(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Several cardiac drugs manifest some form of interaction with each other or with noncardiac drugs. It is of paramount importance for the physician to be aware of these interactions, which may be potentially harmful to patients or may negate salutary effects. In addition, the prescribing physician must be conscious of these interactions so as to avoid errors that may provoke medicolegal action.
The number of cardiac drugs available to the clinician has increased by more than 100 % over the past 25 years. Also, the drug armamentarium for the treatment of psychiatric, rheumatic, neurologic, infectious, and gastrointestinal (GI) diseases has expanded greatly. Consequently, drug interactions have increased.
Although drug interactions may have been briefly described for drug groups in earlier chapters, this chapter gives a structured summary of interactions. This chapter deals with:
The interactions that occur between cardiac drugs
The interaction of cardiovascular drugs with agents used for treating diseases of other systems and other agents with pharmacologic properties, such as caffeine, alcohol, and tobacco
The adverse cardiovascular effects of noncardiac drugs
Drug interactions are usually:
1.
Pharmacodynamic: Occurring between drugs that have similar or opposite pharmacologic effects or adverse effects; for example, these effects may occur because of competition at receptor sites or action of the drugs on the same physiologic system. In some instances, the hemodynamic effects of one agent increase or decrease the hemodynamic effects of another agent.
2.
Pharmacokinetic: Occurring when one drug alters the absorption, distribution, metabolism, or excretion of another, thereby increasing or reducing the amount of drug available to exert its pharmacologic actions.
Interactions of Cardiovascular Drugs
Each cardiac drug (or drug group) interaction is discussed under the following categories:
1.
Cardiovascular effects:
(a)
Vasodilator (arterial or venous, afterload, or preload reduction), hypotension, presyncope
(b)
Inotropic: positive or negative, alteration of ejection fraction (EF), propensity to precipitate congestive heart failure (CHF).
(c)
On the sinoatrial (SA) or atrioventricular (AV) node
(d)
On the conduction system
(e)
Proarrhythmic
2.
Cholinergic effects
3.
Plasma levels
4.
Renal clearance of the drug, effect on renal function and serum potassium (K+) concentration
5.
Hematologic, including anticoagulant activity and/or immune effects
6.
Hepatic and GI
ACE Inhibitors/ARBs
Cardiovascular Effects
When angiotensin-converting enzyme (ACE) inhibitors are used in combination with vasodilators, hypotension may occur. Preload-reducing agents, such as nitrates or prazosin, may cause syncope or presyncope (Table 21-1). Diuretics stimulate the renin angiotensin system (RAS) and enhance the antihypertensive effects, producing a salutary interaction in hypertensive individuals, but hypotension may ensue in patients with CHF. The hypotensive effects are longer lasting with long-acting ACE inhibitors.
Table 21-1
Angiotensin-converting enzyme inhibitors: potential interactions
• Angiotensin receptor blockers: increased risk of hyperkalemia |
• Aspirin: appears to decrease salutary effects |
• Corticosteroids: hypotensive effect of ACE inhibitors antagonized |
Cyclosporine: increased risk of hyperkalemia. Plasma concentration of aliskiren increased by cyclosporine—avoid concomitant use |
Lithium: reduced excretion of lithium (increased plasma concentration) |
Verapamil: plasma concentration of aliskiren increased by verapamil—manufacturer of aliskiren advises avoiding concomitant use |
• Potassium-sparing diuretics: amiloride, Moduretic, Moduret, triamterene, Dyazide, Dytide, spironolactone (Aldactone), Aldactazide—increased risk of hyperkalemia |
• Preload-reducing agents: |
Diuretics |
Nitrates |
Prazosin, other alpha blockers: enhanced hypotensive effect |
• Renally excreted cardioactive agents |
Anti-arrhythmics: beta-blockers (atenolol, sotalol, nadolol) |
• Digoxin: Captopril possibly increases plasma concentration of digoxin |
• Agents that may alter immune status: |
Allopurinol: increased risk of leucopenia |
Acebutolol |
Hydralazine |
Pindolol |
Procainamide |
• Tocainide |
• Furosemide |
• Probenecid |
• NSAIDs: increased risk of renal impairment; hypotensive effect antagonized |
• Lithium |
• Cyclosporine |
• Phenothiazines |
• Imipramine |
Renal Effects: ACE inhibitors and ARBs may decrease glomerular filtration rate (GFR) in some patients with renal dysfunction and may result in decreased clearance of other cardiac drugs that are eliminated by the kidney. Interaction may occur with renally excreted beta-blockers, nadolol, atenolol, sotalol, and antiarrhythmic agents. Serum K+ may increase to dangerous levels if potassium-sparing diuretics (amiloride, eplerenone, triamterene, spironolactone, Moduretic, Moduret, Dyazide) are used concurrently. This occurrence is enhanced in patients with renal dysfunction. A normal serum creatinine level in patients with a lean body mass may not reflect underlying renal dysfunction, and caution is necessary, particularly in the elderly:
Probenecid inhibits the tubular excretion of ACE inhibitors and increases the blood levels of these agents.
