CURRICULUM IN CARDIOLOGY

Update on the influence of quinidine and other agents on digitalis glycosides

Henry I. Bussey, Pharm.D. Austin and San Antonio, Texas

Since this topic was last reviewed,’ additional data on previously described interactions have been pub- lished and certain new interactions have been described. This update follows the format of the earlier review by first discussing new data on the quinidine-digoxin interaction and then discussing related interactions by drug class or mechanism of interaction.

QUINIDINE-DIGITALIS INTERACTIONS

Ouinidine-digoxin interaction. As previously re- viewed,’ quinidine therapy can be expected to dou- ble or triple the serum digoxin concentration (SDC) in most, if not all, patients who achieve a serum quinidine concentration (SQC) of 2 pg/ml or greater. This interaction occurs within a few hours after starting quinidine therapy but may require several days or even weeks before the new steady-state SDC is achieved. It appears that quinidine alters digoxin kinetics by reducing the apparent volume of distri- bution (Vd), renal clearance (Clr), and nonrenal clearance (Clnr). Although the degree of reduction of Clnr is probably not dependent on the SQC, the reduction in Vd and Clr is greater at higher SQC.

Even though the data on the mechanisms of the interaction suggest that the interaction should occur in patients with renal failure, conflicting views exist. Doering erroneously suggested that the interaction should not occur in anuric patients, while others3’4 have demonstrated the interaction in such patients. Hirschberg et a1.3 found that 4 days of quinidine therapy produced a mean increase of 57% in the SDC. However, the graphic presentation of their data appears to suggest that the greatest increases in

From the College of Pharmacy, The University of Texas at Austin; and Clinical Pharmacy Programs, Department of Pharmacology, The Universi- ty of Texas Health Science Center at San Antonio.

Received for publication Apr. 22, 1983; revision received July 1, 1983; accepted July 7. 1983.

Reprint requests: Henry I. Bussey, Pharm.D., Dept of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284.

SDC occurred in those patients with the lowest creatinine clearances. Also, the SQC ranged from 0.9 pg/ml to 5.1 pg/ml, and a correlation between SQC and degree of rise in the SDC was not assessed. In a more recent study by Fenster et a1.,4 in six patients quinidine failed to alter the digoxin Vd but did reduce the total body clearance (Cltb) of digoxin by 43% and increased the digoxin serum half-life by 85%. The degree of rise in the SDC appeared to approach that seen in patients with normal renal function; but it should be noted that only two of the six patients had trough SQC L 1.9 pg/ml, which is the concentration some have suggested is required to alter the digoxin Vd’. As expected, the interaction does appear to occur in patients with renal failure but the full extent of the interaction in such patients remains to be determined.

The data showing that quinidine enhances the rate but not the completeness of digoxin absorption have been previously reviewed.’ More recently, Pe- dersen et a1.5 presented data from a study involving seven patients which showed that the rate and completeness of digoxin absorption was increased by quinidine administration. By comparing the area under the serum concentration vs time curve for orally administered digoxin with that of tritium- labeled digoxin which was administered intrave- nously, these investigators were able to determine the oral bioavailability of digoxin while the patients were receiving quinidine and again 2 months after quinidine was discontinued. Their finding that quinidine increased the bioavailability of digoxin by approximately 16% suggests that this mechanism plays a significant role in the quinidine-digoxin interaction.

Additional data have been added to the majority of earlier work that suggested that quinidine- induced increases in SDC provides additional digox- in effect. Although some authors had suggested that the higher SDC had less effect because quinidine was displacing digoxin from myocardial receptors, the majority of the laboratory and clinical data suggest this is not true. Two recent studies617 have

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American Heart Journal

examined the effects of digoxin alone and in combi- nation with quinidine on the systolic time interval (STD. Belz et al.fi found that digoxin, 0.2 mg daily with quinidine, or digoxin, 0.4 mg daily, produced similar SDC in six healthy males. The effect of digoxin on the ST1 was equivalent with either regimen if the results were adjusted to allow for the negative inotropic effect of quinidine. Schenck- Gustafsson et a1.7 conducted a very similar study in 10 healthy volunteers and found that the ST1 and ejection fraction determinations indicated that the quinidine-induced increase in SDC provided a cor- responding increased digoxin effect, after the nega- tive inotropic effect of quinidine was subtracted. Although one must be cautious in applying these findings in healthy volunteers to patients with car- diac disease, these data do support earlier findings that the quinidine-induced elevation in the SDC does produce an increased digoxin effect and fre- quently requires a reduction in the digoxin dose.

