The influence of quinidine and other agents on digitalis glycosides

The influence of quinidine and other agents on

digitalis glycosides

Henry I. Bussey, Pharm.D. Sun Antonio, Texas

Initial reports of the interaction between quinidine and digoxin have led to attempts to delineate the various facets of this interaction, forced a reexami- nation of our understanding of the pharmacodynamics of digitalis glycosides, helped identify related interactions, and provided additional questions for further research. The following considera- tions delineate the existing data on numerous aspects of the quinidine-digoxin interaction, outline related drug interactions, and identify questions deserving further study. The interaction between quinidine and digoxin, which was first described in 1978, produces a sustained elevation in the serum digoxin concentration (SDC). Since the interaction was first identified several investigators have attempted to define the interaction in terms of its frequency of occurrence, magnitude, time course, and the importance of drug dose or serum level; describe the mechanisms involved; evaluate the clinical significance; and suggest management options.

DEFINING THE INTERACTION

Frequency of occurrence. According to Doherty,’ digoxin is the eighth most frequently prescribed drug and quinidine is the most frequently used antiarrhythmic agent in the United States. This level of use, together with the duration of such therapy in many patients, produces a phenomenally large number of patient-days during which this interaction may produce serious consequences. Although the interaction may not occur in all patients receiving both drugs, it does occur in the majority. One of the initial reports by Leahey et al.’ concluded that the incidence of this interaction was at least 25% in patients receiving both drugs. The conclusion was derived from the observation that the interaction occurred in 25 of 92 patients who

From the College of Pharmacy, University of Texas at Austin.

Received for publication Jan. 22, 1982; accepted Feb. 12, 1982.

Reprint requests: Henry I. Bussey, PharmD., Clinical Pharmacy Pro- grams, Dept. of Pharmacology, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284.

0002.8703/82/080289 + 14$01.40/O E: 1982 The C. V. Mosby Co.

were treated with both drugs. Because their exclu- sion criteria excluded all but 27 of the initial 92 patients, the actual frequency was 25 of 27 patients. This high incidence has also been supported by data from other sources.3-7 The reason an occasional patient may not demonstrate an elevation of the digoxin serum level when quinidine therapy com- mences is discussed below under “effect of quinidine dose or serum concentration.”

Magnitude. Although the wide range of 20% to 330% increase in the SDC reported by Dahlqvist et al.s may be exceeded occasionally, the vast majority of patients can be expected to have a two- to threefold increase in their SDC.2s4,g-‘5 In fact, Fried- man and Chen’O went so far as to propose the formula Y = 2.6(X) - 0.6 to predict the SDC after starting quinidine (Y), based on the pre-quinidine SDC(X). Data discussed below, however, suggest the equation is accurate only for a particular range of serum quinidine concentrations.

Timing. The SDC frequently increases within hours after quinidine therapy is started and contin- ues to increase over several days to a new “steady- state” level. Dahlqvist et al.s found that there was a delay of 6 to 18 hours between the initiation of quinidine therapy and a rise in the SDC. The time required for the interaction to become fully manifest has been more frequently addressed, but is less clearly defined. The conclusion of Mungall et al.‘” which implies that the interaction is complete after 4 days of quinidine has been endorsed by others,l”l l7 but may be inaccurate. Mungall et al’s study measured serum digoxin levels in 15 adult patients on the day before starting quinidine therapy and daily thereafter. The mean quinidine and digoxin serum levels increased daily over the 5-day study period. Their conclusion that “no significant differences were found in serum digoxin or serum quinidine concentrations between days 4 and 5” may be statistically accurate, but their actual data showed a modest increase. Fenster et al.ls agreed that the SDC increased during the first day of quinidine therapy, but noted a continuing increase through day 7. Pedersen et al.lg more specifically reported a 64.5%

289

290 Bussey August, 1982

Amertcan Heart Journal

increase in the serum digoxin levels of nine patients on day 4 of quinidine therapy and a further increase to 107.1% on day 9. Likewise, the patient reported by Reid and Meek” also required 9 days to reach a new “steady-state” SDC after quinidine therapy was begun. Finally, the finding of Ochs et a1.7 that quinidine increased the elimination half-life (T’/z) of digoxin in normal volunteers to 79 hours, indicates that 10 to 16 days (three to five times the T’/z) would be required to achieve a new digoxin steady state. It therefore appears that this interaction occurs during the first day of therapy and progresses to a new steady state over 1 to 2 weeks.

All of the above data on the time course of this interaction apply to the initiation of quinidine therapy without a loading dose. Recently Leahey et all5 demonstrated that a quinidine loading dose of 300 mg given every 3 hours for three doses produced a doubling of the SDC within 24 hours. Although a maintenance dose of 200 mg every 6 hours failed to produce any further statistically significant change in the mean SDC of the 18 patients studied, it should be recognized that a trend toward higher levels occurred over the 14-day study period and a wide variation existed between individual patients. The tendency of the mean SDC to change over the following 14 days of therapy and the intersubject variability are not surprising, since two different mechanisms are involved here. The rapid rise in the SDC following the quinidine loading doses almost certainly reflects primarily an alteration in the tissue distribution of digoxin, while the later SDC values reflect changes in both the tissue distribution of digoxin and its elimination. Such a loading dose approach may well cause most patients to approximate a new steady-state SDC within 1 or 2 days, but it must be remembered that the time required to assure that a new steady-state SDC has been achieved is a function of the altered half-life of digoxin (as discussed above), and will therefore require several days. The occasional patient with an unusually short or long quinidine-altered digoxin half-life would progress over time to a SDC much lower or higher, respectively, than the value re- corded after the loading doses of quinidine. Finally, it should be recognized that there are practically no data on the influence of hepatic or renal dysfunction on the time course of this interaction.

