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Pharmacy Update

Diabetes Spectrum Volume 19, Number 4, 2006

When patients are diagnosed with dia-betes, a large number of medicationsbecome appropriate therapy. Theseinclude medications for dyslipidemia,hypertension, antiplatelet therapy, and

glycemic control. So many medicationscan be overwhelming, and it is impera-tive that patients are thoroughly edu-cated about their drug regimen.

Patients have many concerns whenmultiple medications are started,including prescribing errors, the cost ofmedications, and possible adverseeffects. Significantly, 58% of patientsworry that they will be given medica-tions that have drug interactions thatwill adversely affect their health.1 Theseworries are not unfounded given thatseveral highly publicized drugs have

been withdrawn from the U.S. marketin the past several years because ofadverse effects from drug interactions.Terfenadine, mibefradil, and cisapridehave all been withdrawn from the mar-ket specifically because of drug-druginteractions. When terfenadine or cis-apride were given with a stronginhibitor of their metabolism, torsadesde pointes, a life-threatening drug-induced ventricular arrhythmia associ-ated with QT prolongation, couldoccur.2 Cisapride, for gastroparesis orgastrointestinal reflux disease, and

mibefradil, for hypertension, were pre-scribed for many patients with diabetes.An adverse drug interaction is

defined as an interaction between oneor more coadministered medicationsthat results in the alteration of theeffectiveness or toxicity of any of thecoadministered medications. Druginteractions can be caused by pre-scription and over-the-counter med-ications, herbal products or vitamins,foods, diseases, and genetics (familyhistory). The true incidence of drug

interactions is unknown becausemany are not reported, do not resultin significant harm to patients, or donot require admission to a hospital.When a hospitalization does occur, it

is usually not documented as a druginteraction, but rather as an adversedrug reaction because the drug inter-action may only be one component ofthe reason for admission.3,4 Althoughdrug interactions for a select fewdrugs are well known, we often ignorethe substantial evidence that potentialinteractions exist in many of the med-ications prescribed today.

Minimizing the risk for drug inter-actions should be a goal in drug thera-py because interactions can result insignificant morbidity and mortality.

Health care providers should takeresponsibility for the safe prescribing ofmedications, but we often discusspotential adverse drug reactionsnotdrug interactionswith patients. Wemay overlook this responsibilitybecause there are rarely quick, easilyaccessible, and comprehensiveresources that cover drug interactions.Even when available, comprehensiveresources often list all drug interactionsand do not emphasize those that aremost important.

In addition, many diabetes educa-

tors are confused by drug interactionterminology and rely heavily on phar-macists and prescribers to properlyscreen for drug interactions. Causesand terminology common to druginteractions, common interactionswith medications used in people withdiabetes, and tools that busy diabeteseducators can use will be provided inthis article. Not all drug interactionswill be covered, and drug-herbal5,6

and drug-nutrient6,7 interaction infor-mation can be found elsewhere, as

well as nondiabetes-related drug-drug interactions.7

DRUG-DRUG INTERACTIONSDrug interactions are often catego-

rized as pharmacodynamic or phar-macokinetic in nature. A pharmaco-dynamic drug interaction is related tothe drugs effect on the body. Anexample is the combination of alcoholwith medications that cause sedation.A pharmacokinetic drug interaction isrelated to the bodys effect on thedrug. An example is an increase in thesystemic concentration of a renallyeliminated drug because of renalinsufficiency. A pharmacokinetic druginteraction can be caused by an alter-ation in absorption, distribution,

metabolism, or elimination of a drug.8

Pharmacodynamic InteractionsPharmacodynamic drug interactionscan be either beneficial or detrimentalto patients. A beneficial example is theadditive blood pressureloweringeffect when an ACE inhibitor is addedto a calcium channel blocker (CCB).Likewise, synergistic blood pressurelowering may be seen if a diuretic isadded to an ACE inhibitor. The phar-macodynamic drug interaction canalso be detrimental. When alcohol

and a medication that causes sedationare combined, additive unwantedsedation may occur. Antagonisticeffects may also be encountered, aswith the combination of an acetyl-cholinesterase inhibitor for myasthe-nia gravis or Alzheimers disease withamitriptyline for painful diabeticperipheral neuropathy. The acetyl-cholinesterase inhibitor increasesacetylcholine levels, whereasamitriptyline has antagonistic anti-cholinergic effects.8

Drug Interactions of Medications Commonly Used in Diabetes

Curtis Triplitt, PharmD, CDE


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20Diabetes Spectrum Volume 19, Number 4, 2006

Pharmacy Update

Pharmacokinetic Interactions

Absorption interactions. Drug absorp-tion is the movement of the drug fromits site of administration into thebloodstream (Figure 1). Absorption

interactions are changes in a drugseffects caused by food, drink, or med-ications taken concurrently.Classically, we think of the oraladministration of a medication andabsorption from the gastrointestinalsystem, but it applies to all routes ofadministration, including injection,inhalation, topical, buccal, sublingual,and others.

