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Home , Acetohexamide, Drug interaction, Mibefradil, Nicardipine, Zafirlukast

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Pharmacy Update

Drug of Commonly Used in Diabetes

Curtis Triplitt, PharmD, CDE

When patients are diagnosed with dia- interactions is unknown because well as non–diabetes-related - betes, a large number of medications many are not reported, do not result drug interactions.7 become appropriate therapy. These in significant harm to patients, or do include medications for dyslipidemia, not require admission to a hospital. DRUG-DRUG INTERACTIONS , antiplatelet therapy, and When a hospitalization does occur, it Drug interactions are often catego- glycemic control. So many medications is usually not documented as a drug rized as pharmacodynamic or phar- can be overwhelming, and it is impera- , but rather as an adverse macokinetic in nature. A pharmaco- tive that patients are thoroughly edu- drug reaction because the drug inter- dynamic is related to cated about their drug regimen. action may only be one component of the drug’s effect on the body. An Patients have many concerns when the reason for admission.3,4 Although example is the combination of multiple medications are started, drug interactions for a select few with medications that cause sedation. including prescribing errors, the cost of are well known, we often ignore A pharmacokinetic drug interaction is medications, and possible adverse the substantial evidence that potential related to the body’s effect on the effects. Significantly, 58% of patients interactions exist in many of the med- drug. An example is an increase in the worry that they will be given medica- ications prescribed today. systemic concentration of a renally tions that have drug interactions that Minimizing the risk for drug inter- eliminated drug because of renal will adversely affect their health.1 These actions should be a goal in drug thera- insufficiency. A pharmacokinetic drug worries are not unfounded given that py because interactions can result in interaction can be caused by an alter- several highly publicized drugs have significant morbidity and mortality. ation in absorption, distribution, been withdrawn from the U.S. market Health care providers should take metabolism, or elimination of a drug.8 in the past several years because of responsibility for the safe prescribing of adverse effects from drug interactions. medications, but we often discuss Pharmacodynamic Interactions , , and potential adverse drug reactions—not Pharmacodynamic drug interactions have all been withdrawn from the mar- drug interactions—with patients. We can be either beneficial or detrimental ket specifically because of drug-drug may overlook this responsibility to patients. A beneficial example is the interactions. When terfenadine or cis- because there are rarely quick, easily additive blood pressure–lowering apride were given with a strong accessible, and comprehensive effect when an ACE inhibitor is added inhibitor of their metabolism, torsades resources that cover drug interactions. to a calcium (CCB). de pointes, a life-threatening drug- Even when available, comprehensive Likewise, synergistic blood pressure induced ventricular arrhythmia associ- resources often list all drug interactions lowering may be seen if a is ated with QT prolongation, could and do not emphasize those that are added to an ACE inhibitor. The phar- occur.2 Cisapride, for gastroparesis or most important. macodynamic drug interaction can gastrointestinal reflux disease, and In addition, many diabetes educa- also be detrimental. When alcohol mibefradil, for hypertension, were pre- tors are confused by drug interaction and a that causes sedation scribed for many patients with diabetes. terminology and rely heavily on phar- are combined, additive unwanted An adverse drug interaction is macists and prescribers to properly sedation may occur. Antagonistic defined as an interaction between one screen for drug interactions. Causes effects may also be encountered, as or more coadministered medications and terminology common to drug with the combination of an acetyl- that results in the alteration of the interactions, common interactions cholinesterase inhibitor for myasthe- effectiveness or toxicity of any of the with medications used in people with nia gravis or Alzheimer’s disease with coadministered medications. Drug diabetes, and tools that busy diabetes for painful diabetic interactions can be caused by pre- educators can use will be provided in peripheral neuropathy. The acetyl- scription and over-the-counter med- this article. Not all drug interactions cholinesterase inhibitor increases ications, herbal products or vitamins, will be covered, and drug-herbal5,6 acetylcholine levels, whereas foods, diseases, and genetics (family and drug-nutrient6,7 interaction infor- amitriptyline has antagonistic anti- history). The true incidence of drug mation can be found elsewhere, as cholinergic effects.8 202 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 203

