current problems in cardiology - su

Adverse Cardiovascular DrugInteractions

Lionel H. Opie, MD, FRCP, DPhil, DSc

Heart Research Unit and Hatter InstituteMRC Inter-University Cape Heart Research Group

Cape Heart CentreUniversity of Cape Town

South Africa

Current Problems in

Cardiology®

Volume 25 Number 9 September 2000

622 Curr Probl Cardiol, September 2000

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Current Problems in

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Information for Readers


Foreword 626

Introduction 628

Mechanisms of Drug Interactions 629Perspective on Drug Interactions: Risk of Side-Effect versus Benefit of Combination 629

Hepatic Interactions 630Pharmacokinetic Interactions 630Pharmacodynamic Hepatic Interactions 632

P-Glycoprotein 632

Proarrhythmic Drug Interactions 633

Renal Pharmacokinetic Interactions 633

Plasma Protein Binding as a Site for Drug Interactions 634

Pharmacodynamic Hemodynamic Drug Interactions 635Sinoatrial and Atrioventricular Nodes 635Intraventricular Conduction System 637Myocardial Contractile Mechanism 637Vascular Smooth Muscle 638

β-Adrenergic Blocking Drugs 639

Nitrates 641Pharmacodynamics 641Other Interactions 642

Calcium Channel Blockers 642Verapamil 644Other Drug Interactions with Verapamil 644Diltiazem 645

Curr Probl Cardiol, September 2000 623

Current Problems in

Cardiology®

Nifedipine 645Amlodipine 646Felodipine 646Isradipine 646

Antiarrythmic Agents 647Quinidine 647Procainamide 650Disopyramide 650Lidocaine 651Mexiletine 651Flecainide 651Propafenone 652Amiodarone 652Sotalol 653Bretylium 653Adenosine 653

Positive Inotropic Agents 653Digoxin 653

Sympathomimetic Agents 655Dopamine 655Dobutamine 656Amrinone and Milrinone 656

Diuretics 656Loop Diuretics 656Thiazide Diuretics 656

Vasodilators 657Nitroprusside and Hydralazine 657Prazosin, Doxazosin, and Terazosin 657Cilostazol 658

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers 658

Captopril 659All Other Angiotensin-Converting Enzyme Inhibitors, 659

Including EnalaprilAngiotensin Receptor Blockers 659

Antithrombotic and Thrombolytic Agents 660Aspirin 660Sulfinpyrazone 661Dipyridamole 661Warfarin 661


Heparin 663Tissue-Type Plasminogen Activator 663

Statins and Other Lipid-Lowering Agents 663Lipid-Lowering Drugs and Warfarin 663Statins 664

Antihypertensive Drugs 665

Cyclosporine and Ketoconazole 666Cyclosporine 666Ketoconazole 666

Herbal Drug Interactions 666

References 667


ForewordIn the September 2000 issue of Current Problems in Cardiology, Dr

Lionel Opie, a renowned expert in cardiovascular drug interactions, pre-sents the reader with a comprehensive, well-referenced, state-of-the-artdiscussion of the potential interactions of various cardiovascular drugs.The 20 tables included with this monograph are particularly useful andprovide information readily to readers concerned about the potentialinteractions of 2 or more drugs.

The editorial board of Current Problems in Cardiology is most gratefulto Dr Opie for this important addition to the CPC series.

Robert A. O’Rourke, MD, FACC, MACPEditor in Chief



Lionel H. Opie, MD, DPhil, DSc, is Co-Director of the Cape Heart Centre andDirector of the Medical Research Coun-cil Inter-University Cape Heart Research

Group at the University of Cape Town. After graduation from the Universityof Cape Town, he studied at Oxford and was a Research Fellow at Harvard;Fellow of the Royal College of Physicians of London; Life Fellow of the Uni-versity of Cape Town; Visiting Senior Fellow of the British Heart Foundationat St Thomas’ Hospital, London, and of the Department of Biochemistry atthe University of Oxford; Visiting Research Fellow at Merton College,Oxford, and in the Department of Physiology, University of Oxford; and Vis-iting Professor at the Division of Cardiovascular Medicine, Stanford Uni-versity Medical Center, Stanford University, California. He is a past-Presi-dent of the International Society for Heart Research and has served asChairman of the Committee on Cardiovascular Drugs of the InternationalSociety and Federation of Cardiology. His major publications are Drugs forthe Heart and The Heart, Physiology, from Cell to Circulation.



ith a steadily increasing number of cardiovascular agentsbecoming available, there is also the potential for greater druginteractions, usually adverse. The first cardiovascular drug

interaction that “caught the eye” of cardiologists was the interactionbetween quinidine and digitalis, whereby quinidine elevates digoxin lev-els. This interaction involved 2 classic drugs that had been used in com-bination for many years. Yet the molecular explanation, that quinidineinhibits the digoxin transmembrane transporter, P-glycoprotein, was onlyelucidated in 1999.36 This knowledge has in turn provided a frameworkof much wider understanding of adverse cardiovascular drug interactions.In general, agents that inhibit the digoxin transporter also inhibit thehepatic cytochrome P-450 (CYP) 3A4 system, a minefield of potentialdrug interactions.1 Clinically, the knowledge of the quinidine-digoxininteraction alerted clinicians to the fact that apparently established prop-erties of drugs could perhaps be explained more simply by drug interac-tions. For example, the increased blood digoxin level probably evokedsome arrhythmias thought to be caused by quinidine.

This review will analyze cardiovascular drug interactions in 2 ways.First, the major organ sites of such interactions will be considered, start-ing with 2 newly discovered molecular mechanisms: the liver cytochromeisoenzymes as a major site of cardiovascular drug interactions and thedigoxin transporter, P-glycoprotein. Potentially proarrhythmic drug inter-actions and renal interactions will be considered. All of these interactionsoften could not be predicted by a knowledge of the well-known pharma-cologic properties of the drugs. Predicted interactions will be considered:pharmacodynamic interactions at the level of the heart itself, specificallythe sinoatrial and atrioventricular nodes, the intraventricular conductionsystem, and the myocardial contractile mechanism. An evaluation of vas-cular smooth muscle as a site for drug interactions will be made.

Second, the major classes of cardiovascular drugs are sequentially con-sidered in the following order: β-adrenergic blockers, nitrates, calciumchannel blockers (CCBs; calcium antagonists), antiarrhythmic drugs,digoxin and other positive inotropic drugs, diuretics, vasodilators,angiotensin-converting enzyme (ACE) inhibitors and angiotensin recep-tor blockers (ARBs), antithrombotic drugs, statins and other lipid-lower-ing agents, antihypertensive drugs, cyclosporine, and herbal drugs.

W

Mechanisms of Drug InteractionsToday, knowledge of cardiovascular drug interactions is regarded as

basic to our understanding of the pharmacologic properties of cardiovas-cular drugs. Such interactions can be either pharmacokinetic (whereby 1agent interferes with the metabolism of another) or pharmacodynamic(whereby the hemodynamic properties of 1 agent may be additive or sub-tractive to those of the drugs given as cotherapy). The liver is the chief siteof pharmacokinetic interactions. Examples of this interaction include theincreased danger of myopathy with statins during the coadministration oferythromycin or ketoconazole (both of which inhibit the CYP 3A4 systemwhere most of the statins and CCBs are metabolized) and the decreasedrate of hepatic metabolism of lidocaine during cimetidine therapy, with thepossible risk of lidocaine toxicity. A second example of a pharmacokineticinteraction lies in those drugs that act on the P-glycoprotein that is thedigoxin transmembrane transporter and that show how basic studies canhelp unravel well-known but poorly understood interactions such as thatbetween quinidine and digoxin.36 Pharmacodynamic interaction ariseswhen a CCB is added to β-adrenergic blockade in the therapy of severeangina, sometimes with excess hypotension as a side effect.

Perspective on Drug Interactions: Risk of Side-Effect VersusBenefit of Combination

The existence of a significant interaction does not necessarily mean thatthe apparently adverse combination should be avoided. Rather, the over-all interests of the patient must be considered. For example, in the case ofthe amiodarone–β-blocker combination in patients after infarction, thecombination seems synergistically effective from the point of view ofprolonging life.12 In patients awaiting transplantation, a nonrandomizedstudy suggests that the combination improves mortality rates, albeit at thecost of about 6% of patients who required a permanent pacemaker.111

Another example of the risk of the interaction having to be balancedagainst the expected benefits lies in the combination lipid-modifyingtherapy with statins and fibrates. In some patients with severe lipidemias,this combination brings about the risk of myopathy, albeit relatively low,with a consequent but even lower risk of renal failure. These risks mustbe balanced against the expected increase of life duration as a result of thecombination, which achieves a dual aim: to reduce the low-densitylipoprotein cholesterol (for which statins are very effective) and toincrease the high-density lipoprotein cholesterol (for which the fibratesare very effective). It is likely that computer-based decision making willsoon become available to evaluate the exact probability of harm of a drug


or drug class versus the expected therapeutic life-prolonging benefit sothat patient and doctor can make informed choices rather than rely onshrewd guesses.

Interindividual Variations in ResponsePatient’s disease status.When the topic of cardiovascular drug interac-

tions was last reviewed in this monograph,116 one comment was that “thepharmacodynamic effects are often unpredictable, because the pathophys-iology of each patient with a given clinical abnormality is quite variable.”Thus, 1 patient with good myocardial reserve may respond to a negativeinotropic agent, such as verapamil, without any significant adverse effects,whereas another patient with impaired contractile activity might be putinto left ventricular failure. Aβ-blocker might slow the heart rate when thesinus node is functioning normally, whereas in sick sinus syndrome, thereis a real risk of sinus arrest or advanced sinoatrial block.

Patient’s genetic makeup. It is already known that there can be wide vari-ations in certain liver metabolic functions. For example, the rate of acety-lation of procainamide leads to a major variation in the levels of blood pro-cainamide and its metabolite, N-acetyl-procainamide, so that these shouldboth be monitored during chronic therapy. This is one of the reasons thatchronic procainamide therapy is not used often. It is likely that genetic vari-ations in the activity of the hepatic CYP 3A4 system could explain why afew individuals readily react to the combination of cyclosporine and a statinwith myopathy, whereas many other individuals do not. Clearly, a genetic-based delineation of the risk of adverse drug interactions is going to come.

Patient’s age.With advancing age, the heart becomes more fragile frommany points of view; reflexes become blunted; baroreceptors work lesswell, and the possibility of pharmacodynamic interactions mounts.

Hepatic Interactions

Pharmacokinetic InteractionsMany cardiovascular drugs are metabolized in the liver, generally through

the cytochrome oxidase system, involving one of several isoforms. Of thevarious isoforms, the CYP 3A4 is the site of most hepatic interactions of car-diac drugs (Table 1). A number of interacting drugs (such as phenytoin, bar-biturates, and rifampin) and the herbal remedy, St John’s wort, can inducethe CYP 3A4 isoform. Accordingly, such drugs accelerate the breakdown ofthose cardiovascular drugs that are metabolized by this isoform (such asatorvastatin, cerivastatin, cyclosporine, disopyramide, felodipine, lidocaine,lovastatin, nifedipine, nisoldipine, propafenone, and simvastatin). Thus, theinducers lessen the blood concentrations of these drugs and their therapeu-



TABLE 1. Common cardiac and other drug interactions with the hepatic CYP isoforms of enzymes

Drugs/food CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A

Amiodarone * * * *Amlodipine Weak†Atorvastatin †Candesartan None NoneCarvedilol † †Cerivastatin †(2C8) †Cimetidine * * * *Cyclosporine (?*)†Diltiazem *Disopyramide †Erythromycin *Felodipine †Fluvastatin †Grapefruit juice *Irbesartan †Ketoconazole *Lidocaine †Losartan †Lovastatin †Metoprolol †Mexiletine †Nifedipine †Nisoldipine †Phenytoin ‡ ‡ ‡Phenobarbital ‡ ‡Pravastatin NonePropafenone † †Propranolol † †Quinidine * (*)†Ranitidine (Very weak*) (Very weak*) (Very weak*)Rifampin ‡ ‡ ‡Ritonavir ‡ * ‡ *†Seville oranges *Sildenafil †Simvastatin †St John’s wort ‡Theophylline † † ‡Ticlopidine * *Timolol †Torsemide †Valsartan None NoneVerapamil † *S-warfarin †R-warfarin † † †

Based on data from the Georgetown University Web site, the supplement to SA Pharmaceutical Journal, February 2000,the text of this monograph, and package inserts. Thanks to Dr. J Noble for major contributions to this table.None, Absence of interaction.*Inhibits isoform.(*)Modest decrease.†Metabolized by isoform.‡Induces isoform.

tic efficacy. On the other hand, blood levels of these same drugs areincreased by those agents that act as inhibitors of the CYP 3A4 isoform. Theprototype inhibitors are cimetidine and erythromycin. Grapefruit juice, thecalcium blockers verapamil and diltiazem, and the antifungal agents (suchas ketoconazole) also act as inhibitors. Thus excess circulating levels maybuild up, with a greater risk of adverse effects of statins, including greaterrisk of myopathy.

