Pharmacokinetic Interactions Between Digoxin and Other Drugs

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Provided by82A Elsevier - Publisher Connector JACC Vol. 5, No.5 May 1985:82A-90A

FRANK I. MARCUS, MD, FACC Tucson, Arizona

Drug interactions with digoxin are important because of particularly verapamil, have a similar effect. Potassium this agent's narrow therapeutic index. Amongthe drugs sparing diuretic drugs, such as spironolactone, can alter that can decrease digoxin bioavailability are cholestyr digoxin pharmacokinetics. amine, antacid gels, kaolin-peetate, certain antimicro Indomethacin may decrease renal excretion of dig bial drugs and cancer chemotherapeutic agents. In oxin in preterm infants. Finally, rifampin, an antibiotic selected patients, antibiotics may enhance digoxin bio used in the treatment of tuberculosis, may lower steady availability by eliminating intestinal flora that metabo state serum digoxin levels in patients with severe renal lize digoxin. disease. Physicians must maintain constant vigilance Antiarrhythmic drugs, such as quinidine and amio whenever medications are added to or withdrawn from darone, can markedly increase steady state serum dig a therapeutic regimen that includes digoxin. oxin levels. Certain calcium channel blocking drugs, (J Am Coil CardioI1985;5:82A-90A)

Historical Perspective There is a high incidence of toxicity during the therapeutic use of this class of drugs. Interactions of cardiac glycosides Drug interactions with digoxin could only have been with other drugs contribute significantly to the high prev suspected but not verified before the availability of assays alence of digitalis toxicity. This review will focus on the sufficiently sensitive to measure digoxin in biological fluids pharmacokinetic interactions of digoxin. The drugs that have (1-4). In 1971, Caldwell and Greenberger (5) investigated been investigated for interactions are listed in Table 1 and the possibility that cholestyramine, an anion exchange resin their mechanisms and magnitude are summarized in Table known to bind neutral sterols, might be effective in de 2. creasing the duration of digitalis toxicity. Subsequently, Smith (6) documented that cholestyramine coadministered with digoxin could decrease digoxin absorption. Binnion Drugs That Affect Bioavailability of Digoxin (7) also reported extremely low levels of serum digoxin in Cholestyramine. When 4 to 8 g of cholestyramine are a patient who was taking kaolin-pectate with digoxin and given at the same time as digoxin, there is a 25% decrease identified that kaolin-pectate decreased the bioavailability in steady state serum digoxin levels (12). The mechanism of digoxin. This led to an intensive investigation of drugs of this interference appears to be related to physical binding that might decrease digoxin bioavailability. The startling of digoxin to the resin (5). Administration of digoxin 8 hours observation by Ejvinsson (8) that quinidine coadministered before cholestyramine prevents the interference with ab with digoxin caused a marked elevation in plasma concen sorption of the glycoside (12). This interaction can also be trations of digoxin led to exploration of other antiarrhythmic minimized by prescribing digoxin in a solution contained drug interactions with digoxin. Subsequently, the pace of in a gelatin capsule (Lanoxicap). The Lanoxicap preparation investigation of drug interactions with digoxin has escalated also produces less variability in digoxin absorption when and numerous interactions with digoxin have been unveiled cholestyramine is given with the capsules as compared with (9-11). the tablets. The focus on drug interactions with digoxin is appropriate Antacids. Antacid gels (13), but not the tablets (14), for this agent since it not only is one of the most commonly appear to decrease the absorption of a single dose of digoxin prescribed drugs, but also has a narrow therapeutic index. by approximately 25%. The mechanism of this reduction of digoxin absorption by antacids is unclear. Since only magnesium trisilicate has been found to adsorb digoxin in From the Section of Cardiology, Arizona Health Sciences Center, Tuc vitro (15) while other antacids also lowered plasma levels son, Arizona. Address for reprints: Frank I. Marcus, MD, Section of Cardiology, in human beings, the decreased absorption of digoxin may Arizona Health ~"iences Center, Tucson, Arizona 85724. be due to factors other than adsorption. The effect of con-