ACE inhibitors may cause a 20–30 % decrease in digoxin clearance and an increase in digoxin levels.
Interaction with cyclosporine may cause hyperkalemia.
Hematologic/Immune: The risk of immune adverse effects may increase with concurrent use of agents that alter the immune status: Assess antinuclear antibody levels and also assess for neutropenia with concurrent use of acebutolol, allopurinol, hydralazine, pindolol, procainamide, and tocainide.
Gastrointestinal: The absorption of fosinopril is reduced by antacids.
Interactions of Spironolactone
Aspirin antagonizes the diuretic effect of spironolactone.
ACE inhibitors and spironolactone both cause hyperkalemia.
Digoxin levels are increased (laboratory reaction).
Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with spironolactone may precipitate acute renal failure.
Antiarrhythmic Agents
Adenosine
The electrophysiologic effects of adenosine are competitively antagonized by methylxanthines (theophylline) and are potentiated by dipyridamole, which inhibits its cellular uptake, and severe hypotension may occur (Table 21-2).
Table 21-2
Adenosine: potential interactions
• Carbamazepine |
• Dipyridamole: Caution |
• Methylxanthines (theophylline) |
• Caffeine |
Amiodarone
Cardiovascular Effects
Amiodarone has a mild vasodilator effect, and interaction may occur with antihypertensive agents, causing hypotension. This interaction is more prominent with intravenous amiodarone.
Because of a mild inotropic effect, CHF may be precipitated, especially when amiodarone is combined with agents that possess negative inotropism (e.g., beta-blocking agents, verapamil, or diltiazem).
Combination with verapamil or diltiazem may cause sinus arrest or AV block (Table 21-3).
Table 21-3
Amiodarone: potential interactions
• Antihypertensive agents
• Drugs that are negatively inotropic: verapamil, diltiazem, beta-blockers—increased risk of bradycardia, AV block, and myocardial depression. Avoid concomitant use
• Agents that inhibit SA and AV node conduction: diltiazem, verapamil—avoid concomitant use
• Agents that ↑ the QT interval
Class 1A agents: quinidine, disopyramide, procainamide
Sotalol
Tricyclic antidepressants: increased risk of ventricular arrhythmias—avoid concomitant use
Phenothiazines
Erythromycin (other macrolides)
Pentamidine
Zidovudine
• Agents that decrease serum K+ concentration (diuretics): increased cardiac toxicity with amiodarone if hypokalemia occurs with loop or thiazide diuretics
• Agents that are renally eliminated: digoxin, flecainide, procainamide—amiodarone increases plasma concentration of digoxin (half dose of digoxin)
• Anticoagulants: amiodarone inhibits metabolism of coumarins (enhanced anticoagulant effect)
• Dabigatran etexilate: amiodarone increases plasma concentration of dabigatran etexilate (reduce dose of dabigatran etexilate)
• Cimetidine: plasma concentration of amiodarone increased by cimetidine
• Cyclosporine: amiodarone possibly increases plasma concentration of cyclosporine
• Eplerenone: amiodarone increases plasma concentration of eplerenone (reduce dose of eplerenone)
• Grapefruit juice: plasma concentration of amiodarone increased by grapefruit juice
• Lithium: avoid concomitant use with lithium risk (risk of ventricular arrhythmias)
• Simvastatin: increased risk of myopathy when amiodarone given with simvastatin
The proarrhythmic effect of amiodarone is low, but interaction may occur and may increase the risk of torsades de pointes when amiodarone is used concurrently with the following agents: diuretics, which cause hypokalemia, class IA agents (quinidine, disopyramide, procainamide), sotalol, tricyclics, phenothiazines, and erythromycin.
