A drug interaction usually refers to an unsuspected altered effect that results when a patient is taking two agents at the same time. Such a definition is dramatically illustrated by the recent report that quinidine doubles the serum digoxin concentration when a patient is undergoing stable digoxin therapy."' Although this drug interaction was first noted by Reiffel and colleagues in 1975, they first reported their findings in 1978.' Their retrospective study was restricted to patients who had steady-state serum digoxin concentrations before quinidine therapy was instituted. In 25 (93%) of the 27 patients studied, the serum digoxin concentration rose significantly, from an average of 1.3 to 3.2 ng/ml after quinidine therapy was begun. The resulting toxic effects, such as nausea, vomiting and arrhythmias, could be cured by discontinuing either the digoxin or the quinidine. Even if the study was slightly biased, the results are startling. Ejvinsson,' of the Karolinska Institute in Huddinge, Sweden, has reported the same effects. In all 12 of his patients the average serum digoxin concentration rose from 0.85 to 1.6 ng/ml following the start of quinidine therapy. The mechanism for this dramatic action is uncertain, but it seems that tissue binding is altered, so that digoxin is released into the plasma. There may even be a reduction in the renal clearance of digoxin from the inhibition of renal secretion by quinidine.' It is a sobering thought that more than 90% of the reported cases of "quinidine syncope" have occurred in patients taking digitalis.' Clearly, digoxin therapy should be withheld for at least 24 hours before quinidine treatment is started. After another 48 hours it can be resumed at half the former maintenance dose.' However, when administration of quinidine is stopped, the maintenance dose of digoxin may need to be doubled. While the interaction of quinidine and digitoxin is unknown, one wonders how many other serious drug interactions go unrecognized. Other interactions of digitalis may not be as significant as the digoxin-quinidine interaction. However, the list of such effects is growing,4" and all may be significant if overlooked. Perhaps the most common enhanced effect occurs when potassium loss is induced in a patient taking digitalis. Many diuretics, lithium carbonate, amphotericin B and corticosteroids may promote potassium loss. Any drug that leads to intracellular potassium depletion will likely cause digitalis-induced arrhythmias even if the serum potassium concentration remains normal or elevated.6'7 Such arrhythmias may then occur at "therapeutic" serum digoxin concentrations that were previously well tolerated. In addition to sensitizing the myocardium to digitalis, hypokalemia may

increase the serum digoxin concentration by reducing the tubular secretion of digoxin.8 This effect is not yet clearly documented, but it may help explain some instances of toxic effects. Enhanced myocardial irritability may also occur without potassium depletion or an increase in the serum digitalis concentration. Carbamazepine may cause bradycardia.' Parenteral administration of calcium is still considered dangerous, since two deaths were reported in 1936; it may also precipitate arrhythmias." Succinylcholine or sympathomimetic agents may increase ectopic activity, and must therefore be used cautiously in patients taking digitalis. This is even more true of lithium," which enhances digitalis intoxication by lowering the ventricular fibrillation threshold. More serious is the unexpected increase in serum digoxin concentrations that occurs with two other drugs. If a slowly dissolving digoxin preparation is in use, then the administration of propantheline bromide" may elevate the serum digoxin concentration in about two thirds of patients. Spironolactone,""4 and possibly triamterene, can cause a much more significant increase, although not to the same extent as quinidine. The plasma and renal clearances of digoxin and the volume of distribution are decreased significantly by spironolactone. The total clearance of digoxin is reduced about 25 %, which results in an increase of one third in the serum digoxin concentration. Thus, a patient taking maintenance doses of digoxin could become intoxicated when spironolactone is given. This distal tubular effect occurs because digoxin is partially cleared by active tubular secretion, although most of the drug is removed by glomerular filtration.'3"4 Waldorff and associates" gave their patients 100 mg of spironolactone twice a day; the effect of smaller doses is uncertain at present. Nevertheless, an increase in the serum digoxin concentration from 1.7 to 2.4 ng/ml could be clinically significant. Such unexpected elevations can be critical if direct-current countershock is used." On the other hand, the bioavailability of digoxin can be impaired in any patient with a malabsorption syndrome or rapid transit of the drug through the gut. Thus, neomycin," antacids,'7 kaolin-pectin mixtures, metoclopramide and cathartics may lessen the effectiveness of maintenance therapy with digoxin by reducing the serum concentrations from borderline effective to ineffective. Cholestyramine" decreases the serum digitoxin concentration' by trapping digitoxin in the intestinal lumen, thus interrupting the enterohepatic circulation; absorption of digoxin may also decrease. In such conditions the dose may have to be temporarily increased. CMA JOURNAL/AUGUST 4, 1979/VOL. 121

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Other agents alter metabolism. Barbiturates, and perhaps phenylbutazone, increase the metabolism of digitoxin to digoxin, presumably by the induction of hepatic microsomal enzymes . Thyroid dysfunction will alter renal clearance. Most hyperthyroid patients have a higher creatinine clearance and a shorter digoxin half-life than hypothyroid patients.20 Thyroid supplement administration will usually lower the serum digoxin concentrations owing to an increase in the renal clearance of digoxin. Finally, digoxin is not metabolized the same way by all individuals. The amount of hydrolyzed or reduced digoxin excreted in the urine may vary from 2.2% to 52.0% (average 12.4)%, as reported by Peters, Falk and Kalman.2' At least 7% of their patients excreted more than 35 % of such hydrolyzed reduction products in the urine. Since reduced digoxin is 1/7 to 1/36 as active as the parent drug, it is possible that a high serum digoxin concentration may not induce intoxication. Beware of the drug interactions of digitalis. JOHN A. MILLIKEN, MD, FRCP[C], FACP, FACC Professor of medicine

Hotel Dieu Hospital Queen's University Kingston, Ont.