Pharmacy Update

Pharmacokinetic Interactions

Absorption interactions. Drug absorp- tion is the movement of the drug from its site of administration into the bloodstream (Figure 1). Absorption interactions are changes in a drug’s effects caused by food, drink, or med- ications taken concurrently. Classically, we think of the oral administration of a medication and absorption from the gastrointestinal system, but it applies to all routes of administration, including injection, inhalation, topical, buccal, sublingual, and others. Drug-food interactions can affect the total amount of drug absorbed (), but most often they only slow absorption. For example, Figure 1. Graphic depiction of a theoretical drug absorption interaction. the hypoglycemic effect of “free” drug available to cause an The nomenclature used to classify dif- may be delayed slightly if taken with a effect. ferent subsets of the CYP system has meal versus 30–60 minutes before a In the past, many protein-displac- no functional implications but clini- meal, although hemoglobin A1c (A1C) ing interactions were documented in cally allows us to classify metabolism values are unaffected.9,10 Alteration of vitro, with in vivo consequences interactions. gastrointestinal motility, as is the case assumed. The majority of protein-dis- Drugs can inhibit (decrease) metab- with (Table 1), or pH may placing interactions have since been olism, induce (increase) metabolism, also affect absorption. In addition, documented to be test-tube phenome- or have no effect on each CYP450 components of food may interact. For na and are not clinically important.12 isoenzyme subset. Thus, inhibition of example, vitamin K intake from green Most of the suspected distribution metabolism will likely increase the leafy vegetables interacts with war- interactions have now been reclassi- affected drug’s systemic concentra- farin. Similarly, several medications fied as metabolism interactions. tions, whereas induction of metabo- may complex or chelate with coad- Distribution interactions can be signif- lism often reduces systemic concentra- ministered medications, significantly icant for drugs that have extremely tions. Not all isoenzymes are reducing their absorption.6 For exam- rapid distribution, narrow safety mar- inducible, and only CYP2C9 and ple, absorption is gins, and possibly nonlinear kinetics.12 CYP3A4 induction is clinically rele- reduced when coadministered with No significant distribution interac- vant to people with diabetes. A drug ferrous sulfate or and should tions are pertinent for oral medica- may also be a for (metabo- be moved either 1 hour earlier or at tions commonly used for diabetes.12 lized by) one or more of these least 2 hours after administration of subsets, and clinically, if an inhibitor these drugs.7,11 It is best not to admin- Metabolism interactions. Drug metab- or inducer affects that isoenzyme, it ister other medications with antacids olism is the modification or degrada- could affect the efficacy of the drug. because they can reduce the absorp- tion of drugs. Metabolism can make Drugs can have a complex profile, tion of many medications. drugs more or less toxic, active or being a substrate for or an inhibitor or inactive, or more easily eliminated inducer of multiple subsets. For exam- Distribution interactions. Distribution from the body.13 The primary organ ple, is a potent inhibitor of is the movement of the absorbed drug involved in metabolism is the , CYP2D6, but it is primarily metabo- through the bloodstream and its although metabolism has been docu- lized by CYP3A4. More than 50% of transport throughout extracellular or mented in the kidneys, , gas- all drugs are metabolized at least in intracellular compartments to the site trointestinal system, blood, and other part by CYP3A4 or CYP2D6, and sev- of action (Figure 2). Many medica- tissues.6 The most extensively studied eral important diabetes drugs are tions extensively bind to plasma pro- family of isoenzymes found in the metabolized by these pathways.15 teins such as albumin in the blood- liver and gastrointestinal tract is the Phase 2 metabolism (glucuronidation, stream. When a drug is bound to (CYP) system. The acylation, sulfation, and so forth) these plasma proteins, it is not actively name “cytochrome P450” comes from includes attachment of a water-soluble distributed to the site of action, and the experimental techniques used to molecule to aid elimination and detox- only the “free” drug is available to identify the isoenzymes and is not ification of a drug. Phase 2 metabo- cause an effect. One drug can displace clinically relevant.14 CYP2D6, for lism need not but often does occur another from the binding sites on the example, includes “2,” the genetic after metabolism by the CYP450 sys- plasma proteins if its binding is family; “D,” the genetic subfamily; tem. Research in this area is expand- stronger. This increases the amount of and “6,” the specific gene member. ing, and glucuronidation is the basis of 203 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 204

Pharmacy Update

Table 1. Common Diabetes, Hypertension, and Lipid Drug Interactions

MEDICATION DRUG-DRUG DRUG-NUTRIENT DRUG-DISEASE INTERACTIONS INTERACTIONS INTERACTIONS Glucose Lowering Inhibitors/inducers of CYP2C9 Alcohol: first-generation Metabolized: liver/ (see Table 2) sulfonylureas may cause Caution if dysfunction flushing reaction, if severe ADR: loss of efficacy or nausea/vomiting