Table 1. Generic and Trade Names of Drugs Investigated for Antimicrobial drugs. Certain antimicrobial drugs such Interaction With Digoxin as neomycin, sulfasalazineand paraaminosalicylic acid (PAS), Generic Name Brand Name often used for their effect on intestinal function and flora, appear to depress digoxin absorption (12,20,21). This in Cholestyramine Questran Kaolin-pectate Kaopectate teraction results in an 18 to 28% decrease in the bioavail Neomycin Neomycin ability of digoxin and is not minimized by temporal sepa Sulfasalazine Azulfidine ration of the time of administration of digoxin and the Para-amino salicylic acid PAS, Teebacin concurrently administered antimicrobial agent. Propantheline Probanthine Antibiotic treatment may increase serum digoxin levels Quinidine Quinidine Hydroxychloroquine Plaquenil by an entirely different mechanism. Digoxin undergoes bio Amiodarone Cordarone transformation to dihydrodigoxin and its corresponding Procainamide Pronestyl aglycone, dihydrodigoxigenin. These two metabolites, which Disopyramide Norpace are relatively inactive, are referred to as digoxin reduction Mexiletine Mexitil products. Digoxin reduction products appear to be made F1ecainide F1ecainide Moricizine Ethmozine exclusively by bacteria in the gastrointestinal tract, probably Verapamil Calan; Isoptin in the colon (22). The reduced metabolites virtually dis Diltiazem Cardizem appear from the stool and urine after therapy with certain Nifedipine Procardia antibiotics, and this can lead to an increase in bioavailability Tiapamil* of digoxin (23). In a recent study (23), a 5 day course of Nicardipine* Gallopamil* erythromycin or tetracycline was found to raise the serum Lidotlazin* digoxin concentrations by 43 to 116% in three volunteers Spironolactone Aldactone who produced large amounts of digoxin reduction products Triamterene Dyrenium; also in Dyazide (> 35 to 40% of total urinary digoxin and its metabolites). Midamor; also in Moduretic Amiloride Since only 10% of subjects produce large amounts of these *U.S. trade names not now available. reduced derivatives, this increase in digoxin levels due to antibioticsshould occur in only a minority of patients (22,24). Administration of digoxin in capsule form decreases the comitant administration of antacids and digoxin on steady percent of digoxin reduction products formed, presumably state plasma levels of digoxin remains to be established. by more complete absorption of digoxin in the small intes Until this information is available, it is advisable not to tine (25). Thus, the increase in bioavailability during admin administer digoxin at the same time as antacids. istration of these antibiotics should be minimized with the Kaolin-pectateand bran. The decreased bioavailability use of the capsule forms of digoxin. of digoxin as a result of the coadministration of an antidi Drugs that alter gut motility. Digoxin absorption is arrheal suspension containing 18% kaolin and 0.4% pectin not affected by medications that alter gut motility, such as (Kaopectate) was first reported by Binnion (7) after ob propantheline (Probanthine) or metoclopramide (26). serving ineffective blood levels of digoxin in a patient who Cancer chemotherapeutic agents. Digoxin absorption had taken the antidiarrheal at the same time as digoxin. and steady state levels may be markedly decreased by cancer Brown and Juhl (13) subsequently verified Binnion's find chemotherapy (27). This inhibition of digoxin absorption is ings in a cross-over study employing 10 normal volunteers. reversible after 1 week. The mechanism of this interaction The magnitude of this drug interaction is still not clear since appears to be temporary damage of the intestinal mucosa there have been no studies to determine the effect of this by the cytostatic drugs. combination on steady state plasma levels of digoxin. The decrease in digoxin absorption can be abolished by giving Interaction of Digoxin With digoxin 2 hours before administration of the antidiarrheal agent (16) or may be minimized by administration of the Antiarrhythmic Drugs capsule formulation of digoxin (17). Quinidine. In 1978, Ejvinsson (8) reported that the con When digoxin was given at the beginning of a meal current administration of quinidine to 12 patients increased containing a high content of fiber, there was a 20% decrease average serum digoxin concentrations from 0.9 to 1.6 ng/ml. in cumulative 6 day urinary digoxin excretion (12). Others One of the six patients whose plasma concentrations rose (18) were not able to document a decrease in digoxin ab above therapeutic range developed symptoms of digitalis sorption when digoxin was given 15 to 30 minutes before intoxication. This observation has since been amply con a meal containing high fiber content. The mechanism of this firmed (28-30). The mechanism of this interaction is com possible interaction appears to be an adsorption of digoxin plex. Quinidine may enhance digoxin bioavailability (31), to bran (19). although this is disputed (32). There is a decrease in the 84A MARCUS JACC Vol. 5, No.5 DRUG INTERACTIONS WITH DIGOXIN May 1985:82A-90A

