The role of magnesium in digitalis toxicity

Fundamentals of clinical cardiology

The role of magnesium in digitalis toxicity

Robert H. Seller, M.D. Philadelphia, Pa.

T he effect of magnesium on the cardiovascular system has been studied

since 1900.1*2 Knowledge of magnesium metabolism was difficult to obtain because of the lack of a simple and precise method for measuring magnesium concentrations in biological material. With improved analytic methods for measuring magnesium, especially atomic absorption spectros- copy, knowledge of the biological role of magnesium has increased. Despite the low concentration of magnesium in the extra- cellular fluid where one third to one half is protein bound, magnesium is second only to potassium in intracellular concentration.3 EIagnesium is a metallocoenzyme for many enzymatic reactions of carbo- hydrate and protein metabolism. It is also a metallocoenz.yme in reactions involving oxidative phosphorylation and activates adenosine triphosphatase (ATPase) which is essential for normal cell membrane function. It is intimately related to the electrophysiology of conduction in myocardial tissue.

Most investigations concerning the relationship of electrolytes to the toxic manifestations of digitalis have concerned themselves primarily with potassium and calcium.4s5 These studies have shown that potassium salts protect the myocardium from digitalis toxicity (possibly by in- fluencing myocardial glycoside binding) and that, conversely, digitalis protects

against the toxic manifestations of hyperkalemia.‘j It is well recognized that potassium depletion sensitizes the myocardium to the development of digitalis toxicity.’ Studies of the role of calcium in myocardial function have shown that this ion increases myocardial contractility and excitability. Calcium may also potentiate the development of digitalis toxicity. Thus calcium chelating agents have been recommended for the treatment of digitalis toxicity but their therapeutic benefits are often transient.8Bg

The primary cardiovascular effects of magnesium involve myocardial conduction and contraction as well as blood pressure regulation. The intravenous administration of magnesium sulfate causes a prolongation of the P-R interval as serum magnesium concentration increases. With continued administration, there is a prolonged intra- ventricular conduction. In general, the electrocardiographic manifestations of hy- permagnesemia are similar to those of hyperkalemia, while the changes of hypomagnesemia are similar to those of hypo- kalemia. Some investigators feel that magnesium depresses the conduction and the spontaneous rhythm of the heart. They suggest that one of the mechanisms underlying these effects may be an accumu- lation of intracellular potassium as a result of a magnesium-induced reduction in membrane permeability to potassium out-

From the Department of Medicine, Hahnemann Medical College and Hospital. 230 North Broad St.. Philadelphia Pa. 19102.

Received for publication Nov. 23, 1970.

Vol. 82, No. 4, pp. 551-556 October, 1971 American Heart Journal 551

552 S&r .‘l~rr. IIr~~l J. October, 1971

flow.‘O Magnesium is an essential nletallo-

coenzyme for and activates sodium-potassium dependent membrane ATPase, an enzyme necessary for the active transport of potassium into the cell. On the other hand, digitalis glycosides and acetylstrophanthidin inhibit the activity of mem- ljrane ATPase, leading to cellular loss of potassium. The purpose of this paper is to review the relationship of magnesium to digitalis toxicity with particular emphasis on: (1) the facilitation of digitalis toxicity by hypomagnesemia and (2) the mechanism of antiarrhythmic action of magnesium sulfate in digitalis toxicity.

Hypomagnesemia and digitalis toxicity

The antiarrhythmic effect of magnesium sulfate in digitalis-induced arrhythmias has been recognized for many years.” In most instances, its effects have been transient. We have recently reported a study designed to determine: (1) whether hypomagnesemia facilitates digitalis toxicity and (2) the effect of magnesium sulfate in hypomagnesemic digitalis toxicity.‘2 In these studies, serial acetylstrophanthidin infusions were administered to 19 adult mongrel dogs. Hypomagnesemia was achieved by Kiil kidney dialysis. While dialysate electrolyte concentration corresponded to normal canine plasma, acetylstrophanthidin was infused (100 pg per minute) three times at three-hour intervals. Hypomag- nesemia was then induced by three hours of magnesium-free dialysis and acetylstrophanthidin was again infused. Mean serum magnesium was reduced 44 per cent (1.67 to 0.93 mEq. per liter). This was accompanied by a 26 per cent reduction in the amount of acetylstrophanthidin needed to produce a toxic arrhythmia (42.4 to 31.4 mg. per kilogram). Restitu- tion of sinus rhythm was observed in 13 hypomagnesemic dogs immediately after the intravenous infusion of 2 to 7 ml. of magnesium sulfate. This study demonstrated that hypomagnesemia facilitated the development of digitalis toxicity. It also demonstrated that in arrhythmias of hypomagnesemic digitalis toxicity, in con- trast to normomagnesemic digitalis toxicity, magnesium sulfate was particularly