Drug-food interactions can affectthe total amount of drug absorbed(bioavailability), but most often theyonly slow absorption. For example,the hypoglycemic effect of glipizidemay be delayed slightly if taken with ameal versus 3060 minutes before ameal, although hemoglobin A1c (A1C)values are unaffected.9,10 Alteration ofgastrointestinal motility, as is the casewith exenatide (Table 1), or pH mayalso affect absorption. In addition,components of food may interact. Forexample, vitamin K intake from greenleafy vegetables interacts with war-farin. Similarly, several medicationsmay complex or chelate with coad-ministered medications, significantlyreducing their absorption.6 For exam-

ple, levothyroxine absorption isreduced when coadministered withferrous sulfate or antacids and shouldbe moved either 1 hour earlier or atleast 2 hours after administration ofthese drugs.7,11 It is best not to admin-ister other medications with antacidsbecause they can reduce the absorp-tion of many medications.

Distribution interactions. Distributionis the movement of the absorbed drugthrough the bloodstream and itstransport throughout extracellular or

intracellular compartments to the siteof action (Figure 2). Many medica-tions extensively bind to plasma pro-teins such as albumin in the blood-stream. When a drug is bound tothese plasma proteins, it is not activelydistributed to the site of action, andonly the free drug is available tocause an effect. One drug can displaceanother from the binding sites on theplasma proteins if its binding isstronger. This increases the amount of

free drug available to cause aneffect.

In the past, many protein-displac-ing interactions were documented invitro, with in vivo consequencesassumed. The majority of protein-dis-placing interactions have since beendocumented to be test-tube phenome-na and are not clinically important.12

Most of the suspected distributioninteractions have now been reclassi-fied as metabolism interactions.Distribution interactions can be signif-icant for drugs that have extremelyrapid distribution, narrow safety mar-

gins, and possibly nonlinear kinetics.12No significant distribution interac-tions are pertinent for oral medica-tions commonly used for diabetes.12

Metabolism interactions. Drug metab-olism is the modification or degrada-tion of drugs. Metabolism can makedrugs more or less toxic, active orinactive, or more easily eliminatedfrom the body.13 The primary organinvolved in metabolism is the liver,although metabolism has been docu-mented in the kidneys, lungs, gas-

trointestinal system, blood, and othertissues.6 The most extensively studiedfamily of isoenzymes found in theliver and gastrointestinal tract is thecytochrome P450 (CYP) system. Thename cytochrome P450 comes fromthe experimental techniques used toidentify the isoenzymes and is notclinically relevant.14 CYP2D6, forexample, includes 2, the geneticfamily; D, the genetic subfamily;and 6, the specific gene member.

The nomenclature used to classify dif-ferent subsets of the CYP system hasno functional implications but clini-cally allows us to classify metabolisminteractions.

Drugs can inhibit (decrease) metab-olism, induce (increase) metabolism,or have no effect on each CYP450isoenzyme subset. Thus, inhibition ofmetabolism will likely increase theaffected drugs systemic concentra-tions, whereas induction of metabo-lism often reduces systemic concentra-tions. Not all isoenzymes areinducible, and only CYP2C9 and

CYP3A4 induction is clinically rele-vant to people with diabetes. A drugmay also be a substrate for (metabo-lized by) one or more of these enzymesubsets, and clinically, if an inhibitoror inducer affects that isoenzyme, itcould affect the efficacy of the drug.

Drugs can have a complex profile,being a substrate for or an inhibitor orinducer of multiple subsets. For exam-ple, quinidine is a potent inhibitor ofCYP2D6, but it is primarily metabo-lized by CYP3A4. More than 50% ofall drugs are metabolized at least in

part by CYP3A4 or CYP2D6, and sev-eral important diabetes drugs aremetabolized by these pathways.15

Phase 2 metabolism (glucuronidation,acylation, sulfation, and so forth)includes attachment of a water-solublemolecule to aid elimination and detox-ification of a drug. Phase 2 metabo-lism need not but often does occurafter metabolism by the CYP450 sys-tem. Research in this area is expand-ing, and glucuronidation is the basis of

Figure 1. Graphic depiction of a theoretical drug absorption interaction.


