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Pharmacologic Interactions
Concomitant administration of several drugs is common in the treatment of cardiovascular diseases. Often, combinations of drugs are necessary and result in improved outcomes. With a large number of medications, however, there is also an increased concern about drug interactions. Although the number of potential interactions is great, many are inconsequential. Conversely, drug interactions can have significant adverse effects or even be lethal.
Many drug interactions can be prevented by recognizing the drugs and the patients at risk. Situations with a high likelihood for clinically significant adverse drug interactions include the following :
- 1.
A large number of drugs. The risk is significantly higher when more than 10 drugs are concurrently administered.
- 2.
Drugs with a steep dose response relation when even small changes in the drug level lead to profound changes in its action
- 3.
Drugs with a narrow therapeutic index
- 4.
Concomitant administration of drugs known as liver enzyme inducers or inhibitors (e.g., rifampin and cimetidine)
- 5.
Elderly patients
- 6.
Critically ill patients
It is important to be aware of the possibility of drug interactions in the cardiac intensive care unit (CICU) because many of these patients receive high-risk drugs, are elderly, and may have circulatory failure or be critically ill. It is also important to inquire about the use of herbal supplements and medicines, as many of these products can interact with drugs and cause adverse events. Drug interactions may mimic worsening or progression of the underlying disease with manifestations such as arrhythmia or congestive heart failure (CHF).
Mechanisms of interactions may be pharmacokinetic, affecting drug absorption, bioavailability, metabolism, or renal excretion, or pharmacodynamic, occurring at the sites of action in the heart, such as sinoatrial (SA) and atrioventricular (AV) nodes, the intraventricular conduction system, and the smooth muscle.
This chapter discusses interactions of drugs commonly used in the CICU, with emphasis on interactions with other cardiovascular drugs.
Vasodilators
Nitrates
The chief interactions of nitrates are pharmacodynamic. Nitrates (e.g., nitroglycerin, isosorbide dinitrate, isosorbide mononitrate) are widely used both in patients with angina and in those with CHF. A limitation in nitrate therapy is the development of tolerance, which is time dependent. Many theories are proposed to explain this phenomenon, including nitrate resistance, pseudotolerance (i.e., activation of counterregulatory responses, such as secretion of catecholamines, angiotensin II, and endothelin), and “true” tolerance resulting from impaired bioconversion to nitric oxide (NO) and increased generation of superoxide.
There are several reports of agents that limit or reverse nitrate tolerance when coadministered with nitroglycerin or isosorbide dinitrate. These include N -acetylcysteine, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), carvedilol, hydralazine, ascorbic acid, folic acid, and L-arginine. However, there are not enough data to make definite recommendations on drug combinations to prevent nitrate tolerance.
The combination of nitrates with hydralazine has long been known to be beneficial in CHF and is still used in patients who are intolerant of ACE inhibitors and in African-American patients who have reduced capacity for endogenous production of nitric oxide. These drugs may interact at the site of smooth muscle, involving inhibition of pyridoxal-dependent enzymes by hydralazine and resulting in an increased availability of sulfhydryl groups and prevention of nitrate tolerance by decreasing superoxide production and scavenging of reactive oxygen species.
A clinically significant interaction occurs between nitrates and phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil and tadalafil, commonly used to treat erectile dysfunction. Inhibition of PDE5 results in increased cyclic guanosine monophosphate (cGMP) levels, which are generated from endogenously derived NO. Nitrates exert their effect via biotransformation to NO and generation of cGMP. Coadministration of nitrates and PDE5 inhibitors causes significant reduction of blood pressure via a synergistic increase in cGMP levels, resulting in symptomatic hypotension and even death. PDE5 inhibitors are contraindicated for patients treated with nitrates. Conversely, nitrates should not be started within 24 hours of using sildenafil and 48 hours of using tadalafil.
Another pharmacodynamic interaction occurs when nitrates are used with β-blockers, calcium channel blockers, or both as part of an intensive antianginal regimen, resulting in hypotension with reduced coronary flow. The result may be worsening of angina.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
ACE inhibitors ( Table 41.1 ) are widely used for the treatment of CHF and hypertension and to prevent remodeling after myocardial infarction (MI).