Oral Anticoagulants: Their activity is increased.
Plasma Levels: Digoxin levels may double because amiodarone decreases renal clearance of digoxin. Flecainide and procainamide levels increase.
Disopyramide
Cardiovascular Effects: The negative inotropic effect of disopyramide is increased by beta-blocking agents, verapamil, diltiazem, and flecainide. Proarrhythmic effects, in particular torsades de pointes, are increased with agents that prolong the QT interval or cause hypokalemia. Sinus and AV node effects may occur when disopyramide is used concurrently with drugs that depress the sinus node (verapamil, diltiazem, digitalis).
Cholinergic Effects: Because disopyramide inhibits muscarinic receptors, the anticholinergic activity may cause constipation. Thus, the drug should not be combined with verapamil. Disopyramide may precipitate glaucoma, and this effect may be counteracted by timolol or betaxolol.
Flecainide
Cardiovascular Effects: The powerful, negative, inotropic effect of flecainide is worsened by negative inotropic agents; interaction occurs with verapamil, diltiazem, beta-blockers, and disopyramide; intraventricular conduction defects may occur when the drug is combined with class IA agents.
Plasma levels increase with concomitant amiodarone administration; thus, the flecainide dose should be decreased. Flecainide causes an increase in digoxin levels.
Lidocaine or Lignocaine
Plasma Levels: Lidocaine is metabolized in the liver. An increase in plasma levels may occur with decreased hepatic blood flow caused by beta-blocking agents ( Ochs et al. 1980): Caution is necessary to avoid lidocaine toxicity, which may occur when lidocaine and beta-blockers are administered to patients with acute myocardial infarction. Lidocaine plasma levels decrease with phenytoin, which stimulates the hepatic oxidase system, resulting in accelerated breakdown of hepatically metabolized cardiovascular agents.
Mexiletine
Cardiovascular Effects: Hypotension may occur when mexiletine is combined with vasoactive agents that reduce blood pressure. AV block may worsen with the concomitant use of amiodarone, verapamil, diltiazem, or beta-blocking drugs.
Plasma Levels: Because the drug is partly metabolized in the liver, phenytoin decreases plasma levels.
Phenytoin
Phenytoin activates the hepatic oxidase system and thus accelerates the breakdown of hepatically metabolized cardiac agents, resulting in a decrease in their plasma levels: lidocaine, hepatically metabolized beta-blockers (propranolol, metoprolol, labetalol), diltiazem, verapamil, nifedipine (and other dihydropyridine calcium antagonists), mexiletine, and quinidine. Aspirin metabolism is increased; thus, phenytoin decreases the effects of aspirin.
Propafenone
Cardiovascular Effects: Hypotension may be precipitated by drugs that lower blood pressure. A prominent negative inotropic effect may be increased by other negative inotropic agents. Sinus node suppression may occur when the drug is combined with verapamil or diltiazem. AV block or conduction defects may increase with class IA agents. Digoxin level and warfarin are enhanced.
Plasma Levels: Digoxin levels are increased.
Hematologic: Oral anticoagulant activity is increased.
Procainamide
The negative inotropic effects of oral procainamide are increased by other negative inotropic agents. Torsades de pointes may be precipitated when procainamide is combined with agents that increase the QT interval. ACE inhibitors may enhance immune effects; both agents may cause neutropenia or agranulocytosis.
Quinidine
Hypotension: Because alpha-receptors are inhibited by quinidine, other vasoactive agents that decrease blood pressure may precipitate hypotension (e.g., prazosin, verapamil).