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Fig. 1. After six hours of dialysis with a normal bath composition. A, Sinus rhythm before acetylstrophanthidin infusion. Serum magnesium 1.56 mEq. per liter. B, A-V dissociation after the infusion of 67.5 pg of acetylstrophanthidin (33.8 mcg. per kilogram). Serum magnesium 1.67 mEq. per liter. C, Sinus rhythm before acetylstrophanthidin infusion. Serum magnesium 1.23 mEq. per liter. Note the S-T seg- ment depression and T wave inversion. D, A-V dissociation after infusion of 400 pg of acetylstrophanthidin (20.0 mcg. per kilogram). Serum magnesium 1.2 mEq. per liter. Hypomagnesemia facilitated the development of digitalis toxicity in that 40 per cent less acetylstrophanthidin was required when the serum magnesium was 1.2 mEq. per liter. E, Sinus rhythm returned immediately after 2 C.C. of 25 per cent magnesium sulfate solution was administered intravenously over a two-minute period. Serum magnesium after a total of 5 C.C. of magnesium sulfate was 4.3 mEq. per liter.

effective and its administration resulted in a Drompt, permanent conversion to sinus rh;thm’ (I%;. 1).

Volume 82 Number 4 Magnesium in digitalis toxicity 553

(Nd “) increases Hioh @W)

Fig. 2. An interrelationship of magnesium and digitalis with transmembrane electrolyte transport in which digitalis blocks ATPase resulting in a reduction of active transport of K+ into the cell while passive diffusion continues. This leads to a reduction in intracellular potassium. Hypomagnesemia also leads to a reduction in the active transport of K+ into the cell resulting in a reduction in intracellular potassium.

Mechanism of antiarrhythmic effect of magnesium sulfate

Studies in other laboratories have shown that the slow intravenous administration of 20 ml. of a 20 per cent solution of magnesium sulfate is safe and causes minimal changes in the electrocardiogram. The administration of this amount of magnesium sulfate carries little risk unless hyper- magnesemia is already present, as is com- monly observed in patients with renal in- sufficiency.

Intravenous magnesium sulfate has been used successfully in the treatment of several arrhythmias including paroxysmal atria1 tachycardia, ventricular tachycardia, and digitalis toxicity. In the reported treat- ments of digitalis arrhythmias with magnesium salts, they were given empirically and serum magnesium levels were not measured. Although it has been suggested that magnesium ions have a nonspecific myocardial depressant action, the precise mechanism underlying the antiarrhythmic properties of magnesium sulfate in digitalis toxicity has not been determined. It is well recognized that acetylstrophanthidin interferes with the action of sodium-po-

tassium dependent membrane ATPase leading to a loss of intracellular potassium; hypomagnesemia also leads to a loss of intracellular potassium.l3J* Since digitalis- induced arrhythmias have been attributed to the egress of myocardial potassium, hypomagnesemia and digitalis may have a synergistic effect on the development of these arrhythmias (Fig. 2). Contrariwise, the administration of magnesium may in- crease intracellular potassium.

Observations in our laboratory demonstrated that the intravenous administration of magnesium sulfate alone resulted in a definite prompt but small drop in arterial potassium concentration. Since this occurred within six minutes after the administration of magnesium sulfate without a change in pH, we attributed this to a shift of potassium into cells, perhaps due to magnesium activation of membrane ATPase. The effects of magnesium sulfate on acetylstrophanthidin-induced myocardial potassium egress were then studied.15 Twenty-four adult mongrel dogs, approxi- mately 20 kilograms in weight, were used. Serial Lead II electrocardiograms were obtained. Coronary flow was measured

Magnesium Sulfate alone (averoae of 8 studies)

Catheter m R Atrium for Acetylstrophanthidin

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Fig. 3. Schematic representation of animal experi- ments.

with an electromagnetic flowmeter. Intra- arterial blood pressure was monitored with a Statham strain gauge. Acetylstrophan- thidin and/or magnesium sulfate was injected through a catheter placed in the right atrium. Another catheter was placed in the coronary sinus under fluoroscopic guidance. Simultaneous blood samples were taken from the coronary sinus (CS) and femoral artery (FA) at two-minute intervals (Fig. 3).