Effect of quinidine dose or serum concentration. The ability of quinidine therapy to produce a two- to threefold increase in the SDC appears to be dependent on the quinidine dose or, more specifically, the quinidine serum level. Doering and Risler et al.”

reported some increase in the SDC when quinidine was administered at a dose of 500 mg per day. In both studies, doubling the dose of quinidine produced a further increase in the SDC to approximately twice the pre-quinidine level. Otherslhzl have reported similar findings. As subsequent studies began to report serum quinidine values, some reports6~8~1’.22 found an association between the quinidine serum level and the magnitude of rise in the SDC; otherslo~ l3 did not find such a relationship. This apparent discrepancy can perhaps be explained if the assumption is made that the interaction reaches its maximum effect at a given quinidine serum level. In other words, a correlation would exist up to a certain quinidine level, but not beyond that point. The quinidine serum levels and the degree of elevation in the SDC values reported in the studies which did not find a correlation with the serum quinidine level would support this hypothesis.

Manolas, et al.‘j reported a correlation with the serum quinidine level and noted that the only patient not exhibiting a rise in the SDC had a quinidine level well below the usual therapeutic range. Schenck-Gustafsson and Dahlqvist13 did not find a correlation, but reported quinidine levels from 2.3 wg/ml to 4.3 pg/ml and a doubling of the SDC. The apparent discrepancy between the findings of these two studies could be reconciled if the degree of interaction correlates with the quinidine serum concentration at low levels but plateaus as the quinidine concentration approaches 2.3 pg/ml. Pow- ell et a1.22 provided additional evidence of a correlation at lower quinidine levels by demonstrating that the SDC in one patient fluctuated dramatically hour-to-hour, with the peak quinidine level following a dose of quinidine alone. The peak quinidine levels in this case were approximately 2.5 wg/mi. Although the finding that the degree of elevation in the SDC does not correlate with quinidine concentrations in the range of 2.3 pg/ml to 4.3 pg/ml suggests a plateau effect, the possibility that higher (i.e., “toxic”) quinidine serum concentrations might produce an additional increase in the SDC has not been adequately evaluated.

Effect of digoxin dose or serum concentration. Available information suggests that the degree of the interaction is not influenced by the pre-quinidine SDC. Doering reported that quinidine approximately doubled the SDC regardless of the digoxin dose or SDC prior to quinidine administration. Friedman and Chen’O concluded that the post- quinidine SDC was dependent on the pre-quinidine SDC. It should be noted that the post-quinidine SDC itself, not the degree of increase, was related to

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Number 2, Part 1 Factors affecting quinidine-digoxin and related interactions 291

the pre-quinidine SDC. The degree of increase was approximately 2 to 2% fold no matter what the pre-quinidine SDC. Thus although the pre-quinidine SDC may be used to predict the post-quinidine value, it does not appear to significantly influence the degree of the interaction.

MECHANISMS OF THE INTERACTION

Assay interference. It is obviously prudent to question whether the quinidine-digoxin interaction is real or simply assay interference. Hager et a1.5 and othersz3 have found no such interference.

Enhanced absorption. Although the simultaneous administration of quinidine with digoxin may increase the rate of absorption, this is probably not a major mechanism of this interaction. Several of the studies previously cited demonstrated the interaction with intravenous administration of digoxin. Doering also demonstrated the interaction with fl-methyldigoxin, which is usually totally absorbed. Evidence supporting increased absorption has been provided, however, by Chen and Friedman,24 who found that quinidine given simultaneously with digoxin dramatically increased the rate of absorption of digoxin. Their study period of 4 hours was too short, however, to evaluate any effect on the completeness of absorption. More recently Hager et a1.25 carried out a similar study, but extended the SDC monitoring period to 96 hours. Although their data were consistent with an increased rate of digoxin absorption producing a higher peak SDC, the SDC values over the 96-hour period indicated the extent or completeness of absorption was not altered. Because of the long serum half-life of digoxin, an increase in the rate of absorption is relatively insignificant at routine doses, whereas an increase in the extent of absorption would result in the accumula- tion of additional digoxin in the body and a persis- tent elevation in the SDC. Therefore, although quinidine given with digoxin may increase the rate of absorption, there is no evidence that it affects the extent of absorption or plays a significant role in the interaction.

Altered volume of distribution (Table I). Conceptual- ly, the volume of distribution of a particular drug is the volume which would be occupied by the total amount of drug in the body if it were uniformly distributed at the concentration found in the serum. In other words, the volume of distribution is equal to the amount of drug in the body divided by the serum concentration. Obviously, any factors which decrease the distribution of digoxin into the tissues would increase the SDC and thereby decrease the volume of distribution. It appears that quinidine has

Table I. Alterations in volume of distribution of digoxin

Ref D (LlW D + Q USkd % change

5 10.87 7.37 432 7 15.1 12.4 118

13 10.1 6.3 138 15a 6.9 5.46 421

b 5.56 4.6 117 a+b 6.18 5.0 119

25 9.34 6.6 129 26 6.05 5.41 ill 27 5.58 5.04 110 37 7.3 7.8 t7

D = volume of distribution for digoxin given alone. D + Q = volume of distribution for digoxin when given with quinidine. i = decrease, T = increase. a and b were low-dose and high-dose subgroups, respectively.

such an effect. This is the most plausible explana- tion of the quinidine-induced elevation in SDC reported by Leahey et al.* and by others8in patients who had not received additional digoxin. Hager et al.5*z5 and Schenck-Gustafsson and Dahlqvist13 subse- quently provided more specific data illustrating a 30 % to 40 % reduction in apparent volume of distribution of digoxin when quinidine was administered.

