Drugs 24: 229-239 (1982)

0012-6667/82/0900-0229/$05.00/0
© ADIS Press Australasia Pty Ltd. All rights reserved.

Quinidine and Digoxin

An Important Interaction

J. Thomas Bigger Jr, and Edward B. Leahey Jr

Department of Medicine, Columbia Unfversity, New York and The Arrhythmia Control Unit,
Columbia-Presbyterian Medical Center, New York

Dedicated to the memory of Dr Edward B. Leahey Jr.

Summary An increase in serum digoxin concentration occurs in 90 % of patients given quinidine. On

average, the serum digoxin doubles during treatment with therapeutic doses of quinidine.
Almost every patient treated with quinidine will have a decrease in the renal clearance of
digoxin and many will have a decrease in the volume of distribution of digoxin. Whether
changes in the inotropic effect of digoxin occur during concurrent quinidine administration is
an unsettled area. However, gastrointestinal and cardiac toxicity, which closely resemble
digitalis toxicity, often occur when quinidine causes the serum digoxin concentration to rise.
These effects subside when the digoxin dose is reduced. Therefore it is prudent to monitor
serum digoxin concentrations during concomitant quinidine treatment and to adjust the digox-
in dose according to the results. When the toxicity is severe or dose adjustment is d(fficult,
another antiarrhythmic drug should be selected.

Measurement of serum drug concentrations
greatly facilitates the chance of finding a pharmaco-
kinetic drug interaction. The pharmacodynamic con-
sequences of the interaction may only become ap-
parent after discovery of an interaction by drug con-
centration measurements. So it is with the quinidine
and digoxin interaction. Although quinidine and
digoxin were used together for many years, their in-
teraction was not discovered until 1976 when serum
digoxin measurements became commonplace in some
centres. Many questions were raised by the discovery
of the quinidine-digoxin interaction:
I) How common is it?
2) How much will the serum digoxin concentra-
tion increase?
3) How long does it take digoxin levels to reach a
new steady-state after starting quinidine?
4) What is the mechanism of the increase in
serum digoxin concentration?
 Quinidine and Digoxin: An Important Interaction 230

Table I. Incidence of the quinidine-digoxin interaction patients who had instability of haemodynamics, renal
function or electrolytes.
Author No. of No. (%)
patients with increased
serum digoxin
concentration' 2. How Large is the Serum Digoxin
Concentration Increase during Quinidine
Retrospective studies Therapy?
Doering (1979) 38 32 (84)
Ejvinsson (1978) 11 11 (100)
Leahey et al. (1978) 27 25 (93)
On average, the increase in serum digoxin con-
centration in these studies was 100 %, i.e. the serum
Prospective studies digoxin concentration doubled (see fig. I). The in-
Dahlqvist et al. (1980)2 5 5 (100)
21 (95)
crease varied from 0 to SOO % , and was not predicta-
Leahey et al. (1980a) 22
Mungall et al. (1980) 15 11 (73) ble from baseline clinical characteristics. The large
Pedersen et al. (1980) 11 9 (82) variability in magnitude of the increase in serum
digoxin concentration hampers efforts to anticipate
Total 129 114 (88)
the interaction. One factor that is known to exert a
1 During concomitant digoxin and quinidine therapy.
significant influence on the magnitude of the increase
2 Includes the 12 cases reported by Ejvinsson (1978). in serum digoxin concentration is the serum
quinidine concentration. Doering (1979) and Leahey
et al. (1981) showed that the magnitude of the in-
S) Is the increase in serum digoxin concentration crease in serum digoxin concentration is dependent on
associated with an increase in toxicity? the serum quinidine concentration. However, it
6) Does the inotropic effect of digoxin increase in should be noted that appropriate therapeutic
accordance with the increase in serum digoxin quinidine plasma concentrations may cause the
concentration? serum digoxin concentration to double. Moreover,
7) How should digitalised patients be managed although the dependence of serum digoxin con-
when quinidine treatment is started? centration on serum quinidine concentration is highly
Many of these questions have been answered in significant, it accounts for only a small proportion of
the short time since the quinidine-digoxin interaction the variance in plasma or serum digoxin concentra-
was reported. Others still remain controversial. tions in a group of patients who are treated with
quinidine. Thus, expected or measured serum
quinidine concentrations cannot be used to reliably
i. How Common is the Quinidine-Digoxin predict changes in the serum digoxin concentration in
interaction? an individual patient.