The effect of magnesium sulfate alone on transmyocardial potassium kinetics was studied in eight dogs: 7 ml. of 2.5 per cent magnesium sulfate was injected into the right atrium and samples were obtained simultaneously from the coronary sinus and femoral artery. The administration of magnesium sulfate caused a prompt drop in arterial potassium concentration of 0.34 f 0.17 mEq. per liter (p <O.OS), sug- gesting an intracellular shift of potassium (Fig. 4). No significant changes were noted in the transmyocardial potassium gradient (CS-FA) nor were any significant changes noted in sodium, calcium, or pH. There was a transient drop in blood pressure, which returned to normal within two minutes of administration of magnesium sulfate.

The effects of acetylstrophanthidin alone and the combination of acetylstrophanthidin and magnesium sulfate on myocardial potassium kinetics were studied in a similar fashion in 16 dogs. Serial injections

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Fig. 4. The effect of magnesium sulfate alone on transmyocardial potassium kinetics. Serial deter- mination of magnesium levels in arterial and coronary sinus serum taken after 7 ml. of 25 per cent magnesium sulfate was injected into the right atrium. It is notable that the administration of magnesium sulfate caused a prompt drop in arterial potassium concentrations of 0.34 * 0.17 mEq. per liter, sug- gesting an intracellular shift of potassium.

of acetylstrophanthidin were performed at 2% hour intervals. During the last acetylstrophanthidin injection, magnesium sulfate (25 per cent) was given simultaneously with the acetylstrophanthidin. After the first acetylstrophanthidin infusion, the maximal difference in potassium concentration (CS-FA) occurred between 2 and 8 minutes and averaged 0.47 mEq. per liter. In six studies when the second dose of acetylstrophanthidin was repeated 2% hours after the first, there was a signifi- cantly greater potassium egress (0.80 mEq. per liter) than after the first dose. When magnesium sulfate was given simultaneously with acetylstrophanthidin infusion, there was no significant egress of myocardial potassium (Fig. 5).

The difficulty in interpreting these studies arises because of the inconsistent relationship of myocardial potassium egress to arrhythmia. Although myocardial potassium egress usually occurred after the administration of acetylstrophanthidin alone, it did not always result in the development of an arrhythmia. After the first acetylstrophanthidin infusion, all arrhythmias but one were associated with potassium egress. One third (5 out of 15) had no arrhythmias and no statistically significant

Magnesium in digitalis toxicity 555

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Fig. 5. The effect of acetylstrophanthidin alone and the combination of acetylstrophanthidin and magnesium sulfate on the myocardial potassium kinetics. The graph demonstrates mean serum potassium levels in simultaneous samples of arterial and coronary blood after serial infusions (2% hours apart) of 1 mg. of acetylstrophanthidin (and 7 CC. of magnesium sulfate). The first infusion resulted in a maximal difference in potassium concentration of 0.47 mEq. per liter. After the second dose of acetylstrophanthidin, there was a greater potassium egress as demonstrated by a difference between coronary sinus and arterial samples of 0.80 mEq. per liter. When magnesium sulfate was given simultaneously, no significant egress of potassium was noted.

potassium egress. It is notable that in all six studies, where acetylstrophanthidin alone was administered a second time, arrhythmias occurred and potassium egress was marked. Most importantly, although the coadministration of magnesium sulfate blocked potassium egress in 100 per cent (15 out of 1.5), arrhythmias still occurred in nine animals. In other words, despite the fact that magnesium sulfate consis- tently blocked the egress of myocardial potassium in all studies, arrhythmias occurred in 60 per cent of the animals. Our results imply that factors other than myocardial potassium egress were responsible for these digitalis-induced arrhythmias.

Discussion

In the past, magnesium sulfate has been used in the treatment of digitalis arrhythmias without regard to serum magnesium levels. We have demonstrated that hypo-

magnesemia facilitates digitalis toxicity and that in these instances magnesium sulfate is able to abolish the arrhythmias promptly and permanently. This is particularly important in view of the fact that many clinical conditions have been reported to be associated with hypomagnesemia. They include prolonged magnesium-free intravenous fluid administration, diarrhea, diabetes mellitus, congestive heart failure, cardiopulmonary bypass, prolonged gastro- intestinal drainage, acute pancreatitis, de- lirium tremens, alcoholic cirrhosis, mal- absorption, hyperparathyroidism, aldoster- onism, excessive lactate administration, thyrotoxicosis, malignant osteolytic disease (hypercalcemia and hypomagnesemia), and particularly diuretic therapy.