5. MARTIN EW: Drug Interactions Index 1 978/79, Lippincott, Philadelphia, 1978, pp 124-26 6. BRATER DC, MORRELLI HF: Digoxin toxicity in patients with normokalemic potassium depletion. Cliii Pharmacol Ther 22: 21, 1977 7. STEINL.SS E, OLESEN KH: Cardiac arrhythmias induced by hypokalaemia and potassium loss during maintenance digoxin therapy. Br Heart J 38: 167, 1976

8. STEINESS E: Suppression of renal excretion of digoxin in hypokalemic patients. Cliii Pharinacol Ther 23: 511, 1978 9. KILLIAN JM, FROMM GH: Carbamazepine in the treatment of neuralgia. Use and side effects. A rch Neurol

19: 129, 1968 10. NOLA GT, POPE S. HARRISON DC: Assessment of the synergistic relationship between serum calcium and digit-

alis. Am Heart J 79: 499, 1970 11. OSMAN FH, AMMAR EM, AFIFI AM, et al: Potentiation of lithium and protection by rubidium of digitalis intoxication. Jpn I Exp Med 46: 1, 1976 12. MANNINEN V. APAJALAI-ITI A, MEL1N J, et al: Altered

absorption of digoxin in patients given propantheline and metoclopramide. Lancet 1: 398, 1973 13. WALDORFF 5, ANDERSON JD, HEEBOLLNIELSEN N, et al:

Spironolactone-induced changes in digoxin kinetics. Cliii Pharinacol Ther 24: 162, 1978 14. STEINESS E: Renal tubular-secretion of digoxin. Circa/a-

hon 50: 103, 1974 15. DEGLIN S, DEGLIN J, CHUNG EK: Direct current shock and digitalis therapy. Drug Intell Cliii Pharm 11: 76, 1977 16. LINDENBAUM J, MAULITZ RM, BUTLER VP j.: Inhibition

of digoxin absorption by neomycin. Gasnoenterology 71: 399, 1976

17. BROWN DD, JUHL RP: Decreased bioavailability of di-

References 1. REIFFEL JA, LEAHEY EB, DRUSIN RE, et al: A digoxin! quinidine adverse drug interaction (abstr). Am J Cardiol 41: 368, 1978 2. EJvlNssoN G: Effect of quinidine on plasma concentra-

tions of digoxin. Br Med J 1: 279, 1978 3. HAGER WD, FENSTER P, MAYERSOHN M, et al: Digoxinqu inidine interaction. Pharmacokinetic evaluation. N Engi

J Med 300: 1238, 1979 4. HANSTEIN PD: Drug Ititeractions, 3rd ed, Lea & Febiger,

Philadelphia, 1976, pp 129-33

goxin due to antacids and kaolin-pectin. N Engi I Med 295: 257, 1976 18. BAZZANO G, BAZZANO GS: Digitalis intoxication. Treatment with a new steroid-binding resin. JAMA 220: 828,

1972 19. SOLOMON HM, ABRAMS WB: Interactions between digitoxin and other drugs in man. Am Heart 1 83: 277, 1972 20. CRoxsoN MS. IBBERTSON HK: Serum digoxin in patients

with thyroid disease. Br Med 1 3: 566, 1975 21. PETERS U, FALK LC, KALMAN SM: Digoxin metabolism in patients. Arch Intern Med 138: 1074, 1978

Historical notes - Digitalis Digitalis is derived from a purple-flowering herb, the foxglove, of which there are about 20 species. The foxglove grows wild in Europe, western Asia and the Canary Islands, and although seldom found wild in North A inerica is cultivated commercially in Michigan and Oregon. The name "foxglove" is believed to be derived from "folk's glove", which also means "fairies' glove". In Scotland it is variously known as "bloody fingers "deadman's bells" - probably a reference to its use as a poison - "ladies' thimbles" and "wild mercury". The plant's latin name, Digitalis purpurea was given it by a Ger,nan botanist, Leonard Fuchs, in 1542; the name was suggested by the foxglove's German name, Fingerhut (thimble). In the late 18th century William Witherington of Birmingham, England used digitalis as a diuretic for dropsy sufferers, and he later published an "A ccount of the Fox-glove and Some of its Medical Uses" in 1785. Digitalis was known for a long time as Witherington's infusion.E 264 CMA JOURNAL/AUGUST 4, 1979/VOL. 121