volume of distribution of digoxin, suggestive of a displace portant mechanisms responsible for the digoxin-quinidine ment of digoxin binding by quinidine (33,34). interaction are a quinidine-induced reduction of both renal Renal and nonrenal clearance ofdigoxin. The most im- and nonrenal clearances of digoxin (33-35). Since glorner-

Table 2. Pharmacokinetic Drug Interactions With Digoxin

Type of Study Mechanism of Mean Interaction: Magnitude Single Dose Steady Suggested Drug Effect on Digoxin of Interaction* Digoxin State Intervention References

Cholestyramine Adsorption of ~ 25% X I) Give digoxin 8 12 digoxin hours before cholestyramine 2) Use solution or capsule form of digoxin Antacids Unclear ~ 25% X Temporal separation 13 of time of administration Kaolin-pectate Adsorption of ? X I) Give digoxin 2 13,16,17 digoxin hours before kaolin-pectate 2) ? Use solution or capsule form of digoxin Bran Adsorption of ~ 20% X Temporal separation 12,18 digoxin of time of administration Neomycin Unknown ~ 28% X Increase dose 21 Sulfasalazine ~ 18% X of digoxin 20 PAS I ~ 22% X 12 Erythromycin 1 Bioavailability 143 to 116% X I) Measure serum 23,25 Tetracycline I by 1 intestinal digoxin (in <10% metabolism of concentration of subjects) digoxin by 2) Decrease digoxin certain gut flora dose 3) Use solution or capsule form of digoxin Quinidine ? ~ Bioavailability 1100% X X I) Decrease 28-30 ~ volume of dose by 50% distribution, 2) Measure serum ~ renal and nonrenal digoxin clearance concentration Amiodarone ~ Renal and nonrenal 170 to 100% X Same as for 53,54,57 clearance quinidine Verapamil ~ Renal and nonrenal 170 to 100% X Same as for 66,67 clearance quinidine Diltiazem ? ~ Renal clearance 122% X None 71,72 Nicardipine Unknown 115% X None 76 Tiapamil Unknown 160% X Same as for 76 quinidine Spironolactone ~ Renal and nonrenal 130% X Measure serum 86,90 clearance digoxin concentration Triameterene ~ Nonrenal clearance 120% X Measure serum 86 digoxin concentration Indomethacin ? ~ Renal clearance 150% X Decrease dose by 97 (preterm infants) 25%