Others,7,26,27*37 however, have not found the volume of distribution to change significantly with quinidine administration. The studies which found no such change in the volume of distribution either employed low serum quinidine 1eve1s26~37 or failed to accurately report such data7pz7 The suggestion by some authoritieP3 28 that a reduction in the volume of distribution is dependent on achieving adequate serum quinidine levels has been recently demonstrated by Leahey et a1.15 Although the mean data of Leahey et all5 indicated no significant quinidine- induced change in the volume of distribution of digoxin, a more detailed analysis revealed a 30% decrease in the eight subjects with a serum quinidine concentration of 1.9 pg/ml or greater, but only a 7% decrease in the seven subjects with a serum quinidine concentration of less than 1.9 pug/ml. Although the previously cited studies calculated the volume of distribution, Doering failed to do so when he concluded that the interaction could be totally explained by a decrease in renal clearance of digoxin rather than by a reduction in tissue distribution. His finding that quinidine does not alter the binding of ouabain to the sarcolemma fraction of the lamb myocardium was questionably extrapolated as evidence that there is no displacement of digoxin from various human tissues; and the fact that a change in clearance may actually involve an underlying change in the volume of distribution (Equation 1, Table II)


American Heart Journal

Table II. Equation for total body clearance Table Ill. Effects of quinidine on renal clearance

Equation I: Cl,, = Kel X Vd Clrs = total body clearance Kel = elimination rate Vd = volume of distribution

was overlooked. Because a decrease in clearance may include a reduction in the volume of distribution (Equation l), Doering’s actual data are not inconsis- tent with those of others showing a reduced volume of distribution for digoxin. In summary, the available data are consistent with the finding that a serum quinidine level of approximately 2 pg/ml or greater will produce a 30% to 40% reduction in the volume of distribution of digoxin.

Altered elimination. What is known about the elimination of digoxin should be reviewed before discuss- ing alterations induced by quinidine. The elimination of digoxin is frequently considered to be primarily dependent on the glomerular filtration rate (GFR). Renal tubular secretion, however, also provides a major route of elimination. The renal clearance of digoxin has been reported to exceed the creatinine clearance13z lg, zor 2g and the GFR 3o Stei- . ness31 found that approximately 50% of renally eliminated digoxin is due to renal tubular secretion. More recently, Cogan et a1.3o provided additional data supporting Steiness’ conclusion and also demonstrated that the use of vasodilators in congestive heart failure patients could increase renal tubular secretion of digoxin so that this route accounted for approximately two thirds of renal digoxin elimination. Thus one should think of renal elimination of digoxin as two processes-glomerular filtration and tubular secretion.

The hepatic clearance of digoxin is also given inadequate consideration in many instances, although this route has been evaluated. Beerman et a1.32 and Doherty et a1.33 found that as much as 12% of a given dose was cleared nonrenally. Koup et al.,2g using different terminology, concluded that nonrenal clearance approximated 45 ml/min/1.73 m2 of body surface area. In patients with declining renal function, the reduced renal clearance of digoxin increases the significance of hepatic elimination,32-35 and the decreased tissue distribution of digoxin may enhance the hepatic elimination rate by making more of the drug available in the circulation for metabolism. 36 In evaluating the quinidine-digoxin interaction, it is appropriate to consider all of these routes of elimination (glomerular filtration, renal tubular secretion, and hepatic clearance), together

Ref D D+Q 7, change

4

13

15a b a+b

16 19 20

26

21

37

38

39

91.6* 40.6*

1.64t 1.09t 130* 62*

1.937 1.32t 1.47t 0.689

1.69f 0.9st

53.41 351 84.6* 60.6*

186$ 1211 2.717 1.64t

2.1t 1.86t

1.3t 1.0t

95* 61.7'

156 134

152 b2 154

142

134 128.5

135

/40

$11 123 135 157-84

D = renal clearance of digoxin given alone. D + Q = renal clearance of digoxin given with quinidine. 1 = decrease.

a and b were low-dose and high-dose subgroups, respectively. *Units are ml./min. tUnits are ml./min/kg. IUnits are ml/min/1.73 ml.

with alterations in the volume of distribution of digoxin.

The available data indicate that quinidine decreases renal clearance of digoxin (Table III) by blocking renal tubular secretion. Although Doering did not take into account &her mechanisms when he concluded that the interaction is based only on decreased renal clearance of digoxin, others* have provided solid evidence that reduced renal elimination is one component of this interaction. Although quinidine has been reported to decrease renal clearance of digoxin by as little as 11% 27 or as much as 84% ,3g most reports? have found a decrease in renal clearance of approximately 30% to 40%. The observation in several of these reports13v 15, lg, 20, 3g that there was essentially no change in the creatinine clearance, suggests a reduction in tubular secretion rather than GFR is involved. Whether this process or its inhibition by quinidine is saturable has been addressed by several authors. The finding by Risler et a1.2o that an increase in the quinidine dose produced a further increase in the SDC but no further decrease in digoxin renal clearance, suggests that the effect of quinidine on renal secretion of digoxin is a saturable or limited process.

The more detailed report of Leahey et al.,15 however, challenges this conclusion by providing data

*Refs. 5, 7, 13, 15, 16, 19, 20, 26, 27, 37, 39. tRefs. 5, 15, 16, 19, 20, 26, 38.

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Table IV. Effects of quinidine on nonrenal clearance Table V. Effects of quinidine on total body clearance

Ref D (7% TB) D+Q % change

5 1.4* (47) 0.87* 440 13 5W (31) 21t 164 15a 2.92* (60) 2.06* 129

b 1.74* (54) 1.36* 422 a+b 2.29* (58) 1.69* 126

26 1.66” (38) 1.28* 123 27 2.6* (55) 1.36* /48 37 2.1* (64 0.8* 1-62 38 35t (27) lot 171

D = non-renal clearance of digoxin given alone. CC TB = percent of total body clearance of digoxin given alone attributed to nonrenal clearance. D + Q = nonrenal clearance of digoxin given with quinidine. 1 = decrease. a and b were low-dose and high-dose subgroups, respectively.