TABLE 41.1
Drug Interactions With Angiotensin-Converting Enzyme Inhibitors (ACEI)
| Interacting Drug | Effect | Mechanism | Comments |
|---|---|---|---|
| Potassium supplements or potassium-sparing diuretics | Hyperkalemia | Inhibition of aldosterone release | Avoid combinations, monitor potassium levels |
| Angiotensin receptor blockers | Hyperkalemia | Dual inhibition of RAS | Monitor potassium levels, blood pressure, and renal function |
| Hypotension | |||
| Renal failure | |||
| Diuretics | Hypotension | Inhibition of angiotensin II–mediated response to hypovolemia | Reduce dose or temporarily discontinue the diuretic before starting ACEI |
| Renal failure | |||
| NSAIDs | Inhibition of hypotensive effect of ACEI | Inhibition of kinin-mediated prostaglandin synthesis | Monitor blood pressure |
| Lithium | Lithium toxicity | Reduction of Na concentration in the proximal tubules by ACEI, causing increased lithium reabsorption | Reduce lithium dose by 50%, monitor lithium blood levels |
| Sulfonylurea | Hypoglycemia | Increased sensitivity to insulin | Monitor blood glucose |
NSAIDs, nonsteroidal antiinflammatory drugs; RAS, renin-angiotensin system.
Interactions involving ACE inhibitors are primarily pharmacodynamic and are based on their mechanism of action. The principal mechanism of action is lowering of angiotensin II levels, resulting in vasodilation and suppression of aldosterone release. ACE inhibitors also inhibit the degradation of bradykinin and increase prostaglandin synthesis, both of which may contribute to vasodilation.
The main interaction of concern is between ACE inhibitors and potassium supplements or potassium-sparing diuretics. These combinations can result in rapid development of hyperkalemia, especially in the presence of diminished renal function.
There is a beneficial effect in the synergism between ACE inhibitors and diuretics (e.g., thiazides and furosemide) in the treatment of hypertension and CHF. In a sodium-depleted patient or one with high renin levels, however, the combination can result in hypotension and worsening of renal failure. In such patients, the physician should start with a lower-than-normal dose of ACE inhibitor, temporarily lower the dose of diuretic, or discontinue the diuretic before administration of an ACE inhibitor. There is no evidence of a significant pharmacokinetic interaction between ACE inhibitors and diuretics. A synergistic effect on blood pressure reduction was also observed between various ACE inhibitors and calcium antagonists without pharmacokinetic interactions. No significant interactions have been found between ACE inhibitors and β-blockers or digoxin.
Among the interactions of ACE inhibitors with noncardiovascular drugs, the most notable is with nonsteroidal antiinflammatory drugs (NSAIDs) because of their opposing effects on prostaglandin synthesis. The result is an attenuation of the antihypertensive effects of ACE inhibitors, predisposition to renal failure, or both. There are conflicting reports on the interactions between ACE inhibitors and low-dose aspirin. However, a retrospective analysis did not demonstrate an adverse effect of aspirin on the survival of patients with left ventricular (LV) systolic dysfunction treated with ACE inhibitors.
There are reports of lithium toxicity when patients on chronic lithium therapy were started on ACE inhibitors. Because renal excretion of lithium is dependent on glomerular filtration and on sodium concentration in the proximal tubule, the possible mechanism of interaction may be the reduction of both by ACE inhibitors, especially in volume-depleted patients.
A life-threatening anaphylactoid reaction has been described in a patient treated with ACE inhibitors while on hemodialysis with a polyacrylonitrile membrane (AN69). The possible mechanism of this interaction is activation of the kinin-kallikrein system by the surface of the AN69 membrane, resulting in an increased production of bradykinin, the breakdown of which is inhibited by ACE inhibitors. No adverse reactions were reported with other dialysis membranes.
ACE inhibitors increase insulin sensitivity; there have been several reports of hypoglycemia when captopril or enalapril was given to patients receiving glibenclamide, although others did not observe this effect. It seems prudent to monitor for possible hypoglycemia when ACE inhibitors are given to patients who are already receiving oral antihypoglycemic agents.
ARBs have low potential for interaction with other drugs. Among ARBs, only losartan and irbesartan undergo significant metabolism by cytochrome P-450 enzymes (CYP2C9 and CYP3A4). Rifampin significantly reduces the area under the drug concentration in blood plasma versus time curve (AUC) as well as the half-life of losartan and its active metabolite; an increased dose of losartan may be indicated during concomitant administration with rifampin. However, no clinically significant interactions have been found between losartan and erythromycin, digoxin, or warfarin and between irbesartan and digoxin, nifedipine, or hydrochlorothiazide. There was a report of a significant interaction between valsartan and lithium resulting in lithium toxicity.