*Alteration in bioavailability or serum concentration. For single dose studies, the magnitude of the anticipated change in serum digoxin concentration was estimated from pharmacokinetic data, particularly the change in total body clearance. 1 = increased; ~ = decreased; ? = questionable. JACC Vol. 5, No.5 MARCUS 85A May 1985:82A-90A DRUG INTERACTIONS WITH DIGOXIN

ular filtration rate is unchanged during concurrent digoxin Amiodarone. In 1981, Moysey et al. (52) observed a quinidine administration, it is clear that the decreased renal mean increase in plasma digoxin concentration of 70% in elimination of digoxin in human beings results from a quin seven patients when amoidarone, 600 mg/day, was admin idine-induced decrease in tubular secretion of digoxin (36). istered concurrently with digoxin. The mean concentration Decisive evidence for a decrease in the nonrenal excretion of digoxin after amiodarone was 2 ng/ml. Four patients of digoxin under the influence of quinidine was established developed symptoms compatible with digoxin toxicity. The by comparing the kinetics of digoxin in anuric patients on plasma digoxin level increased by 25% within 24 hours after chronic hemodialysis when given digoxin alone and con the initiation of amiodarone treatment. These observations comitantly with quinidine (37-39). The combination ther have subsequently been confirmed (53.54). There is sugges apy resulted in a rise in serum digoxin concentration in these tive evidence that the increase in digoxin levels may in part anuric patients . be directly related to the dose of amiodarone since a linear The increase in digoxin serum concentration is directly, correlation was observed between plasma amiodarone levels but not linearly, related to the dose of quinidine (11,40). and digoxin serum levels (55). However. a daily amiodarone The rate at which a new digoxin steady state is achieved is dose of 400 mg is sufficient to reduce clearance of a digoxin dependent on the digoxin elimination half-life. If the half concentration by 26% (56). life of digoxin is 36 hours, approximately 7 days (1'12 days Mechanism. The digoxin-amiodarone interaction is due x 5 half-lives) are required to achieve a new steady state in part to a decrease in the renal clearance of digoxin, a digoxin level. However, in patients with a glomerular fil decrease in nonrenal clearance and an increase in digoxin tration rate of less than 50 ml/rnin , the time required for half-life . No significant decrease in the volume of distri digoxin to reach a new steady state with the addition of bution of digoxin was observed after amiodarone therapy quinidine may be considerably longer. (56,57). Electrophysiologic and inotropic effects. It is clear that Digitalis toxicity . When serum digoxin levels are raised the elevation of digoxin levels by concurrent quinidine as a result of the arniodarone-digoxin interaction, digitalis admini stration results in enhanced electrophysiologic effects toxicity may result. Generally, the toxic manifestations con demon strated on the surface electrocardiogram as a prolon sist of bradycardia or variou s degree s of atrioventricular gation of the PR interval , by