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Pharmacy Update

MEDICATION DRUG-DRUG DRUG-NUTRIENT DRUG-DISEASEINTERACTIONS INTERACTIONS INTERACTIONS

Glucose Lowering

Sulfonylureas Inhibitors/inducers of CYP2C9 Alcohol: first-generation Metabolized: liver/kidney(see Table 2) sulfonylureas may cause Caution if dysfunction

flushing reaction, if severe ADR: loss of efficacy ornausea/vomiting hypoglycemia

Meglitanides Nateglinide: none None Liver dysfunction: caution withReplaglinide: both agents-gemfibrozil: effect ADR: loss of efficacy or-other inducers/inhibitors of 2C8 hypoglycemia

Metformin Cimetidine may compete with Vitamin B12 depletion; Lactic acidosis: renal insufficiencymetformin for renal elimination, periodic monitoring if at risk and hypoxic states (congestivewhich may increase levels of heart failure, surgery, shock, ormetformin liver disease, including alcohol intake)

ADR: hospitalization/death

TZDs Strong inducers/inhibitors of None Fluid retentionCYP2C8 (see Table 2) ADR: peripheral edema, heart

Clinical effect of interaction: failure, pulmonary edemaunknown ALT 3 upper normal limit:do not start therapy; stop if taking

-Glucosidase May decrease digoxin absorption None Noneinhibitors May increase effect of warfarin

Action: space administration

Exenatide May slow absorption of medications: None Renal insufficiency: potential forcaution if rapid adsorption needed increased nausea/vomiting(e.g. acetaminophen, pain meds) Gastroparesis: may worsen symptoms

Hypertension

ACE inhibitors, Captopril: see CYP2D6 Caution with potassium Renal insufficiency, pregnancyARBs Enalapril: see CYP3A4 supplements with moexipril,

(See Table 2) captopril, and valsartan.Aspirin, NSAIDs: may reduce Take 1 hour before orantihypertensive effects of ACE 2 hours after mealsinhibitorLithium: levels may increase

CCBs CYP3A4 inducers/inhibitors Grapefruit juice may increase Verapamil, ditiazem: cautionheart(see Table 2) antihypertensive effects failure and cardiac conduction

problems/heart blockDihydropyridine: peripheral edema

Diuretics NSAIDS and phenytoin may reduce Thiazide and loop diuretics Caution in hyperuricemia or gout;effectiveness of loop diuretics may cause hypokalemia. may exacerbate attackThiazides may affect lithium levels Potassium sparing diuretics May exacerbate lupus

may cause hyperkalemia May worsen or cause severephotosensitivity reactions

Lipid-Lowering

HMG-CoA Lovastatin, simvastatin, atorvastatin: Lovastatin: food increases Watch for myopathy andreductase inhibitors 3A4 (see Table 2) absorption rhabdomyolysis(statins) Fluvastatin: CYP2C9 (see Table 2) Lovastatin extended-release:

Pravachol: sulfated, but still cases food decreases absorptionof rhabdomyolysis reported

Lovastatin: food increasesabsorption

Fibric acids Gemfibrozil: inhibitor of 3A4, 2C8, None Do not use if active cholecystitis(See Table 2)Increase ezetimibe levelsFenofibrate: 3A4, less risk ofinteraction (See Table 2)

ADR, adverse drug reaction

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


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one important drug-drug interactioninvolving gemfibrozil and severalhydroxymethylglutaryl (HMG) CoAreductase inhibitors (statins).

High-risk groups for drug interac-tions include neonates, infants, the

elderly, and those with significantorgan disease (i.e., renal or hepaticdisease) warranting increased screen-ing vigilance. Neonates, infants, andthe elderly will often metabolize drugsslower than healthy adults, andlifestyle choices such as smoking(induces metabolism) and alcohol use(may induce or inhibit metabolism)can alter metabolism. Metabolismpatterns can also be altered by geneti-cally determined variations. Forexample, ~ 510% of Caucasians, butonly 01% of Asians, have little

CYP2D6 enzyme activity, makingthem CYP2D6 poor metabolizers,the consequences of this are depen-dent on the drug and alternative path-ways available for metabolism.16

Elimination interactions. Drug elimi-nation is the removal of a drug fromthe body. The major organs involvedin elimination are the kidneys andliver, although other bodily processes,including saliva, sweat, or exhaled air,may be pathways for elimination.