*Units are mi/min/kg. tUnits are ml/min.

Ref D D+Q % change

5 3.08” 1.96* $36 7 6.06* 2.18* 464

13 188? 83 /57 15a 4.85* 3.38* 430

b 3.21* 2.04* 136 a+b 3.9@ 2.26* 143

25 2.75’ 1.7* i38 26 4.37* 2.92* 133 27 4.7” 3.22* 131 37 3.3’ 1.7* 148

D = total body clearance of digoxin given alone.

D + Q = total body clearance of digoxin given with quinidine. 1 = decrease. a and b were low-dose and high-dose subgroups, respectively.

*Units are ml/min/kg. tUnits are ml/min.

that doubling the quinidine dose from 800 mg daily to 1600 mg daily increased the degree of renal clearance inhibition from 32% to 54%. Further- more, Leahey et al. l5 found the magnitude of this effect, which occurred at even very low serum quinidine values, strongly correlated with the serum quinidine concentration. It is difficult to reconcile the conflicting results of these two reports, since the quinidine doses employed by Leahey et a1.15 were similar to, though slightly larger than, those of Risler et al.‘O Although it is difficult to determine whether the quinidine-induced inhibition of digoxin renal clearance is saturable, Pederson, et alIs found that digoxin, at a SDC range of 0.57 to 1.53 rig/ml, did not saturate this process.

were described, two other studies demonstrated a high degree of inhibition with both low and moder- ate serum quinidine concentrations. Schenck-Gus- tafsson and Dahlqvist13 and Steiness et a1.37 found nonrenal clearance of digoxin was similarly reduced 64% and 72 % , respectively, even though the mean quinidine serum levels were different at 3.3 pg/ml and 0.9 hg/ml, respectively. More recently, Leahey et a1.15 found that the inhibition of nonrenal clearance of digoxin was independent of the serum quinidine concentration. It is therefore concluded that quinidine induces a significant reduction in nonrenal clearance of digoxin, but the wide range of inhibition (23% to 71% ) can not be predicted or explained by the serum quinidine concentrations.

The influence of quinidine on the nonrenal (presumably hepatic) clearance of digoxin can be evaluated by examining the data from various studies* which either reported nonrenal clearance of digoxin or allow extrapolation of these data by subtracting renal clearance from total body clearance. These studies also supported the significance of this route of elimination by demonstrating that nonrenal clearance accounted for 27 % 37 to 64 % 36 of total body clearance of digoxin before quinidine therapy was instituted. The degree to which quinidine reduced nonrenal clearance (Table IV) ranged from 23 % 25 to 71%.36 It is very difficult, however, to attribute this wide range of inhibition to variations in serum quinidine concentrations. Although the lowest reduction came from a study by Leahey et a1.26 in which fairly low serum quinidine concentrations

While it is certainly important to be aware of the influence of quinidine on nonrenal or renal clearance of digoxin in certain situations, the influence on total body clearance is likely to be more useful in managing patients with normal renal and hepatic function. Although Ochs et a1.7 and Schenck-Gus- tafsson and Dahlqvist13 found total body clearance of digoxin was reduced 64% and 56%) respectively; others52 15.25-27s37 found that the magnitude of this decrease ranged from 31% to 48% (Table V).

*Refs. 5, 7, 13, 15, 26, 27, 37, 38.

Recalling the relationship of clearance to the elimination rate and the volume of distribution (Equation 1) raises the question of whether the reduced clearance of digoxin might be due to altered distribution alone rather than to any direct inhibition of elimination. Obviously, from Equation 1, if the volume of distribution (Vd) decreases and the rate of elimination of the drug from the serum (Kel) remains unchanged, clearance (Cl,,) would decline.



As previously discussed, a decrease in the volume of distribution increases the amount of drug in the serum compartment, which in turn makes more of the drug available for elimination.40s41 These effects would be expected to increase the elimination rate (or decrease the serum half-life) so that clearance would remain relatively unchanged. Hager et a1.5 and others73 13. I52 26* 27 have found either no increase or, in some instances, a decrease in the elimination rate. Furthermore, Leahey et a1.15 recently found that low serum quinidine values reduced renal clearance without altering the volume of distribution. It is therefore concluded that a reduction in clearance is mediated by direct inhibition of elimination in addition to changes in the volume of distribution.

Summary of mechanisms. The existing data indicate assay interference does not play a role, and that while concomitantly administered quinidine may enhance the rate of digoxin absorption, this is not of major importance. The interaction usually involves a 30% to 40% reduction in the volume of distribution and a 30% to 50% reduction in clearance of digoxin. The reduction in the volume of distribution is presumed to result from alterations in the concentration of digoxin in certain body tissues, and appears to be dependent on the serum quinidine concentration which may produce hour-by-hour fluctuations in the SDC. Reduced renal clearance appears to result from inhibition of tubular secretion and may be dependent on the quinidine serum level even though it occurs at very low levels of quinidine. Although nonrenal clearance is also reduced, the magnitude of this effect does not correlate with the serum quinidine concentration.