There may also be a greater therapeutic effect as the result of such druginteractions. For example, the dose of the expensive immunosuppressivecyclosporine can be reduced by cotherapy with verapamil or ketocona-zole or high levels of grapefruit juice intake. Cimetidine inhibits a varietyof other isoforms, so that it can increase blood levels of a host of drugs,including the antiarrhythmics quinidine, lidocaine, and procainamide;the CCB verapamil; and the β-blocker propranolol (Table 1). Cimetidinetherefore increases the blood levels of many of the cardiovascular drugsthat are metabolized in the liver. Ranitidine inhibits fewer isoforms and isless likely to interact in this way (Table 1).

Pharmacodynamic Hepatic InteractionsPharmacodynamic hepatic interactions occur whenever altered hepatic blood

flow changes the rate of first-pass liver metabolism. For example, when aβ-blocker and lidocaine are given together, as may occur during acutemyocardial infarction, the β-blocker reduces both the hepatic blood flow to


TABLE 2. Proposed P-glycoprotein–mediated interactions of cardiac drugs: comparison with the inhi-bition of hepatic cytochrome isoformsP-Glycoprotein interaction Cytochrome inhibition

AntiarrhythmicsAmiodarone Inhibits several, including 3A4Quinidine Inhibits 2D6Propafenone None

CCBsVerapamil Inhibits 3A4Diltiazem (weak) Inhibits 3A4

Other cardiac agentsDigoxin NoneReserpine NoneSpironolactone None

Other agentsCyclosporine NoneDipyridamole NoneErythromycin Inhibits 3A4HIV protease inhibitors Inhibit 2D6, 3A4Ketoconazole Inhibits 3A4Phenothiazines None

Data from Abernathy and Flockhart2 and from Table I.

the liver and the rate of hepatic metabolism of lidocaine.113 The conse-quence is an increased blood lidocaine level, with the risk of lidocaine tox-icity. Conversely, by increasing the hepatic blood flow, nifedipine has theopposite effect so that the breakdown of propranolol is increased, whichresults in lower blood levels of propranolol.76 The combination of nifedi-pine and atenolol (the latter not being metabolized in the liver at all) there-fore seems theoretically better than that of nifedipine and propranolol.

P-Glycoprotein This newly discovered digoxin transporter36 operates whenever

digoxin crosses the cell membrane (Table 2), for example during renalexcretion or when being taken up through the gut wall. Inhibition of thetransporter explains the major effects of quinidine and verapamil on blood digoxin levels and lays aside the previous concept that erythromycin and tetracycline increased digoxin levels by inhibiting thegut flora that break down digoxin.87 Rather, these agents and especiallyerythromycin may act at least in part by inhibiting the P-glycoprotein.Possible interactions at this molecular site can be deduced from Table 2.

Proarrhythmic Drug InteractionsThese do not fit neatly into the standard differentiation between phar-

macodynamic and pharmacokinetic interactions. They must be consideredseparately. There are basically 3 possible proarrhythmic mechanisms.


TABLE 3. Potentially proarrhythmic drug interactions: prolongation of QT interval with risk of torsadesde pointesCardiac drug Interacting drugs Mechanism Prophylaxis Reference

Antiarrhythmics: Predisposing: Inhibition of Avoid cotherapy of 95Class IA diuretic use repolarizing predisposing agents; 176

Quinidine with decreased potassium current avoid bradycardia;Disopyramide plasma K; all with prolongation avoid low plasma K;

Class III bradycardiac agents, of action potential use K-sparing diuretics;Sotalol especially β- duration avoid hypokalemia,Amiodarone blockers, including hypomagnesemiaDofetilide sotalol; cotherapyIbutilide with class IA

or class III drugsCalcium As above Presumed inhibition As above 50

antagonists of repolarizing 127Bepridil K current[mixed agent]

Mood altering drugs As above Presumably by As above 98Thioridazine prolongation of 176Chlorpromazine action potentialAmitriptyline duration; complexMaprotiline mechanism,Nortriptylene including

antimuscariniceffects, adrenergiceffects, andquinidine-like effects

First, prolongation of the QT interval may occur, especially in the presenceof hypokalemia and/or bradycardia (Fig 1; Table 3). The type of arrhyth-mia produced by QT prolongation is highly specific, namely torsades depointes. Second, agents that increase myocardial levels of cyclic adenosinemonophosphate or cytosolic calcium levels cause arrhythmias through adifferent mechanism, namely the precipitation of ventricular tachycardiaand/or fibrillation (Fig 1; Table 4). Third, β-adrenergic stimulants decreaseplasma potassium levels, which in turn promote automaticity.

Renal Pharmacokinetic Interactions A number of drugs interact with each other by competing for renal clear-

ance mechanisms by altering the rate of renal clearance of the other drug(Table 5). For example, the renal clearance of digoxin is decreased byquinidine (by inhibition of the transporter P-glycoprotein), which leads to


FIG 1. Major proarrhythmic mechanisms. On the left, widening of the action potential duration with QTprolongation and risk of torsades de pointes. Antiarrhythmics may interact by way of QT prolongationand in the presence of early after depolarizations (EADs) to produce proarrhythmic effects with risk oftorsades de pointes. Class IA and III antiarrhythmic agents prolong the action potential duration so thattorsades becomes more likely, especially when there is predisposing QT prolongation as result of diuretic-induced hypokalemia or hypomagnesemia. Less commonly, torsades may develop on initiation of antiar-rhythmic drug therapy when there is a preexisting QT prolongation. A combination of class IA agents(eg, quinidine or disopyramide) and class III agents (eg, amiodarone, sotalol, ibutilide, dofetilide) maystrongly interact. On the right, arrhythmias are produced directly as result of increased cytosolic calcium,including digitalis toxicity, β-adrenergic agonist stimulation, and phosphodiesterase inhibitors. Increasedinternal calcium cycling gives rise to delayed after depolarizations (DADs) and triggers automaticity.Note the role of drug summations (eg, digoxin and phosphodiesterase inhibitors). Figure copyright L.H.Opie. (From Drugs for the Heart. 4th ed. Philadelphia: Saunders; 1995. With permission.)

an elevation of blood digoxin levels. This renal interaction attracted theattention of cardiologists because it explained certain strange aspects ofthe effects of these 2 drugs when they were administered in combina-tion. The knowledge of this interaction showed that established proper-ties of a drug could perhaps be explained more simply as drug interac-tions.45 For example, “quinidine syncope” could be caused bydigitalis-induced arrhythmias, precipitated by cotherapy with quinidine.Other antiarrhythmics that inhibit the renal excretion of digoxin includeverapamil, amiodarone, and propafenone, all acting on the transporter(Table 2).

Plasma Protein Binding as a Site for Drug InteractionsSulfinpyrazone powerfully displaces warfarin so that the dose of war-

farin required may be dramatically less.6 In dogs, prazosin displacesdigoxin from plasma and other binding sites.129


TABLE 4. Potentially proarrhythmic drug interactions: agents increasing myocardial cyclic adenosinemonophosphate or cell calcium levels or decreasing plasma potassium levelsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Phosphodiesterase All proarrhythmic Increase of Risk of Beware of acute 90III inhibitors: drugs, particularly myocardial VT/VF myocardial

Amrinone β-adrenergic cyclic ischemia; avoidMilrinone stimulants adenosine chronic use inEnoximone monophosphate, left ventricleCilostazol especially in failure; monitor ECG;

presence of avoid cotherapyischemia with proarrhythmic

drugsβ-Adrenergic All proarrhythmic Increase of Risk of As above; check 90

stimulants: drugs myocardial VT/VF plasma potassiumDopamine cyclic AMP;Dobutamine decrease ofNoradrenaline plasmaAdrenaline potassium

Bronchodilators: All proarrhythmic Inhibition of phos- Risk of Caution in asthmatic 17Theophylline drugs phodiesterase; VT/VF patients withAminophylline increase of cyclic (not cardiac arrhythmia

AMP; decrease common) or heart failure;of plasma avoid broncho-potassium dilators

for asthma ifproarrhythmicdrugs arebeing given

Digitalis: All proarrhythmic Inhibition of VT associated Caution in 89Digoxin drugs, particularly sodium pump with atrio- hypokalemia or

β-adrenergic with increase of ventricular cotherapy withstimulants or cytosolic calcium nodal block pro-arrhythmicphosphodiester- and calcium- drugsase inhibitors induced after depo-

larizationsDiuretics: Digoxin; other Decreased plasma VT/VF; Check plasma 145

Thiazides proarrhythmic K with increased torsades de potassium; useLoop diuretics drugs, including afterdepolari- pointes K-retaining

those prolonging zations; diuretic, such asaction potential sensitization to triamterene orduration digoxin amiloride

arrhythmias

VF, Ventricular fibrillation; VT, ventricular tachycardia.

Pharmacodynamic Hemodynamic Drug InteractionsSinoatrial and Atrioventricular Nodes

The sinoatrial node responds to at least 3 pacemaker currents, includingthe inward “funny” sodium current, If, initially described in Purkinje fibers;the long-acting calcium current (ICa[L]); and the delayed rectifier, outwardpotassium current Ik.

115 Of these pacemaker currents, 2 are susceptible to β-blockers, and 1 is susceptible to calcium antagonists (Table 6). The reasonsthat the combination of a β-blocker with a CCB does not arrest the heart areseveral fold. First, neither type of drug affects 1 of the several pacemakercurrents, the outward potassium current Ik. Second, the CCB effect is on the


TABLE 5. Renal interactions of cardiovascular drugsDrug Interactingcategory drug Mechanism Consequence Prophylaxis Reference

Digoxin Quinidine Decreased renal Increased risk — 45Propafenone clearance of of toxicity 51

Amiodarone digoxin, may act 96Verapamil on P-glycoprotein 125

digoxin transporter(Table 2)

Diuretic Probenecid Decreased tubular Decreased diuretic Increase diuretic 109excretion of diuretic effect dose or avoid

cotherapyCaptopril Probenecid Probenecid inhibits Small rise in Decrease dose 147

tubular excretion captopril levels of captoprilof captopril

Furosemide Captopril Captopril decreases Decreased Care during 158renal excretion of furosemide efficacy interaction;furosemide adjust drug

dosageACE inhibitors NSAIDs Both may reduce Added risk of renal Avoid cotherapy; 136

renal plasma flow failure and test dose forhyperkalemia ACE inhibitor–

inducedhypotension

TABLE 6. Drug interactions at the level of the sinoatrial node to cause excess bradycardiaDrug Mechanism Prophylaxis Reference

β-Blockers Inhibition of pacemaker Care during cotherapy; 148current If; inhibition of monitor sinus rate;adrenergic-stimulated caution in sick sinuspacemaker current ICa(L) syndrome (elderly patients)

Other adrenergic Indirectly decreased As abovemodifiers: adrenergic drive to

Methyldopa sinus nodeReserpineClonidine

Amiodarone Mild β-blocking effect As above; cotherapy may be 12indicated for severe 95arrhythmias

CCBs (especially Inhibition of pacemaker As above; avoid intravenous 44verapamil and current ICa(L) verapamil during cotherapy diltiazem) with other listed drugs

Digitalis Stimulation of vagus with As above; avoid intravenous 136increased current Ik(ACh), digoxinhyperpolarization andinhibition of If and ICa

ICa(L). The transient calcium current, which probably accounts for the initialphases of depolarization in the sinoatrial and atrioventricular nodes, is notaffected by standard CCBs. Third, only CCBs of the verapamil and dilti-azem types are effective on the sinoatrial node in clinically used therapeuticlevels.