central nervous system man (AV) block rather than digitalis-toxic tachyarrhythmias ifestations of toxicity such as anorexia, nausea , vomiting (57.58). Recommendations for digoxin dose adjustment during and scotomata and also by enhanced ventricular ectopic concomitant amiodarone therapy are similar to those when activity (41-45). quinidine is given with digoxin . The elevated serum digoxin levels induced by concurrent Other antiarrhythmic drugs. There are several antiar administration of digoxin and quinidine have been reported rhythmic drugs that do not appear to have any clinically not to show an enhanced inotropic effect as measured by relevant pharmacokinetic interactions with digoxin. These systolic time intervals (46-48). Schenck-Gustafsson et al. include procainamide (59), disopyramide (59-61), mexi (49), however, measured inotropic effects of digoxin at letine (59,62), flecainide (63) and ethmozine (64). steady state during digoxin administration alone and during digoxin and quinidine administration. They then gave suf Interaction of Digoxin With Calcium Channel ficient digoxin to achieve a serum digoxin concentration similar to that obtained when digoxin and quinidine were Blocking Drugs given concomitantly. They concluded that digoxin elevation The pharmacokinetic interaction between digoxin and due to quinidine was accompanied by an increased cardiac calcium channel blocking drugs varies from none with ni effect. fedipine to an increased serum digoxin level of more than Digitalis toxicity . Clinical evidence indicates that there 70% when verapamil and digoxin are given concomitantly. are increased electrophysiologic and inotropic effects as Verapamil. In 1980. Klein et al. (65) reported that serum sociated with the elevation of serum digoxin as a result of digoxin levels increased 70% during concurrent treatment concurrent quinidine admini stration . This combination of with verapamil . They found (66) that the effect of verapamil drugs can cause signs and symptoms of digitalis toxicity. on serum digoxin concentration developed gradually within Therefore, the dose of digoxin should be decreased by ap the first few days after verapamil was coadministered with proximately 50% and the serum digoxin levels should be digoxin and approached the new steady state value within measured approximately I week after the tWQ drugs are 7 days after the start of verapamil therapy. The interaction given together. If the dose of quinidine is increased, one is dose-dependent. The mechanism of the digoxin-verapamil can anticipate a further increase in serum digoxin levels. interaction consists of decreases in both renal and extrarenal Quinine, the I-isomer of quinidine, also reduces total clearance of digoxin by verapamil (67). Since the creatinine body clearance and increases the half-life of digoxin (50). clearance does not change under the influence of verapamil , It is likely that hydroxychloroquine, a quinine derivative, the decreased renal clearance of digoxin appears to be due has similar interactions with digoxin (51). to an inhibition of tubular secretion. 86A MARCUS JACC Vol. 5, No.5 DRUG INTERACTIONS WITH DIGOXIN May 1985:82A-90A