CLINICAL SIGNIFICANCE

The quinidine-digoxin interaction is definitely clinically significant and, even though the data are conflicting, the majority support the contention that quinidine does not alter the usual relation between the SDC and the effects of the drug. Attempts to assess this relationship have examined alterations in digoxin tissue levels, changes in receptor site binding and activity, and clinical observations. Although animal data28z42-44 are conflicting as to whether quinidine alters myocardial tissue levels, the issue may be relatively insignificant. The finding of Coltart et a1.45 that there is no correlation between serum and left ventricular tissue concentrations of digoxin, is consistent with the data of Weintraub and Lasagna46 that postmortem serum digoxin levels correlated with recent digoxin toxicity but left ventricular tissue concentration did not. Furthermore, the data

from patients with renal failure36~47~48 suggest these patients have a reduced volume of distribution for digoxin (similar to that induced by quinidine), and that their myocardial-to-serum concentration ratios for digoxin decrease with declining creatinine clearance; yet there are no data that they require or can tolerate higher serum digoxin levels.

The central nervous system is another compartment in which alterations in tissue concentrations of digoxin might be expected to alter centrally mediated effects of the drug. The only information on the effect of quinidine on the concentration of digoxin in the central nervous system, however, is conflicting animal data.28~ 42-44

If the myocardial tissue concentration of digoxin is not crucially significant, the concentration or activity at the receptor site should be. Although Doering found quinidine did not alter the binding of ouabain to the sarcolemmal fraction of lamb myocardium in vitro, Straub et a1.4g found that quinidine reduced the binding of ouabain to beef heart membrane NA+-K+ ATPase by decreasing the number of receptors. It is tempting to discard these conflicting results from in vitro animal studies in favor of the findings of Doering and Belz,so who examined the influence of quinidine on the ability of digoxin to inhibit erythrocyte membrane NA+-K+ ATPase. This effect, as measured by decreased erythrocyte uptake of rubidium, was found to be unaltered by quinidine. This suggests there is no alteration of digoxin activity at the receptor site.

Although data from reports which involved clinical monitoring of healthy subjects and patients have provided some basis for debate, most of the patient- generated data suggest there is little, if any, quinidine-induced alteration in the SDC-response relationship. Hirsch et a1.51 measured the mean left ventricular ejection time index in nine healthy volunteers who were pretreated with digoxin and found a greater than expected increase, from 406 msec to 419 msec, when quinidine was given. Their conclusion was that this increase was too large to be explained by the negative inotropic effect of quinidine alone and suggested the positive inotropic effect of digoxin was also partially blocked. Several factors, however, question the practical value of these findings. The change of 13 msec, although “significant,” is not impressive; the subjects were normal volunteers, not heart disease patients; the mean serum quinidine level was relatively high (3.9 pg/ml) while the mean serum digoxin level was relatively low (1.04 rig/ml); cardiac output was not measured; the influence of other antiarrhythmics

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was not evaluated; and the study period covered only 24 hours of quinidine therapy. Similarly, however, Steiness et a1.37 found subjects pretreated with quinidine did not have the expected decline in the preejection period index following a single intravenous dose of digoxin. Here again, the findings of this single-dose digoxin study, which was performed in six healthy volunteers and did not include cardiac output monitoring, may not be applicable to patients with symptomatic cardiac disease.

While the data cited above are inconclusive, clinical observations of the influence of quinidine on the toxic and therapeutic effects of digoxin in patients are helpful. Numerous reports* have described signs and symptoms of digoxin toxicity developing following quinidine administration despite a constant digoxin dose and normal serum potassium. In several of these instances,8~“~19*55 the signs and symptoms of toxicity resolved with a reduction in digoxin dose even though quinidine therapy was continued. Cody et a1.57 evaluated the problem of digoxin toxicity with quinidine coadministration by retrospectively comparing the records of 7573 patients who received digoxin alone with those of 315 patients who received digoxin and quinidine. Adverse reactions (gastrointestinal and cardiac) attributable to digoxin were 2.7 times more frequent in the group receiving both agents. Furthermore, maximum difference in such effects occurred at 2 to 10 days after quinidine was started, which is when the quinidine- digoxin interaction should approach its full effect. Although several of the previously mentioned reports6, 11,19,52-56 attributed ECG changes to the quinidine-induced elevations in the SDC, Koster and Wellens made the interesting observation that reports of “quinidine syncope” almost always involved digoxin therapy, suggesting this entity may actually result from digoxin toxicity. Thus, a sizable body of data indicate that quinidine-induced elevations in the SDC produce subjective and objective indicators of digoxin intoxication.

Because many of the manifestations of digoxin toxicity may be centrally mediated, the assumption that quinidine-enhanced toxicity also means enhanced efficacy can not be made. The influence of quinidine on the efficacy of digoxin therapy has been reported for patients with atrial fibrillation and congestive heart failure. Dahlqvist et a1.8 and Schenck-Gustafsson and Dahlqvist13 found the extent of the quinidine-digoxin interaction had no effect on the successful conversion of atria1 fibrilla-

*Refs. 8, 9, 11, 15, 19, 39, 52-56.

tion to normal sinus rhythm. Moench,58 on the other hand, reported one patient with atria1 fibrillation in whom discontinuation of quinidine produced a decline in the serum digoxin concentration which was accompanied by the development of a more rapid ventricular response with signs and symptoms of congestive heart failure.

The work of Hirsch et a1.51 and Steiness et a1.37 suggests the addition of quinidine to a digoxin regimen would have a larger than expected negative inotropic effect and would tend to cause decompen- sation in congestive heart failure patients. Such a case of decompensated failure has not yet appeared in the literature even though several authors reduced the digoxin dose to prevent a higher SDC with quinidine therapy. In addition to the previously discussed case report by Moench,58 in which congestive heart failure may have been secondary to the atria1 fibrillation-induced rapid ventricular response which occurred when discontinuation of quinidine therapy caused a decline in the serum digoxin level, Leahey et a1.53 reported one patient whose congestive heart failure was stable for 3 months on a reduced dose of digoxin until discontinuation of quinidine therapy allowed her SDC to decline, exacerbating her congestive failure.