Elimination through the liver is pri-marily through bile. There are notmany true drug-drug interactionsthrough bile elimination, but drug-dis-ease interactions, as described below,can be important when bile elimina-

tion is affected, as with severe biliaryor liver disease. Renal drug-druginteractions are dependent on the pHof the urine and the pH of the drug oron competition for the same pathwayof elimination. If the pH of the urineand the drug are the same, renal reab-sorption of the drug will be increased.When two drugs compete for elimina-tion through a single route, one drugmay competitively inhibit the elimina-tion of the other.8 Metformin andcimetidine, both cationic (positivelycharged) drugs, can compete for elimi-

nation through kidneys by renal tubu-lar secretion, resulting in higher met-formin concentrations in the plasma.17

DRUG-DISEASE INTERACTIONSMany comorbid diseases can affectmetabolism in people with diabetes.Patients with diabetes have higherrates of cardiovascular, renal, gas-trointestinal, neurological, and thy-roid diseases and ophthalmologicalcomplications compared with indi-viduals without diabetes. All may

increase the chance of having drug-disease interactions. Metformin andimpaired renal function is a well-doc-umented drug-disease interaction.Serum creatinine 1.4 mg/dl inwomen or 1.5 mg/dl in men war-

rants discontinuation of metforminbecause systemic concentrations canbe elevated, increasing the risk of lac-tic acidosis.18 Drug-disease interac-tions for specific medications used inpeople with diabetes will be coveredbelow.

Diabetes Drug Interactions

Sulfonylurea drugs. Several drug-druginteractions occur with sulfonylureas.First-generation sulfonylureas, espe-cially chlorpropramide, may cause a

facial flushing reaction when alcoholis ingested. This may be similar tothat caused by disulfiram, whichblocks aldehyde dehydrogenase,resulting in increased levels ofacetaldehyde. Acetaldehyde can resultin flushing and possibly nausea orvomiting at higher levels.7,19 A switchto a second-generation sulfonylureawould be advised (Table 1).

Sulfonylureas are commonly listedas having protein-binding drug inter-actions, and the first-generation sul-


Pharmacy Update

Figure 2. Graphic depiction of a theoretical drug distribution interaction.


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Pharmacy Update

fonylureas (acetohexamide, chlor-propamide, tolazamide, and tolbu-tamide), which bond ionically to plas-ma proteins, are thought to have ahigher risk of protein-binding druginteractions.20 If they do occur, they

should occur shortly after the secondmedication is added to the sulfony-lurea by displacing the sulfonylureaand increasing the active drug avail-able. This would result in a reductionof plasma glucose and possibly hypo-glycemia, if the plasma glucose wasnear normal. As stated previously,most of these have now been restatedas interactions resulting from theCYP450 isoenzyme system.12

Sulfonylureas are a substrate ofCYP2C9. Thus, inducers andinhibitors of CYP2C9 can affect themetabolism of sulfonylureas.Common medications that may inter-act with sulfonylureas are listed inTable 2. Sulfonylureas have two sig-nificant drug-disease interactions.Most are metabolized in the liver toactive or inactive metabolites. Whensignificant impairment in liver func-tion is present, sulfonylurea metabo-lism may be altered. Active or inactivemetabolites of sulfonylureas are elimi-nated by the kidneys, and renal insuf-ficiency may reduce elimination(Table 3).

Short-acting secretagogues. Nateglin-ide, which is metabolized byCYP2C9 (70%) and CYP3A4 (30%),could be affected by stronginhibitors/inducers of CYP2C9, butsignificant drug-drug interactionshave not been reported. Repaglinideis metabolized by the CYP3A4 andCYP2C8 isozyme systems and thenextensively glucuronidated. A seriousdrug-drug interaction may occurwith gemfibrozil, which is used fortriglyceride lowering. This is likelycaused by gemfibrozils inhibition of

CYP2C8 and glucuronidation. Invivo, gemfibrozil increases the totalexposure of repaglinide eightfold.21

Several reports of severe, prolongedhypoglycemia have been documentedwith the combination.22 Stronginhibitors of CYP3A4, such as azoleantifungal agents and erythromycinderivatives, may also enhance thehypoglycemic effect of repaglinide.Drugs that are inducers ofCYP2C8/3A4 may reduce the effica-

cy of repaglinide, and a higher doseof repaglinide may be necessary23

(Table 2).

The main drug-disease interaction ofconcern is impaired liver function, andthe risk of hypoglycemia in this popu-

2C8 2C9 2D6 3A4Substrates (Metabolized By)

Repaglinide Sulfonylureas Captopril RepaglinidePioglitazone Nateglinide Metoprolol CCBsRosiglitazone Losartan Carvedilol EnalaprilCavedilol Irbesartan Losartan

Warfarin IrbesartanZafirlukast

Inhibitors ( Drug Levels of Substrates)Gemfibrozil Fluconazole Amiodarone ClarithromycinFluconazole Trimethoprim Cimetidine ErythromycinNicardipine Amiodarone Fluoxetine (NOT Azithromycin)Delavirdine Zafirlukast Paroxetine VerapamilKetoconazole Delavirdine Diltiazem