Meglitanides : none None Liver dysfunction: caution with Replaglinide: ↓ both agents -gemfibrozil: effect ADR: loss of efficacy or -other inducers/inhibitors of 2C8 hypoglycemia may compete with Vitamin B12 depletion; Lactic acidosis: renal insufficiency metformin for renal elimination, periodic monitoring if at risk and hypoxic states (congestive which may increase levels of heart failure, surgery, shock, or metformin liver disease, including alcohol intake) ADR: hospitalization/death TZDs Strong inducers/inhibitors of None Fluid retention CYP2C8 (see Table 2) ADR: peripheral edema, heart Clinical effect of interaction: failure, pulmonary edema unknown ALT ≥ 3 ϫ upper normal limit: do not start therapy; stop if taking ␣-Glucosidase May decrease absorption None None inhibitors May increase effect of Action: space administration Exenatide May slow absorption of medications: None Renal insufficiency: potential for caution if rapid adsorption needed increased nausea/vomiting (e.g. acetaminophen, pain meds) Gastroparesis: may worsen symptoms Hypertension ACE inhibitors, : see CYP2D6 Caution with Renal insufficiency, pregnancy ARBs Enalapril: see CYP3A4 supplements with moexipril, (See Table 2) captopril, and valsartan. , NSAIDs: may reduce Take 1 hour before or antihypertensive effects of ACE 2 hours after meals inhibitor : levels may increase CCBs CYP3A4 inducers/inhibitors juice may increase , ditiazem: caution—heart (see Table 2) antihypertensive effects failure and cardiac conduction problems/heart block Dihydropyridine: peripheral edema NSAIDS and may reduce and loop diuretics Caution in hyperuricemia or gout; effectiveness of loop diuretics may cause . may exacerbate attack may affect lithium levels Potassium sparing diuretics May exacerbate lupus may cause hyperkalemia May worsen or cause severe photosensitivity reactions Lipid-Lowering HMG-CoA , , atorvastatin: Lovastatin: food increases Watch for myopathy and reductase inhibitors 3A4 (see Table 2) absorption rhabdomyolysis (statins) Fluvastatin: CYP2C9 (see Table 2) Lovastatin extended-release: Pravachol: sulfated, but still cases food decreases absorption of rhabdomyolysis reported Lovastatin: food increases absorption Fibric Gemfibrozil: inhibitor of 3A4, 2C8, None Do not use if active cholecystitis (See Table 2) Increase ezetimibe levels Fenofibrate: 3A4, less risk of interaction (See Table 2) ADR, 204 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 205

Pharmacy Update

Figure 2. Graphic depiction of a theoretical drug distribution interaction. one important drug-drug interaction Elimination through the liver is pri- increase the chance of having drug- involving gemfibrozil and several marily through . There are not disease interactions. Metformin and hydroxymethylglutaryl (HMG) CoA many true drug-drug interactions impaired renal function is a well-doc- reductase inhibitors (statins). through bile elimination, but drug-dis- umented drug-disease interaction. High-risk groups for drug interac- ease interactions, as described below, Serum creatinine ≥ 1.4 mg/dl in tions include neonates, infants, the can be important when bile elimina- women or ≥ 1.5 mg/dl in men war- elderly, and those with significant tion is affected, as with severe biliary rants discontinuation of metformin organ disease (i.e., renal or hepatic or liver disease. Renal drug-drug because systemic concentrations can disease) warranting increased screen- interactions are dependent on the pH be elevated, increasing the risk of lac- ing vigilance. Neonates, infants, and of the urine and the pH of the drug or tic acidosis.18 Drug-disease interac- the elderly will often metabolize drugs on competition for the same pathway tions for specific medications used in slower than healthy adults, and of elimination. If the pH of the urine people with diabetes will be covered lifestyle choices such as smoking and the drug are the same, renal reab- below. (induces metabolism) and alcohol use sorption of the drug will be increased. (may induce or inhibit metabolism) When two drugs compete for elimina- Diabetes Drug Interactions can alter metabolism. Metabolism tion through a single route, one drug patterns can also be altered by geneti- may competitively inhibit the elimina- drugs. Several drug-drug cally determined variations. For tion of the other.8 Metformin and interactions occur with sulfonylureas. example, ~ 5–10% of Caucasians, but cimetidine, both cationic (positively First-generation sulfonylureas, espe- only 0–1% of Asians, have little charged) drugs, can compete for elimi- cially chlorpropramide, may cause a CYP2D6 enzyme activity, making nation through kidneys by renal tubu- facial flushing reaction when alcohol them “CYP2D6 poor metabolizers,” lar secretion, resulting in higher met- is ingested. This may be similar to the consequences of this are depen- formin concentrations in the plasma.17 that caused by disulfiram, which dent on the drug and alternative path- blocks aldehyde dehydrogenase, ways available for metabolism.16 DRUG-DISEASE INTERACTIONS resulting in increased levels of Many comorbid diseases can affect acetaldehyde. Acetaldehyde can result Elimination interactions. Drug elimi- metabolism in people with diabetes. in flushing and possibly nausea or nation is the removal of a drug from Patients with diabetes have higher vomiting at higher levels.7,19 A switch the body. The major organs involved rates of cardiovascular, renal, gas- to a second-generation sulfonylurea in elimination are the kidneys and trointestinal, neurological, and thy- would be advised (Table 1). liver, although other bodily processes, roid diseases and ophthalmological Sulfonylureas are commonly listed including saliva, sweat, or exhaled air, complications compared with indi- as having protein-binding drug inter- may be pathways for elimination. viduals without diabetes. All may actions, and the first-generation sul- 205 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 206