In summary, the majority of the data on altered tissue concentrations of digoxin, altered receptor site affinity and activity, and clinical observations suggest that the SDC-effect relationship is not significantly altered by quinidine, and that the usual toxic or therapeutic effects of digoxin may be antic- ipated at a given SDC.

MANAGEMENT OPTIONS

In view of the data presented above, Bigger’s3 suggestion to reduce the digoxin dose by half and follow serum levels closely seems wise and prudent. Because the interaction occurs quickly, it may also be wise to omit the digoxin dose on the day quinidine is started, especially if a loading dose of quinidine is administered. Although the finding of Steiness et a1.37 and Hirsch et al.5’ that quinidine counteracts the inotropic effects of digoxin could be cited as reason to not adjust the digoxin dose or serum concentration, the occurrence of digoxin toxicity by extracardiac routes and clinical observations indicate an adjustment in digoxin therapy is required when quinidine therapy is initiated.

Another possible option would be to avoid using these agents in the same patient. Such new agents as amrinone,5s captopril,60*61 and several adrenergically active agents 62*63 offer additional methods for man-



Table VI. Influence of quinidine on digitoxin

68 750 129 129 131 NC 23,69 7149 463 NC 70 t42 T30%

Numerical values represent percentage of change induced by quinidine in the pharmacokinetic properties of digitoxin. T% = elimination half-life; Cl,, = total body clearance; Cl, = renal clearance; C,, = nonrenal clear-

ance; Vd = volume of distribution; Cp = serum concentration; t = increase; J = decrease; NC = no change.

aging congestive heart failure, but they are not expected to replace digitalis glycosides. Whether the interaction may be avoided by substituting digitoxin for digoxin or another antiarrhythmic for quinidine, is discussed below under “related interactions.”

RELATED INTERACTIONS

It seems logical to examine the influence of digoxin on quinidine serum levels before examining related interactions involving other drugs. Although animal data64 suggest that similar digoxin-induced decreases in the volume of distribution and the elimination half-life of quinidine should counterbal- ance each other so that mean serum quinidine concentrations would remain relatively unchanged, limited human data5 indicate a statistically significant increase in the mean quinidine serum level from 2.25 pg/ml to 2.5 Kg/ml. While such a change may be statistically significant, its clinical importance is uncertain. The data of Mungall et a1.16 that the quinidine serum level continued to increase daily throughout the 4-day study period suggest this question should be studied more thoroughly. Fur- thermore, the findings of Leahey et a1.15 indicate that relatively small changes in the serum quinidine concentration increase the SDC by significantly reducing the volume of distribution and the renal clearance of digoxin. Therefore, a fairly small digoxin-induced elevation in the serum quinidine concentration may produce an additional increase in the SDC.

QUINIDINE-DIGITOXIN INTERACTION (TABLE VI)

Amiodarone. Amiodarone appears to produce a significant increase in the SDC if given in large enough doses. Achilli and Serra71 found 200 mg of amiodarone given twice a day did not alter the SDC. Moysey et al., 72 however, found 200 mg given three times a day produced a 69% increase in the SDC over a 7-day period.

The early reports indicated there is no interaction Verapamil. Initial reports claimed there was no between quinidine and digitoxin, but subsequent interaction between verapamil and digoxin, but studies have proven that such an interaction does subsequent studies substantiated this interaction. exist. The conclusion of Ochs et a1.65 in “Non- Doering found no interaction between verapamil interaction of digitoxin and quinidine” that quini- and digoxin, and Pedersen et al-l9 initially found no dine did not alter serum digitoxin levels, has been verapamil-induced alteration in renal elimination of criticized on grounds of faulty study design.@ Fur- digoxin. A later study by Pedersen et al.,73 however, thermore, closer scrutiny of their data reveals the found that a 20% and 60% reduction in renal and mean quinidine serum levels were no greater than nonrenal clearance, respectively, produced a 31%

1.65 pg/ml (usual therapeutic range is approximately 3 &g/ml to 5 fig/ml), and the digitoxin half-life of one of their 10 subjects more than doubled with quinidine administration. The only other data supporting the findings of Ochs et al. is in a difficult to understand abstract by Storstein et a1.,67 which did not report quinidine serum concentrations. In con- trast to these two reports, several publica- tionss~23~3s,68-70 have noted an influence of quinidine on digitoxin.

Fenster et a1.68 and Peters et a1.7o found similar quinidine-induced increases in the digitoxin half-life of 50 % and 42 % , respectively. These data and the finding that the volume of distribution of digitoxin is not changed23. 68, 6g indicate that quinidine should produce a 40 % to 50% increase in the serum digitoxin concentration. This is much less than the 2- to 2Y2fold increase seen with digoxin and quinidine. Garty et a1.,23s6g however, reported a 2Yzfold increase in the digitoxin half-life. Once again the differences may be due to different quinidine serum levels. The 50% increase in the mean digitoxin half-life previously mentioned was seen in patients whose mean quinidine serum levels ranged from 1.3 pg/ml to 2.9 pg/ml, but only two of the five subjects had values greater than 1.7 clg/ml.6s The reports23,6g indicating a 2% fold increase in digitoxin half-life, however, reported trough quinidine levels of 1.9 pg/ml to 3.9 pg/ml. Since available data do not support an altered volume of distribution, the quinidine-digitoxin interaction may not progress as rap- idly as the quinidine-digoxin interaction, but the full potential may be approximately equivalent. Also, as found with digoxin, digitoxin increases the serum quinidine level to a statistically significant degree of uncertain clinical significance.‘”

OTHER ANTIARRHYTHMICS (TABLE VII)