Attenuation of the hypertensive effect of ARBs may result from concomitant administration of NSAIDs via mechanisms similar to the interaction with ACE inhibitors.
Combination of ACE inhibitors and ARBs provides a dual and more effective blockade of the renin-angiotensin system (RAS). However, the combination therapy is associated with a significantly increased risk of adverse events, such as hyperkalemia, kidney damage, and hypotension, particularly in patients with diabetic nephropathy. There are conflicting data on the use of dual RAS blockade with β-blockers in patients with CHF. The Valsartan Heart Failure Trial (Val-HeFT) suggested an increased mortality in patients treated with triple therapy compared with an ACE inhibitor and β-blocker alone, while the Candesartan in Heart failure—Assessment of Mortality and Morbidity (CHARM) and Valsartan in Acute Myocardial Infarction (VALIANT) trials did not find any increase in mortality in patients on triple therapy. The meta-analysis of more than 68,000 patients from 33 randomized controlled trials of combination therapy with an ACE inhibitor and an ARB found an 18% decrease in hospitalizations for CHF but did not find any mortality benefit with combination therapy compared with monotherapy, while the risk of adverse events was very high (41% to 68%). Thus combination therapy should be avoided in the majority of the patients.
Sacubitril/Valsartan
Recently, a fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan was approved for patients with CHF. Reduced LV function after the combination was shown to reduce the risk of cardiovascular death and hospitalizations due to CHF exacerbation. Drug interactions are similar to those occurring with ARBs—that is, increased risk of hyperkalemia with potassium-sparing diuretics or potassium supplements, particularly in patients with chronic kidney disease, diabetes, or hypoaldosteronism. Worsening of renal failure can occur with concomitant use of NSAIDs; lithium toxicity has also been described.
Inotropic Drugs
Dopamine and Dobutamine
Vasoactive amines are used in the CICU to treat CHF and shock. Both drugs are metabolized in the liver: dopamine by catechol- O -methyltransferase and monoamine oxidase; dobutamine by catechol- O -methyltransferase. Dopamine is inactivated in alkaline pH and, therefore, should not be administered in the same infusion as bicarbonate.
Although there are not many reports in the literature about drug interactions involving vasoactive amines, such interactions could be expected in patients treated with monoamine oxidase inhibitors, requiring lowering the dose of dopamine. The dose of vasoactive amines should be adjusted in patients treated with tricyclic antidepressants because of the possibility of an increased pressor effect.
Changes in blood pressure and in blood flow to the liver will affect the metabolism of high-extraction drugs, such as lidocaine and lipophilic β-blockers (e.g., propranolol, metoprolol). As a result, doses of inotropic drugs that increase cardiac output will also increase liver blood flow and accelerate the clearance of lidocaine, requiring an increased dose of lidocaine. Conversely, when dopamine is used in high doses, resulting predominantly in α-activation and vasoconstriction, liver blood flow decreases and lidocaine clearance would be expected to do the same.
Low-dose dopamine prevents norepinephrine-induced decreases in renal plasma flow in healthy volunteers. However, it is not clear whether the same effect is found in critical care patients. A multicenter study of low-dose dopamine use in critical care patients did not find any improvement in renal outcomes and there were more adverse effects in patients on dopamine.
There is a report of interaction between dobutamine and low-dose carvedilol resulting in severe hypotension. The proposed mechanism is a fall in systemic vascular resistance due to excessive β 2 receptor activation caused by a selective β 1 receptor blockade by low-dose carvedilol. This interaction may be expected with other selective β 1 blockers.
Digoxin
Digoxin is a drug with a narrow therapeutic range and is subject to many drug interactions, both pharmacokinetic and pharmacodynamic ( Table 41.2 ).