Ritonavir ItraconazoleRopinirole Ketoconazole

FluoxetineFluvoxamineHIV protease inhibitorsDelavirdine

Inducers ( Drug Levels of Substrates)Rifampin Rifampin None CarbamazepinePhenobarbital Phenobarbital RifampinPrimidone Rifabutin

PhenobarbitolPhenytoinSt. Johns Wort

Table 2. Common Inducers, Inhibitors, and Substrates of SelectCYP450 Isozymes

DRUG METABOLISM ELIMINATIONFirst generation

Acetohexamide Metabolized in liver; metabolite Renalpotency equal parent compound

Chlorpropamide Metabolized in liver Also renallyeliminated unchanged

Tolazamide Metabolized in liver; metabolite Renalless active than parent compound

Tolbutamide Metabolized in liver to inactive Renal

metabolites

Second generation

Glipizide Metabolized in liver to inactive Renalmetabolites

Glyburide Metabolized in liver to inactive 50% renal,metabolites: elimination 50% feces

Glimepiride Metabolized in liver; one 60% urine,metabolite one-third activity 40% fecesof glimepirideunclearcontribution to effects

Table 3. Metabolism and Elimination of Sulfonylureas


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lation may be increased. No adjust-ment in dosing is needed in renalimpairment until the patient has end-stage renal disease. When low-dose sul-fonylureas cause hypoglycemia inrenally impaired type 2 diabetic

patients, repaglinide or nateglinide maybe a good therapeutic alternative.Neither has significant drug-food inter-actions, but both should be takenpreprandially to better match pancreat-ic insulin release with a meal (Table 1).

Metformin. Although not because of adrug interaction, metformin should betaken with a meal to limit gastroin-testinal side effects. Metformin maycause malabsorption of vitamin B12,which may result in B12 deficiencyand subsequent anemia. The mecha-nism by which metformin causes mal-absorption of B12 is not clearlydefined, although oral or injected B12(cyanocobalamin) or calcium supple-mentation may be effective for correc-tion24,25 (Table 1).

Metformin does not undergo metab-olism and is eliminated renally bytubular secretion and glomerular filtra-tion. Metformin is a cationic (positivelycharged) molecule and may competewith other cationic drugs for renalsecretion through organic cation trans-porters in the kidneys.17 Procainamide,digoxin, quinidine, trimethoprim, and

vancomycin are all cationic drugs thathave the potential to interact with met-formin, but only cimetidine, which isavailable over the counter for heart-burn, has been implicated in one caseof metformin-associated lactic acidosis(MALA)26,27 (Table 1).

Metformin has many drug-diseaseinteractions that can increase the riskof MALA. Metformin may increaselactic acid production from thesplanchnic tissues slightly, but MALAoccurs in the setting of comorbid dis-eases that increase systemic levels of

lactic acid or reduce elimination ofmetformin. Any disease that mayincrease lactic acid production ordecrease lactic acid metabolism maypredispose to lactic acidosis. Tissuehypoperfusion from congestive heartfailure, hypoxic states, shock, or sep-ticemia can increase lactic acid pro-duction, and alcohol or severe liverdisease can reduce removal of lacticacid in the liver, increasing the risk oflactic acidosis.

Metformin use in renal insufficien-cy, defined as a serum creatinine 1.4mg/dl in women and 1.5 mg/dl inmen, is contraindicated because it isrenally eliminated. Elderly patients,who often have reduced muscle mass,

should have their creatinine clearancerate estimated before use. If the creati-nine clearance rate is < 7080 ml/min,metformin should not be given.Because of the risk of acute renal fail-ure during intravenous dye proce-dures, metformin should be withheldstarting the day of the procedure andresumed in 23 days, when normalrenal function has been documented.

Clinical presentation of lactic aci-dosis is often nonspecific flu-likesymptoms and may include alteredconsciousness, heavy, deep(Kussmaul) breathing, and abdomi-nal pain and thirst. Thus, the diagno-sis is usually made by laboratoryconfirmation.18,28

Thiazolidinediones. Pioglitazone androsiglitazone can both be taken with-out regard to meals. Rosiglitazone is asubstrate for the CYP2C8 and to alesser extent CYP2C9 pathways, andpioglitazone is a substrate forCYP2C8 (39%) and CYP3A4 (17%),as well as several other CYP450 path-ways.29,30 Rosiglitazone and pioglita-zone metabolism in vivo can be affect-

ed by inhibitors or inducers ofCYP2C8, but no significant drug-druginteractions have been reported todate30,31 (Table 2). Neither drug hassignificant elimination drug-druginteractions.

