LETI-ERS TO THE EDITOR

IS THERE A CLINICALLY RELEVANT INTERACTION

BETWEEN QUININE AND DIGOXIN IN HUMAN BEINGS?

Wilkerson et a1.l reported that coadministration of quinine resulted in a significant increase in serum digoxin concen- tration in dogs. They concluded that quinine should be used cautiously in conjunction with cardiac glycosides. However, the dose of quinine (per kilogram body weight) administered to the dogs exceeded by far the common therapeutic dose recommended for human beings2

We3 recently conducted a study administering 750 mg of quinine daily for 7 days to 17 patients aged 57 to 81 years who were on steady state digoxin maintenance therapy. Serum digoxin concentration was measured by immunoassay. In 10 patients plasma quinine concentrations were determined with high pressure liquid chromatography. Data were analyzed for statistical significance with Student’s t test for paired values; mean values & 1 standard deviation are given. As shown in Figure 1, the mean serum digoxin concentration was not sig- nificantly influenced by 1 week of coadministration of quinine (0.80 f 0.32 versus 0.91 f 0.32 ng/ml). In 11 of the 17 patients the serum digoxin concentration values remained virtually constant, in 2 they decreased slightly and in 4 they increased markedly. This latter subgroup did not differ in any respect from the rest of the patients. The mean plasma quinine con- centration in the subgroup of 10 of the 17 patients was 3.68 & 1.61 pg/ml on the morning of day 7.

In contrast, coadministration of 750 mg of quinidine/day resulted in a significant increase in serum digoxin concen- tration in all 19 patients treated (1.02 f 0.42 versus 1.94 f 0.57 ng/ml, p <O.OOl, Fig. 1). The mean plasma quinidine con- centration of these patients was 1.41 f 0.32 pg/ml 12 to 14 hours after the last dose.

Quinine is frequently used for nocturnal cramps and in combination with antiinflammatory drugs. Goodman and Gilman recommend a maximal daily dose of 600 mg whereas WiIkerson et a1.l administered a daily dose of 975 mg to dogs

20 1

Ix17

z F 10

s 05

0 D D*Ql-l D D+Q

FfGURE 1. The serum dfgoxin concentration @DC) of 17 palients receiving digonln therapy (D). was not significantly increased by coadministratiMI of 750 mg of quinme (D + Dn) daily ovar a period of 1 week. In contrast. the $ame dose of qulnidine (D + D) administered concomitantly to 19 patients racafvlng digaxin therapy resulted in a sigmbcant increase in serum dlgonin concentration; n = number of patients: n ?. = not signlffcant, p = proba- bility.

weighing 11 to 14 kg. Wilkerson and his colleagues have dis- covered a new group of drugs that interact with digoxin. However, one must be extremely cautious in applying results from animal experiments to human beings. Our results dem- onstrate that when quinine is given to human beings according to accepted therapeutic guidelines it does not significantly affect the serum digoxin concentration. On the basis of our experience clinicians may continue to administer quinine to their digitalized patients without the risk of causing digoxin intoxication. However, careful monitoring is to be recom- mended in patients receiving extremely large doses of quinine, such as those being treated for malaria.

Wittich Doering, MD

Medical Service

Cardiac Unit Akademisches

Lehrkrankenhaus Miinchen-Schwabing

Munich, West German Federal Republic

References

1.

2

3.

Wflkerson RD. Mockridge PB, Massing GK. Effects of selected &cgs ~1 serum dlgoxin concentration in dogs Am J Card101 1980;45.1201-20. Rotlo IM. Drugs used I” the chemottwapy of malaria. In: Gocdman LS. G~lman A. eds The Pharmacological &IS of Therapeutics. 5th ed New York Macmillan, 1975 1062-5. Doerlog W. Hohne M, Konig E. New aspects of digoxlnqulntdlne Interaction. VIII ELI- ropean Congress of Cardiology, Paris, 1980.

REPLY

Doering points out that (1) the dose of quinine utilized in our study (975 mg/day) is considerably larger than the maximal dose recommended for human beings in a standard pharma- cology text, and (2) the animals used in our study were much smaller than the average human being. Both of these facts are correct, but it is quite clear that the serum concentration of any drug is much more closely related to the magnitude of its effect than is the oral dose. It would appear that Doering’s objection is based on the assumption that the relation between dose and serum concentration is the same for all animals (including human beings), in which case 975 mg/day of qui- nine administered to a 12 kg dog would be expected to produce an extraordinarily high serum concentration, since the usual human dose is 1.3 g/day.’ In fact, data presented in our paper clearly demonstrate that the relation between oral dose and serum concentration for a number of drugs is not the same from one species to another. For example, a daily digoxin dose of 0.25 mg given to the animals in this study produced a serum concentration of approximately 1.0 ng/ml, a level equivalent to that expected from the same dose in a human being weighing 7 to 10 times as much as a dog. Similarly, a daily dose of 600 mg of quinidine (a stereoisomer of quinine) produced a serum concentration of less than 1.0 fig/ml in our study an- imals, whereas a daily dose of 750 mg of quinidine produced a serum concentration of approximately 1.4 pg/ml in his pa- tients. Likewise, the 2.6 g/day dose of aspirin given to our study animals may seem inappropriately large, because this represents a typical human dosage regimen, but this regimen produced therapeutic serum salicylate concentrations (15 to 30 mg/lOO ml) in only 60 percent of the study animals. The

November 1981 the American Journal of CAADfOLOGY Volume 48 975