Table I summarises the findings in 7 clinical

retrospective or prospective studies of the interaction.
Altogether the results in 129 patients are shown.
Almost 90 % of the patients had an increase of
O.Sng/mlor greater in the serum digoxin concentra-
tion when quinidine was given. There is remarkably
good agreement among the studies considering the
small sample sizes and the variability in study design.
The increase occurred even in studies which excluded
3. How Long after Starting Quinidine does it
Take to Reach a New Steady Level of Serum
Digoxin Concentration?
Quite a few studies have measured serum digoxin
concentrations for several days after quinidine treat-
ment was begun. Leahey et al. (I 981) and Dahlqvist
et aI. (1980) began therapy with a loading dose that
Quinidine and Digoxin: An Important Interaction 231

n 27

a.

E
4.0
'"
oS
'"cQ
~0; 3.0
<.>
c::
0
<.>
c::
;;: 2.0
0
'"
il n 22
E
:>
Q;
en 1.0

b.

Fig. 1. The magnitude of increase in serum digoxin concentration during the quinidine-digoxin interaction.
(a) The change in serum digoxin concentration (ng/mil in 27 patiei'ltsin a retrospective study (Leahey etal .• 1978),
(b) The change in serum digoxin concentration (ng/mil in 22 patients in a prospective study (Leahey et al .. 1979).
 Quinidine and Digoxin: An Important Interaction
Table II. The quinidine-digoxin interaction: effects of quinidine on the pharmacokinetics of digoxin
Author No. Volume of
of patients distribution
Hager et al. (1979) 6 t
Leahey et al. (1981) 15
t ••
Pedersen et al. (1980)
Schenck-Gustafson et al. (1981)
Steiness et al. (1980)
11
5
6 ....t
quickly stabilised serum quinidine concentration;
under these conditions the serum digoxin concentra-
tion also stabilises within 48 hours. When quinidine
is begun without a loading dose, the serum digoxin
concentration may continue to increase for 3 to 4
days. This finding is a manifestation of the depen-
dence of serum digoxin COllcentration on the serum
quinidine concentration; serum digoxin concentration
can only stabilise fully after quinidine reaches a
steady-state.
4. What is the Mechanism for the Increase in
Serum Digoxin Concentration during
Quinidine Treatment?
Leaheyet al. (1978) discussed 3 possible mechan-
isms for the interaction. The increase in serum digox-
in concentration during quinidine treatment could be
due to increased absorption, reduced volume of dis-
tribution, or reduced elimination of digoxin. The
decrease in elimination could be accounted for by
reduced renal clearance, reduced non-renal clearance,
or both. Table II gives the results of 5 studies which
measured the effect of quinidine on the pharmaco-
kinetics of digoxin.
4.1 Increased Absorption
Leahey et al. (1978) discounted increased absorp-
tion of digoxin during quinidine treatment as the
main cause of the increase in serum digoxin con-
232
Elimination Total Renal Non-renal
.... .. ..
half-life clearance clearance clearance
.... .- .-
.- ....
t
• .. t
t
centration, because they noted an increase in serum
digoxin even when quinidine was given after digoxin
dosing was discontinued. However, there has been 1
report that quinidine did increase the absorption of
digoxin (Chen and Friedman, 1980). The results of
this study are subject to other interpretations and
have yet to be confirmed. Doering (1979) reported
that the increase in serum glycoside concentration
caused by quinidine was just as great in patients
treated with ~-methyldigoxin, a glycoside that is very
lipid-soluble and is almost 100 % absorbed.
Therefore, increased absorption could only play a
small role in the quinidine-digoxin interaction.
4.2 Reduced Volume of Distribution
Digoxin is taken up avidly by tissues, and at
steady-state the tissue: serum ratios are very high.
Thus, a small change in the tissue concentration of
digoxin could account for a substantial increase in
serum digoxin concentration.
The first evidence for this mechanism was pro-
vided by Leahey et al. (1978) in a group of patients
given quinidine after digoxin dosing ceased. In these
patients, the serum digoxin concentration rose sub-
stantially during the first 36 hours of quinidine treat-
ment. Leahey et al. argued that only a displacement of
digoxin from tissue compartments to plasma could
account for this phenomenon. Dahlqvist et al. (1980)