However, both thiazolidinediones(TZDs) have significant drug-diseaseinteractions. Both can cause fluidretention that may result in peripheraledema or, rarely, pulmonary edemaand/or heart failure. Mechanistically,this may relate to increased renalreabsorption of sodium, a reduction

of systemic vascular resistance, orother mechanisms.32,33 Unlike troglita-zone, no data link pioglitazone orrosiglitazone to drug-induced hepato-toxicity.34,35 Nevertheless, it is recom-mended that drug therapy not bestarted if the alanine aminotransferase(ALT) is > 2.5 times the upper limit ofnormal and stopped if the ALT is > 3times the upper limit of normal (Table1). Prudent clinical judgment is need-ed for TZD drug-disease interactions,

but a full discussion is beyond thescope of this review.36,37

-Glucosidase inhibitors. Because nei-ther acarbose nor miglitol is exten-sively metabolized, neither has signifi-

cant metabolism interactions. Severalcase reports have documented areduction in absorption of digoxinand an increase in absorption of war-farin.38,39 It is recommended that anydrug with a very small dose and a nar-row safety margin be administeredapart from acarbose or miglitol.Drug-disease interactions are relatedto -glucosidase inhibitorinducedgastrointestinal side effects (gas, diar-rhea, and abdominal gas pain), whichcould harm patients with certain gas-trointestinal diseases (e.g., shortbowel syndrome, Crohns disease, orulcerative colitis).

Hypertension- and Lipid-ReducingMedications

Antihypertensive drugs. Many differ-ent classes of antihypertensive medica-tions may be used for blood pressurecontrol in diabetes, but the four mostcommon include ACE inhibitors,angiotensin-II type 1 receptor blockers(ARBs), thiazide diuretics, and CCBs.CCBs can be further subdivided intodihydropyridine CCBs, so called for

their chemical structure, and thenondihydropyridine CCBs, diltiazemand verapamil, which are pharmaco-dynamically linked because of theireffect on the heart. Drug interactionsmay be present for some but not allmedications within an antihyperten-sive class.

ACE inhibitors and ARBsDrug-food interactions are importantfor two ACE inhibitors, moexipril andcaptopril, which should be adminis-tered 1 hour before or at least 2 hours

after a meal.7 A 4050% decrease insystemic levels may be seen when val-sartan, an ARB, is taken with food.40

Because both classes may increaseserum potassium levels, cautionshould be taken when potassium sup-plements or a high-potassium diet areconsumed with either class (Table 1).

ACE inhibitors and ARBs have sev-eral interactions of importance.Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may


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blunt the antihypertensive effect of anACE inhibitor, presumably throughinhibition of ACE inhibitorinducedprostaglandin synthesis. Clinically, theinteraction does not appear to affectthe ACE inhibitors ability to prevent

adverse cardiovascular or renal out-comes.41 ACE inhibitors may increasehypersensitivity reactions, such as flu-like symptoms and skin rash, withallopurinol, although the exact mech-anism is not known.7 ACE inhibitorsand ARBs may increase lithium levels,and concurrent use warrants closemonitoring of lithium levels.7

Captopril, a CYP2D6 substrate,and enalapril, a CYP3A4 substrate,may be affected by strong inhibitorsor inducers of these pathways7 (Table2). Concentration changes resulting

from these interactions should bemonitored by following the ambulato-ry blood pressure. Losartan is the onlyARB with significant interactions withCYP3A4, although losartan and irbe-sartan are substrates of CYP2C9.Strong inhibitors or inducers of thesepathways would likely increase ordecrease the antihypertensive effec-tiveness of losartan (Table 2).

Despite potential interactions, veryfew clinically significant drug interac-tions have been documented withARBs. Caution should be taken wheneither class is started in renal insuffi-ciency because both can worsen renalfunction or even cause acute renal fail-ure in patients with renal artery steno-sis. Neither class is recommended inpregnancy because severe birth defectsto neonatal kidneys can occur.

Calcium channel blockers. MostCCBs are metabolized by CYP3A4and will be affected by stronginhibitors and inducers of CYP3A4(Table 2). Grapefruit juice in sufficientquantities can block intestinalCYP3A4, which can lead to an

enhancement of the effects of CCBs.This could affect the blood pressureresponse for all CCBs and furtherlower the pulse rate when diltiazemand verapamil are used. Studies thathave explored the effect of grapefruitjuice on diltiazem and verapamil havenot reported changes in blood pres-sure or heart rate, despite increases insystemic drug concentrations.4244

Alcohol ingestion appears to havevariable effects on the antihyperten-

sive effects of CCBs, and intakeshould be limited. In addition, dilti-azem and verapamil are weakinhibitors of CYP3A4, and drug inter-actions with HMG-CoA inhibitors,which will be discussed later, have

been documented.The risk of cardiac conductionabnormalities with diltiazem or vera-pamil is the main drug-disease interac-tion to monitor. Diltiazem or vera-pamil given in combination with a -blocker can further lower the pulserate, increasing the risk for heart block.Dihydropyridine CCBs do not causeheart conduction drug-disease interac-tions, but they may cause peripheraledema, which may worsen preexistingedema present from heart failure,venous insufficiency, or other causes.