Dihydropyridines (nifedipine, felodipine, isradipine, amlodipine, andothers) have a much less marked effect on the sinoatrial node. In contrast,sinoatrial arrest has been reported when an intravenous bolus of verap-amil or diltiazem is administered to predisposed patients who are alreadyreceiving β-blocker therapy. Thus, adverse drug reactions at the level ofthe sinoatrial node that cause excess bradycardia (Table 6), excess tachy-cardia (Table 7), or atrioventricular block (Table 8) often involve β-block-ers, CCBs, or digitalis.


TABLE 7. Drug interactions at the level of the sinoatrial node to cause excess tachycardiaDrug Mechanism Predisposing drugs Reference

Quinidine Anticholinergic, binds to Tricyclic antidepressants; 97muscarinic receptor; vasodilators including 105vasodilator (α-blocker) nitrates

Disopyramide Anticholinergic, binds ×40 As above 105more strongly to muscarinicreceptor than does quinidine

Procainamide Anticholinergic, binds less As above 105strongly to muscarinic receptor than quinidine

Dihydropyridines (ie, Vasodilation and reflex Anticholinergics; other 82nifedipine-like agents) adrenergic activation* vasodilators; tricyclic

antidepressants

*May be diminished by use of ultra long-acting preparations.

TABLE 8. Drug interactions at the level of the atrioventricular node to cause atrioventricular conductiondelayDrug Mechanism Predisposing conditions Reference

Verapamil or diltiazem Inhibition of ICa(L) Atrioventricular nodal disease 142(ischemia, myocarditis,old age); cotherapy

Digoxin Vagomimetic As above 5489

β-Blockers Inhibition of β-adrenergic As above 168stimulation of ICa(L)

TABLE 9. Drug interactions at the level of the intraventricular conduction systemDrug Mechanism Predisposing conditions Reference

Antiarrhythmic class IA: Sodium channel Conduction delay (ischemia, 107quinidine, disopyramide inhibition old age, myocarditis);

antiarrhythmic cotherapyAntiarrhythmic class IC: Sodium channel block As above 152

Flecainide with prolonged recoveryEncainide from blockPropafenone

Intraventricular Conduction SystemThere are a number of antiarrhythmics that inhibit the intraventricular

(His-Purkinje) conduction system. When these are administered ascotherapy, they may interact to produce serious additive intraventricularconduction defects (Table 9).


TABLE 10. Negatively inotropic drug interactions at the level of myocardial contractile systemPredisposing

Drug Mechanism conditions Reference

β-Blockers: Decreased calcium entry Left ventricle failure; 23Probably all by calcium channel, cotherapy

decreased heart rate,decreased uptake ofcalcium into sarcoplasmicreticulum

CCBs: Direct negative inotropic As above 117Verapamil effect, more marked inDiltiazem clinical practice forNifedipine verapamil and diltiazemOther dihydropyridines than for the dihydropyridines

Antiarrhythmic agents: Unknown, possible direct As above 66Disopyramide interference with 130Flecainide calcium fluxes

TABLE 11. Vascular smooth muscle: drug interactions to cause excess vasoconstrictionDrug Interactingcategory drug Mechanism Consequence Prophylaxis Reference

Mood-altering drug: All vaso- Major inhibition Increased risk Avoid 18Cocaine constrictors of reuptake or of coronary

norepinephrine vasoconstriction;by nerve Prinzmetal’sterminals angina;

myocardialinfarction

Antidepressants: All vaso- Inhibition of Excess Avoid cotherapy 55Monoamine constrictors reuptake of hypertension; with other vaso-

oxidase norepinephrine risk of constrictiveinhibitors coronary spasm drugs,

especiallydopamine; carein states of highadrenergic driveor nicotine use;care in Raynaud’sdisease

Inotropic All vaso- α-Adrenergic– As above As above 55vasoconstrictors: constrictors mediated

Dopamine (high vasoconstrictiondose)

Norepinephrine

Antimigraine agents: All vaso- Ergotamine- Coronary Avoid in patients 92Ergotamine constrictors induced “direct” vasoconstriction; with ischemicSumatriptan vasoconstriction; Prinzmetal’s heart disease,

5HT1 agonism angina; previous myocardial myocardialinfarction infarction,

Prinzmetal’sangina, oruncontrolledhypertension

5HT1, 5-Hydroxytryptamine receptor subtype 1.

Myocardial Contractile MechanismThere are a number of drugs with negative inotropic effects, including

β-blockers, calcium antagonists, and certain arrhythmic agents (Table10). Often, a relatively well-functioning left ventricle is able to withstandcotherapy with these drugs; but, when the left ventricle is diseased, evenone of these drugs may precipitate heart failure.

Vascular Smooth Muscle In vascular smooth muscle, there can be interactions to cause excess

vasoconstriction (eg, the combination of a drug [such as cocaine] thatinhibits the reuptake of norepinephrine from the nerve terminals togetherwith therapeutic administration of monoamine oxidase inhibitors, whichalso inhibit the reuptake of norepinephrine in the nerve terminals). Thecombination of cocaine with these inhibitors could, theoretically, power-fully promote coronary vasoconstriction (Table 11). When dopamine isinfused into a patient receiving monoamine inhibitors, there is a risk ofsevere hypertension from excess sensitivity to dopamine.55

Conversely, there may be a number of drug interactions that cause excessvasodilation and hypotension (eg, the combination of the α1-blocker pra-zosin with the powerful calcium antagonist vasodilator nifedipine; Table12).


FIG 2. Cardiac pharmacodynamic interactions at the levels of the sinoatrial (SA) node, atrioventricular(AV) node, conduction system, and myocardium. The predisposing disease conditions are shown on theleft. Figure copyright L.H. Opie. (Modified from Drugs for the Heart. 5th ed. Philadelphia: Saunders; inpress. With permission.)

Vascular smooth muscle can also be the site of drug interactions thatlessen the effects of antihypertensive or antifailure therapy (Table 12).

β-Adrenergic Blocking Drugsβ-Adrenergic blockers, by their inhibitory effects on the sinoatrial and

atrioventricular nodes can potentially interact negatively with severalother cardioactive drugs, including some of the CCBs (verapamil and dil-tiazem) and amiodarone (Fig 2). Otherwise they create relatively few seri-ous drug interactions (Table 13). An example of a pharmacokinetic inter-action is cimetidine,73 which reduces hepatic blood flow and increasesblood levels of propranolol and metoprolol, which are both metabolized in


TABLE 12. Vascular smooth muscle: drug interactions to cause excess vasodilation and hypotensionDrug Interactingcategory drug Mechanism Consequence Prophylaxis References

ACE inhibitors Excess diuretics Inhibition of First-dose Caution in conditions 91ARBs vasoconstrictive hypotension of renin

AII-receptor activation, suchstimulation as volume

depletion,diuretics,renal artery stenosis, saltdepletion; perindopril maydiminish first-dose hypotension

α1-Blocker: CCBs Inhibition of Excess Initial low dose of 74prazosin, and vasoconstrictor hypotension prazosin; sometimesprobably all α1-receptors reduce dose ofothers nifedipine

CCBs: Prazosin, Inhibition of Excess Caution during 74Verapamil quinidine vascular smooth hypotension cotherapy; 135Nifedipine muscle calcium start with lowOther dihydro- channel initial dosepyridines

Antiarrhythmics: Prazosin, Peripheral α1- Excess Caution during 97Class IA CCBs receptor hypotension cotherapy; avoidQuinidine blockade intravenous

quinidine

Nonsteroidal Antihypertensive; Inhibition of Decreased Avoid nonsteroidal 27antiiflammatory antifailure formation of effect of antiiflammatory 173drugs drugs acting vasodilatory antihyper- drugs if

by vasodilation prostaglandins; tensive drugs; possiblesodium retention worsening of

heart failureAspirin ACE inhibitors; Inhibition of Decreased Cautious cotherapy 46

possibly ARB vasodilatory efficacy of if indicated; useprostaglandins antiotensin- low dose of aspirin,

converting high dose ofenzyme antiotensin-inhibitor converting enzymewhen used inhibitorfor heartfailure(ARBs arenot licensedfor heartfailure)

ARBs, Angiotensin receptor blocks.

the liver (Table 1). However, there is no interaction of cimetidine with β-blockers such as atenolol, sotalol, and nadolol, which are not metabolizedin the liver. Another pharmacokinetic interaction is when verapamil raisesblood levels of metoprolol through a hepatic interaction.102 Presumablyother β-blockers metabolized by the liver may be subject to a similar inter-action.

Now often used in the acute phase of myocardial infarction, β-block-ers may depress hepatic blood flow, thereby decreasing hepatic inactiva-tion of lidocaine.113 Thus, β-blockade increases lidocaine blood levelswith enhanced risk of toxicity. An example of pharmacodynamic inter-action is that with nonsteroidal antiinflammatory drugs (NSAIDs),including indomethacin, which may attenuate the antihypertensiveeffects of β-blockers, possibly by decreasing the formation of vasodila-tory prostaglandins.170

Nitrates


TABLE 13. Drug interactions of β-adrenergic blocking agentsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Hemodynamic interactions

All β-blockers Calcium Added hypotension Risk of myocardial Blood pressure control, 120antagonists, Added negative ischemia adjust dosesespecially inotropic effect Risk of myocardial Check for congestivenifedipine, failure heart failure,verapamil, or adjust dosesdiltiazem

Flecainide Hypotension Check left ventricle function, 122flecainide levels

Electrophysiologic interactions

All β-blockers Verapamil Added inhibition of sino- Bradycardia, asystole, Exclude “sick-sinus” 29atrial, atrioventricular complete heart syndrome, atrioventricularnodes block nodal disease

Diltiazem Added negative Excess hypotension Adjust dose, exclude predrug 57inotropic effect left ventricle failure

Hepaticinteractions

Propranolol Cimetidine Cimetidine decreases Excess propranolol Reduce both drug doses 102propranolol effectsmetabolism

Lidocaine Low hepatic blood flow Excess lidocaine Reduce lidocaine dose 113effects

Metoprolol Verapamil Verapamil decreases Excess metoprolol Reduce metoprolol dose 102metoprolol metabolism effects

Cimetidine Cimetidine decreases Excess metoprolol Reduce both drug doses 68metoprolol metabolism effects

Labetalol Climetidine Climetidine decreases Excess labetalol Reduce both drug doses 25labetalol metabolism effects

Antihypertensive interactionsβ-blockers Indomethacin (I), Indomethacin inhibits Decreased antihyper- Omit indomethacin; use 170

NSAIDs vasodilatory tensive effect alternative drugs (ie, notprostaglandins NSAIDs)

PharmacodynamicsThe major pharmacodynamic drug interaction of nitrates is with sildenafil

(Viagra), both being powerful vasodilatory agents. Thus, there is risk oflife-threatening hypotension, so that the combination is absolutely con-traindicated.2 Other interactions of nitrates are also largely pharmacody-namic (Table 14). For example, during triple therapy of angina pectoris(nitrates, β-blockers, calcium antagonists), the efficacy of the combinationmay be lessened because each drug can predispose to excess hypoten-sion.157 Even 2 components of triple therapy, such as diltiazem and nitrates,may interact adversely to cause moderate hypotension.16 Nonetheless, highdoses of diltiazem can improve persistent effort angina when added to max-imum doses of propranolol and isosorbide dinitrate without any report ofsignificant hypotension.9 Therefore, individual patients vary greatly in theirsusceptibility to the hypotension of triple therapy.

Other InteractionsUnexpectedly, high doses of intravenous nitrates may induce heparin

resistance by altering the activity of antithrombin III.7 In dogs, nitroglyc-erin interferes with the therapeutic efficacy of the tissue plasminogenactivator, alteplase (for clinical application, see section on alteplase).104

There is a beneficial interaction between nitrates and hydralazinewhereby the latter helps to lessen nitrate tolerance.39 The proposed mech-anisms are speculative but may include the vasodilation by a differentmechanism to overcome the vasoconstriction of nitrate intolerance and inpart as a free radical scavenger because peroxynitrite triggers the vaso-constriction.