TABLE 41.2
Drug Interactions With Digoxin
| Interacting Drug | Serum Digoxin Levels | Mechanism | Comments |
|---|---|---|---|
| Cholestyramine, colestipol | D | Decreased absorption | Wait 1 h after digoxin administration |
| Metoclopramide | D | Decreased absorption due to increased GI motility | Monitor digoxin levels; substitute elixir for tablets |
| Erythromycin | I (only in small percentage of patients) | Increased bioavailability due to decreased gut metabolism | Monitor digoxin levels, adjust dose |
| Anticancer drugs | D | Decreased absorption due to mucosal injury | Monitor digoxin levels; substitute elixir for tablets |
| Sucralfate | D | Decreased absorption | Do not administer within 1 h of digoxin |
| Amiodarone | I | Decreased clearance (P-gp inhibition) | Decrease digoxin dose, monitor levels |
| Dronedarone | I | Decreased clearance (P-gp inhibition) | Decrease digoxin dose, monitor levels |
| Cyclosporine | I | Decreased clearance of digoxin (P-gp inhibition) | Monitor digoxin levels, decrease dose |
| Diuretics | I | Decreased renal clearance in hypovolemia; increased toxicity due to hypokalemia/hypomagnesemia | Monitor serum potassium and magnesium levels; monitor digoxin levels |
| Itraconazole | I | Decreased clearance (P-gp inhibition) | Decrease digoxin dose, monitor levels |
| Propafenone | I | Decreased renal clearance | Monitor digoxin levels, adjust dose |
| Quinine, quinidine | I | Decreased renal clearance (P-gp inhibition) | Decrease digoxin dose, monitor blood levels |
| Spironolactone | I | Decreased renal clearance (P-gp inhibition) | Monitor levels |
| Ticagrelor | I | Decreased renal clearance (P-gp inhibition) | Monitor levels |
| Verapamil | I | Decreased renal excretion (P-gp inhibition) | Decrease digoxin dose, monitor levels |
| Rifampin | D | Increased bioavailability (intestinal P-gp induction) | Monitor levels |
D, Decrease; GI, gastrointestinal; I, increase; P-gp, P glycoprotein.
Interactions Affecting Absorption and Bioavailability.
Digoxin tablets are absorbed slowly; therefore agents that increase gastrointestinal motility (e.g., metoclopramide) may decrease its absorption, whereas agents that slow gastrointestinal transit (e.g., propantheline, other anticholinergic agents) may increase its absorption. Elixir preparations are usually not subject to these interactions because their absorption is more rapid.
Treatment with high-dose chemotherapeutic agents resulting in intestinal mucosal injury can reduce digoxin absorption from tablets by as much as 50% but does not significantly affect absorption from elixir.
In about 10% of patients, digoxin that is not absorbed in the upper gastrointestinal tract or that is excreted in the bile is reductively metabolized by the anaerobic bacterium Eubacterium lentum , which is part of the normal flora of the colon. Such metabolism can account for about 40% of digoxin elimination. These patients may be recognized by the characteristic of needing higher-than-usual doses of digoxin to achieve therapeutic levels. In this group of patients, treatment with broad-spectrum antibiotics (e.g., erythromycin, tetracycline) can result in significantly increased bioavailability and digoxin toxicity.
Cholesterol-binding resins (e.g., cholestyramine, colestipol) bind digoxin in the gut and may reduce its absorption by 20% to 30%. This effect can be avoided by giving digoxin at least 1 hour before the resins. Sucralfate has been reported to decrease the absorption of digoxin. No significant interaction has been found between digoxin and antacids.
Intestinal P-glycoprotein (P-gp) plays an important role in the bioavailability of digoxin. Rifampin increases P-gp content in the intestine and decreases digoxin bioavailability, resulting in significantly lower digoxin AUC after oral administration. On the other hand, drugs that inhibit intestinal P-gp increase digoxin bioavailability and AUC. Dipyridamole was shown to increase digoxin bioavailability in vitro and in vivo; however, the effect on AUC was slight and clinically insignificant. Carvedilol significantly decreased oral clearance of digoxin in children, resulting in digoxin toxicity in some cases. However, in adults, carvedilol caused only a modest increase in digoxin bioavailability and AUC.
St. John's wort ( Hypericum perforatum ) is an herbal medicine frequently used for treatment of depression. H. perforatum induces intestinal P-gp, resulting in a 1.4-fold increased expression of duodenal P-gp in humans. Coadministration of St. John's wort and digoxin caused a 25% decrease in AUC and a 33% reduction in trough and C max concentrations of digoxin.
Interactions Affecting Elimination.
Digoxin is eliminated primarily by renal excretion via the ATP-dependent efflux pump, P-gp. Basic drugs—among them, amiodarone, dronedarone, clarithromycin, itraconazole, quinine, quinidine, verapamil, spironolactone, cyclosporine A, propafenone, and ritonavir—decrease the renal clearance of digoxin by inhibiting P-gp in the kidney. Carvedilol causes significant increases in digoxin AUC and C max in men but not in women. The explanation may be that men have a higher P-gp activity compared with women and, thus, are more sensitive to the effects of inhibiting drugs.