Nicardipine is an inhibitor ofCYP3D6, CYP2C8, CYP2C9,CYP2C19, and CYP3A4, and alcoholingestion may enhance its antihyper-tensive effects.45 Nicardipine is notrecommended because other medica-tions within the class have fewer druginteractions (Tables 1 and 2).

DiureticsThiazide diuretics are the most com-monly used diuretics for blood pres-sure control in people with diabetes.No significant drug-food interactionsexist for diuretics, but bile acid seques-trants, used rarely to reduce choles-terol, may cause a significant reductionin absorption, and thus dosing shouldbe separated by several hours.7 Loopand thiazide diuretics may depletepotassium and magnesium; adequateintake of these minerals is essential.Hypokalemia may greatly increase thetoxicity of some concurrent medica-tions (e.g., digoxin and antiarryth-mics).7 Potassium-sparing diuretics (tri-amterene, amiloride, and spironolac-tone) may cause hyperkalemia.Monitoring of serum potassium is rec-

ommended for all diuretics on initia-tion and periodically thereafter.Thiazide diuretics decrease lithiumexcretion, and monitoring of lithiumlevels in conjunction with a reductionin dose is recommended. NSAIDs andphenytoin may decrease the effective-ness of loop diuretics.7 Diuretics mayalso exacerbate several diseases, includ-ing hyperuricemia or gout and systemiclupus erythematosus, and cause photo-sensitivity reactions46 (Table 1).

Lipid-lowering medications

Fibric acid derivativesBoth gemfibrozil and fenofibrateshould be taken with food to reducegastrointesinal upset. Bile acid seques-

trants may interfere with absorptionof fibric acid derivatives and shouldbe separated from each other by atleast 2 hours.7 Gemfibrozil can signifi-cantly block CYP2C8/9/19, glu-curonidation, and possibly humanorganic anion transporting polypep-tide-2 (OATP2).47,48 Several medica-tions commonly used in the treatmentof patients with diabetes are metabo-lized by these pathways, including sul-fonylureas, repaglinide, sertraline, flu-oxetine, and carvedilol. These medica-tions may need dose reductions or

close monitoring when combined withgemfibrozil7 (Table 2).The interaction of gemfibrozil with

statins may be caused by a glu-curonidated metabolite of gemfibrozilcompeting for metabolism after theOATP2 allows it into hepatocytes.Details can be further explored in arecent review article.48 Further infor-mation on this important interactioncan be found in the statins section.

When gemfibrozil is added to eze-timibe (Zetia), it likely blocks glu-curonidation of ezetimibe, increasingsystemic levels, but the clinical rele-vance of this interaction has yet to bedocumented.49 Fenofibrate, whichappears to have less potential to inter-act with the aforementioned drugs,also has a questionable ability tolower cardiovascular events in peoplewith type 2 diabetes.50

StatinsDrug interactions that inhibit metabo-lism of statins increase systemic expo-sure, which may predispose to agreater risk of myopathy. The exactpathophysiological mechanism lead-ing to myopathy is unknown, butdirect effects of statins on the myocytehave been hypothesized.51

Although most myopathy casesoccur as a result of drug-drug interac-tions, statins in monotherapy havealso caused myopathy.51 Patientsoften present with muscle aches withor without creatinine phosphokinaseelevations, which are indicative ofmuscle destruction. If the myopathy isallowed to progress, it may lead to


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rhabdomyolysis, with proximalweakness in the arms or legs.Myoglobinuria, characterized bybrown or black urine, may also devel-op and is associated with acute renalfailure. The risk of rhabdomyolysis is

low, but the majority of cases occurin patients with potential drug-druginteractions.52 Proper education tostop the medication and report symp-toms to their health care provider isessential to minimize risk to patients.

Caution should be taken whenstrong inhibitors of CYP3A4 are givenwith lovastatin, simvastatin, or ator-vastatin. Strong inhibitors of CYP2C9may increase fluvastatin and rosuvas-tatin levels (Table 2). Common classes


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Name: _____________________________ Provider/Diabetes Educator: _______________________

Date: ______________________________ Email address ___________ Phone number: __________

Diagnoses: ___ Diabetes ___Hypertension ___Hyperlipidemia ___ Other: __________________

Allergies: ____________________________________________________________________________

Diet/Vitamin Supplements: ___________ Herbal Supplements: ______________________________

Over-the Counter: ____________________________________________________________________

Figure 3: Medication documentation/drug-drug interaction tool for diabetes educators.