Intraventricular Conduction Defects: These increase when quinidine is combined with class IC agents (flecainide, encainide, propafenone, lorcainide).
Proarrhythmic Effects: Drugs that prolong the QT interval and diuretics that cause hypokalemia may precipitate torsades de pointes.
Hematologic: Oral anticoagulant activity may increase.
Plasma Levels: Quinidine levels decrease with phenytoin or nifedipine and increase with verapamil (Trohman et al. 1986) or diltiazem administration.
Antiplatelet Agents/Anticoagulants
Anticoagulants have several interactions with cardiac and noncardiac drugs (see Table 19-3).
Aspirin. The metabolism of aspirin is increased by agents such as phenytoin, barbiturates, and rifampin that induce the hepatic oxidase system. Phenytoin, therefore, decreases the effects of aspirin. The risk of bleeding is increased with concurrent administration of anticoagulants. Aspirin and thiazide diuretics inhibit urate excretion, whereas ACE inhibitors and sulfinpyrazone increase renal urate excretion.
Clopidogrel interacts unfavorably with atorvastatin and simvastatin. Clopidogrel and proton pump inhibitors caution: Both use the hepatic cytochrome pathway, and beneficial effect on intracoronary stent occlusion is probably reduced. See Chap. 19.
Morphine has been shown to decrease clopidogrel absorption, decreases concentrations of clopidogrel active metabolite, and diminishes its salutary effects. This can cause treatment failure in susceptible patients (Hobl et al. 2014 ).
Beta-Blockers
Cardiovascular Effects: Hypotension may be precipitated when beta-blockers are combined with calcium antagonists and other antihypertensive agents. Hypertension may ensue with concurrent use of vasoactive agents that are sympathomimetic (e.g., phenylpropanolamine).
Effects on the SA and AV nodes: Electrophysiologic interaction occurs with verapamil, diltiazem, and amiodarone; severe bradycardia, complete heart block, or asystole may be precipitated (Table 21-4).
Table 21-4
Beta-adrenergic blockers: potential interactions
• Anti-arrhythmics: amiodarone, disopyramide, flecainide, lidocaine, procainamide, propafenone
• Calcium antagonists: diltiazem, verapamil, nifedipine
• Sympathomimetics (phenylpropanolamine)
• Phenytoin
• K+-losing diuretics (sotalol only)
• Cimetidine-like agents (hepatically metabolized; metoprolol, propranolol; see Chap. 1)
• NSAIDs
• Fluvoxamine
• Tobacco smoking (propranolol)
Inotropic effects: Other negative inotropic agents (verapamil, diltiazem, flecainide, disopyramide, procainamide, propafenone) increase the risk of CHF.
Proarrhythmic effects: Sotalol, because of its unique class III activity, is the only beta-blocking agent with proarrhythmic effects, and it can induce torsades de pointes, especially if the serum K+ level is low. Avoid K+-losing diuretics. Do not combine sotalol with agents that prolong the QT interval.
Beta-blockers must not be combined with valsartan. In Val-HeFT, valsartan administered in a heart failure RCT combined with a beta-blocker caused significantly more cardiac events. Often in patients with HF, a beta-blocker is needed as proven therapy. Thus an ACE inhibitor must be used.
Caution: Valsartan must not be combined with a beta-blocker.
Plasma Levels: Metoprolol and propranolol plasma levels are increased by verapamil. Atenolol, sotalol, and nadolol plasma levels are not increased because they are not hepatically metabolized beta-blockers. Nifedipine plasma levels increase.
Immune Effects: Acebutolol and pindolol may alter immune status. The risk is additive when these agents are used concomitantly with hydralazine, procainamide, or ACE inhibitors.
Calcium Antagonists
Other antihypertensive agents interact favorably to lower blood pressure, but hypotension may occur. The combination of magnesium sulfate may cause severe hypotension. Verapamil decreases the hepatic metabolism of prazosin and other alpha blockers: concurrent use may cause hypotension. The combination of verapamil and quinidine may cause hypotension because of combined inhibition of peripheral alpha-receptors:
Amiodarone: increased risk of bradycardia, AV block, and myocardial depression when verapamil or diltiazem is given.< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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