Calcium Channel BlockersMany of the interactions of CCBs (Table 15) are pharmacody-

namic,134 such as the added effects on the atrioventricular or sinusnodes (verapamil or diltiazem plus β-blockers, excess digitalis, or


TABLE 14. Drug interactions of nitratesHemodynamic interactions

Cardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

All nitrates CCBs Excess vasodilation Syncope, dizziness Monitor blood pressure 79Prazosin Excess vasodilation Syncope, dizziness Check blood pressure,Other α-blockers low initial dosesSildenafil (Viagra) Excess hypotension; Viagra Excess hypotension, Before giving nitrates Package

is metabolized by 3A4 syncope, myocardial for unstable angina, insert forisoform, so that inhibitors infarction question the use of kinetic(erythromycin, others) Viagra in the dataand ritonavir predispose preceding 24 hto excess Viagra levelsand to nitrate interaction


TABLE 15. Drug interactions of CCBsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Verapamil β-Blockers Sinoatrial and Added nodal and Care during cotherapy; 29atrioventricular negative inotropic check electrocardiogram,nodal inhibition; effects blood pressure, and myocardial failure heart size

Cimetidine, other Hepatic metabolic Blood verapamil Adjust dose 1inhibitors of interaction rises 126CYP 3A4

Cyclosporine, Inhibited hepatic Increased blood levels Decrease dose of 1other drugs metabolism of of cyclosporine or cyclosporine or Viagrametabolized by cyclosporine or other drugs, other drug packageCYP 3A4 of other drug including Viagra insert

(Table 1)Digitalis Added sinoatrial and Asystole; complete Avoid intravenous verapamil 119

poisoning atrioventricular heart block after in digitalis poisoningnodal inhibition intravenous verapa-

milDigoxin Decreased digoxin Risk of digoxin Halve digoxin dose; 1

clearance, inhibition toxicity blood digoxin level 125of P-glycoprotein

Disopyramide Pharmacodynamic Hypotension, Check blood pressure, Noneconstipation left ventricle, and gut

Flecainide Added negative Hypotension Check left ventricle and Noneinotropic effect flecainide levels

Prazosin, other Hepatic interaction Excess hypotension Check blood pressure 135α-blockers during cotherapy

Quinidine Added α-receptor Hypotension; in- Check quinidine levels 94inhibition; verapamil creased quinidine and blood pressuredecreases quinidine levelsclearance

Theophylline Inhibition of hepatic Increased blood Reduce theophylline, 48metabolism theophylline levels check levels

Diltiazem β-Blockers Added sinoatrial nodal Bradycardia, Check electrocardiogram 57inhibition; negative hypotension and left ventricle functioninotropism

Cimetidine, Hepatic metabolic Increased diltiazem Reduce diltiazem dose 126other interaction levels by one-thirdinhibitorsof CYP 3A4

Cyclosporine, Inhibited hepatic Increased blood le- Decrease dose 1other drugs metabolism of vels of cyclosporine of cyclosporine or 43metabolized cyclosporine or or other drugs, other drug Viagraby CYP 3A4 of other drug including Viagra package

(Table 1) insertDigoxin Some fall in digoxin Only in renal failure Check digoxin levels 126

clearanceFlecainide Added negative Hypotension Check left ventricle None

inotropic effect and flecainide levelsAmlodipine Few Metabolized very No clinically relevant Add amlodipine with Package

slowly by CYP 3A4 changes no major concern insertFelodipine Cimetidine, other Metabolized by Increased blood Reduce felodipine dose Table 1

inhibitors of CYP 3A4 felodipine levels and watch for dietaryCYP 3A4 grapefruit juice

Nicardipine Cyclosporine Hepatic metabolism Increased blood Decrease cyclosporine dose 11(see also of cyclosporine cyclosporinenifedipine) inhibited levels

Nifedipine β-Blockers Added negative Excess hypotension Check blood pressure, 120inotropism use low initial dose

Cimetidine, other Hepatic metabolic Increased blood Decrease nifedipine 126inhibitors of interaction nifedipine levels dosage by 40%CYP 3A4

Digoxin Minor/modest Increased digoxin Check digoxin levels 76changes in digoxin levels

Prazosin, other Prazosin blocks α Postural hypotension Low initial dose of 74α-blockers reflex to nifedipine nifedipine or prazosin

or other α-blockerPropranolol Nifedipine and Nifedipine decreases Readjust propranolol 76

propranolol have propranolol levels; and nifedipine doses, opposite effects on propranolol increases if neededblood liver flow nifedipine levels

Quinidine Nifedipine improves Decreased quinidine Check quinidine levels 32poor LV function; effectquinidine clearancefaster

amiodarone) or on the systemic vascular resistance (eg, nifedipine plusβ-blockers causing excess hypotension). However, it is now increas-ingly recognized that verapamil and especially diltiazem (but perhapsnot nifedipine) inhibit the hepatic oxidation of some drugs by the CYPsystem, the blood levels of which consequently increase. Such agentsinclude cyclosporine (verapamil and diltiazem), the antiepileptic car-bamazepine (verapamil and diltiazem), prazosin (verapamil), theoph-ylline (verapamil), and quinidine (verapamil). Conversely, all CCBsare oxidized by the CYP 3A4 system, so the inhibition of this isoen-zyme by erythromycin or ketoconazole will increase blood levels ofCCBs with increased risks of adverse effects such as hypertension orheart block, depending on the variety of CCB. Amlodipine, weaklymetabolized by CYP 3A4, is an exception.

Grapefruit juice is also an inhibitor of the CYP 3A4 system, which leadsto a doubling of the bioavailability of felodipine and lesser effects onmost other dihydropyridines with the exception of amlodipine.

VerapamilIntravenous verapamil (Calan, Isoptin) is now less often used for

acute supraventricular tachycardias than, for example, intravenousadenosine. Yet, it is still sometimes given intravenously to patients whoare already receiving β-adrenergic blockers, with the additional risk ofadded hypotension or nodal inhibition.29 Verapamil also directly inter-acts with the β-receptors.26 In patients with angina pectoris who arealready receiving β-blockers, verapamil given intravenously70 ororally122 can reduce contractility,122 increase heart size,64 and causesinus bradycardia.172 By a hepatic pharmacokinetic interaction,47 vera-pamil may raise blood levels of the β-blockers that are metabolized bythe liver. Despite such hepatic interactions (eg, verapamil with propra-nolol) in normal subjects, pharmacodynamic changes are more impor-tant.110 In those with chronic exertional angina, the combination of ver-apamil and β-blockade in the therapy of angina pectoris must be usedwith care with preexisting depression of the sinoatrial or atrioventricu-lar nodes and clinically detectable myocardial failure. The combinationof verapamil and β-blockers improves myocardial function during exer-cise more than either agent alone.63 Verapamil plus a β-blocker mayhave an additive therapeutic effect in hypertension, with a small risk ofexcess inhibition of sinus rate, atrioventricular conduction, or left ven-tricular function.100

Other Drug Interactions with Verapamil


Digoxin. Verapamil can increase blood digoxin levels by about50%.125 The mechanism is that verapamil inhibits the activity of the P-glycoprotein that transports digoxin across cell membranes.140 The doseof digoxin must be cut to about one half, and blood levels of digoxinmust then be rechecked. In digitalis toxicity, rapid intravenous vera-pamil is absolutely contraindicated because the sum of the inhibitoryeffects of these 2 agents on the atrioventricular node can be fatal.Experimentally, verapamil can inhibit the calcium-dependent delayedafterdepolarization, which causes the ventricular automaticity found indigitalis toxicity. Oral verapamil and digitalis can, however, be com-bined in the absence of digitalis toxicity or atrioventricular blockbecause their pharmacologic sites of action are different; nonetheless,the digoxin level must be monitored. The combination is sometimesused for the management of supraventricular tachycardias.

Prazosin. The combination of verapamil with prazosin for hypertensionprovides added and synergistic effects.28 A hepatic pharmacokinetic interac-tion with enhanced bioavailability or prazosin may explain these effects.123,135

Quinidine. Verapamil and quinidine may interact to cause excesshypotension,94 either by the combined inhibition of peripheral receptors orby an increase of quinidine levels161; the latter may be a hepatic interaction.

Disopyramide. Both verapamil and disopyramide are powerful negativeinotropes, so the combination can only be given when the left ventricularfunction is good before the initiation of therapy and can be closely monitored.

Theophylline. Verapamil may inhibit the hepatic metabolism of the-ophylline and lead to increased blood theophylline levels.48

DiltiazemDiltiazem (Cardizem, Tildiem, Herbesser, Tilazem) plus long-acting

nitrates occasionally causes excess hypotension.16 The combination ofhigh-dose diltiazem with β-blockade may cause bradycardia or hypoten-sion.57 Relatively few life-threatening interactions have been describedfor diltiazem, perhaps because intravenous diltiazem is relatively new.Clinicians have applied the cautionary experiences gained with intra-venous verapamil to the use of diltiazem. Because diltiazem is metabo-lized by the liver, it interacts with cyclosporine, which results in anincreased cyclosporine blood level.43 Its metabolism also should bedecreased, with an expected increase in blood levels, by all agents thatinhibit the CYP 3A4 system (such as grapefruit juice, verapamil, cimeti-dine, erythromycin, or ketoconazole). Diltiazem may increase plasmadigoxin levels by about 20% (according to the package insert), probablybecause it inhibits the digoxin transporter, P-glycoprotein.140


Nifedipine

Hepatic interactions. Nifedipine (Procardia, Adalat), like the other CCBs,is metabolized through the hepatic P-450 3A4 system. Therefore, cimetidineshould and does increase nifedipine plasma levels, by almost 80% (accord-ing to the package insert). Likewise, grapefruit juice ingestion increases thebioavailability of nifedipine by about one third.133 Although not listed in thepackage insert, all the other inhibitors of the P-450 3A4 system (such aserythromycin and ketoconazole) should increase plasma nifedipine levels.

Pharmacodynamic interactions. The combination of nifedipine with β-blockade is generally well tolerated, except for the risk of hypotension.120

This risk is lessened by slow release forms that liberate the drug less rapidly.Nifedipine and propranolol may have a pharmacokinetic interaction wherebyblood levels of propranolol are increased; it is thought that nifedipineincreases the hepatic blood flow so that propranolol breakdown in the liver islessened.76 Although nifedipine is an afterload reducer, it also has a potentialdirect negative inotropic effect that is usually offset by reflex adrenergicstimulation. Hence, a combination with β-blockers, disopyramide, or othernegative inotropic agent should be undertaken with caution when depressedleft ventricular function is present. Nifedipine combined with prazosin maycause excess hypotension,74 so low initial additive doses are recommended.Similar interactions may take place with doxazosin and other α1-blockers.

AmlodipineBecause of the gradual onset of action of this drug, acute pharmacody-

namic interaction with hypotension as a result is not common although itis still a potential risk. Like nifedipine, the absence of nodal effects in clin-ical doses means that a combination with a β-blocker is relatively straight-forward. There are few drug pharmacokinetic interactions. Amlodipine(Norvasc) does not change blood levels of digoxin or the effects of war-farin. Neither a significant cimetidine nor a grapefruit juice interaction65

has been found (according to the package insert). These observations, andthe long half-life of amlodipine, can be explained by the low affinity of theCYP 3A4 system for amlodipine, which distinguishes it from the otherCCBs. It is not listed as 1 of the 7 CCBs that inhibit 3A4 in the CYP-450drug interaction table on the Georgetown University Web site.1 This pro-posal, in turn, means that amlodipine would be the CCB of choice in thosewho are receiving known inhibitors of the CYP 3A4 system (such asgrapefruit juice, cimetidine, erythromycin, or ketoconazole). In each case,it could be anticipated that there would be a low but not zero probabilityof an interaction.


FelodipineBioavailability is influenced by food (a high fat or high carbohydrate

diet can increase the maximal plasma concentration by 60%); by grape-fruit juice, which can double the bioavailability (according to the packageinsert); and by cimetidine, which increases area under the curve of theplasma concentration by 50%. Thus, felodipine (Plendil) is clearly metab-olized by the CYP-450 3A4 system, and blood levels should increase dur-ing cotherapy with erythromycin or ketoconazole, or other inhibitors andthis enzyme.