confirmed this finding in 13 patients who had their
last digoxin dose 36 hours prior to beginning
quinidine therapy. The majority of their patients had
 Quinidine and Digoxin: An Important Interaction
an absolute increase in serum digoxin concentration
12 to 24 hours later. This study was well designed to
show this effect; quinidine treatment was begun with
a loading dose of 600 to 800mg in order to quickly
establish steady.state serum quinidine concentrations.
4 pharmacokinetic studies have measured the change
in the apparent volume of distribution (V d) of digoxin
before and during quinidine treatment. Altogether 32
patients were studied; of these, 21 (66 %) had a
decrease in V d of I 0 % or more.
Leahey et al. (J 981) pointed out that the mag-
nitude of the decrease in the Vd of digoxin is depen-
dent on the serum quinidine concentration. 7 of his
15 subjects had low serum quinidine concentrations
which may account for the lack of a striking overall
effect on digoxin Vd in his study.
Interestingly, Wandell et aI. (\980) found that the
Vd of digoxin did not change significantly during
treatment with quinine, the optical isomer of
quinidine.
Several critical questions about the displacement
of tissue digoxin by quinidine remain to be answered.
Do all the tissues release similar amounts of digoxin
during quinidine treatment? The most critical tissue
to understand in this respect is heart muscle. If heart
muscle releases digoxin during quinidine treatment,
then it is hard to understand how the cardiac effect of
digoxin could increase. Two studies were carried out
in dogs in an attempt to answer this question. Doher-
ty et al. (\980) gave tritiated digoxin to 2 groups of
dogs: one treated with digoxin alone and the other
with both quinidine and digoxin. They studied
various body tissues and found that quinidine caused
a reduction in tissue digoxin in many tissues, includ-
ing the heart. The cardiac digoxin concentration fell
by about 20 % after 2 days of quinidine treatment and
the tissue/ serum ratios also fell. In contrast, the
digoxin concentration in subcortical white matter of
the brain increased by 50 % and the tissue/serum
ratios rose sharply. These findings led to the specula-
tion that any increase in cardiac effect of digoxin oc-
curring during quinidine treatment must be mediated
via the central nervous system.
Warner et al. (\98J) conducted a similar study,
233
but found no decrease in cardiac digoxin concentra-
tion or tissue/serum ratio. On the contrary, the
myocardial: serum ratio for digoxin was increased.
These workers sampled many brain sites but failed to
find any striking increase in brain digoxin concentra-
tion; however, samples from the brain stem showed a
tendency toward increased digoxin concentration.
This fmding is interesting considering that the area
postrema of the medulla oblongata is known to be an
important site for digitalis action (Somberg and
Smith, 1979).
The effect of quinidine on the binding of digoxin to
physiologically important brain stem centres deserves
further work, since both of these studies suffer from a
lack of a substantial increase in serum digoxin con-
centration in the quinidine-treated group. This is un-
fortunate and puzzling since both groups have shown
that their dog models are capable of sustaining a rise
in serum digoxin concentration under the influence of
quinidine.
4.3 Renal Clearance
Perhaps the most uniform pharmacokinetic fmd-
ing in the quinidine-digoxin interaction is a substan-
tial (40 to 50 %) reduction in the renal clearance of
digoxin which was experienced by most subjects.
Thus, it is by far the least variable of the pharmaco-
kinetic changes in digoxin that can occur as a result of
quinidine treatment.
The detailed mechanism of the renal handling of
digoxin is poorly understood. It is clear that digoxin is
excreted by the kidney not only by glomerular filtra-
tion but also by tubular secretion. Presumably there
is no change in the glomerular filtration of digoxin
during quinidine treatment. The creatinine clearance
during the interaction was measured by several
groups and no cllange was found. Also, Steiness et al.
(\980) and Dahlqvist et aI. (\980) report unpublished
data that shows no change in serum protein binding
of digoxin in the presence of quinidine. It is likely that
tubular secretion of digoxin is active and that