Pharmacy Update

fonylureas (, chlor- cy of , and a higher dose The main drug-disease interaction of propamide, , and tolbu- of repaglinide may be necessary23 concern is impaired liver function, and tamide), which bond ionically to plas- (Table 2). the risk of hypoglycemia in this popu- ma proteins, are thought to have a higher risk of protein-binding drug Table 2. Common Inducers, Inhibitors, and Substrates of Select 20 interactions. If they do occur, they CYP450 should occur shortly after the second medication is added to the sulfony- 2C8 2C9 2D6 3A4 lurea by displacing the sulfonylurea Substrates (Metabolized By) and increasing the active drug avail- Repaglinide Sulfonylureas Captopril Repaglinide able. This would result in a reduction Nateglinide Metoprolol CCBs of plasma glucose and possibly hypo- Enalapril glycemia, if the plasma glucose was Cavedilol Irbesartan Losartan near normal. As stated previously, Warfarin Irbesartan most of these have now been restated

as interactions resulting from the Inhibitors ( ↓ Drug Levels of Substrates) CYP450 isoenzyme system.12 Gemfibrozil Fluconazole Sulfonylureas are a substrate of Fluconazole Trimethoprim Cimetidine CYP2C9. Thus, inducers and Amiodarone (NOT Azithromycin) inhibitors of CYP2C9 can affect the Delavirdine Zafirlukast Paroxetine Verapamil metabolism of sulfonylureas. Delavirdine Common medications that may inter- act with sulfonylureas are listed in Ropinirole Ketoconazole Table 2. Sulfonylureas have two sig- Fluoxetine nificant drug-disease interactions. Most are metabolized in the liver to HIV protease inhibitors active or inactive metabolites. When Delavirdine significant impairment in liver func- Inducers (↓ Drug Levels of Substrates) tion is present, sulfonylurea metabo- Rifampin Rifampin None lism may be altered. Active or inactive Phenobarbital Rifampin metabolites of sulfonylureas are elimi- Rifabutin nated by the kidneys, and renal insuf- Phenobarbitol ficiency may reduce elimination Phenytoin (Table 3). St. John’s Wort

Short-acting secretagogues. Nateglin- ide, which is metabolized by Table 3. Metabolism and Elimination of Sulfonylureas CYP2C9 (70%) and CYP3A4 (30%), could be affected by strong ELIMINATION inhibitors/inducers of CYP2C9, but First generation significant drug-drug interactions Acetohexamide Metabolized in liver; metabolite Renal have not been reported. Repaglinide potency equal parent compound is metabolized by the CYP3A4 and CYP2C8 systems and then Metabolized in liver Also renally extensively glucuronidated. A serious eliminated unchanged drug-drug interaction may occur Tolazamide Metabolized in liver; metabolite Renal with gemfibrozil, which is used for less active than parent compound triglyceride lowering. This is likely caused by gemfibrozil’s inhibition of Metabolized in liver to inactive Renal CYP2C8 and glucuronidation. In metabolites vivo, gemfibrozil increases the total Second generation exposure of repaglinide eightfold.21 Several reports of severe, prolonged Glipizide Metabolized in liver to inactive Renal hypoglycemia have been documented metabolites with the combination.22 Strong inhibitors of CYP3A4, such as azole Glyburide Metabolized in liver to inactive 50% renal, agents and erythromycin metabolites: elimination 50% feces derivatives, may also enhance the Metabolized in liver; one 60% urine, hypoglycemic effect of repaglinide. metabolite one-third activity 40% feces Drugs that are inducers of of glimepiride—unclear CYP2C8/3A4 may reduce the effica- contribution to effects 206 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 207