IsradipineIsradipine (Cynacirc CR) can be expected to have the standard pharma-

codynamic and hepatic interactions of these agents. It is metabolized bythe P-450 3A4 system. Thus, plasma levels should rise in response to thecoadministration of grapefruit juice, cimetidine, cyclosporine, eryth-romycin, or ketoconazole.

Antiarrhythmic AgentsThe emphasis of antiarrhythmic therapy has moved away from agents

that that do not save lives, such as the class 1a agents quinidine anddisopyramide, and from class 1c agents such flecainide or propafenone.All of these have potentially proarrhythmic drug interactions (Tables 3 and9). The new emphasis is on drugs that are known to save lives, such as theβ-blockers and amiodarone. Increasingly, there is another trend to inter-vene invasively in those patients with serious recurrent supraventricularreentrant tachycardias of the Wolff-Parkinson-White syndrome rather thanto face prolonged drug therapy. In ventricular tachycardia, the highest riskpatients are now ideally treated by an implantable cardioverter defibrilla-tor. Thus, lesser importance is now attached to some of the numerous druginteractions of these agents, which must nevertheless be understood (Table16).8,58 The most frequent antiarrhythmic drug interactions are withdigoxin (the levels of which increase with quinidine and verapamil), withdiuretics (there is a risk of QT prolongation with antiarrhythmics, such asquinidine, disopyramide, amiodarone, sotalol, dofetilide, and ibutilide,which all prolong the duration of the action potential), and at the level ofhepatic enzyme inhibition (cimetidine decreases hepatic metabolism ofquinidine).49 There is also the risk of antiarrhythmic drug-drug interac-tions. Thus, amiodarone when added to quinidine enhances the risk of QTprolongation although quinidine levels increase so that quinidine toxicityis also more likely.58 The combination of antiarrhythmic drugs that depress



TABLE 16. Drug interactions of antiarrhythmic drugsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Class IAQuinidine Amiodarone Added QT effects; blood Torsades de pointes Check QT and 95

quinidine rises potassium levelsAntibiotics Quinidine inhibits Increased antibiotic- Clinical care; check 5

(some) muscarinic receptors induced muscular drug levels 58weakness

Anticholinesterases Quinidine inhibits Decreased Avoid quinidine, if 5muscarinic receptors acetylcholine possible blood

efficacy inmyastheniagravis

Antihypertensive Added hypotensive and Hypotension, excess Regulate blood pressure Noneagents added sinoatrial bradycardia Check blood pressure 88

β-Blockers nodal effects and electrocardiogramCimetidine Cimetidine inhibits Increased quinidine Quinidine levels; consider 32

oxidative metabolism levels, risk of ranitidine 49of quinidine toxicity

Warfarin, other Hepatic interaction Bleeding Check prothrombin time 77coumarin with quinidineanticoagulants

Digoxin Decreased digoxin Risk of digoxin toxicity Check digoxin dose levels 36clearance; inhibition 45of P-glycoprotein

Disopyramide Added QT prolongation Torsades de pointes Check QT and potassium 95levels

Diuretic, Hypokalemia and QT Torsades de pointes Check QT and potassium 139potassium loses prolongation levels

Hepatic enzyme Increased quinidine Decreased quinidine Check quinidine levels 24inducers hepatic metabolism levels and doses Table 2(phenytoin, by CYP 3A4barbiturates,rifampin)

Nifedipine Increased quinidine Decreased quinidine Check quinidine levels 31clearance levels and doses

Class III agents: Added QT prolongation Torsades de pointes Check QT and potassium 101sotalol, levels Table 2amiodarone,dofetilide,ibutilide

Verapamil Decreased quinidine Excess bradycardia Check electrocardiogram 94clearance and quinidine levels

Warfarin Hepatic interaction Bleeding Check prothrombin time 77with quinidine

Procainamide Cimetidine Decreased renal Prolonged Reduce Procainamide 19Procainamide Procainamide half- dose; consider ranitidineclearance life, excess

Procainamide effectDisopyramide Agents prolonging Added QT prolongation, Torsades de pointes Check QT and potas- Package

action potential especially if sium levels insertduration hypokalemia(quinidine,amiodarone,sotalol)

Pyridostigmine Inhibition of cholinesterase Beneficial effect In myasthenia gravis, 153activity, reduces of P on disopyra- avoid disopyramidedisopyramide side mide; harmfuleffects effect of disopyra-

mide on pyridostigmineClass 1A Drugs inhibiting Pharmacodynamic Sinoatrial, Check electrocardiogram; (—)

sinoatrial or additive effects atrioventricular decrease dosesatrioventricular block; conductionnodes/conduction blocksystem(β-blockers,methyldopa,digoxin)

Class 1BLidocaine Verapamil Combined negative Hypotension Avoid intravenous digoxin 81

(lignocaine) inotropism or verapamil cotherapyCimetidine Decreased hepatic Increased lidocaine Decrease lidocaine 33

metabolism levels infusion rate

(—), Expected interaction, no reference.

the sinus node, like amiodarone and β-blockers, can occasionally lead tolife-threatening bradycardia, which requires a pacemaker.

QuinidineThis is a complex drug to manage in part because of the numerous drug

interactions (Table 16) and in part because of lack of any evidence that itcan prolong life. There is a bold death warning in the package insert.Nonetheless, quinidine continues to be used.

Pharmacodynamic and receptor interactions. Quinidine may enhance


Halothane Decreased hepatic Increased lidocaine Decrease lidocaine 13blood flow levels infusion rate

Propranolol Decreased hepatic Increased lidocaine Decrease lidocaine 113blood flow levels infusion rate

Other β-blockers Decreased hepatic Increased lidocaine Decrease lidocaine 112blood flow levels infusion rate

Mexiletine Hepatic enzyme Increased hepatic Decreased plasma Increase mexiletine (—)inducers metabolism mexiletine levels dose(phenytoin,barbiturates,rifampin)

Class ICFlecainide Amiodarone Unknown Blood flecainide rises; Decrease flecainide 146

added effect on dosenodes andmyocardium

Digoxin Decreased digoxin Blood digoxin rises Check digoxin level 86clearance slightly

Drugs inhibiting Pharmacodynamic Sinoatrial, Avoid combinations; 66sinoatrial or additive atrioventricular decrease dosesatrioventricular block; conductionnodes, intraventri- block, cardiogeniccular conduction shockor myocardial function

Cimetidine Decreased hepatic Blood flecainide Check flecainide dose 93flecainide loss rises

Propafenone Digoxin Inhibition of Increased digoxin Decrease digoxin dose 51P-glycoprotein level Table 2

Class IIIAmiodarone Drugs prolonging Additive effects on Torsades de pointes Avoid low K+; avoid 95

QT interval repolarization and combinations(quinidine, cardiac output disopyramide, intervalphenothiazines,tricyclics, thiazidediuretics, sotalol,dofetilide; ibutilide)

β-Blockers Added nodal Bradycardia; Cotherapy can be 111depression heart block very effective; may

need pacemakerQuinidine Inhibition of Blood quinidine Check quinidine levels 58

CYP 2D6 rises Table 1Procainamide Pharmacokinetic Blood procainamide Check procainamide dose 58

risesSotalol, As for amiodarone Hypokalemia plus Torsades de pointes Exclude low K+; use K+- 101

dofetilide, and including class III action, as retaining diureticibutilide amiodarone for amiodarone

Class IVAdenosine Dipyridamole Dipyridamole inhibits Excess nodal Reduce adenosine dose 169

breakdown of inhibition to 25% or lessadenosine

TABLE 16 Continued. Drug interactions of antiarrhythmic drugsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

the effects of other hypotensive agents (including verapamil94) or ofagents that inhibit the sinus node (β-blockers, verapamil, diltiazem, andmethyldopa). Quinidine is a vagolytic drug that reduces the effects of pro-cedures that enhance vagal activity, such as carotid sinus massage. Quini-dine also inhibits muscarinic receptors to reduce the effects of anti-cholinesterases in myasthenia gravis.

Hepatic and other pharmacokinetic interactions. The mechanism ofthis well-known interaction, whereby quinidine increases blood digoxinlevels, has only recently been elucidated.36 Quinidine and digoxin share acommon transport system across the cell membranes, a P-glycoproteinthat is part of the adenosine triphosphate–binding cassette superfamily.By inhibiting the transport of digoxin into the gut and urine, the blooddigoxin level is forced up and may become toxic. The dose of quinidinemust be decreased, or the dose of digoxin must be lowered, and the blooddigoxin levels must be checked.45

Hepatic interactions. Quinidine increases the effects of warfarin and othercoumarin anticoagulants by a hepatic interaction.77 When hepatic enzymesare induced by drugs such as phenytoin, phenobarbital and rifampin, thehepatic metabolism of quinidine may markedly increase with decreasedsteady-state-concentrations of quinidine.24,162 Because quinidine is metabo-lized by the P-450 3A4 system, it should be susceptible to all those agentsthat inhibit this system, such as grapefruit juice, verapamil or diltiazem,cimetidine, erythromycin, or ketoconazole. All of these should raise quini-dine blood levels. Nonetheless, nifedipine may lower plasma quinidine lev-els, probably by improving left ventricular systolic function.32,41,163

Proarrhythmic interactions. Hypokalemia decreases the antiarrhyth-mic effect of quinidine and predisposes to QT prolongation by quinidine.When quinidine is combined with other drugs that also prolong the QTinterval (such as amiodarone, sotalol, ibutilide or dofetilide, or thiazidediuretics), caution and careful monitoring of the QT interval arerequired.95 Amiodarone should not be given with quinidine (risk of tor-sades); the package insert notes that quinidine levels rise during coad-ministration thereby increasing the risk. The best policy may be simply toavoid the use of quinidine, except as a last option.

ProcainamideClearance by the kidneys, the major route of elimination, is inhibited by

cimetidine. The elimination of half-life lengthens so that the dose of pro-cainamide (Pronestyl) must be reduced.19 As a class Ia agent, it may haveproarrhythmic effects without evidence for improved survival (a warning is


printed in boldface type in the package insert). Interaction with other agentsthat prolong the QT interval may be expected, with a risk of torsades.165

DisopyramideFrom the pharmacodynamic of view, disopyramide (Norspace) is nega-

tively inotropic and is used in the therapy of hypertrophic cardiomyopa-thy. Thus, there is a potential danger of the reduction of the cardiac out-put in patients who are already receiving other negative inotropes (suchas the CCBs diltiazem and verapamil,81 the β-blockers, or flecainide) andin patients with preexisting myocardial failure. The package insert specif-ically warns against administering disopyramide 48 hours before or 24hours after verapamil. It is also potentially dangerous to combine disopyr-amide with other drugs that are likely to depress nodal or conduction tis-sues, such as quinidine, digoxin, β-blockers, and methyldopa. Disopyra-mide is ineffective in digitalis toxicity and should be avoided. There is nointeraction between disopyramide and lidocaine.

Proarrhythmic interactions may occur. The risk of QT prolongationrequires that disopyramide not be combined with other drugs that prolongthe QT interval (such as the tricyclics), with certain other antiarrhythmicagents (such as other type 1a agents), or with class III agents (such asamiodarone or sotalol, or with dofetilide or ibutilide). There is a warningin boldface type in the package insert that disopyramide has proarrhyth-mic potential and has not been shown to improve survival.

Hepatic interactions may be expected because it is metabolized by theCYP 3A4 system (according to the package insert). Phenytoin67 and otherinducers of hepatic enzymes (barbiturates, rifampin) may lower disopyr-amide plasma levels. Inhibitors of CYP 3A4 system (such as grapefruitjuice, verapamil or diltiazem, cimetidine, erythromycin, or ketoconazole)can all be expected to predispose to adverse effects. The package insertgives an example of a potentially fatal interaction with erythromycin.

LidocaineLidocaine (Xylocaine, Lignocaine) is metabolized in part by the hepatic

CYP 2D6 and in part by the 3A4 isoforms, according to the GeorgetownUniversity Web site.1 In patients who are receiving cimetidine,33 propran-olol,113 or halothane therapy,13 the hepatic clearance of lidocaine isreduced, so toxicity may occur more readily. Presumably other inhibitorsof the 3A4 isoforms also decrease lidocaine metabolism. Lidocaine maycause sinoatrial arrest, especially during the coadministration of otheragents that potentially depress nodal function,61 including β-blockers.


