely interact with 2) concurrent use of fibrates; 3) con- increase HDL cholesterol. lovastatin, simvastatin, and atorvas- current use of CYP3A4 inhibitors; tatin but not with fluvastatin or and 4) acute viral infections, major Statins pravastatin. Inhibitors and inducers of trauma, surgery, hypothyroidism, and Atorvastatin, lovastatin, simvastatin, CYP3A4 are listed in Table 1. other conditions.33 pravastatin, and fluvastatin (Lescol) Induction of CYP3A4 can lead to sub- Rhabdomyolysis is severe skeletal are the currently available statins. optimal cholesterol control, whereas muscle breakdown. The leakage of Cerivastatin was removed from the inhibition of CYP3A4 can predispose myoglobulin (skeletal muscle con- market because of its association with susceptible patients to drug toxicity tents) into the blood or urine can unusually high rates of rhabdomyolyis from statins. cause acute renal failure and death. and death. As a class, the statins are Adverse effects on skeletal muscle In clinical trials with patients treat- the most potent drugs for reducing are the most serious side effects of the ed with lovastatin, the risk of rhab- LDL cholesterol. However, they only statins. They can range from myalgia domyolyis was 0.15% with lovastatin modestly increase HDL cholesterol to myositis to myopathy and rarely to monotherapy, 5% for lovastatin-gem- and lower TGs. rhabdomyolysis.32 In large clinical tri- fibrozil (Lopid) combination therapy, Table 1. Clinically Significant Drug Interactions in the Treatment of Dyslipidemia1,2,5,6,32,33*

Medication Interacting Medication Mechanism Effects Recommendations** Atorvastatin, Macrolide antibiotics Inhibition of Myopathy or Alternative antibiotic or temporarily lovastatin, or (erythromycin or statin rhabdomyolysis stop statin or change to pravastatin or simvastatin clarithromycin) metabolism fluvastatin Azole antifungals Inhibition of Myopathy or Alternative antifungal (topical or (fluconazole, ketoconazole, statin rhabdomyolysis terbinafine) or temporarily stop statin or or itraconazole) metabolism change to pravastatin or fluvastatin Cyclosporine Unknown Myopathy or Change to pravastatin or fluvastatin Rhabdomyolysis Verapamil or diltiazem Inhibition of Myopathy or Alternative antihypertensive or change to statin rhabdomyolysis pravastatin or fluvastatin metabolism Gemfibrozil Unknown Myopathy or Counsel patient and monitor CPK Rhabdomyolysis and myalgias Protease inhibitors Inhibition of Myopathy or Change to pravastatin or fluvastatin (indinavir, nelfinavir, statin rhabdomyolysis ritonavir, saquinavir, metabolism amprenavir†) Nefazodone Inhibition of Myopathy or Alternative antidepressant or counsel statin rhabdomyolysis patient and monitor CPK and myalgias, or metabolism change to pravastatin or fluvastatin

Niacin Unknown Myopathy or Counsel patient and monitor CPK and rhabdomyolysis myalgias Lovastatin, Warfarin Inhibition of Increased INR Counsel patient and monitor INR simvastatin, warfarin with potential for fluvastatin, metabolism bleeding gemfibrozil, or fenofibrate

*This list is not all-inclusive **Based on literature and the author’s professional opinion †Indinavir (Crixivan); nelfinavir (Viracept); ritonavir (Norvir); saquinavir (Fortovase, Invirase); amprenavir (Agenerase) CPK, Creatine phosphokinase INR, International Normalized Ratio: a standardized test to monitor warfarin therapy 252 Diabetes Spectrum Volume 15, Number 4, 2002 2% for lovastatin-niacin combination should be the statins of choice because cholesterol 18–55%, decrease TGs Polypharmacy: Boon or Bane? / From Research to Practice therapy, and 28% for cyclosporine cyclosporine and protease inhibitors 7–30%, and increase HDL cholesterol (Neoral, Sandimmune)-gemfibrozil- most significantly increase statin plas- 5–15%.31 Niacin and fibrates have lovastatin combination therapy.33 ma concentrations.5 much less effect on LDL