Pharmacy Update

lation may be increased. No adjust- Metformin use in renal insufficien- but a full discussion is beyond the ment in dosing is needed in renal cy, defined as a serum creatinine ≥ 1.4 scope of this review.36,37 impairment until the patient has end- mg/dl in women and ≥ 1.5 mg/dl in stage renal disease. When low-dose sul- men, is contraindicated because it is ␣-Glucosidase inhibitors. Because nei- fonylureas cause hypoglycemia in renally eliminated. Elderly patients, ther nor is exten- renally impaired type 2 diabetic who often have reduced muscle mass, sively metabolized, neither has signifi- patients, repaglinide or nateglinide may should have their creatinine cant metabolism interactions. Several be a good therapeutic alternative. rate estimated before use. If the creati- case reports have documented a Neither has significant drug-food inter- nine clearance rate is < 70–80 ml/min, reduction in absorption of digoxin actions, but both should be taken metformin should not be given. and an increase in absorption of war- preprandially to better match pancreat- Because of the risk of acute renal fail- farin.38,39 It is recommended that any ic release with a meal (Table 1). ure during intravenous dye proce- drug with a very small dose and a nar- dures, metformin should be withheld row safety margin be administered Metformin. Although not because of a starting the day of the procedure and apart from acarbose or miglitol. drug interaction, metformin should be resumed in 2–3 days, when normal Drug-disease interactions are related taken with a meal to limit gastroin- renal function has been documented. to ␣-glucosidase inhibitor–induced testinal side effects. Metformin may Clinical presentation of lactic aci- gastrointestinal side effects (gas, diar- cause malabsorption of vitamin B12, dosis is often nonspecific flu-like rhea, and abdominal gas pain), which which may result in B12 deficiency symptoms and may include altered could harm patients with certain gas- and subsequent anemia. The mecha- consciousness, heavy, deep trointestinal diseases (e.g., short nism by which metformin causes mal- (Kussmaul) breathing, and abdomi- bowel syndrome, Crohn’s disease, or absorption of B12 is not clearly nal pain and thirst. Thus, the diagno- ulcerative colitis). defined, although oral or injected B12 sis is usually made by laboratory (cyanocobalamin) or calcium supple- confirmation.18,28 Hypertension- and Lipid-Reducing mentation may be effective for correc- Medications tion24,25 (Table 1). . Pioglitazone and Metformin does not undergo metab- rosiglitazone can both be taken with- Antihypertensive drugs. Many differ- olism and is eliminated renally by out regard to meals. Rosiglitazone is a ent classes of antihypertensive medica- tubular secretion and glomerular filtra- substrate for the CYP2C8 and to a tions may be used for blood pressure tion. Metformin is a cationic (positively lesser extent CYP2C9 pathways, and control in diabetes, but the four most charged) molecule and may compete pioglitazone is a substrate for common include ACE inhibitors, with other cationic drugs for renal CYP2C8 (39%) and CYP3A4 (17%), angiotensin-II type 1 blockers secretion through organic cation trans- as well as several other CYP450 path- (ARBs), thiazide diuretics, and CCBs. porters in the kidneys.17 , ways.29,30 Rosiglitazone and pioglita- CCBs can be further subdivided into digoxin, quinidine, trimethoprim, and zone metabolism in vivo can be affect- dihydropyridine CCBs, so called for vancomycin are all cationic drugs that ed by inhibitors or inducers of their chemical structure, and the have the potential to interact with met- CYP2C8, but no significant drug-drug nondihydropyridine CCBs, diltiazem formin, but only cimetidine, which is interactions have been reported to and verapamil, which are pharmaco- available over the counter for heart- date30,31 (Table 2). Neither drug has dynamically linked because of their burn, has been implicated in one case significant elimination drug-drug effect on the heart. Drug interactions of metformin-associated lactic acidosis interactions. may be present for some but not all (MALA)26,27 (Table 1). However, both thiazolidinediones medications within an antihyperten- Metformin has many drug-disease (TZDs) have significant drug-disease sive class. interactions that can increase the risk interactions. Both can cause fluid of MALA. Metformin may increase retention that may result in peripheral ACE inhibitors and ARBs lactic production from the edema or, rarely, pulmonary edema Drug-food interactions are important splanchnic tissues slightly, but MALA and/or heart failure. Mechanistically, for two ACE inhibitors, moexipril and occurs in the setting of comorbid dis- this may relate to increased renal captopril, which should be adminis- eases that increase systemic levels of reabsorption of sodium, a reduction tered 1 hour before or at least 2 hours lactic acid or reduce elimination of of systemic vascular resistance, or after a meal.7 A 40–50% decrease in metformin. Any disease that may other mechanisms.32,33 Unlike troglita- systemic levels may be seen when val- increase lactic acid production or zone, no data link pioglitazone or sartan, an ARB, is taken with food.40 decrease lactic acid metabolism may rosiglitazone to drug-induced hepato- Because both classes may increase predispose to lactic acidosis. Tissue toxicity.34,35 Nevertheless, it is recom- serum potassium levels, caution hypoperfusion from congestive heart mended that drug therapy not be should be taken when potassium sup- failure, hypoxic states, shock, or sep- started if the aminotransferase plements or a high-potassium diet are ticemia can increase lactic acid pro- (ALT) is > 2.5 times the upper limit of consumed with either class (Table 1). duction, and alcohol or severe liver normal and stopped if the ALT is > 3 ACE inhibitors and ARBs have sev- disease can reduce removal of lactic times the upper limit of normal (Table eral interactions of importance. acid in the liver, increasing the risk of 1). Prudent clinical judgment is need- Aspirin and other nonsteroidal anti- lactic acidosis. ed for TZD drug-disease interactions, inflammatory drugs (NSAIDs) may