transport involves both free and serum protein-bound
 Quinidine and Digoxin: An Important Interaction
digoxin. The amount of digoxin secreted by the renal
tubule, estimated as the difference between urinary
digoxin excretion and the amount filtered, is quite
variable from person to person. If transport is active,
then presumably the tubular secretory mechanism for
digoxin has a maximum. The great variability in the
serum digoxin concentration response to quinidine
could be due either to a decrease in the tubular
secretory rate or a decrease in the tubular maximum
for secretion. There is a precedent for substances
which act in the kidney to decrease the renal tubular
secretion of digoxin. Spironolactone, triamterene,
amiloride and hypokalaemia have been reported to
have this effect (Pedersen et al., 1980) - spironolac-
tone is the best studied of these, but even this is some-
what controversial. Much additional work needs be
done to fully comprehend the details of the renal han-
dling of digoxin.
4.4 Non-renal Digoxin Clearance
About 40 % of a digoxin dose is not eliminated by
the kidney. Non-renal digoxin clearance is not well
characterised, but probably includes hepatic metabol-
ism and biliary secretion. Most of the subjects in
pharmacokinetic studies have shown a decrease in the
non-renal clearance of digoxin during quinidine treat-
ment, which is usually somewhat smaller than
changes in renal clearance. However, the fraction of
unchanged digoxin excreted during quinidine treat-
ment is about the same as before it. Leahey et al.
(1981) showed that there is no significant relationship
between the serum quinidine concentration and the
magnitude of the change in non-renal clearance. In-
terestingly, Wandell (1980) showed in 5 volunteers
that quinine was qualitatively different from
quinidine in its effect on non-renal digoxin clearance.
Quinine had no effect on the distribution volume or
renal clearance of digoxin, but substantially decreased
its non-renal clearance. This also was manifested as
an increase in the fraction of the digoxin dose excreted
in the urine as unchanged digoxin. It is extremely in-
teresting that the body 'distinguished' between the op-
234
tical isomers quininel quinidine with respect to the
metabolism of digoxin.
5. Does the Increase in Serum Digoxin
Concentration Induced by Quinidine Increase
the Likelihood of Digitalis Toxicity?
Serum digoxin measurements cannot be used
alone to establish toxicity because of the many factors
that alter the relationship between serum digoxin con-
centration and digoxin effect. However, it is well
established that among a group of patients taking
digoxin, the likelihood of toxicity becomes greater
with increasing serum digoxin concentration. On the
other hand, if the serum digoxin concentration rises
at the expense of myocardial tissue digoxin concentra-
tion (that is, in the case of reduced tissue distribution),
one might expect the digoxin effect to fall while
serum digoxin concentration rises. Such a dissocia-
tion between serum and myocardial digoxin con-
centration is seen during treatment of severe digoxin
toxicity with Fab fragments of digoxin specific anti-
bodies. During Fab treatment the serum digoxin in-
creases markedly while myocardial digoxin con-
centration and effect falls (Smith et ai., 1976).
In the initial reports of the quinidine-digoxin in-
teraction, Ejvinsson (1978) and Leahey et al. (1978)
noted toxicity among their patients. Ejvinsson
reported that the serum digoxin concentration rose
above the 'therapeutic range' in 6 of his 12 patients.
One of those 6 patients (I 7 %) developed 'symptoms
of digitalis toxicity'. Leaheyet al. (978) reported that
11 of their 27 patients (41 %) developed nausea,
vomiting or ventricular arrhythmias during the initial
days of quinidine treatment. In all 10 patients with
gastrointestinal symptoms, the symptoms disap-
peared when the digoxin dose and serum digoxin con-
centration were reduced, even though the quinidine
dose was held constant. 7 patients (22 %) developed
ventricular tachycardia or ventricular fibrillation dur-
ing the first week of quinidine treatment; 3 of these
had no ventricular arrhythmias before quinidine was
started. In the 7 patients who had ventricular ar-
 Quinidine and Digoxin: An Important Interaction