The elevated plasma digoxin concentration induced by dietary sodium is increased may show some moderate de verapamil is associated with an inotropic effect as assessed crease in steady state serum digoxin levels (81). by a measurement of systolic time intervals (68). When the Diuresis-induced hypokalemia. Although thiazides and serum digoxin levels are markedly elevated as a result of loop diuretic drugs themselves do not alter the kinetics of coadministration of verapamil, lethal cardiac toxicity may digoxin excretion, they induce a dose-dependent loss of occur (69). This is more likely to take the form of severe potassium from the body, resulting in a decreased serum bradycardia or asystole, rather than initiation of the tach potassium concentration. It is well known that hypokalemia yarrhythmias that are observed when quinidine induces el is associated with sensitivity to digitalis and, thus, increases evated serum digoxin levels (67,70). It seems prudent to its toxicity (82,83), but it is not well appreciated that when decrease the dose of digoxin by 50% when verapamil and the serum potassium is as low as 2 to 3 mEq/liter, the tubular digoxin are given concurrently. secretion of digoxin is nearly blocked. This reduced tubular Diltiazem. There is minimal pharmacokinetic interac secretion of digoxin results in a diminished plasma clearance tion between diltiazem and digoxin (71). An average in of digoxin and thereby a prolonged elimination half-life of crease in steady state plasma digoxin concentration of 22% digoxin (84,85). Thus, hypokalemia itself can result in an was observed when diltiazem, 180 mg/day, was given to increase in serum digoxin level as well as enhancing toxicity 24 normal subjects who were receiving l3-acetyldigoxin, 0.2 (85). mg daily (72). This interaction may be due to a diltiazem Potassium-sparing diuretic drugs. The potassium induced decrease in renal clearance of digoxin (71). The sparing diuretic drugs, spironolactone, triamterene and ami magnitude of the diltiazem interaction is small; therefore, loride, have been reported to induce changes in digoxin digoxin dose adjustment is probably unnecessary. kinetics (86-89). Spironolactone increases the plasma con Nifedipine. There is no pharmacokinetic interaction be centration of digoxin by inhibiting tubular secretion of di tween nifedipine and digoxin, either in patients (73) or in goxin. This results in a decrease in the renal clearance of normal subjects (74,75). digoxin. The extrarenal clearance of digoxin also decreases Other calcium channel blocking drugs. Tiapamil, a (88,90). In contrast, amiloride alters digoxin pharmacoki congener of verapamil, causes an increase in serum digoxin netics by different mechanisms. This drug causes an increase levels of60%, similar to that of verapamil (76). Nicardipine in renal clearance, but a marked decrease in extrarenal clear is related to nifedipine and increases plasma digoxin min ance. The net result is a tendency to decrease digoxin total imally, in the order of 15%. A similar minimal increase in body clearance (87). Possible mechanisms for these obser digoxin levels is induced by gallopamil (77). There is no vations include an increased tubular secretion of digoxin to pharmacokinetic interaction between digoxin and lidoflazine account for the increased renal clearance and a decrease in (78). the hepatic elimination rate of digoxin to account for the decrease in extrarenal clearance. Triamterene does not alter renal elimination of digoxin, but reduces the extrarenal Interaction With Diuretic Drugs clearance of digoxin. When triamterene is given with di Furosemide and sodium-induced diuresis. Diuresis goxin, the total digoxin elimination is reduced by 20% (86). induced by furosemide does not significantly affect the ex The effects of the potassium-sparing diuretic drugs on cretion of digoxin (79,80). However, Naafs et al. (81) re steady state serum digoxin levels have not been adequately ported that diuresis caused a 70% increase in digoxin clear evaluated. Potassium-sparing diuretic drugs have different ance and a 20% decrease in serum digoxin levels in 10 mechanisms and sites of action, which may account for their patients who were taking digoxin for atrial fibrillation and differing effects on digoxin pharmacokinetics. Spironolac who did not have congestive heart failure. These subjects tone exerts its effects from the capillary side of the renal were initially sodium-depleted, both by dietary restriction tubular cell, whereas triamterene and amiloride act on the of sodium as well as by diuretic drugs. When the sodium luminal side (91). Spironolactone does not increase intra diet was liberalized to a moderately high sodium diet, the cellular potassium concentration, whereas triamterene and digoxin clearance increased by 70% and the serum digoxin amiloride do. levels decreased by 20%. Mechanisms that have been iden Combined digitalis, quinidine and diuretic drug ther tified for renal excretion of digoxin include glomerular fil apy. Patients with cardiac disease are frequently treated tration, tubular secretion and proximal tubular reabsorption with multiple medications and the combination of a potas of digoxin. Naafs et al. (81) postulated that one of the sium-sparing diuretic drug, digoxin and quinidine is not mechanisms responsible for the increase in digoxin clear unusual. This combination of quinidine and spironolactone ance due to sodium loading was diminished passive prox caused significant reductions in total body clearance of di imal back diffusion of filtered and secreted digoxin. Sodium goxin, nonrenal digoxin clearance and digoxin renal clear loading has been shown to diminish proximal fractional ance beyond the reductions induced by either drug alone reabsorption of glomerular ultrafiltrate. Thus, it is possible (90). Therefore, the effects of these two drugs on steady that patients who are on a strict low sodium diet and whose state serum digoxin concentrations should be additive. JACC Vol. 5, No.5 MARCUS 87A May 1985:82A-90A DRUG INTERACTIONS WITH DIGOXIN