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Pharmacy Update

blunt the antihypertensive effect of an sive effects of CCBs, and intake Lipid-lowering medications ACE inhibitor, presumably through should be limited. In addition, dilti- inhibition of ACE inhibitor–induced azem and verapamil are weak Fibric acid derivatives prostaglandin synthesis. Clinically, the inhibitors of CYP3A4, and drug inter- Both gemfibrozil and fenofibrate interaction does not appear to affect actions with HMG-CoA inhibitors, should be taken with food to reduce the ACE inhibitor’s ability to prevent which will be discussed later, have gastrointesinal upset. seques- adverse cardiovascular or renal out- been documented. trants may interfere with absorption comes.41 ACE inhibitors may increase The risk of cardiac conduction of fibric acid derivatives and should hypersensitivity reactions, such as flu- abnormalities with diltiazem or vera- be separated from each other by at like symptoms and skin rash, with pamil is the main drug-disease interac- least 2 hours.7 Gemfibrozil can signifi- allopurinol, although the exact mech- tion to monitor. Diltiazem or vera- cantly block CYP2C8/9/19, glu- anism is not known.7 ACE inhibitors pamil given in combination with a ␤- curonidation, and possibly human and ARBs may increase lithium levels, blocker can further lower the pulse organic anion transporting polypep- and concurrent use warrants close rate, increasing the risk for heart block. tide-2 (OATP2).47,48 Several medica- monitoring of lithium levels.7 Dihydropyridine CCBs do not cause tions commonly used in the treatment Captopril, a CYP2D6 substrate, heart conduction drug-disease interac- of patients with diabetes are metabo- and enalapril, a CYP3A4 substrate, tions, but they may cause peripheral lized by these pathways, including sul- may be affected by strong inhibitors edema, which may worsen preexisting fonylureas, repaglinide, sertraline, flu- or inducers of these pathways7 (Table edema present from heart failure, oxetine, and carvedilol. These medica- 2). Concentration changes resulting venous insufficiency, or other causes. tions may need dose reductions or from these interactions should be Nicardipine is an inhibitor of close monitoring when combined with monitored by following the ambulato- CYP3D6, CYP2C8, CYP2C9, gemfibrozil7 (Table 2). ry blood pressure. Losartan is the only CYP2C19, and CYP3A4, and alcohol The interaction of gemfibrozil with ARB with significant interactions with ingestion may enhance its antihyper- statins may be caused by a glu- CYP3A4, although losartan and irbe- tensive effects.45 Nicardipine is not curonidated metabolite of gemfibrozil sartan are substrates of CYP2C9. recommended because other medica- competing for metabolism after the Strong inhibitors or inducers of these tions within the class have fewer drug OATP2 allows it into hepatocytes. pathways would likely increase or interactions (Tables 1 and 2). Details can be further explored in a decrease the antihypertensive effec- recent review article.48 Further infor- tiveness of losartan (Table 2). Diuretics mation on this important interaction Despite potential interactions, very Thiazide diuretics are the most com- can be found in the statins section. few clinically significant drug interac- monly used diuretics for blood pres- When gemfibrozil is added to eze- tions have been documented with sure control in people with diabetes. timibe (Zetia), it likely blocks glu- ARBs. Caution should be taken when No significant drug-food interactions curonidation of ezetimibe, increasing either class is started in renal insuffi- exist for diuretics, but bile acid seques- systemic levels, but the clinical rele- ciency because both can worsen renal trants, used rarely to reduce choles- vance of this interaction has yet to be function or even cause acute renal fail- terol, may cause a significant reduction documented.49 Fenofibrate, which ure in patients with renal artery steno- in absorption, and thus dosing should appears to have less potential to inter- sis. Neither class is recommended in be separated by several hours.7 Loop act with the aforementioned drugs, pregnancy because severe birth defects and thiazide diuretics may deplete also has a questionable ability to to neonatal kidneys can occur. potassium and ; adequate lower cardiovascular events in people intake of these minerals is essential. with .50 blockers. Most Hypokalemia may greatly increase the CCBs are metabolized by CYP3A4 toxicity of some concurrent medica- Statins and will be affected by strong tions (e.g., digoxin and antiarryth- Drug interactions that inhibit metabo- inhibitors and inducers of CYP3A4 mics).7 Potassium-sparing diuretics (tri- lism of statins increase systemic expo- (Table 2). in sufficient amterene, , and spironolac- sure, which may predispose to a quantities can block intestinal tone) may cause hyperkalemia. greater risk of myopathy. The exact CYP3A4, which can lead to an Monitoring of serum potassium is rec- pathophysiological mechanism lead- enhancement of the effects of CCBs. ommended for all diuretics on initia- ing to myopathy is unknown, but This could affect the blood pressure tion and periodically thereafter. direct effects of statins on the myocyte response for all CCBs and further Thiazide diuretics decrease lithium have been hypothesized.51 lower the pulse rate when diltiazem , and monitoring of lithium Although most myopathy cases and verapamil are used. Studies that levels in conjunction with a reduction occur as a result of drug-drug interac- have explored the effect of grapefruit in dose is recommended. NSAIDs and tions, statins in monotherapy have juice on diltiazem and verapamil have phenytoin may decrease the effective- also caused myopathy.51 Patients not reported changes in blood pres- ness of loop diuretics.7 Diuretics may often present with muscle aches with sure or heart rate, despite increases in also exacerbate several diseases, includ- or without creatinine phosphokinase systemic drug concentrations.42–44 ing hyperuricemia or gout and systemic elevations, which are indicative of Alcohol ingestion appears to have lupus erythematosus, and cause photo- muscle destruction. If the myopathy is variable effects on the antihyperten- sensitivity reactions46 (Table 1). allowed to progress, it may lead to 208 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 209