Quinidine-digitoxin interaction. The interaction between quinidine and digitoxin may reach the same magnitude as that seen with quinidine and digoxin, but the underlying mechanisms do not include a reduction in Vd. Abrupt increases in the serum digitoxin concentration would therefore be less like- ly to occur, but the completion of the interaction would be expected to require a longer time period.’ These differences between the effects of quinidine on digoxin and digitoxin, as well as differences with other interactions described below, add support to earlier arguments that digitoxin may be a preferred alternative to digoxin8-”

INTERACTIONS WITH OTHER ANTIARRHYTHMICS

Verapamil. Various recent reports’“-l6 have present- ed additional data showing that verapamil can induce a 60% to 75% increase in the SDC by decreasing Clr, Clnr, and Vd. Pedersen et a1.,16 however, provided interesting new data by following healthy volunteers for 6 weeks or longer. They found that the verapamil-induced increase was somewhat dose-dependent and was partially reversible with continued therapy. Although verapamil, 240 mg/ day, produced a 62% increase in the SDC after 1 week of combined therapy, the mean SDC after 6 weeks of therapy (0.27 rig/ml) was not significantly different from the SDC (0.21 rig/ml) prior to vera- pamil. A more thorough evaluation revealed that Clr had returned to normal. This suggests that this interaction may be a temporary problem in healthy individuals. In patients with severe renal impair- ment, however, one might postulate that the effects of verapamil on the Clnr and Vd of digoxin might produce a significant lasting alteration in the SDC.

Nifedipine. The potential interaction between nifedipine and digoxin appears to be less extensive than that seen with verapamil, if it occurs at all. Two reports12z l9 suggest that such an interaction occurs, while two other publications17, I8 found no interac- tion. Belz et a1.12 studied 12 normal volunteers and found that nifedipine (30 mg daily) produced a 45% increase in the SDC in 9 of the 12 subjects. Another larger study by Belz et a1.13 presented similar results in 36 males given nifedipine, 30 mg daily. The mean SDC increased by 43% and the Clr of digoxin decreased by 29 % . On the other hand, Pedersen et alI7 and Schwartz et al.‘* failed to find a significant interaction. Pedersen et a1.17 administered 30 mg of nifedipine daily to eight healthy volunteers and found that nifedipine increased the Clnr of digoxin by 33% (p < 0.05). No other significant alterations were found and Cltb was unchanged. These data suggest that a significant change in the SDC should not occur in individuals with normal renal function. In patients with poor renal function where Clnr accounts for a larger percent of Cltb, a nifedipine- induced increase in Clnr would be expected to reduce the SDC. The study by Schwartz et al.lx administered 30 to 60 mg of nifedipine daily to 11 patients with coronary artery disease. The mean SDCs were unchanged after 5 days or 1 to 2 months of combined therapy. In summary, it appears that nifedipine may alter the pharmacokinetic parame- ters of digoxin but the magnitude of any change in the SDC should be less than that seen with vera- pamil or quinidine.

The possibility that calcium channel blockers may alter the SQC has not been well studied. Green et al.,ly however, have presented one case report in which nifedipine apparently caused a significant reduction in the SQC.

Diltiazem. Potential interactions with diltiazem have not been well studied. Data on file with Marion Laboratories (Personal communication, E.J. Hester- lee), however, indicate that diltiazem (60 mg every 6 hours) produced less than a 20% increase in the SDC of 12 healthy volunteers.

Amiodarone. Although it is unclear if amiodarone increases the SDC, a recent report?* suggests that this drug can produce a 50% increase in the SQC, which can cause serious dysrhythmias. Such an increase in SQC would also be expected to increase the SDC in patients receiving ail 3 drugs.

Procainamide, disopyramide, and mexiletine. These agents appear to have no significant effect on the SDC.’

Diuretics. For a discussion of the effects of various diuretics on SDC, the reader is refered to the earlier review.’