Because the combination of digoxin with drugs that inhibit its elimination results in increased toxicity, the physician should reduce the digoxin dose by 50% when starting another drug, such as quinidine or amiodarone. Because of the long half-life of digoxin, even after dose reduction there is still a potential for toxicity during the first week after adding another drug to the regimen. Patients must be monitored closely during this period.
Pharmacodynamic Interactions.
Digitalis effect and toxicity are enhanced in the presence of hypokalemia and hypomagnesemia. Toxicity may be present even when digoxin blood levels are within the therapeutic range. Because digoxin is often used with diuretics, which can cause electrolyte abnormalities, it is important to monitor and correct deficiencies even though potassium and magnesium blood levels do not always accurately reflect body stores. Concomitant administration of digoxin and sympathomimetic or vagolytic drugs may mask digitalis toxicity because of opposing effects on cardiac conduction. This effect is used therapeutically when digoxin is administered at the beginning of quinidine therapy to prevent rapid AV node conduction as a result of the vagolytic effect of quinidine.
Coadministration of digoxin with sympatholytic drugs (e.g., β-blockers) or calcium antagonists (e.g., verapamil, diltiazem) may result in additive AV block or bradyarrhythmia.
Antidysrhythmic Drugs
Drug interactions with antidysrhythmic drugs are presented in Table 41.3 . A detailed review was published by Trujillo and Nolan.
TABLE 41.3
Drug Interactions With Antidysrhythmic Drugs
| Drug | Interacting Drug | Effect | Mechanism | Comments |
|---|---|---|---|---|
| Quinidine (Q) | Rifampin | Decrease in Q levels | Induction of Q metabolism | Increase Q dose, monitor Q levels |
| Phenytoin | ||||
| Phenobarbital | ||||
| Cimetidine | Increase in Q levels | Inhibition of Q metabolism | Decrease Q dose, monitor Q levels | |
| Amiodarone | ||||
| Verapamil | ||||
| Antacids | Increase in Q levels | Alkalinization of urine, reduced Q tubular secretion | Monitor Q levels, change can be minor | |
| Procainamide | Proarrhythmic effect | Additive Q-T prolongation | Use combination with caution; monitor Q-T and potassium levels | |
| Disopyramide | Torsades de pointes | |||
| Amiodarone | ||||
| Sotalol | ||||
| Succinylcholine | Prolonged neuromuscular blockade | Inhibition of neuromuscular transmission (muscarinic receptors) | ||
| Procainamide (P) | Cimetidine | Increased P levels | Reduced tubular secretion of P | Reduce P dose, monitor P levels |
| Trimethoprim | ||||
| Levofloxacin | ||||
| Disopyramide (Di) | Rifampin | Decreased Di levels | Acceleration of Di metabolism | Increase Di dose or avoid combination (increased anticholinergic effects with Di metabolite) |
| Phenytoin | ||||
| Macrolides | Increased Di levels | P-450 inhibition | Decrease Di dose or avoid combination | |
| Lidocaine (L) | Cimetidine | Increased L levels | Inhibition of L metabolism | Reduce L infusion rate |
| Amiodarone | ||||
| Fluvoxamine | ||||
| Phenobarbital | Decreased L levels | Acceleration of L metabolism | Increase L dose | |
| β-Blockers | Increased L levels | Decrease in L clearance due to reduction in hepatic blood flow | Reduce L infusion rate | |
| Mexiletine (M) | Quinidine | Increased M levels | Inhibition of M metabolism | Reduce M dose or avoid combination |
| Rifampin | ||||
| Phenytoin | Decreased M levels | Acceleration of M metabolism | Increase M dose | |
| Flecainide (F) | ||||
| Cimetidine | ||||
| Amiodarone | ||||
| Quinine | Increased F levels | Inhibition of F metabolism | Decrease F dose | |
| Antacids | Increased F levels | Alkalinization of urine, decrease in tubular secretion | Minor effect | |
| Encainide (E) | Quinidine | Increased E levels; diminished efficacy due to reduced formation of active metabolite | Inhibition of E metabolism | Avoid combination |
| Cimetidine | Increased E levels; enhanced activity due to inhibition of active metabolite clearance | Inhibition of E metabolism | Avoid combination | |
| Propafenone (Pr) | Quinidine | Increased Pr levels and β-blockade | Inhibition of Pr metabolism | Decrease Pr dose or avoid combination |
| Amiodarone (A) | Digoxin | Increased levels of the interacting drugs | Inhibition of the drug's metabolism by A | Monitor serum A levels, adjust dosages |
| Flecainide | ||||
| Lidocaine | ||||
| Procainamide | ||||
| Quinidine | ||||
| Simvastatin | ||||
| Cyclosporine | ||||
| Phenytoin | ||||
| Warfarin | ||||
| Class 1A and 1C drugs | Proarrhythmic effect, torsades de pointes | Additive Q-T prolongation | Avoid combination or monitor Q-T. | |
| β-Blockers Ca channel blockers | Hypotension, bradycardia, AV | Additive depression of conduction | Monitor blood pressure and pulse rate; avoid combination in conduction disorders and heart failure | |
| Adenosine (Ad) | Theophylline (T) | Antagonizes Ad effect | Competition for Ad receptors | Ad ineffective for patients on T |
| Dipyridamole | Increased Ad levels and effect | Inhibition of Ad reuptake | Decrease Ad dose by 50%–75% |
Class 1A
Quinidine.