Pharmacy Update

rhabdomyolysis, with proximal low, but the majority of cases occur Caution should be taken when weakness in the arms or legs. in patients with potential drug-drug strong inhibitors of CYP3A4 are given Myoglobinuria, characterized by interactions.52 Proper education to with lovastatin, simvastatin, or ator- brown or black urine, may also devel- stop the medication and report symp- vastatin. Strong inhibitors of CYP2C9 op and is associated with acute renal toms to their health care provider is may increase fluvastatin and rosuvas- failure. The risk of rhabdomyolysis is essential to minimize risk to patients. tatin levels (Table 2). Common classes

Name: ______Provider/Diabetes Educator: ______Date: ______Email address ______Phone number: ______Diagnoses: ___ Diabetes ___Hypertension ___Hyperlipidemia ___ Other: ______Allergies: ______Diet/Vitamin Supplements: ______Herbal Supplements: ______Over-the Counter: ______MEDICINE DRUG/ DRUG/ DRUG/ NAME/DOSE INSTRUCTIONS DRUG FOOD DISEASE Interactions Interactions Interactions

Inducers 3A4/2C9 3A4 Inhibitors 2C9 Inhibitors Binders Metformin Rifampin Fluconazole Itraconazole Bactrim Antacids Cimetidine Carbamazepine Erythromycin Clarithromycin Fluconazole Bile acid sequestrants Rifabutin Fluoxetine Fluvoxamine Amiodarone Phenytoin Verapamil* Diltiazem* Cimetidine Action: do not administer drugs at same time as above Phenobarbital Cimetidine Cyclosporine Bactrim ointment St. John’s wort HIV protease inhibitors Grapefruit juice in large amounts

Drugs that may Drugs that may be affected Drugs that may Drugs that may Cimetidine will be affected be affected be affected renally compete for elimination and may increase metformin levels. All drugs listed here Statins† CCBs Sulfonylureas All Fluvastatin Warfarin * Not pravastatin, fluvastatin (CYP2C9), or † Weak inhibitors: caution with lovastatin or simvastatin CCB, calcium channel blockers

Figure 3: Medication documentation/drug-drug interaction tool for diabetes educators. 209 Diabetes Spectrum Volume 19, Number 4, 2006 0202.qxd 11/8/06 4:38 PM Page 210