Mexiletine

Narcotics delay the gastrointestinal absorption of mexiletine (Mexitil).Rifampin, barbiturates, and phenytoin all induce hepatic enzymes so that theplasma levels of mexiletine are reduced. Cimetidine should, but does not,increase plasma levels of mexiletine.75 Rather, cimetidine has a beneficialside effect of decreasing the gastrointestinal symptoms that are associatedwith mexiletine. Disopyramide and mexiletine administered together maypredispose to a negative inotropic effect.14 Mexiletine may, however, becombined with quinidine,26,42 β-adrenergic blockers,80 and amiodarone,167

provided that the appropriate contraindications for each drug are observedand that the patient is closely monitored for heart failure.

FlecainideFlecainide (Tambocor) inhibits the sinus and atrioventricular nodal

function, so its combination with β-blockers, verapamil, diltiazem, anddigitalis can cause bradycardia and requires care. Flecainide also hasadditive negative inotropic effects that may exaggerate those of β-block-ers,86 verapamil, or disopyramide. Combined inhibitory effects on His-Purkinje conduction may arise during cotherapy with quinidine or pro-cainamide, and to a lesser extent with disopyramide. Flecainide bloodlevels are increased by amiodarone; when both of these drugs are used,the flecainide dose should be decreased by approximately one-third.146

Studies of healthy volunteers suggest that (1) cimetidine delays the clear-ance of flecainide93 and (2) flecainide increases blood digoxin levels.86

The mechanisms of the latter effect are not known; it does not appear toinhibit the digoxin transporter, P-glycoprotein.1

PropafenonePropafenone (Rythmol, Arytmol, Rytmonorm) is a class IC antiarrhyth-

mic drug; therefore, it may interact adversely with other drugs, depress-ing nodal function, intraventricular conduction, or the inotropic state.Nonetheless, propafenone can be combined with quinidine or pro-cainamide at reduced doses of both drugs.75 Propafenone substantiallyincreases serum digoxin levels.51 The probable mechanism is by the inhi-bition of the P-glycoprotein digoxin transmembrane transporter.36

AmiodaroneAmiodarone (Cordarone) itself, in contrast to other class III agents,

including sotalol, has little proarrhythmic proclivity. Yet, torsades de


pointes is a risk when amiodarone is combined with other drugs thatprolong the QT interval.95 Thus, an additive proarrhythmic effect mayarise with class IA antiarrhythmic agents, with the mixed class II-IIIagent sotalol, phenothiazines, tricyclic antidepressants, and thiazidediuretics (Table 16). Amiodarone does not normally depress the sinusnode, yet it may do so when it is combined with calcium antagonistssuch as verapamil or diltiazem or β-blockers.111,134 Cotherapy of amio-darone with β-blockers has a newly recognized therapeutic importance,because this combination may be life-saving in patients with severeventricular arrhythmias59 who experience heart failure or in patientsafter infarction.12 Yet, there is risk of excess bradycardia, whichrequired a permanent pacemaker in about 6% of patients in 1 series.111

Also of importance in heart failure patients, amiodarone may doubledigoxin levels (Table 4). The probable mechanism is by the inhibitionof the digoxin transmembrane transporter, P-glycoprotein.36 In addition,there a weak inhibition of several CYP hepatic isoforms, including 3A4,2C9, and others, by amiodarone and its metabolite, desethylamio-darone.114 This observation makes it theoretically possible that amio-darone could also predispose to toxicity by agents such as ery-thromycin, cyclosporine, and ketoconazole. In patients receivingwarfarin therapy, amiodarone further prolongs the prothrombin timeand, if not monitored closely, can lead to excessive bleeding.99 Themechanism is presumably by interaction at the level of the hepatic CYP2C9 isoform.1

SotalolCotherapy with any other agents that may cause hypokalemia (such as

diuretics) or prolong the action potential duration (such as quinidine,disopyramide, amiodarone, ibutilide, dofetilide, or tricyclic antidepres-sants) may precipitate torsades de pointes (Table 16).

Because sotalol (Betapace, Betapace AF) is not metabolized but is water-soluble and therefore excreted in the urine, there are no hepatic interactions.

BretyliumExperimentally, bretylium (Bretylol) may worsen digitalis-induced ven-

tricular tachycardia.38 Nonetheless, the drug may be life-saving for patientswith ventricular fibrillation that is thought to be induced by digitalis.164

AdenosineAdenosine (Adenocard) is an ultra short-acting agent that is increas-

ingly used to terminate supraventricular reentrant tachycardias. Dipyri-


damole inhibits its breakdown, so the adenosine dose must be markedlyreduced, perhaps to about one-eighth, in those patients who are under-going dipyridamole therapy.169 Rarely, in the presence of digoxin or ver-apamil, it may precipitate ventricular fibrillation (according to the pack-age insert). As a nodal inhibitor (Fig 2), it may have additive inhibitoryeffects in the presence of digoxin, verapamil, diltiazem, amiodarone, orβ-blockade.

Positive Inotropic Agents

Digoxin


TABLE 17. Drug interactions of digitalis and other positive inotropic agentsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Digoxin Amiodarone Reduced renal Digoxin level Check digoxin level; 1clearance of may double halve dosedigoxin; P-glycoprotein,(Table 2)

Atorvastatin Not known Digoxin level may Check digoxin level Package rise 20% insert

Captopril Reduced digoxin Blood digoxin Check digoxin dose 20clearance increases

Diltiazem Variable decrease of Variable blood Check digoxin level 1digoxin clearance; digoxin increases 71P-glycoprotein(Table 2)

Diuretics Reduced extrarenal Digoxin levels vary, Check digoxin level 166(potassium- digoxin clearance; may rise by 20%sparing amilorideor triamterene)

Spironolactone Spironolactone Digoxin levels reduces digoxin increase, threat of clearance, inhibits toxicityP-glycoprotein(Table 2)

Erythromycin Inhibits P-glycoprotein Decreased digoxin Check digoxin levels; 1(Table 2) loss into bowel; reduce dose if needed

increased digoxinlevels, threat oftoxicity

Nifedipine Variable effect on Variable blood Check digoxin levels 126digoxin clearance digoxin rises

Nitrendipine Reduced digoxin Blood digoxin Check digoxin levels; 72clearance; doubles halve dosemechanism not clear

Prazosin Prazosin displaces Blood digoxin rises Needs confirmation 129digoxin from in humansbinding sites

Propafenone P-glycoprotein Digoxin level Check digoxin level 51(Table 2) increases

Quinidine, P-glycoprotein Blood digoxin Check digoxin levels; 45quinine (Table 2) doubles half dose

Verapamil P-glycoprotein Blood digoxin Check digoxin levels; 125(Table 2) doubles or more halve dose

Sympathomimeticinotropes

Dobutamine, Diuretics, high Additive hypokalemic Arrhythmias Check blood potassium (—)amrinone, doses effectsmilrinone


The quinidine-digoxin interaction is best known (Table 17). Quinidineapproximately doubles the blood digoxin levels, which decreases bothrenal and extrarenal clearance.45,84,125 The mechanism is by the inhibitionof the digoxin transmembrane transporter, P-glycoprotein.36 Quininegiven for muscle cramps acts likewise. The verapamil-digoxin interactionis equally significant; digoxin levels increase by 60% to 90%.84,125 Again,the mechanism is by inhibition of the digoxin transporter.1 Nitrendipine,not available in the United States but used in Europe, resembles verap-amil by approximately doubling the digoxin levels.72 In the case of theaddition of quinidine, verapamil, or nitrendipine in a patient who isalready undergoing digoxin therapy, the previous dose of digoxinshould be reduced by one half, and the plasma digoxin level should berechecked. The other CCBs, nifedipine and diltiazem, increase digoxinlevels much less than verapamil.71,85,126 An adjustment of the digoxindose with these agents is usually not necessary, except in the presenceof renal failure (which decreases digoxin excretion). Amlodipine doesnot increase digoxin levels. Thus, there are no simple rules to explainwhich class of CCBs or which specific agent is likely to increasedigoxin levels significantly.

Among other vasodilators, prazosin increases digoxin levels in dogs bythe reduction of plasma and tissue binding.129

Among antiarrhythmics other than quinidine or verapamil, amiodarone andpropafenone51 also elevate serum digoxin levels. Both inhibit the digoxin P-glycoprotein transporter.1 Other antiarrhythmics, including procainamide andmexiletine, have no interaction with digoxin except for a relatively small riseof digoxin levels with flecainide.86 When cotherapy elevates digoxin levels,the features of digitalis toxicity may depend on the agent added. With quini-dine, tachyarrhythmias become more likely, whereas amiodarone and verap-amil seem to repress the ventricular arrhythmias of digitalis toxicity so that b-radycardia and atrioventricular block are more likely.

Diuretics may indirectly precipitate digitalis toxicity by causinghypokalemia, which, when severe (plasma potassium level, <2-3 mEq/L),may stop the tubular secretion of digoxin. Potassium-sparing diuretics(amiloride, triamterene, and spironolactone) and captopril decreasedigoxin clearance by about 20% to 30% and may also elevate serum K+

levels. When these combinations with digoxin are used in the therapy ofcongestive heart failure, the blood digoxin level must be monitored.Unexpectedly, spironolactone and its metabolite canrenone may decreasefeatures of digitalis toxicity,166 probably through increased K+ levels thatresult from aldosterone inhibition. Nonetheless, the combination digoxin-quinidine-spironolactone markedly elevates digoxin levels.35


The decreased gastrointestinal absorption of digoxin may be caused bycholestyramine, probably because of the binding of digoxin to the resin;digoxin should therefore be administered several hours before the resin orelse digoxin capsules may be used (Lanoxicaps; 0.2 mg = 0.25 mg ofdigoxin). Digoxin capsules also decrease interaction with kaolin-pectate,which reduces digoxin absorption, and with erythromycin and tetracy-cline. Cancer chemotherapeutic agents may damage intestinal mucosa todepress digoxin absorption.

Increased digoxin bioavailability with erythromycin and tetracycline87

was previously ascribed to changes in the gut flora caused by the antibi-otics. An alternative and current explanation is that erythromycin inhibitsthe P-glycoprotein transporter.1

Sympathomimetic AgentsDopamine

Dopamine (Intropin) is contraindicated during the use of cyclopropaneor halogenated hydrocarbon anesthetics (enhanced risk of arrhythmias).Monoamine-oxidase inhibitors decrease the rate of dopamine metabo-lism by the tissues; the dose of dopamine should therefore be cut to onetenth of usual.

DobutamineDobutamine (Dobutrex) decreases plasma potassium and should be

administered with care together with diuretics, especially intravenousfurosemide (Table 17).

Amrinone and MilrinoneAmrinone (Inocor) and milrinone (Primacor) are phosphodiesterase

inhibitors that can also provoke arrhythmias. During diuretic therapy,plasma K must be monitored. When these drugs are combined with digitalis,


TABLE 18. Drug interactions of diureticsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Diuretic loop Indomethacin and Pharmacodynamic Decreased antihyper- Adjust diuretic dose 170and thiazide other NSAIDs tensive effect or add another agent

Probenecid Decreased intratubular Decreased diuretic Increased diuretic dose 109secretion of diuretic effect

ACE inhibitors, Excess diuretics, Excess hypotension; Lower diuretic dose; 52ARBs high renins prerenal uremia initial low dose of ACE

inhibitor or ARBLoop Captopril Possible interference Loss of diuretic Change to another ACE 158

with tubular secretion efficacy of inhibitorfurosemide

the digoxin level does not change, but digoxin toxicity should be guardedagainst because of multiple mechanisms for arrhythmia development.

Diuretics Loop Diuretics

Loop diuretics that are administered acutely and intravenously maycause hypokalemia, which precipitates digitalis toxicity.109 Furosemidedecreases renal clearance of lithium. Certain NSAIDs may antagonizethe action of furosemide and other diuretics (Table 18). In normal sub-jects, concurrent captopril therapy lessens the diuretic effect offurosemide.