MEDICINE DRUG/ DRUG/ DRUG/NAME/DOSE INSTRUCTIONS DRUG FOOD DISEASE

Interactions Interactions Interactions

Inducers 3A4/2C9 3A4 Inhibitors 2C9 Inhibitors Binders MetforminRifampin Fluconazole Itraconazole Bactrim Antacids Cimetidine

Carbamazepine Erythromycin Clarithromycin Fluconazole Bile acidsequestrants

Rifabutin Fluoxetine Fluvoxamine AmiodaronePhenytoin Verapamil* Diltiazem* Cimetidine Action: do not

administer drugs atsame time as above

Phenobarbital Cimetidine Cyclosporine Bactrimointment

St. Johns wort HIV protease inhibitorsGrapefruit 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 competefor elimination and

may increasemetformin levels.

All drugs listed here Statins CCBs Sulfonylureas AllFluvastatinWarfarin

* Not pravastatin, fluvastatin (CYP2C9), or rosuvastatin Weak inhibitors: caution with lovastatin or simvastatinCCB, calcium channel blockers


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Pharmacy Update

of drugs that are strong inhibitors ofCYP3A4 include azole antifungals,macrolide antibiotics (exceptazithromycin), protease inhibitorsused for HIV, amiodarone, diltiazem,and verapamil52 (Table 2).

Gemfibrozil and the immunosuppres-sant cyclosporine appear to increasethe risk of myopathy with all statins.

To minimize the risk of myopathyand rhabdomyolysis, the maximumrecommended dose of immediate-release lovastatin is 20 mg/day withcyclosporine, niacin (> 1 g/day), andfibric acid derivatives and 40 mg withverapamil or amiodarone. If the lovas-tatin sustained-release dosage form isused, the maximum recommendeddose is one-half of the above-statedlovastatin doses.53 The maximum rec-ommended dose of simvastatin is 10mg with cyclosporine, niacin (> 1g/day), and fibric acid derivatives and20 mg with verapamil oramiodarone.53,54

Other potential inducer/inhibitordrug-drug interactions of signifi-cance can be found in Table 2. Foodmay increase the absorption ofimmediate-release lovastatin butdecrease the absorption of extended-release lovastatin.

DRUG INTERACTIONS ANDDIABETES EDUCATORSIt is nearly impossible to memorizethe plethora of possible interactionscurrently affecting drug therapy indiabetes. Because of this complexity, itis essential that drug-drug interactiontools be used. This responsibility isusually shouldered by prescribers andpharmacists, but only diabetes educa-tors may have a complete and up-to-date list of medications, and theyshould not assume that someone elsewill cover these topics. Strive to keepthe conversation succinct and patientspecific (only cover possible problems

with drugs they are currently taking)when discussing possible drug interac-tions. Often, this involves not dis-cussing the interaction itself, butrather the possible adverse conse-quences of the interaction.

Tools to list medications and eval-uate potential drug interactions mayhelp. Resources such as drug productinserts, websites for a specific drug,reference books, and printed primaryliterature review articles are often dia-

betes educators best resources forevaluating the potential for druginteractions. It is important to involvea patients health care team, and apharmacist can be especially helpfulwhen it is unclear whether drugs may

interact. Pharmacists receive special-ized training in drug interactions,often have software or referencebooks that specifically address druginteractions, and have additionalbackground that can aid with an edu-cated recommendation if no data areavailable.

Abbreviated forms to help busydiabetes educators keep a currentmedication list and ascertain whetherpatients with diabetes may be at riskfor possible drug interactions can befound in Figure 3.

CONCLUSIONSDetecting potential drug interactionsneed not be burdensome, but it mustnot be ignored. Drug interactionsresulting from absorption, distribu-tion, metabolism, or elimination, aswell as pharmacodynamic factors, arepresent for many common medica-tions given to people with diabetes.The team approach is best, and itshould not be assumed that pre-scribers and pharmacists are the onlyteam members responsible for detect-ing and resolving drug interactions.

Diabetes educators can and should beactive team members in screening,educating, and following up on sus-pected drug interactions. This willlikely lead to a lower risk of adverseeffects and an improved quality of lifefor people with diabetes.

AcknowledgmentsThe author thanks Magda Ortiz, RN,who was involved in the development,formatting, and editing of Figure 3and several tables.

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Curtis Triplitt, PharmD, CDE, is aclinical assistant professor in theDepartment of Medicine, Division ofDiabetes, and Clinical PharmacyPrograms of the University of TexasHealth Science Center and the TexasDiabetes Institute in San Antonio.


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