cholesterol. Myalgia or myopathy usually pre- However, TGs are reduced by cedes rhabdomyloysis.6 Bile Acid Sequestrants 15–35% with niacin and 20–50% Given the propensity for drug Bile acid sequestrants (e.g., colestipol with fibrates, and HDL cholesterol is interactions, why wouldn’t providers [Colestid] and cholestyramine increased 15–35% with niacin and always prescribe either pravastatin or [Questran]) are generally not used in 10–20% with fibrates.31 fluvastatin when a statin is indicated? the treatment of hypercholesterolemia The same precautions should be Fluvastatin is the least potent of the in patients with diabetes because they followed for combination therapy statins and may not produce the LDL can raise TGs that may already be with fibrates and statins or niacin and cholesterol reductions needed to reach above target levels. Because bile acid statins as if a CYP3A4 inhibitor were aggressive goals. Simvastatin and sequestrants reduce the absorption of prescribed. In a retrospective analysis, atorvastatin are both more potent many oral medications, patients ~10% of 70 patients who received than pravastatin. Lovastatin has should be advised to take other drugs lovastatin plus gemfibrozil experi- recently become available generically at least 2 hours before or 6 hours after enced mild elevations in CK without and can lead to considerable cost sav- the bile acid sequestrant.1,2 Clinically muscle weakness or pain.34 ings in the treatment of dyslipidemia. significant interactions have been In addition, drug interactions with reported with digoxin (Lanoxin), DRUG INTERACTIONS statins are well documented and can furosemide, hydrocortisone, HCTZ, IN HYPERTENSION be monitored. Patient education can and warfarin;1,2 however, it is proba- As with dyslipidemia, the treatment reduce complications from the drug bly a good idea to separate administra- of hypertension in patients with dia- interaction. Patients should be advised tion times for all medications and bile betes needs to be aggressive. Recom- to discontinue their statin if they acid sequestrants. mendations from both the ADA19 and develop generalized muscle aches or the Joint National Committee on weakness, especially if accompanied Combination Antilipemic Agents Prevention, Detection, Evaluation, by flu-like symptoms or tea-colored Niacin, gemfibrozil, and fenofibrate and Treatment of High Blood urine. A CK should be ordered if mus- (Tricor) can interact with statins by an Pressure20 suggest a goal blood pres- cle breakdown is suspected. unknown mechanism.1,2 (See Table 1.) sure of <130/80–85 mmHg for When multiple CYP3A4 inhibitors This is important because either patients with diabetes. At least are prescribed, it is best to choose fibrates (gemfibrozil, fenofibrate) or 40–55% of patients will require more pravastatin or fluvastatin because the niacin may be prescribed with a statin than one medication to reach this risk of rhabdomyloysis is increased to lower TGs and LDL cholesterol goal.27 In clinical practice, we take with other statins. When either and increase HDL cholesterol. Mixed advantage of pharmacodynamic drug cyclosporine or protease inhibitors are dyslipidemia is often seen in patients interactions in the treatment of hyper- prescribed, pravastatin or fluvastatin with diabetes. Statins decrease LDL tension to prescribe medications that will have additive effects to lower blood pressure. Case Study 1: Statins CCBs, -blockers, ACE inhibitors, and angiotensin receptor blockers P.R. is a 56-year-old woman with type 2 diabetes, hypertension, and dyslipidemia. (ARBs) are metabolized by CYP450, Her medications include metformin, 1 g twice daily; glyburide (Micronase), 10 mg twice daily; enteric-coated aspirin, 325 mg daily; lisinopril (Prinivil, Zestril) 20 mg and drug concentrations may be daily; HCTZ, 12.5 mg daily; and lovastatin, 40 mg daily. She developed an upper res- decreased when combined with enzyme piratory infection (URI) for which she was prescribed erythromycin, 333 mg three inducers (rifampin, carbamazepine, phe- times daily for 10 days. nobarbital, phenytoin) or increased when combined with enzyme inhibitors Questions: (azole antifungals, cimetidine, ery- 1. Identify any significant drug interactions with the patient’s lovastatin. 