Clinical significance. The clinical significance of an an in tum, the interaction between quinidine and digoxin was ticipated elevation of steady state serum digoxin levels in diminished, thereby lowering seurm digoxin levels. It is duced by the potassium-sparing diuretic drugs is not clear. possible that digoxin metabolism was directly accelerated Waldorff et al. (86,87) found that both spironolactone and by rifampin. This case report (10 I) illustrates the complex amiloride attenuated the positive inotropic effect of digitalis interaction that may occur with multiple drug therapy. evaluated by systolic time intervals and echocardiography, Cimetidine. Fraley et al. (102) reported a 25% decrease whereas triamterene induced no changes in digoxin-elicited in steady state serum digoxin concentrations when digoxin inotropy. Since the magnitude of this interaction of potas was given together with cimetidine. These results are in sium-sparing diuretic drugs has not been established, mea contrast to those of Jordaens et al. (103) who studied the surement of the steady state serum digoxin levels may be pharmacokinetics of oral digoxin in eight healthy volun warranted. teers, both with and without concurrent cimetidine. They concluded that cimetidine had no effect on the area under Miscellaneous Drug Interactions the plasma concentration versus time curve of digoxin. Vasodilator drugs. Total renal clearance of digoxin was With Digoxin increased by 50% in 8 patients during administration of Anti-inflammatory drugs. No pharmacokinetic inter nitroprusside or hydralazine (104). Because the glomerular action has been observed with aspirin (92), benoxaprofen filtration rate was unchanged and the estimated renal blood (93) or tiaprofenic acid (94). Elevated serum levels of di flow was increased, the mechanism of this alteration in goxin were observed after I week of concomitant therapy digoxin renal clearance was thought to be an increase in with ibuprofen, but this increase in digoxin level did not tubular secretion of digoxin. It is not yet known whether persist after 28 days (95). long-term vasodilator therapy increases the dosage require Indomethacin therapy did not alter digoxin pharmaco ments for digoxin in patients with congestive heart failure. kinetics in healthy adult volunteers with normal renal func tion (96), but was found to cause an increase of 45% in serum digoxin levels in preterm infants when coadminis Summary tered with digoxin for the treatment of patent ductus arte An intensifying myriad of interactions with digoxin is riosus (97). Administration of indomethacin to the infants now being revealed. It is no wonder that digoxin intoxication was associated with a significant decrease in urinary output, has been so difficult to avoid. Patients with heart disease suggesting that the increase in serum digoxin level was due may be treated concomitantly with anticholesterolemic drugs, to a decreased glomerular filtration rate and a decrease in diuretic drugs, calcium channel blocking agents, vasodila the renal clearance of digoxin. These authors (97) suggested tors and antimicrobials, some of which have been shown to that when indomethacin is added to digoxin therapy in pre interact with digoxin. The accumulated information regard term infants, the digoxin dose should be reduced by 50%. ing drug interactions with digoxin should contribute to greater The increase in serum digoxin level associated with indo safety in the use of the drug, provided that the physician methacin may also apply to adult patients since a lowering maintains constant vigilance whenever any medication is of effective renal plasma flow has been observed in patients added to or withdrawn from a therapeutic regimen that in after indomethacin administration (96). Therefore, the po dudes digoxin. tential for digoxin-indomethacin interaction may be greater Although there has been a tremendous increase in our in patients with abnormalities in renal function. knowledge of the drug interactions, more investigation is Rifampin. Rifampin, an antibiotic used for the treat needed to define the full scope and magnitude of these ment of tuberculosis, has been shown to remarkably lower interactions with digitalis, particularly during steady state. the steady state serum digoxin level in several patients de We are also greatly in need of accurate and sensitive meth pendent on dialysis (98,99). There is limited evidence (98) ods to reliably measure the inotropic and vagotonic effects to suggest that this interaction is due to an increased bio of digitalis to assess the effects of these drug interactions. transformation of digoxin in these patients with minimal to no renal function. Rifampin accelerates the metabolism of [ am indebted to Paul Fenster, MD and Paul Nolan, MD for critical review numerous drugs, including digoxin (100). Other possible of this manuscript. [ gratefully acknowledge the secretarial assistance of Debbie Hunter. explanations for the digoxin-rifampin interaction include decreased absorption of digoxin or increased biliary excretion. A complex drug interaction involving rifampin. digoxin and quinidine has been reported (1O/). Therapy with ri References fampin produced a decline in both the serum quinidine con I. Lowenstein 1M. A method for measuring plasma levels of digitalis centration and serum digoxin concentration. It was postu glycosides. Circulation 1965;31:228-33. lated that rifampin increased the metabolism of quinidine; 2. OliverGC Jr. Parker BM, Brasfield DL, ParkerCW. The measurement 88A MARCUS rxcc Vol. 5, No.5 DRUG INTERACTIONS WITH DIGOXIN May 1985:82A-90A

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