Volume 107

Number 1 Quinidine-digoxin and related interactions 145

AGENTS WHICH ALTER ABSORPTION OF DIGOXIN OR DIGITOXIN

Antacids. For a discussion of this interaction which has probably been overemphasized in the literature, the reader is referred to the earlier review.’

Antibiotics. The initial findings of Lindenbaum et al.2l that a small portion (approximately 10%) of patients exhibit a significant (40%) reduction of digoxin by gut flora and that altering this flora can produce a significant increase (as much as twofold in the SDC, has been substantiated in a report by Friedman.22 In this case report only four 250 mg doses of erythromycin were required to increase the SDC from 1.5 to 2.6 rig/ml.

Cholestyramine and colestipol. Two new reports have recently been published as further support of the effects of these agents on digoxin and digitoxin. Baciewicz et alz3 reported a single case in whom three doses of cholestyramine, 4 gm orally every 8 hours, produced only a slight improvement in digi- toxin elimination (half-life decreased from 7.4 to 6 days). It is difficult to reconcile this finding with earlier data which showed a more significant effect of cholestyramine on digitoxin. On the other hand, Kilgore and Lehmanz4 described an elderly woman in whom 10 gm of colestipol given orally every 8 hours enhanced the elimination of digoxin and reduced the serum half-life from approximately 3 to 4 days to 2 days. Either binding agent may be expected to decrease the serum concentration of digoxin or digitoxin.

Charcoal. Pond et a1.25 described an elderly female who overdosed on digitoxin (serum concentration of -300 rig/ml) and was treated with activated char- coal (6 gm) and magnesium citrate (250 ml) orally every 8 hours for 72 hours. During this treatment period her serum digitoxin concentration decline reflected a half-life of 18 hours; without treatment the half-life increased to 162 hours.

Propantheline and metoclopramide. Data discussed in the earlier review’ suggest that the absorption of digoxin may be increased by propantheline and decreased by metoclopramide.’

Cytotoxic agents. Kuhlmann et al, who initially demonstrated that several chemotherapeutic agents could decrease the absorption of digoxin and there- by reduce the SDC by 40% to 50%) has more recently published two reports26*27 which demon- strated that various chemotherapeutic regimens may decrease the rate but not the extent of digitoxin absorption. For this reason, patients undergoing cancer chemotherapy might avoid fluctuations in their serum concentrations if they were treated with digitoxin rather than digoxin.

Sulfasalazine. This agent has been recently incrim- inated by Juhl et al.,” who reported that sulfasala- zine decreased digoxin absorption by - 18 % to 25 % . Because this study utilized digoxin elixir, which is better absorbed than the tablets, the inhibition of absorption might be more significant in patients receiving the tablet form of digoxin.

AGENTS WHICH ALTER METABOLISM OF DIGOXIN AND DIGITOXIN

Quinine. Since the earlier report by Wandell et al.,2g another case report has supported the finding that quinine can cause a significant elevation in the SDC.30 The data to date suggest this interaction may produce approximately a 50% increase in the SDC, but the possibility that higher SDC values might result from larger doses of quinine can not be ruled out at this time.

Cimetidine. As discussed in the earlier review,’ cimetidine has been reported to increase both quin- idine and digitoxin serum concentrations, but whether cimetidine has a direct effect on the metab- olism of digitoxin or digoxin has not been estab- lished.

Rifampin. Although the ability of rifampin to induce quinidine metabolism has been previously discussed,’ a recent report of three cases suggests: (1) that a three-way drug interaction is likely to result when rifampin, quinidine, and digoxin are combined; (2) that rifampin may directly increase digoxin metabolism; and (3) that the increased concentration of quinidine metabolites may main- tain the therapeutic effects of quinidine in the face of a rifampin-induced decline in the SQC. These possibilities are not firmly proved but deserve fur- ther study.

Anticonvulsants and phenylbutazone. The ability of phenytoin, barbiturates, and phenylbutazone to induce hepatic metabolism of digoxin or digitoxin was discussed in the earlier review; I am unaware of any new data on these interactions.

CONCLUSIONS

The quinidine-digoxin interaction, which was first described in 1978, has been relatively well studied and defined. The magnitude of this interaction and the delineation of the mechanisms involved have led many investigators to uncover numerous related interactions involving drugs that have been used for some time and to be more curious about potential interactions with newly marketed agents.

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