35 2. What option is best to protect this patient from a clinically significant drug inter- thromycin). Diuretics are eliminated action? by the kidney and, therefore, are not a. Counsel her regarding the drug interaction. Instruct her to stop taking lovastatin, subject to CYP450 interactions. The and call her health care provider if she develops any unexplained muscle aches or same is true for the hydrophilic - weakness, especially if accompanied by fever, fatigue, or tea-colored urine. blockers nadolol and atenolol. b. Have her hold off on the lovastatin until the course of erythromycin is finished. CCBs are classified as dihydropyri- c. Consider changing her prescription to another antibiotic such as amoxicillin dine (nifedipine [Procardia XL and (Amoxil, Trimox) or azithromycin (Zithromax). Adalat CC], nicardipine [Cardene], d. Consider changing the lovastatin prescription to either pravastatin or fluvastatin. isradipine [DynaCirc], nisoldipine Answers: [Sular], felodipine [Plendil], and 1. Erythromycin can increase lovastatin drug concentrations through inhibition of the amlodipine [Norvasc]) and nondihy- CYP3A4 isoenzyme. Myopathy, myositis, and rhabdomyolysis are possible clinical ropyridine (verapamil [Calan, Isoptin, outcomes. Covera-HS, and Verelan], diltiazem 2. Any of the four options are reasonable. However, answer c probably makes the [Cardizem, Dilacor, and Tiazac]). most sense since there are many available antibiotics for URI treatment that will not interact with statins. Instructing to hold off on the lovastatin until finishing the This is an important distinction not antibiotic could give P.R. the idea that the lovastatin is not really important. only because of different effects on heart rate (verapamil and diltiazem 253 Diabetes Spectrum Volume 15, Number 4, 2002 decrease heart rate; others increase or Indomethacin (Indocin) has been DRUG INTERACTIONS have neutral effects on heart rate) but the most reported NSAID to blunt IN ERECTILE DYSFUNCTION also because of different metabolic antihypertensive effects. However, Approximately 50% of men with fates. Although all CCBs are sub- given the mechanism of the interac- diabetes have erectile dysfunction strates for CYP3A4, only diltiazem tion, most, if not all, NSAIDs are like- (ED).40 Since sildenafil (Viagra) and verapamil also inhibit CYP3A4.35 ly to interact. There is some contro- became available in 1998, it has Thus, drug interactions shared by ver- versy with this issue related to sulin- become the drug of choice for most apamil and diltiazem may not trans- dac (Clinoril).37,38 men with ED. late to the dihydropyridine CCBs. With the introduction of cyclooxy- When sildenafil is combined with Rifampin, phenobarbital, carba- genase type 2 inhibitors for the treat- nitrates (e.g., isosorbide dinitrate, mazepine, and phenytoin can induce ment of pain and inflammation, one isosorbide mononitrate, and nitroglyc- the metabolism of all CCBs because wonders if the same interaction is pos- erin) severe hypotension and possible all CCBs are substrates for CYP3A4.35 sible. To date, there has been one death may result.40,41 Therefore, con- This could lead to loss of blood pres- published case report of a 59-year-old comitant use of nitrates and sildenafil sure control. Azole antifungals (keto- man who was successfully treated is absolutely contraindicated.40–42 The conazole, fluconazole, itraconazole), with lisinopril, 10 mg/day.39 After American College of Cardiology in macrolide antibiotics (erythromycin, staring rofecoxib (Vioxx), 25 mg/day, collaboration with the American clarithromycin), nefazodone blood pressure control was dimin- Heart Association published guide- (Serzone), cimetidine, and protease ished. Eventually, the patient main- lines for sildenafil use in 1999.42 inhibitors can increase serum concen- tained good blood pressure control Those guidelines emphasize that all trations of the CCBs through inhibi- with lisinopril, 20 mg/day, and rofe- men must be warned of the danger of tion of CYP3A4.35 The net effect is coxib, 25 mg/day. Although the mech- taking sildenafil 24 hours before or the potential for increased CCB side anism for the interaction has not been after taking a nitrate preparation. (See effects and symptomatic hypotension. established, it is theorized that rofe- Case Study 2.) -blockers exhibit significant phar- coxib-induced inhibition of renal In addition to the pharmacodynam- macodynamic drug interactions with prostaglandins is probable.39 ic interaction with nitrates, sildenafil some drugs.36 Noncardioselective Lithium is considered a narrow- also has the potential for clinically sig- beta-blockers and cardioselective therapeutic-index drug. Thiazide nificant drug interactions with beta-blockers in larger doses can diuretics, ACE inhibitors, and ARBs inhibitors of CYP3A4 because silde- antagonize the effects of -agonists can increase lithium concentrations by nafil is primarily metabolized by and lead to bronchoconstriction.36 - interfering with lithium’s renal excre- CYP3A4.41 Macrolide antibiotics,2,41 blockers in combination with amio- tion.1,2 In general, thiazides should be azole antifungals,41 protease inhib- darone (Cordarone), diltiazem, digox- avoided in patients prescribed lithium. itors,1,2,41 and cimetidine41 can increase in, and verapamil can have increased If a diuretic is needed, a loop diuretic sildenafil concentrations and increase effects on heart rate and possibly lead such as furosemide is recommended. side effects from it. to significant bradycardia.36 Patients who are on ACE inhibitors or Probably one of the most common ARBs and lithium should have lithium SUMMARY and often unrecognized drug interac- levels checked and should be coun- Drug interactions can be complex, tions in clinical practice is that seled to seek medical attention for especially if multiple interactions exist between nonsteroidal anti-inflammato- signs of lithium toxicity. These include in an individual patient. The literature ry drugs (NSAIDs) and antihyperten- nausea, vomiting, diarrhea, coarse on drug interactions is always chang- sives. The NSAIDs ibuprofen (Motrin) tremor, slurred speech, and disorien- ing as new information and new drugs and naproxen (Naprosyn) are avail- tation. become available. able by prescription as well as over- the-counter. All other NSAIDs are Case Study 2: Sildenafil available by prescription only. Inhibition of renal prostaglandins and promotion of sodium and water reten- G.M. is a 55-year-old man with type 2 diabetes, dyslipidemia, coronary artery dis- ease, hypertension, ED, and gastroesophageal reflux disease. His medications include tion by NSAIDs antagonize the actions atenolol, 50 mg daily; atorvastatin, 20 mg daily; enteric-coated aspirin, 325 mg of thiazide and loop diuretics. This daily; glyburide, 5 mg twice daily; lisinopril, 10 mg daily; nitroglycerin, 0.4 mg sub- interaction has also been documented lingual as needed; and omeprazole, 20 mg daily. He carries sublingual nitroglycerin for ACE inhibitors, ARBs, -blockers, with him but has not had to use it in the past 3 years since he had angioplasty with and peripheral -blockers.37,38 The cardiac stent placement. He is interested in obtaining a prescription for sildenafil. same interaction does not appear to occur with CCBs.37,38 Question: Pooled data indicate that the aver- Assume a history, physical exam, and lab