rhythmias develop or worsen during quinidine treat-
ment, the serum digoxin concentration rose from a
mean of 1.4ng/ml before to 3.7ng/ml after
quinidine.
In 1979, Leahey et al. reported 3 patients studied
prospectively who had developed the following in-
creased digoxin effects during quinidine toxicity: (a)
slowing of ventricular response to atrial fibrillation;
(b) increased PR interval and haemodynamic effect;
and (c) non-paroxysmal A-V junctional tachycardia.
Reid and Meek (I 979), Moench (I 980) and Leaheyet
al. (I 980a) also reported substantial decreases in the
ventricular response to atrial fibrillation or increases
in the PR interval during the quinidine-digoxin in-
teraction.
Although further work is needed, it seems clear
that, when the increased serum digoxin concentration
caused by quinidine is in the range of 2 to 6ng/ml,
A-V conduction will be slowed and the likelihood of
A-V junctional or ventricular tachycardia increased.
The A-V conduction delay could be due to a central
vagal effect and the A-V junctional or ventricular
tachycardia could be due to increased activity on car-
diac sympathetic nerves. Thus, the most frequently
occurring cardiac adverse effects could have a central
origin as suggested by Doherty et aI. (I 980).
Myocardial monovalent cation uptake: Smith and
co-workers have shown that 86-rubidium uptake is
an in vivo indicator of Na,K-ATPase inhibition by
cardiac glycosides or by antibodies directed at Na,K-
ATPase (Hougen and Smith, 1978; Smith and
Wagner, 1975 ). To elucidate the direct effect of the
increased serum digoxin concentration on myocardial
Na,K-ATPase during the quinidine-digoxin interac-
tion, Leahey collaborated with the Harvard group to
measure 86-rubidium uptake in dogs subjected to the
quinidine-digoxin interaction and in several control
groups. Quinidine alone had little or no effect on
86-rubidium uptake. Digoxin alone produced a sub-
stantial decrease in 86-rubidium uptake at an
average serum digoxin concentration of 2. 7ng/ ml.
The largest decrease in myocardial 86-rubidium up-
take was seen in the group of dogs given both
quinidine and digoxin (mean serum digoxin con-
235
centration 3.2ng/mO. This study is compromised by
2 problems: (a) the serum digoxin concentration rose
only slightly in the group of dogs that received both
quinidine and digoxin; and (b) there was some overlap
between dogs in the digoxin group and those receiv-
ing both quinidine and digoxin. Despite these
problems, this important study suggests that, when
the serum digoxin concentration rises during
quinidine toxicity, there is an increased inhibition of
Na,K-ATPase. Unless nullified by some other effect
of quinidine, the reduced Na,K-ATPase activity
should lead to an increase in myocardial contractility
and, if the effect is of sufficient magnitude, to ventric-
ular arrhythmias.
6. Does the Inotropic Effect of Digoxin
Increase in Accordance with the Increase in
Serum Digoxin Concentration?
It is very difficult to quantitate the magnitude of
the effects of chronic digoxin treatment using non-
invasive means. This has given rise to controversy
about whether digoxin has much, if any, effect on
ventricular performance during chronic oral therapy.
We have already discussed clinical and experimental
evidence that myocardial contractility is increased
when the serum digoxin concentration increases dur-
ing quinidine treatment. The clinical evidence comes
from patient observations.
Leahey et al. (1979) noted a patient who developed
heart failure when her serum digoxin concentration
fell as a consequence of discontinuing quinidine treat-
ment. Doering (1979) noted that no cardiac failure
developed during long term observation of 15 con-
secutive patients who were subject to the policy of
reducing the digoxin dose by half when adding
quinidine to the therapeutic regimen. Also, the
biochemical correlate of increased myocardial con-
tractility - inhibition of Na,K-A TPase activity - is
reduced during quinidine treatment. However, 2
clinical studies have reported findings that suggest a
reduction in myocardial performance during the
quinidine-digoxin interaction.
 Quinidine and Digoxin: An Important Interaction
Steiness et al. (t 980) measured the systolic time
intervals over a 4-day period after 15~g/kg digoxin