Thiazide DiureticsSteroids, estrogens, and indomethacin and other NSAIDs lessen the

antihypertensive effect of thiazide diuretics and may worsen congestiveheart failure.27 ACE inhibitors tend to be potassium-retaining and maycause hyperkalemia if combined with other potassium retainers, espe-cially when there is renal failure. Less well known is that cyclosporineplus potassium-sparing diuretics may cause hyperkalemia (according tothe cyclosporine package insert) presumably through nephrotoxicity ofthe cyclosporine. Diuretic-induced hypokalemia and/or hypomagne-semia may predispose to ventricular arrhythmias including torsades depointes; when that occurs, usually an antiarrhythmic agent (such asclass III agents including sotalol,101 dofetilide, ibutilide and probably to


TABLE 19. Drug interactions of vasodilators Cardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Hydralazine β-Blockers Hepatic shunting β-Blockers Propranolol, 144(hepatic metabolism (↓); metoprololmetabolized) blood levels (↑) dose (↓)

Hydralazine Nitrates Renal blood flow (↑); Less nitrate Could be serious 39added vasodilation; tolerance (benefit); interaction with free radicals risk of excess Viagra (Table 14)scavenged hypotension

Hydralazine/ Digoxin Increased renal Decreased digoxin Check digoxin 21nitroprusside digoxin excretion levels levels

Prazosin, other Nifedipine; other Pharmacodynamic Excess hypotension Start with low dose 74alpha1 blockers dihydropyridines of α-blocker or

dihydropyridineNitrates Pharmacodynamic Syncope, Decrease prazosin Package insert

hypotension doseVerapamil Hepatic metabolism Synergistic Adjust doses 135

antihypertensiveeffect

Cilostazol Inhibitors of CYP Hepatic interaction Increased cilostazol Lessen cilostazol Package insert3A4 (diltiazem, levels, risk of dose or avoidverapamil; increased deatherythromycin, from heart failureketoconazole,cyclosporine)

a lesser extent amiodarone, and class 1a agents such as quinidine ordisopyramide) is administered. The common mechanism of action isthat all may prolong the QT interval. There is also some suggestion thatdiuretics may also promote torsades independently of hypokalemia.138

Probenecid interferes with the urinary excretion of thiazide and loopdiuretics, so diuretic efficacy is reduced. Diuretics may impair the renalclearance of lithium so that the blood level rises, with the risk of lithiumtoxicity.60

Vasodilators

Nitroprusside and Hydralazine

Nitroprusside (Nipride) and hydralazine (Apresoline; Table 19) maydecrease digoxin levels, possibly as a result of increased tubular excretion,by improving congestive heart failure, renal plasma flow, and renal excre-tion of digoxin.21 Hydralazine, by creating hepatic shunts, may substantiallyincrease the blood levels of those β-blockers that undergo hepatic metabo-lism,144 such as propranolol and metoprolol. Hydralazine interacts benefi-cially with nitrates, helping to lessen nitrate tolerance.39

Prazosin, Doxazosin (Cardura), and Terazosin


TABLE 20. Drug interactions of ACE inhibitors and ARBs Cardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

ACE inhibitor Diuretics High renin levels “First” dose Low test dose 52(class effect) in over diuresis hypotension: risk

of renal failurePotassium-sparing Added potassium Hyperkalemia Avoid combination, 128

diuretics retention or combine with 154care as in RALES

Indomethacin Less vasodilation Less blood pressure Avoid if possible 131(↓); less antifailure 159effect

Aspirin, nonsteroidal Less vasodilation Less antifailure Low-dose aspirin 132antiinflammatory effectdrugs

Captopril Loop diuretic Possible interference Lessened diuretic Consider alternate 158with tubular secretion effect of ACE inhibitor drug

furosemideImmunosuppressive Added immune Increased risk of Avoid combination; 22

drugs, procainamide, effects neutropenia check neutrophilshydralazine, possibly acebutolol

Probenecid Probenecid inhibits Small risk in Decrease dose of 147tubular secretion captopril levels captoprilof captopril

ARBs (class Volume depletion High renin levels Care; first dose Correct hypovolemia Packageeffect) hypotension inserts

NB thus Excess diuretics;far only rare inlicensed for hypertensionhypertension

RALES, Randomized Aldactone Evaluation study.

There is an interaction between prazosin (Minipress) and the calciumantagonists verapamil and nifedipine, which results in excessive hypoten-sion. In the case of verapamil, part of the effect may be explained by a phar-macokinetic hepatic interaction. Both nitrates and prazosin may cause syn-cope, and these agents should be combined with care. Similar interactionsmay hold for the other agents in this group such as doxazosin. The packageinsert for terazosin (Hytrin) warns of a specific hypotensive interactionwith verapamil.

CilostazolThis is a newly licensed peripheral vasodilator that is indicated for

intermittent claudication. It acts by phosphodiesterase inhibition; othersimilarly acting agents have increased mortality rates in heart failure pre-sumably by increasing cell calcium (Fig 1). It is metabolized by thehepatic CYP 3A4 system, so that there is a potential interaction withinhibitors of this system such as verapamil, diltiazem, erythromycin, andketoconazole, which could all elevate cilostazol levels with an increasedrisk of adverse effects in heart failure.

Angiotensin-Converting Enzyme Inhibitors andAngiotensin Receptor Blockers

In general, ACE inhibitors have few drug interactions.53 The most com-mon interaction is with diuretics, with a risk of excess hypotension inoverdiuresis (Table 20). The K+-retaining diuretics or K+ supplementstogether with an ACE inhibitor can cause hyperkalemia. Nonetheless in theRandomized Aldactone Evaluation study trial,128 spironolactone was cau-tiously given in low doses to patients with heart failure who were alreadyreceiving an ACE inhibitor, with reduced mortality rates and no serioushyperkalemia. Of note, in some patients, the dose of the ACE inhibitor hadto be reduced. Also, significant renal impairment, which predisposes tohyperkalemia, was an exclusion criterion. Indomethacin and NSAIDs maydecrease the antihypertensive effects of ACE inhibitors (and almost all anti-hypertensives except for agents such as nifedipine). Thus, NSAIDs maydiminish the benefits of ACE inhibitors in heart failure.159 Aspirin may alsointeract negatively with ACE inhibitors in heart failure. The extent of thisinteraction is still controversial, and low-dose aspirin may lessen it.118 Forexample, although few clinicians would regard such cotherapy as con-traindicated in a patient after infarction who has left ventricle dysfunction,


common sense would advise the use of the lowest dose of aspirin thoughtto be protective.

CaptoprilCotherapy of high-dose captopril (Capoten) with other drugs that alter

or impair the immune status (such as hydralazine and procainamide) maypredispose to neutropenia. Probenecid inhibits the renal tubular excretionof captopril, thereby increasing blood captopril levels147; doses of capto-pril may need downward adjustment. Captopril may decrease digoxinclearance by 20% to 30%.166

All Other Angiotensin-Converting Enzyme Inhibitors, IncludingEnalapril


TABLE 21. Drug interactions of antithrombotic agentsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Aspirin ACE inhibitors Vasodilation (↓) Less antifailure Low aspirin dose Table 91-6effect

Hepatic enzyme Increased aspirin Decreased Adjust aspirin dose; (—)inducers metabolism check aspirin side effects(barbiturates, aspirin effectphenytoin,rifampin)

Sulfinpyrazone, Aspirin decreases Decreased uricosuric Increase dose of 40probenecid urate excretion effect of sulfinpyrazone

sulfinpyrazone or probenecidor probenecid

Thiazide diuretics Aspirin decreases Hyperuricemia Check blood urate 40urate excretion

Warfarin Aspirin is Excess bleeding Check INR or 121antithrombotic prothrombin time

Sulfinpyrazone Warfarin Sulfinpyrazone displaces Excess bleeding Check INR or 6warfarin from prothrombin timeplasma proteins

Warfarin Potentiating drugsAllopurinol Mechanism Excess bleeding Check INR or 150

unknown prothrombin timeAmiodarone Mechanism unknown Sensitizes to Avoid combination 99

warfarin for months

Aspiring Added bleeding Excess bleeding Check INR or 121tendency prothrombin time

Cimetidine Decreased warfarin Excess bleeding Check INR or 1degradation prothrombin time

Quinidine Hepatic interaction Excess bleeding Check INR or 77prothrombin time

Statins Hepatic interaction? Excess bleeding Check INR or 160prothrombin time

Sulfinpyrazone Displaces warfarin Excess bleeding Check INR or 6from plasma proteins prothrombin time

Inhibitory drugsCholestyramine, Decrease absorption Decreased warfarin Check INR or 150colestipol of warfarin effect prothrombin time

Alteplase, tPA Nitrates Decreased tPA effect Less thrombolytic Avoid or reduce nitrate 141benefit dose; policy not clear


Drug interactions are similar to those of captopril, except that theimmune system is not involved and the risk of neutropenia is much less.It must be considered that all these agents including enalapril have alonger duration of action; adverse hypotensive interactions in patientswho have undergone diuresis are therefore potentially more serious.Perindopril may give relative protection from first dose hypotension.

Angiotensin Receptor BlockersLosartan and irbestartan, but not candesartan and valsartan, are metab-

olized by the hepatic 2C9 isoform. This isoform is inhibited by fluva-statin, as shown in the Georgetown University Web site,1 which shouldcreate a potential interaction. Nonetheless, a clinical study found no suchinteraction with losartan.103 The hepatic enzymes responsible for candesar-tan and valsartan breakdown have not yet been identified and are not partof the CYP isoform family (according to the package inserts). Regardingpharmacodynamic interactions, excess hypotension with excess diuretics orhigh-renin states and hyperkalemia with potassium retainers are risks, asare ACE inhibitors, especially when ARBs are used for heart failure (notlicensed for use in the United States). When used for hypertension, theserisks are still there but are reduced because the patient is usually muchhealthier. There are no interactions with hydrochlorothiazide, digoxin, war-farin, or cimetidine (according to the package inserts). For valsartan, thepackage insert also indicates no significant interaction with indomethacin.

Antithrombotic and Thrombolytic Agents Aspirin

Blood levels of uric acid may be increased by both aspirin and thiazidediuretics, so special care is required in patients with a history of gout.40

Conversely, aspirin may decrease the uricosuric effects of sulfinpyrazoneand probenecid (Table 21). Aspirin also reduces the natriuretic effect ofspironolactone. Aspirin-induced gastrointestinal bleeding may be agreater hazard in patients who are receiving other NSAIDs or cortico-steroid therapy. Antacids, by altering the pH of the stomach, maydecrease the efficacy of enteric-coated preparations.

Hepatic enzyme inducers of CYP (barbiturates, phenytoin, rifampin)increase aspirin breakdown. Aspirin tends to cause hypoglycemia inpatients who receive oral hypoglycemics or insulin therapy. Aspirin,especially in high doses, may exaggerate a bleeding tendency and antico-agulant-induced bleeding.108


SulfinpyrazoneSulfinpyrazone (Anturane) is highly bound to plasma proteins (98%

and 99%) and may displace warfarin to precipitate bleeding. Like aspirin,sulfinpyrazone may sensitize patients who receive sulfonylureas andinsulin therapy to hypoglycemia.

DipyridamoleDipyridamole (Persantine) is a potent vasodilator; care is required when

it is used in combination with other vasodilators. Dipyridamole inhibitsthe breakdown of adenosine.

WarfarinNumerous drug and diet-drug interactions. Warfarin (Coumadin) may

be subject to many (≤80) drug interactions.150 Furthermore, there is adiet-drug interaction. Warfarin has its effects lessened by a diet rich inthe precursor of prothrombin, vitamin K (as found in dark, green veg-etables), and certain plant oils including those used in margarines andsalad dressings.10 Therefore, to avoid undue fluctuations in the interna-tional normalized ratio (INR), an index of the prothrombin time, thedietary intake of these should be constant. Overall, the safest rule is topersuade patients who are undergoing oral anticoagulation to stay on aconstant diet and not to use any new or over-the-counter drugs withoutconsultation, although the physician carefully checks any planned addedcompounds. More frequent measurements of the INR and dose adjust-ments are required when potentially interfering drugs, including herbalagents, are added.