tests were unremarkable regarding a cause age NSAID-induced increase in mean for G.M.’s ED. How would you advise him? arterial pressure is 10 mmHg. The Answer: effect can be transient or chronic. Sildenafil may be an option for this patient since he is not taking nitrates on a regular Significant drug interactions between basis. However, he should be counseled that if he does experience chest pain or dis- NSAIDS and antihypertensive agents comfort, he cannot take a sublingual nitroglycerin if he has taken sildenafil within the are estimated to occur in about 1% of past 24 hours. He should seek immediate medical attention for his chest pain/discom- patients per year.37 Elderly patients, fort. He must also realize that sexual intercourse may increase the risk of cardiac African Americans, and patients with ischemia and chest pain. low-renin states are at greatest risk.37,38 254 Diabetes Spectrum Volume 15, Number 4, 2002 11 When patients are prescribed drugs White JR Jr, Campbell RK: Dangerous and blood pressure and diabetes mellitus: are all anti- Polypharmacy: Boon or Bane? / From Research to Practice known to interact, they should be common drug interactions in patients with dia- hypertensive drugs created equal? Arch Intern betes mellitus. Endocrinol Metab Clin North Am Med 160:2447–2452, 2000 monitored appropriately and coun- 29:789–802, 2000 seled about signs and symptoms that 28Lindenmayer JP, Nathan AM, Smith RC: 12 should trigger a call to the health care White JR Jr, Campbell RK: Drug/drug and Hyperglycemia associated with the use of atypi- drug/disease interactions and diabetes. Diabetes cal antipsychotics. J Clin Psychiatry 62 (Suppl. provider. Educ 21:283–289, 1995 23):30–38, 2001 Patients should also be advised to 13 29 have all of their prescriptions filled at Pandit MK, Burke J, Gustafson AB, Minocha Nissen D: Mosby’s Drug Consult. St. Louis, A, Peiris AN: Drug-induced disorders of glucose Mo., Elsevier Science, 2002 one pharmacy so their drug regimens intolerance. Ann Intern Med 118:529–539, 1993 can be routinely screened for drug 30Heart Protection Study Group: MRC/BHF 14 interactions. At the very least, they Nilsson JE, Gip LJ: Systemic effects of local Heart Protection Study of cholesterol lowering should keep an updated list of their treatment with high doses of potent corticos- with simvastatin in 20,536 high-risk individuals: teroids in psoriatics. Acta Dermato- a randomized placebo controlled trial. Lancet medications with them to share with Venereologica 59:245–248, 1979 360:7–22, 2002 all health care providers. 15 Garg R: Lipid-lowering therapy and macrovas- 31Expert Panel on Detection, Evaluation, and cular disease in diabetes mellitus. Diabetes Treatment of High Blood Cholesterol in Adults: Acknowledgments 2:111–115, 1992 Executive summary of the third report of the The author would like to acknowledge 16Oki JC: Dyslipidemias in patients with diabetes National Cholesterol Education Program Dennis C. Ritchey, the assistant med- mellitus: classification and risks and benefits of (NCEP) Expert Panel on Detection, Evaluation, ical librarian at Kaiser Permanente therapy. Pharmacotherapy 15:317–337, 1995 and Treatment of High Blood Cholesterol in

Drug Information Services in Downey, 17 Adults (Adult Treatment Panel III). JAMA Haffner SM: Management of dyslipidemia in 285:2486–2496, 2001 Calif., for his assistance with the litera- adults with diabetes. Diabetes Care 21:160–178, ture searches and Christine B. 1998 32Beaird SL: HMG-CoA reductase inhibitors: assessing differences in drug interactions and Schaefer, RN, BC-ADM, CDE, dia- 18Elam MB, Hunninghake DB, Davis KB, Garg betes care manager at Kaiser Perm- safety profiles. J Am Pharm Assoc 40:637–644, R, Johnson C, Egan D, Kostis JB, Sheps DS, 2000 anente in Denver, Colo., for her edito- Brinton EA: Effect of niacin on lipid and lipopro- rial assistance. tein levels