Quinidine is a drug with many adverse side effects and interacts with many other drugs.
Pharmacokinetic interactions.
Quinidine is primarily metabolized in the liver with only about 20% excreted in the urine. It is subject to interactions with drugs that either induce or inhibit liver enzymes. Among the enzyme inducers, phenobarbital, phenytoin, and rifampin accelerate the metabolism of quinidine, resulting in decreased blood levels. Therefore, when any of these drugs is added, the quinidine dose should be increased, and when these drugs are stopped, the quinidine dose should be decreased. The dose adjustment may be as great as threefold.
There have been conflicting reports about the effect of nifedipine on quinidine blood levels. However, quinidine pharmacokinetics do not appear to be significantly changed by nifedipine or felodipine. Cimetidine, verapamil, and amiodarone inhibit quinidine metabolism and necessitate downward dose adjustment.
Even though renal excretion accounts for only 20% of quinidine clearance, clearance is influenced by urine pH; alkalinization of urine (e.g., with intensive antacid therapy) may result in a moderate increase in quinidine levels.
Pharmacodynamic interactions.
The combination of quinidine with other class 1A drugs (e.g., disopyramide, procainamide) or with class 3 drugs (e.g., amiodarone, sotalol) can result in QT prolongation and increased risk of torsades de pointes.
Moxifloxacin, a methoxyquinolone antibiotic, prolongs QT interval, and must be used with caution with class 1A or class 3 drugs. Hypokalemia, hypomagnesemia, or both—common with diuretic treatment—can increase QT prolongation and the risk of torsades de pointes from quinidine or other drugs.
A proarrhythmic effect of combining amiloride and quinidine has been described, probably resulting from a synergistic increase in sodium channel blockade.
Quinidine has also been reported to potentiate the anticoagulant effects of warfarin by direct inhibition of clotting factor synthesis in the liver. It inhibits neuromuscular transmission and prolongs the duration of anesthesia when used with curare or succinylcholine.
Procainamide.
Procainamide is both metabolized and excreted renally; its active metabolite, N -acetyl procainamide (NAPA), is cleared primarily by renal excretion. The major mechanism is tubular secretion with little reabsorption; therefore, urine pH changes do not cause significant changes in blood procainamide concentration. Conversely, other basic drugs that are secreted by renal tubules (e.g., cimetidine, ranitidine, trimethoprim) significantly inhibit procainamide secretion. Levofloxacin, but not ciprofloxacin, significantly inhibits renal clearance of procainamide and NAPA.
Additive effects of combined treatment with other class 1A or class 3 drugs, or other drugs that cause QT prolongation, are the same as for quinidine.
Disopyramide.
Disopyramide is metabolized by liver enzymes. Enzyme inducers (e.g., rifampin, phenytoin, barbiturates) enhance the metabolism of disopyramide and may cause subtherapeutic blood levels. Enzyme inhibitors such as cimetidine are expected to decrease disopyramide clearance and to increase blood levels. Macrolide antibiotics—including erythromycin, clarithromycin, and azithromycin—inhibit P450 enzymes and there are reports of disopyramide toxicity during concomitant administration.
Class 1B
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