was administered intravenously to each of 6 normal
subjects (aged 21 to 28 years) on 2 occasions; once in
the absence of any other drug and again after 8 days
of treatment with 200mg slow-release quinidine
given orally twice daily. Before quinidine, the pre-
ejection period index decreased substantially on the
first and second day of digoxin treatment and showed
a significant correlation with the serum digoxin con-
centration. After 8 days of quinidine treatment, the
change in pre-ejection period index was much less and
did not correlate with the serum digoxin concen-
tration. Left ventricular end-diastolic diameter
(measured by echocardiography), arterial blood
pressure and heart rate did not change significantly
during quinidine treatment. Also, the PR and QRS
duration did not change significantly. Since preload
(left ventricular end-diastolic diameter) and afterload
(arterial blood pressure) did not change significantly,
Steiness et al. interpreted their findings to mean that
quinidine prevented the positive inotropic response
usually seen with digoxin. This group urged caution
in the use of quinidine and digoxin together in
patients with congestive heart failure.
Hirsh et al. (t 980) conducted a similar study in 7
normal subjects (aged 26 to 31 years). The left ven-
tricular ejection time index and Q-S2 index were used
to compare the subjects during digoxin treatment and
during combined quinidine (400mg thrice daily) and
digoxin treatment. 4 subjects were then studied on
quinidine alone. Digoxin alone shortened the left ven-
tricular ejection time index and the Q-S2 index, while
quinidine alone lengthened both intervals. During
treatment with quinidine, the effect of digoxin on
these 2 systolic time intervals was lessened despite the
fact that the serum digoxin concentration increased
more than 50 % during quinidine treatment. Thus,
Hirsh et al. (t 980) concluded that quinidine reduced
the inotropic action of digoxin, and they speculated
that this effect was due to displacement of digoxin
from the myocardium by quinidine.
They called into question the recommendation that
the digoxin dose be reduced before initiating quinidine
236
treatment, particularly in patients with congestive
heart failure, and emphasised the rather poor correla-
tion between serum digoxin concentration and clinical
toxicity. However, these workers acknowledged the
possibility that the increased serum digoxin con-
centration during quinidine treatment may increase
the likelihood of toxicity while, at the same time,
decreasing the effects of digoxin on myocardial con-
tractility.
These fmdings by Steiness et al. (t 980) and by
Hirsh et al. (t 980) add to the complexity of the
quinidine-digoxin interaction. Giardina et al. (I 981 )
commented on potential problems in using the results
of systolic time intervals to judge the inotropic effects
of drugs that slow conduction of the cardiac impulse.
During a study of 2 tricyclic antidepressants that have
quinidine-like effects on the myocardium, they found
discordance between the pre-ejection period index, left
ventricular ejection time index and Q-S2 index and
the extent of left ventricular shortening measured
echocardiographically. That is, systolic time intervals
gave the impression of a drug-induced impairment of
left ventricular performance when none existed. This
also may be the C&'Ie with studies using systolic time
intervals to examine myocardial performance during
the quinidine-digoxin interaction. Nevertheless, pend-
ing further studies, the hypothesis must be taken
seriously that haemodynamic states may worsen dur-
ing the quinidine-digoxin interaction even though the
serum digoxin concentration is increased.
7. How Should the Quinidine-Digoxin
Interaction be Managed?
The uncertainties about the relationships between
the increase in serum digoxin concentration, likeli-
hood of digitalis toxicity and change in the myocar-
dial inotropic effects of digoxin confound the manage-
ment of the quinidine-digoxin interaction. Leahey et
al. (t 978) originally urged vigilant observation of
digitalised patients when quinidine treatment is
begun, recommending that the clinical course, serum
digoxin concentration and ECG be carefully moni-
 Quinidine and Digoxin: An Important Interaction
Table III. Ability of antiarrhythmic drugs to elevate serum
digoxin concentrations