Mechanisms. The major known sites of interaction are, first, the plasmaproteins where warfarin is bound while circulating and, second, the hepaticCYP system where warfarin is broken down by the CYP 2C9 isoform. Forexample, with amiodarone, a given dose of warfarin has a greater inhibi-tion of prothrombin time with an increased risk of bleeding, which resultsfrom the inhibition by amiodarone of the CYP 2C9 isoform.1 It should berecalled that coagulation is a complex process and that any drug thatimpairs platelet function (such as aspirin, ticlopidine, or clopidogrel) mayindirectly promote bleeding by warfarin. Very high doses of aspirin (6-8tablets/d) may act differently by impairing synthesis of clotting factors.Heparin also potentiates the risk of bleeding; there are large individualvariations.121

Interfering drugs. Interfering drugs include those that reduce absorp-tion of vitamin K, warfarin (cholestyramine), or sulfinpyrazone (whichdisplaces warfarin from the plasma protein binding sites) and those drugs


that induce hepatic enzymes (barbiturates, phenytoin, rifampin). The lat-ter drugs, and also the herbal agent St John’s wort,30 increase the rate ofwarfarin metabolism in the liver.

Potentiating drugs. Potentiating drugs include those that decreasewarfarin degradation by inhibiting the CYP 2C9 isoform.1 Theseinclude a variety of antibiotics such as metronidazole (Flagyl) and cot-rimoxazole (Bactrim). Other antifungals such as fluconazole and vagi-nal suppository miconazole also potentiate warfarin.155 Cimetidine like-wise inhibits hepatic degradation; ranitidine does not. Otherpotentiating drugs include the cardiovascular agents allopurinol,propafenone, quinidine,77 and amiodarone.99 Amiodarone is especiallydangerous because of its excessively long half-life, so this interactioncan occur even after the withdrawal of amiodarone. Grapefruit juicedoes not act on the CYP 2C9 but does act on the 3A4; it has no interac-tion with warfarin.151 It must be restressed that sulfinpyrazone power-fully displaces warfarin from blood proteins, so the dose of warfarinmay have to be reduced to only 1 mg in some patients.

Lipid-lowering drugs. Fibrates may markedly potentiate warfarin,although the statins in general have little or no effect. The latter is not toosurprising because most of them (exceptions: pravastatin and fluvastatin)are metabolized by the CYP 3A4 isoform and not through the isoformthat metabolizes warfarin. In one case, when warfarin was added to sim-vastatin, rhabdomyolysis with acute renal failure was precipitated.106 In


TABLE 22. Drug interactions of lipid-lowering agentsCardiac drug Interacting drugs Mechanism Consequence Prophylaxis Reference

Fibric acids Warfarin; Hepatic interference Risk of bleeding Check prothrombin 150(gemfibrozil, statins timeclofibrate (see below)bezafibrate,fenofibrate)

Bile acid seques- Warfarin Decreased absorption Decreased warfarin Check prothrombin 150trates (choles-, Many other Decreased absorption effect timetyramine drugs Decreased drug Space dosescolestipol) effect

HMG-Co-A Fibrates, Added damage to Rhabdomyolysis and Check creatine 83reductase inhibitors of muscle with risk of renal failure; phosphokinase 156inhibitors CYP 3A4 myositis increased levels; avoid(atorvastatin, (erythromycin, cyclosporine levels if possiblelovastatin, antifungal azolessimvastatin, others, nicotiniccerivastatin) acid, cyclospo-

rine)Statins Warfarin Hepatic interaction Increased risk Check INR or Table 22

of bleeding prothrombin timePravastatin Cyclosporine Hepatic interaction; Rhabdomyolysis Check creatine 69

and risk of renal phosphokinase levels; avoid Package insertcyclosporine failure; increased if possiblehepatotoxicity cyclosporine level

Probucol Thiazides, groups Probucol-induced QT prolongation Check potassium; 15(no longer Ia and III, diarrhea with avoid combinations;available) antiarrhythmics potassium loss? choose other

lipid-lowering agents

the case of fluvastatin, the absence of interaction noted in the packageinsert is surprising because this statin, unlike the others, inhibits thehepatic CYP 29C, according to the Georgetown University Web sitedata.1 Nonetheless, caution is advised. On first principles, the simpleststatin to combine with warfarin would be pravastatin because it is metab-olized by a route quite different from the CYP system.

HeparinPhysically, heparin is incompatible in a water solution with certain sub-

stances, including antibiotics, antihistamines, phenothiazines, and hydro-cortisone. It is also incompatible with reteplase. However, direct pharma-cokinetic or pharmacodynamic interactions have not been described,except for the controversial interaction with nitrates.78

Tissue-Type Plasminogen ActivatorConcurrent use of intravenous nitroglycerin diminishes the efficacy

of recombinant tissue-type plasminogen activator (tPA; or alteplase)possibly because of increased hepatic blood flow and enhanced catab-olism of tPA.141

Statins And Other Lipid-Lowering Agents

Lipid-Lowering Drugs and WarfarinA number of lipid-lowering agents may interact with warfarin (Table

22), either by decreased absorption (cholestyramine) or by hepatic inter-ference (bezafibrate, fenofibrate, and gemfibrozil). No interaction occurswith niacin. The package inserts for gemfibrozil and fenofibrate, the only2 fibrates licensed in the United States, both give prominent warnings thatthe warfarin dose should be reduced and that the prothrombin time shouldbe determined more frequently. The exact mechanism is not clear, butinhibition of the hepatic CYP 2C9 that breaks down warfarin is possible.There has been a case report of profound hypoprothrombinemia andbleeding 4 weeks after the start of gemfibrozil therapy.137 With fenofi-brate the INR increased after 5 to 10 days.3

StatinsIn general, there appear to be less severe interactions between statins

and warfarin than with the fibrates. The package inserts indicate that therehave been no interactions detected with fluvastatin, pravastatin, ceriva-statin, or atorvastatin. There may be a modest increase of the INR withlovastatin and simvastatin. These effects cannot directly be related to the


hepatic P-450 isoform known to be concerned with the specific statin. Forexample, fluvastatin is the only statin that is an inhibitor of the CYP 2C9that breaks down warfarin,1 but no interaction has been noted (accordingto the package insert).

The HMG-COA (3-hydroxy-3-methylglutaryl-coenzyme A) reductaseinhibitors such as lovastatin (Mevacor), simvastatin (Zocor), pravastatin(Pravachol), fluvastatin (Lescol), and atorvastatin (Lipitor) should ideallynot be combined with the fibrates because of the higher risk of myositiswith rhabdomyolysis and possible renal failure. Likewise, concurrenttherapy with niacin, cyclosporine, or erythromycin may also carry anincreased risk of myopathy with further risk of rhabdomyolysis. Addingan antifungal azole (a group that includes ketoconazole, used in trans-plantation) has precipitated myolysis in a patient who are already receivingstatin and niacin therapy.83 Serum creatine kinase levels should be checkedperiodically, especially after doses have been increased or after combina-tion therapy has started. However, sometimes in clinical practice, theadvantages of better lipid control with cautiously combined and monitoredtherapy seem to outweigh these risks, which may have been overestimated.

Pravastatin. Pravastatin is not metabolized by the CYP system, as areall the other statins. Theoretically, this may avoid many interactions thatlead to myopathy. The package insert details cotherapy with cyclo-sporine, niacin, and gemfibrozil without referring to clinical myopathy.In a stepped care trial, pravastatin alone reduced low-density lipoproteincholesterol sufficiently in approximately one half of the patients, andalmost all the others responded to added niacin, without an elevation ofliver enzymes or creatine kinase levels.124 However, with added gemfi-brozil, 4 of 75 patients showed marked increases in plasma creatinekinase levels although without clinical myopathy. A positive interactionof pravastatin with cyclosporine is reported, whereby there appears to beincreased immunosuppression.69 Pravastatin could be chosen for cau-tious and monitored cotherapy of a statin with cyclosporine or otherdrugs that act on the CYP 3A4 isoform or with gemfibrozil.

Fluvastatin. Fluvastatin (Lescol) is metabolized by a different hepatic P-450 enzyme system (2C9) from the others, except for pravastatin, whichmay explain why it has not been associated with an increased incidence ofmyopathy during cotherapy with nicotinic acid (according to the packageinsert). Thus, fluvastatin could be chosen when combination therapy withnicotinic acid (niacin) is desired. It would be prudent, nonetheless, to con-tinue to check plasma creatine kinase levels, as advised by the manufac-turers. The package inserts issue the class warning against cotherapy witherythromycin, cyclosporine, niacin, or gemfibrozil.


Simvastatin. The feared interaction between statins as a group andfibrates may not be so serious, even with a statin that is metabolized by thehepatic P-450 3A4 system. In a safety trial with 102 patients that lasted upto 3 years, in which most patients received bezafibrate and simvastatintherapy, no patient had myopathic symptoms or an elevation of plasmacreatine kinase levels over 3 years.34 In a relatively large trial with 389patients, simvastatin or pravastatin was combined with a fibrate (gemfi-brozil or ciprofibrate) for a mean of 29 months.4 There were no instancesof myopathy or of a significant elevation of plasma creatine kinase levels.

Statins combined with niacin or fibrates. Although all the packageinserts warn against such combinations, and prudence suggests that clin-icians should be on the alert for myopathy (and hepatotoxicity) when giv-ing such cotherapy, the documented cases in trials are not common andsuggest a low incidence of myopathy, which could be estimated at wellbelow 1%. Theoretically, the statin least likely to give interactions pre-disposing to myopathy is pravastatin, which does not undergo metabo-lism by the hepatic P-450 system. The other major risk of combined addi-tive hepatotoxic effects also seems not to have materialized. Clearly,blood liver enzymes and creatine kinase levels need to be checked evenmore regularly than during simple statin therapy.

Statins and digoxin. There is no interaction with lovastatin, pravastatin,or cerivastatin. There is a small increase in blood digoxin levels with sim-vastatin and fluvastatin, and a 20% increase with atorvastatin.

Antihypertensive DrugsInteractions for diuretics, β-adrenergic blockers, CCBs, ACE inhibitors,

and α1-adrenergic blockers have already been considered. In general,NSAIDs interfere severely with antihypertensive efficacy of all antihy-pertensives.56 An exception is nifedipine (and, presumably, other dihy-dropyridines).143 Unlike other NSAIDs, aspirin170 and sulindac may giverelative protection from the negative interaction.56 When CCBs are usedas antihypertensives, part of their effect is by natriuresis, so that adding adiuretic is often relatively ineffective.171

Cyclosporine and KetoconazoleThese agents are often used in patients who have undergone cardiac

transplantation.

CyclosporineCyclosporine, often used in cardiac transplantations, is metabolized by

the hepatic 3A4 isoform cytochrome system, without inhibiting it. Thus,


the potential interactions are with the inhibitors of this system. For exam-ple, grapefruit juice increases the area under the curve of cyclosporine byabout 45%.174 Both verapamil and diltiazem increase the levels ofcyclosporine and may permit a lower dose to be used for a cost-savings.1

High levels of cyclosporine increase the risk of renal toxicity and hyper-tension. It is not clear why cyclosporine predisposes to myopathy withsome statins; it does not inhibit the CYP 3A4 that breaks down the statins.Presumably cyclosporine hepatoxicity damages the statin breakdown sys-tem. In addition, cyclosporine nephropathy could inhibit that low per-centage of the statin that is lost by renal secretion. Cyclosporine may pre-dispose to digoxin toxicity, reducing the renal clearance and decreasingthe volume of distribution. The mechanism may be by inhibition of thetransmembrane digoxin transporter, P-glycoprotein.1

KetoconazoleThis is an antifungal agent that increases blood cyclosporine levels by

the inhibition of the 3A4 isoform, so the dose of the more expensive agent,cyclosporine, can be reduced. Its interactions are therefore both direct bythe inhibition of the breakdown of those many drugs metabolized by thisisoform and indirect by increasing blood levels of cyclosporine.

Herbal Drug InteractionsHerbal drugs are now commonly used. Often the physician is igno-

rant of the fact that the patient is taking a herbal drug and does notknow that such drugs may have harmful interactions. Garlic andginkgo promote the action of warfarin, perhaps by causing platelet dys-function.37 Danshen increases the INR, probably by decreasing theelimination of warfarin.37 Dong qual increases the INR because it con-tains coumarin.37 St John’s wort may lower serum warfarin by itscapacity to stimulate hepatic CYP.30 It decreases the blood digoxinconcentration by about one third.62

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