and glycemic control in patients with 33Hamilton-Craig I: Statin-associated myopathy. diabetes and peripheral arterial disease. The Med J Aust 175:486–489, 2001 ADMIT study: a randomized trial. JAMA 34 References 284:1263–1280, 2000 Wirebaugh SR, Shapiro ML, McIntyre TH, Whitney EJ: A retrospective review of the use of 19 1Tatro DS: Drug Interaction Facts. St. Louis, American Diabetes Association: Standards of lipid-lowering agents in combination, specifical- Mo., Facts and Comparisons, 2000 medical care for patients with diabetes mellitus ly, gemfibrozil and lovastatin. Pharmacotherapy (Position Statement). Diabetes Care 25 (Suppl. 12:445–450, 1992 2Hansten PD, Horn JR: Drug Interactions 1):33–49, 2002 Analysis and Management: A Clinical 35 20 Flockhart DA, Tanus-Santos JE: Implications Perspective and Analysis of Current Joint National Committee on Prevention, of cytochrome P450 interactions when prescrib- Detection, Evaluation, and Treatment of High Developments. St. Louis, Mo., Facts and ing medication for hypertension. Arch Intern Comparisons, 2002 Blood Pressure: The sixth report of the Joint National Committee on Prevention, Detection, Med 162:405–412, 2002 3Raschetti R, Morgutti M, Menniti-Ippolito F, Evaluation, and Treatment of High Blood 36Anderson JR, Nawarskas JJ: Cardiovascular Belisari A, Rossignoli A, Linghini P, La Guidara Pressure. Arch Intern Med 157:2413–2446, 1997 C: Suspected adverse drug events requiring emer- drug-drug interactions. Cardiol Clin gency department visits or hospital admissions. 21Warram JH, Laffel LM, Valsania P, Christlieb 19:215–234, 2001 Eur J Clin Pharmacol 54:959–963, 1999 AR, Krolewski AS: Excess mortality associated 37Houston MC: Nonsteroidal anti-inflammatory with diuretic therapy in diabetes mellitus. Arch 4Bates DW, Spell N, Cullen DJ, Burdick E, Laird drugs and antihypertensives. 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JAMA 276:1886–1892, Pharmacother 34:1486, 2000 6 1996 White CM: An evaluation of CYP3A4 drug 40Lue TF: Erectile dysfunction. N Engl J Med interactions with HMG-CoA reductase 23 Moser M: Why are physicians not prescribing 342:1802–1812, 2000 inhibitors. Formulary 34:343–352, 2000 diuretics more frequently in the management of hypertension? JAMA 279:1813–1816, 1998 41 7Glucophage package insert, Bristol-Myers Viagra package insert, Pfizer Labs, New York, N.Y., 2000 Squibb Company, Princeton, N.J., Revised May 24United Kingdom Prospective Diabetes Study 2001 Group: Efficacy of atenolol and captopril in 42Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz 8Horlen C, Malone R, Dennis B, Carey T: reducing the risk of macrovascular and microvas- P, Kaul S, Russell RO Jr, Zusman RM: Use of Frequency of inappropriate metformin prescrip- cular complications in type 2 diabetes: UKPDS sildenafil (Viagra) in patients with cardiovascular tions (Research Letter). JAMA 287:2504–2505, 39. BMJ 317:713–720, 1998 disease. Circulation 99:168–177, 1999 2002 25Shorr RI, Ray WA, Daugherty JR, Griffin MR: 9McEvoy CE, Niewoehner DE: Corticosteroids Antihypertensives and the risk of serious hypo- Beverly A. Kroner, PharmD, BCPS, is in chronic obstructive pulmonary disease: clinical glycemia in older persons using insulin or sul- a primary care clinical pharmacy ser- benefits and risks. Clin Chest Med 21:739–752, fonylureas. JAMA 278:40–43, 1997 2000 vices supervisor and specialist at the 26 10 Arauz-Pacheco C, Parrott MA, Raskin P: The Kaiser Permanente Colorado Region White JR Jr, Hartman J, Campbell RK: Drug treatment of hypertension in adult patients with and an adjunct assistant professor at interactions in diabetic patients: the risk of losing diabetes. Diabetes Care 25:134–147, 2002 glycemic control. Postgrad Med 93:131–139, the University of Colorado School of 1993 27Grossman E, Messerli FH, Goldbourt U: High Pharmacy in Denver. 255 Diabetes Spectrum Volume 15, Number 4, 2002