Drugs that elevate serum Drugs that do not elevate
digoxin concentration serum digoxin concentration
Amiodarone Ajmaline
Quinidine Disopyramide
Quinine Imipramine
Verapamil Lidoflazine
Mexiletine
Procainamide
Propafenone
tored when quinidine is given to digitalised patients.
Doering (1979) recommended that digoxin doses
should be halved when quinidine treatment is begun
because serum digoxin concentration usually doubled.
He reported that, in 15 patients so treated, no addi-
tional rhythm disturbances or extracardiac adverse
effects developed during combined quinidine and
digoxin therapy except for 2 cases of diarrhoea that
were attributed to quinidine. The results so struck
this author that he 'dispensed with a systematic
prospective investigation of the relation of possibly
dangerous side effects to increased serum digoxin
concentrations.' Hirsh et al. (J 980) have called for
just such a prospective trial, and have suggested that
blinded and random allocation of patients to alterna-
tive treatments should be an essential feature of the
trial de ,ign.
Until further clarification of key issues is avail-
able, how should a clinician manage digitalised
patients when he begins quinidine treatment? He has
several choices: (a) no initial adjustment of the digox-
in dose; (b) initial adjustment of the digoxin dose; (c)
use an alternative digitalis glycoside; or (d) use an
alternative antiarrhythmic drug. A clinician who
follows Leahey's original recommendation (see
above) to carefully monitor digitalised patients who
are given quinidine will rarely encounter difficulties.
237
The intensity of observation is governed by the mag-
nitude of the increase in serum digoxin concentra-
tions, whereas adjustments in dosing are determined
more by clinical and/or electrocardiographic find-
ings. However, the likelihood that toxicity will
develop at some stage is greater with this method
than if the dose of digoxin is reduced by half when
quinidine is begun. The serum digoxin concentration
should be monitored and the digoxin dose adjusted
further to obtain a serum digoxin concentration simi-
lar to that existing prior to quinidine administration.
Patients with a history of significant congestive heart
failure 'should be observed carefully for several weeks
for symptoms and signs of worsening cardiac failure.
Either of these 2 methods is facilitated by using a
loading dose of quinidine. This permits a new steady-
state serum digoxin concentration to be approached
on the second day of quinidine treatment, shortens
the observation period, and accelerates any adjust-
ments that need to be made. If a cardiac glycoside
were available that did not interact with quinidine, it
would be preferable to digoxin for combined treat-
ment. Doering (1979) reported that the interaction
also occurred with ~-methyldigoxin. 6 reports of
studies on a possible interaction between quinidine
and digitoxin have been published (Fenster et al.,
1980; Garty et al., 1981; Keller and Kreutz, 1980;
Ochs et al., 1980; Peters et al., 1980; Storstein et al.,
1979). Unfortunately, 3 of these studies support the
idea that quinidine interacts with digitoxin and 3 do
not. For the present, then, we are uncertain whether
an alternative glycoside is readily available. Finally,
one may choose to use an alternative antiarrhythmic
drug in place of quinidine in order to avoid the in-
teraction. Doering (J 979), Leahey (J 980a) and
Wellens et al. (J 980) have reported that a number of
type I cardiac antiarrhythmic drugs do not cause an
increase in serum digoxin concentration, including
procainamide, disopyramide and mexiletine (see
table III). However, some other antiarrhythmic
drugs, for example verapamil and amiodarone,
probably do cause an increase in the serum
digoxin concentration (Lang et aI., 1981; Moysey
et aI., 198 J).
 Quinidine and Digoxin: An Important Interaction
Acknowledgements
Original research cited in this paper was supported by
HL-12738 and HL-26653 from the National Heart, Lung
and Blood Institute and by the Winthrop and Chernow
Foundations.
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digoxin. British Medical Journal I: 279-280 () 978).
Fenster, P.E.; Powell, lR.; Graves, P.E.; Conrad, K.A.; Hager,
W.O.; Goldman, S. and Marcus, F.I.: Digitoxin-quinidine in-