Volume 104


t31z

CP CL, CLR WVR VD T%

?6& t70%J

135% l20% 160% 0

(No effect on Na+-K+ ATPase) 0 0

t1& 0 0 0

Table VII. Influence of other antiarrhythmics on digoxin

Amiodarone Verapamil

Procainamide

Disopyramide

Mexiletine

Ref

71

72 74 73 19 75 54 76

14 6 54 77 54

Cp = serum concentration; Cl,, = total body clearance; Cl, = renal clearance; Cl NII = nonrenal clearance; Vd = volume of distribution; TM = elimination half-life. Table VIII. Influence of diuretics on digoxin and digitoxin

Digorin

Hypokalemia

Triamterene Spironolactone

Amiloride Bumetanide

Ref

78

19 81 79

80 31 84 85

GFR Set Tot CL? Vd CP TX? Assay

f 1 INS 130%

t1EL +(?)

t t +WS)

1 0 0

Ref Digitoxin av* Vd T’h

Spironolactone 82 t34z 83 t /16% /20%

Cl, = renal clearance; GFR = glomerular filtration rate; Set = tubular secretion; Tot = total renal clearance; Cl NR = non-renal clearance; Vd = volume of distribution; Cp = serum concentration; TM = elimination half-life; Assay = assay interference.

increase in the half-life of digoxin without a significant change in the volume of distribution. Klein et a1.74 provided additional support for such an interaction by reporting a 70 % increase in the SDC in 39 of 41 patients given verapamil. While this degree of increase in the SDC is not of the same magnitude as that attributed to quinidine, it is significant. Fur- thermore, the finding by Wisslen et al.75 that verapamil does not alter the ability of digitalis to inhibit the erythrocyte membrane Na+-K+ ATPase indicates that the elevated SDC should produce a greater effect.

Procainamide. Data from studies by Leahey et al. 54,76 indicate there is no interaction between procainamide and digoxin.

Disopyramlde. Manolas et al6 found that relatively

high levels (mean of 5.05 pg/ml) of disopyramide produced a 15% increase in the SDC, which was statistically significant but of limited clinical importance. Others14*54*77 likewise have found no clinically important interaction between these two agents.

Mexlletine. Leahey et al.” found no interaction between mexiletine and digoxin.

DIURETICS (TABLE VIII)

The finding that spironolactone, like quinidine, blocks renal tubular secretion of digoxin has led others to study the effects of this and other diuretics on digoxin elimination. Because diuretics frequently alter potassium homeostasis, it is important to be aware of the finding that renal secretion of digoxin declines with hypokalemia.7s



Triamterene. Triamterene, which also has potassium retaining properties, has been reportedIs to decrease renal tubular secretion of digoxin.

Spironolactone. While the available data suggest spironolactone may produce as much as a two- to threefold increase in the SDC, the data are too few and too conflicting to draw any conclusion regarding its effects on digitoxin. Although a small study7’ found no significant interaction between spironolactone and digoxin, the remainder of the litera- ture31.*o,81 supports the existence of an interaction. Data from Lichey*O and one patient from the report by Steiness31 suggest the SDC may increase by as much as two- to threefold, although smaller incre- ments appear more typical. Spironolactone appar- ently alters digoxin kinetics by decreasing renal elimination, 81 by reducing u t bular secretion31 by decreasing nonrenal clearance,Sl and by reducing the volume of distribution.81 Although LicheysO specu- lated that the increase in SDC was due to interference of spironolactone with the digoxin assay, Stei- ness31 found that spironolactone therapy produced a false elevation in the digoxin assay of less than 0.2 rig/ml.

The influence of spironolactone on digitoxin has been studied with conflicting results. Carruthers and Dujovnes2 found the digitoxin half-life increased 34% from 144 hours to 193 hours when spironolactone was given to healthy volunteers. Wirth et a1.,83 however, found a spironolactone-induced decrease of 16% in the volume of distribution and an increased rate of hepatic metabolism which decreased the digitoxin half-life 20% from 273.5 hours to 193 hours in patients with cardiovascular disease. Whether the disagreement here may result from differences in dosages used, or the fact that one study utilized healthy volunteers while the other studied actual patients remains speculative. The true magnitude of this interaction therefore remains uncertain.

Amiloride. There are insufficient data to delineate the clinical significance of the complex interaction that may occur between amiloride and digoxin. Waldorff et a1.84 found that amiloride in healthy volunteers opposed the inotropic effects of digoxin, increased renal tubular secretion of digoxin, and decreased its extrarenal clearance without producing a change in the volume of distribution. The net result was a slight, but statistically insignificant, decline in total body clearance of digoxin. The clinical significance of this interaction in actual patients remains to be established.

Bumetanide. This new “loop” diuretic was found by Hayes et a1.85 to have no effect on the SDC or the renal clearance of digoxin.

ADDITIONAL AGENTS WHICH ALTER ABSORPTION OF DIGOXIN

Although the quinidine-enhanced rate of absorption of digoxin may not be a major factor in that interaction, agents which alter the completeness of digoxin absorption may produce clinically significant alterations in the SDC.

Antacids. Ascione and Poiriera6 recently reviewed the data on this frequently accepted interaction and found the information less than entirely supportive. Furthermore, Allen et al.87 found that 60 ml of Maalox or Kaopectate, when given with digoxin tablets or capsules, reduced the peak SDC but did not significantly alter the time at which the peak occurred nor the completeness of absorption. Albert et a1.,88 however, found that a larger dose of Kaopec- tate (90 ml) could decrease the extent of absorption by 15% if given simultaneously with digoxin, but not if given 2 hours before and after digoxin administration. This interaction is therefore likely to be significant only if a fairly large dose of the binding agent is given simultaneously with digoxin to the patient in whom the maintenance of a specific SDC is unusually critical.