Pharmacy Update

of drugs that are strong inhibitors of betes educators’ best resources for interactions and consequences of potential flu- CYP3A4 include azole , evaluating the potential for drug conazole drug interactions. Pharmacoepidemiol Drug Saf macrolide (except interactions. It is important to involve 14:755–767, 2005 azithromycin), protease inhibitors a patient’s health care team, and a 4Malone DC, Hutchins DS, Haupert H, Hansten used for HIV, amiodarone, diltiazem, can be especially helpful P, Duncan B, Van Bergen RC, Solomon SL, 52 Lipton RB: Assessment of potential drug-drug and verapamil (Table 2). when it is unclear whether drugs may interactions with a prescription claims database. Gemfibrozil and the immunosuppres- interact. receive special- Am J Health Syst Pharm 62:1983–1991, 2005 sant cyclosporine appear to increase ized training in drug interactions, 5Hu Z, Yang X, Ho PCL, Chan SY Chan, Hen the risk of myopathy with all statins. often have software or reference PWS, Chan E, Wei D, Koh HL, Zhow S: Herb- To minimize the risk of myopathy books that specifically address drug drug interactions: a literature review. Drugs and rhabdomyolysis, the maximum interactions, and have additional 65:1239–1282, 2005 recommended dose of immediate- background that can aid with an edu- 6Sorenson JM: Herb-drug, food-drug, nutrient- release lovastatin is 20 mg/day with cated recommendation if no data are drug, and drug-drug interactions: mechanisms cyclosporine, (> 1 g/day), and available. involved and their medical implications. J Altern fibric acid derivatives and 40 mg with Abbreviated forms to help busy Complement Med 8:293–308, 2002 verapamil or amiodarone. If the lovas- diabetes educators keep a current 7Lexi-comp’s Clinical Reference Library Online: tatin sustained-release dosage form is medication list and ascertain whether Lexi-interact [article online]. Available from used, the maximum recommended patients with diabetes may be at risk http://online.lexi.com/crlsql/servlet/crlonline dose is one-half of the above-stated for possible drug interactions can be 8Rowland M, Tozer T: Clinical lovastatin doses.53 The maximum rec- found in Figure 3. : Concepts and Applications. ommended dose of simvastatin is 10 3rd ed. Baltimore, Md., Williams & Wilkins, mg with cyclosporine, niacin (> 1 CONCLUSIONS 1995 g/day), and fibric acid derivatives and Detecting potential drug interactions 9Wahlin-Boll E, Melander A, Sartor G, Schersten 20 mg with verapamil or need not be burdensome, but it must B: Influence of food intake on the absorption and amiodarone.53,54 not be ignored. Drug interactions effect of glipizide in diabetics and in healthy con- trols. Eur J Clin Pharmacol 18:279–283, 1980 Other potential inducer/inhibitor resulting from absorption, distribu- drug-drug interactions of signifi- tion, metabolism, or elimination, as 10Berelowitz M, Fischette C, Cefalu W, Schade cance can be found in Table 2. Food well as pharmacodynamic factors, are DS, Sutfin T, Kourides IA: Comparative efficacy of a once-daily controlled-release formulation of may increase the absorption of present for many common medica- glipizide and immediate-release glipizide in immediate-release lovastatin but tions given to people with diabetes. patients with NIDDM. Diabetes Care decrease the absorption of extended- The team approach is best, and it 17:1460–1464, 1994 release lovastatin. should not be assumed that pre- 11Campbell NRC, Hasinoff BB, Stalts H, Rao B, scribers and pharmacists are the only Wong NCW: Ferrous sulfate reduces thyroxine DRUG INTERACTIONS AND team members responsible for detect- efficacy in patients with hypothyroidism. Ann DIABETES EDUCATORS ing and resolving drug interactions. Intern Med 117:1010–1013, 1992 It is nearly impossible to memorize Diabetes educators can and should be 12Benet L, Hoener B: Changes in plasma protein the plethora of possible interactions active team members in screening, binding have little clinical relevance. Clin currently affecting drug therapy in educating, and following up on sus- Pharmacol Ther 71:115–121, 2002 diabetes. Because of this complexity, it pected drug interactions. This will 13Sikka R, Magauran B, Ulrich A, Shannon M: is essential that drug-drug interaction likely lead to a lower risk of adverse Bench to bedside: pharmacogenomics, adverse tools be used. This responsibility is effects and an improved quality of life drug interactions, and the cytochrome P450 sys- Acad Emerg Med usually shouldered by prescribers and for people with diabetes. tem. 12:1227–1235, 2005 pharmacists, but only diabetes educa- 14Estabrook RW: The remarkable P450s: a his- tors may have a complete and up-to- torical overview of these versatile hemeprotein FASEB J date list of medications, and they Acknowledgments catalysts. 10:202–204, 1996 The author thanks Magda Ortiz, RN, 15 should not assume that someone else Guengerich FP, Hosea NA, Parikh A, Bell- who was involved in the development, will cover these topics. Strive to keep Parikh LC, Johnson WW, Gillam EMJ, Shimada formatting, and editing of Figure 3 T: Twenty years of biochemistry of human the conversation succinct and patient and several tables. P450s: purification, expression, mechanism and specific (only cover possible problems relevance to drugs. Drug Metab Dispos with drugs they are currently taking) 26:1175–1178, 1998 when discussing possible drug interac- References 16Hasler JA, Estabrook R, Murray M, Pikuleva I, tions. Often, this involves not dis- Waterman M, Capdevila J, Holla V, Helvig C, 1American Society of Health-System Falck JR, Farrell G, Kaminsky LS, Spivack SD, cussing the interaction itself, but Pharmacists: ASHP national concerns research Boitier E, Beaune P: Human cytochromes P450. rather the possible adverse conse- report [article online]. 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19Groop L, Eriksson CJ, Huupponen R, Ylikahri 32Zanchi A, Chiolero A, Maillard M, Nussberger unteers. Eur J Clin Pharmacol 58:515–520, 2002 R, Pelkonen R: Roles of chlorpropamide, alcohol J, Brunner HR, Burnier M: Effects of the peroxi- 45 and acetaldehyde in determining the chlor- somal proliferator-activated receptor-gamma Nakamura K, Ariyoshi N, Iwatsubo T, propamide-alcohol flush. Diabetologia pioglitazone on renal and hormonal Fukunaga Y, Higuchi S, Itoh K, Shimada N, 26:34–38, 1984 responses to salt in healthy men. J Clin Nagashima K, Yokoi T, Yamamoto K, Horiuchi Endocrinol Metab 89:1140–1145, 2004 R, Kamataki T: Inhibitory effects of nicardipine 20White JR, Campbell RK: Dangerous and com- to cytochrome P450 (CYP) in human liver mon drug interaction in patients with diabetes 33Nesto RW, Bell D, Bonow RO, Fonseca V, microsomes. Biol Pharm Bull 28:882–885, 2005 mellitus. 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