teraction: Pharmacokinetic evaluation. Annals of Internal
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Garty, M:; Sood, P. and Rollins, D.E.: Digitoxin elimination
reduced durina quinidine therapy. Annals of Internal Medicine
94: 35-37 (198)).
Giardina, E.G.V.; Bigger, IT., Jr; Glassman, A.H.; Perel, lM.;
Roose, S.P.; Siris, S.G. and Davis, J.C.: A comparison of
desmethylimipramine and imipramine on the electrocar-
diogram and left ventricular function: A randomized crossover
design. Archives of Internal Medicine. InternationaIJournal of
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Marcus, F.I. and Goldman, S.: Digoxin-quinidine interaction.
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Medicine 300: 1238-1241 () 979).
Hirsh, P.O.; Weiner, H.1. and North, R.L.: Further insights into
digoxin-quinidine interaction: Lack of correlation between
serum digoxin concentration and inotropic state of the heart.
American Journal of Cardiology 46: 863-867 () 980).
Holt, D.W.; Hayler, A.M.; Edmonds, M.E. and Ashford, R.F.V.:
Clinically significant interaction between digoxin and
quinidine. British Medical Journal 4: 140 I () 979).
Hougen, T.1. and Smith, T.W.: Inhibition of myocardial
monovalent cation active transport by subtoxic doses of oua-
238
bain in the dog. Circulation Research 42: 856-863 () 978).
Keller, F. and Kreutz, G.: Chinidin interaktion mit digitoxin.
Deutsche Medizinische Wochenschrift 105: 701-702 () 980).
Lang, R.; Klein, H.O.; Weiss, E.; Libhaber, C. and Kaplinsky, E.:
Effect of verapamil on blood level and renal clearance of
digoxin. Circulation 62 (Suppl. 3): 11\-83 () 980).
Leahey, E.B., Jr; Reiffel, J.A.; Drusin, R.E.; Heissenbuttel, R.H.;
Lovejoy, W.P. and Bigger, J.T., Jr: Interaction between digox-
in and quinidine. Journal of the American Medical Associa-
tion 240: 533-534 (1978).
Leahey, E.B., Jr; Reiffel, J.A.; Heissenbuttel, R.H.; Drusin, R.E.;
Lovejoy, W.P. and Bigger, IT., Jr: Enhanced cardiac effect of
digoxin durina quinidine treatment. Archives of Internal
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Leahey, E.B., Jr; Reiffel, J.A.; Giardina, E.G.V. and Bigger, J.T.,
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on serum digoxin. A prospective study. Annals of Internal
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Leahey, E.B., Jr; Hougen, TJ.; Bigger, J.T., Jr and Smith, T.W.:
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Leahey, E.B., Jr; Bigger, IT., Jr; Butler, V.P., Jr; Reiffel, lA.;
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digoxin interaction. Time course and pharmacokinetics.
American Journal of Cardiology. 48: 1141-1146 ()98\).
Leahey, E.B., Jr; Giardina, E.G.V. and Bigger, IT., Jr: Personal
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Moysey, lO.; Jaggarao, N.S.V.; Grundy, E.N. and Chamberlain,
D.A.: Amiodarone increases plasma digoxin concentrations.
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digoxin in patients subjected to the quinidine-digoxin interac-
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« 98)),
Smith, T.W. and Wagner, H., Jr: Effects of Na,K-ATPase-specific
 Quinidine and Digoxin: An Important Interaction
antibodies on enzymatic activity and monovalent cation
transport. Journal of Membrane Biology 25: 341-360 (975).
Smith, T.W.; Haber, E.; Yeatman, L. and Butler, V.P., Jr: Rever-
sal of advanced digoxin intoxication with Fab fragments of
digoxin-specifIC antibodies. New England Journal of Medicine
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mediated arrhythmogenic properties of digitalis. Science 204:
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239
P.E.; Conrad, K.A. and Goldman, S.: Effect of quinine on
digoxin kinetics. Clinical Pharmacology and Therapeutics 28:
425-430 (980).
Warner, N.1.; Leahey, E.B" Jr and Bigger, IT., Jr: Effect of
quinidine on the steady -state tissue concentration of digoxin in
dogs. Circulation. American Journal of Cardiology 49: 1026
(1982)
Wellens, H.1.1.; Gorgels, A.P.; Braat, S.1.; Bar, F.W.; Vanagt, E.-
J. and Phaf, B.: Effect of oral disopyramide on serum digoxin
levels. A prospective study. American Heart Journal 100:
«
934-935 980).
Author's address: Dr J. Thomas Bigger Jr, Arrhythmia Con-
trol Unit, Columbia-Presbyterian Medical Center, 630 West
168th Street, New York, New York 10032 <USA).