Antibiotics. The ability of various antibiotics to increase the absorption of digoxin has been recently described by Lindenbaum et a1.8s and discussed by Doherty.’ According to Lindenbaum et a1.,8s approximately 10% of patients exhibit a significant degree of digoxin reduction by gut florr Alteration of the gut flora by antibiotic therapy may reduce this method of digoxin metabolism and produce as much as a twofold increase in the SDC.

Cholestyramine and colestipol. Both of these agents are known to bind digoxin and digitoxin. Either agent, therefore, would be expected to decrease the absorption of orally administered digitalis glycosides if given simultaneously with both agents. Because a large amount of the digitoxin in the body is being continually secreted into and reabsorbed from the intestines (i.e., enterohepatic recycling), agents which can bind digitoxin in the intestinal lumen should dramatically increase its elimination from the body. This is the basis for the dramatic decline in the serum digitoxin half-life reported following the administration of cholestyramine82*90 and colestipol.sl Although digoxin does not undergo as much enterohepatic recycling, Payne et a1.9’ recently applied this concept in treating digoxin toxicity and found significantly enhanced elimination of digoxin when colestipol was given on an every 6-hour schedule. The decline in the digoxin half-life of almost 50% is not as great as that reported for digitoxin, but the interaction appears clinically significant and may therefore be useful in managing

Volume 104

Number 2. Part 1 Factors affecting quinidine-digoxin and related interactions 299

patients who are intoxicated with either digitoxin or digoxin.

PfOpanth8lin8. This anticholinergic agent was shown by Manninen et alg3 to increase the SDC when administered with digoxin tablets, but not when administered with digoxin elixir. The effect was attributed to increased absorption, since no change was seen with the elixir which is usually well absorbed.

~8toclopramid8. The decline in the SDC seen when digoxin was administered with this agent provides additional evidence that digoxin absorption may vary inversely with gastrointestinal motili- tY,93 although mechanisms other than altered absorption were not evaluated.

Cytotoxic agents. Kulhman et a1.g4 found that each of four different regimens of combination chemo- therapy reduced the rate and degree of digoxin absorption, decreased renal excretion, and reduced the SDC by 40 % to 50%. The resolution of these changes approximately 8 days after the chemothera- py regimen was stopped led the authors to suggest the probable cause was altered absorption due to damage of the gastrointestinal mucosa.

ADDITIONAL AGENTS WHICH ALTER METABOLISM OF

DIGOXIN

Quinine. It is not surprising that quinine, the L-isomer of quinidine, was found by Wandell et als5 to decrease the nonrenal clearance of digoxin by 55%. The overall effect, however, was a 26% decrease in the total body clearance with no change in the volume of distribution. Although the mean values for renal clearance of digoxin did not change, two or three subjects with higher quinine levels did show a decline. These alterations appear less dramatic than those seen with quinidine and should, therefore, be less clinically significant.

Cim8tidin8. Polish et als6 recently described a patient in whom cimetidine produced an elevation in serum quinidine and digitoxin levels. Whether the effect on digitoxin was due directly to the effects of cimetidine or resulted from cimetidine-induced elevations in the serum quinidine level cannot be determined from their data.

Rifampin. Rifampin has been shown, presumably through the induction of hepatic enzymes, to effect a three to fourfold decrease in the elimination half-life of quinidine.s7ss8 The resulting abrupt decline in the quinidine serum concentration would be expected to produce a significant reduction in the SDC of patients stabilized on digoxin and quinidine. This sequence of events has been observed in one patient at our institution.

Anticonvulsants. The ability of some anticonvul-

sants to induce hepatic enzymes and thereby increase hepatic clearance of some drugs has been cited as the underlying mechanism for interactions with digoxin and digitoxin. Chapron et algg suggested that the withdrawal of pentobarbital from one patient produced a dramatic decrease in her rate of quinidine metabolism which, in turn, led to higher quinidine levels which produced digoxin toxicity. Solomon et al.,‘O” however, attributed decreased serum digitoxin concentrations directly to phenytoin-induced hepatic enzyme activity. The influence of anticonvulsants other than phenytoin and the barbiturates on the metabolism of digitalis glycosides has not been evaluated.

Phenylbutazone. Solomon et al.‘O” also found that phenylbutazone decreased digitoxin serum levels. Hepatic enzyme induction was cited as the likely mechanism, since binding of digitoxin to albumin was not altered.

CONCLUSIONS

The quinidine-digoxin interaction occurs frequently and predictably when these two agents are given in therapeutic doses. Although the degree of the interaction and most of the mechanisms involved are dependent on the quinidine serum concentration, the typical interaction involves an acute elevation in the SDC which progresses for several days to a new “steady state” level of two to three times the value observed in the absence of quinidine. Whether the relationship between the SDC and toxic or therapeutic effects is altered may be debatable, but the bulk of the clinical data suggest there is no great change in this relationship. The prudent course appears to require a reduction in the daily digoxin dose, frequent monitoring of the SDC, and close monitoring for signs and symptoms of digitalis intoxication.

Attempts to fully delineate the specifics of this interaction have forced a reassessment of our understanding of the pharmacodynamics of digoxin and digitoxin. Interest in this area has also led to the description of an ever-growing number of related interactions, and, as is so often the case, attempts to answer basic questions have raised further issues for study. Should the use of digoxin and quinidine be avoided? Should the use of other agents increase? What other related interactions have been overlooked? What other agents or pharmacokinetic factors may alter the quinidine-digoxin interaction? What alterations in the interaction might occur in patients with liver disease or renal failure? Although a surprisingly large number of publications have in a relatively short period of time contributed to our understanding of this important interaction which



was overlooked for so long, there is a growing number of questions which will continue to stimu- late further research.

The author gratefully acknowledges the advice of Dr. J. O’Neal Humphries and the technical assistance of Ms. Rhonda Hassell in the preparation of this manuscript.

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The influence of quinidine and other agents on digitalis glycosides