Rather than the empiric use of magnesium sulfate as an antiarrhythmic agent, we believe that it is important to determine both serum magnesium and potassium in

all cases of digitalis toxicit),. If hypo~n;tgnc:- semia is present, we recommend that 7 t-o 1.5 c.c. of 25 per cent magnesium sulfate be administered slowly intravenously under electrocardiographic monitoring.

Although several investigators believe that the loss of myocardial potassium underlies the development of digitalis arrhythmias, other investigators have suggested that myocardial potassium egress is but one of the factors leading to digitalis arrhythmias.16ti7 The fact that several antiarrhythmic agents, including quinidine sulfate, diphenylhydantoin, procaine amide, glucose, and insulin, as well as magnesium sulfate, all reduce the digitalis-induced myocardial loss of potassium and suppress the arrhythmia suggests that egress of potassium underlies the genesis of some digitalis arrhythmias. On the other hand, propranolol and reserpine, also useful in digitalis arrhythmias, do not affect myocardial potassium kinetics. This suggests that factors in addition to myocardial potassium egress play a role in the genesis of some digitalis arrhythmias. Our studies demonstrated that magnesium sulfate shares with other antiarrhythmic agents the ability to reduce the loss of myocardial potassium induced by digitalis. The latter property may explain magnesium’s antiarrhythmic activity. Since the magnesium ion is a coenzyme for membrane ATPase, which is inhibited by digitalis glycosides, it is interesting to speculate that the pres- ence of magnesium in excess may, to some degree, overcome digitalis blockade of this enzyme.

The author gratefully acknowledges the assistance of Drs. Stanley Banach, Martin Neff, Saul Mendels- sohn and Jose Cangiano in performing some of the work reported in this paper.

REFERENCES 1. Engbaek, L.: The pharmacologic action of mag-

nesium ions with particular reference to the neuromuscular and cardiovascular systems, Pharmacol. Rev. 4:396, 1952.

2. Welt, L. G., and Gitelman, H.: Disorders of magnesium metabolism, in Disease-A-Month, Chicago, 1965, Year Book Medical Publishers, Inc.

3. Martill, II. E., XIehl, J. W., and \\“ertnlan, M.: Clinical studies of magnesium metabolism, Med. Clin. N. Amer. 36:11.57, 19.52.

4. Lawn, B., S&berg, H., Enselberg, C. D., and Eston, R. E.: Interrelationship between potassium metabolism and digitalis- toxicity in-heart failure. Proc. Sot. Exo. Biol. Med. 76:797. 1951.

5. Page, k., and Real, j. D.: Interrelation&p between cardiac effects of ouabain, hypocalcemia and hyperkalemia, Circ. Res. 3:501; i955.

6. Sampson. T. 1.. Albertson. E. C.. and Kondo. B.: The ‘effec”t ‘on man oi potassium adminis: tration in relation to digitalis glycosides, AMER. HEART 1. 26:164. 194.1.

7. Lown, G., WelLi: J. n/r:, Wyatt, N., Hoigne, R., and Merrill, 1. P.: Effects of alterations of bodv potassium on digitalis toxicity, J. Clin. Inves;. 31:648, 1952,

8. Jick, S., and Karsh, R.: The effect of calcium chelation on cardiac arrhythmias and conduction disturbances, Amer. J. Cardiol. 4:287, 1959.

9. Surawicz, B., MacDonald, M. G., Kalijot, V., and Bettinger, J. C.: Treatment of cardiac arrhythmias with salts of ethylenediamine tetra-acetic acid (EDTA), AMER. HEART J, 58:493, 19.59.

10. Skou, J. C.: Further investigation on a Mg++ and Na+ activated adenosine-triphosphatase, possibly related to the active, linked transport of Na+ and K+ across the nerve membrane, Biochim. Biophys. Acta 42:6, 1960.

11. Szekely, P., and Wynne, N. A.: Effects of magnesium on cardiac arrhythmias caused by digitalis, Clin. Sci. 10:241, 1951.

12. Seller, R. H., John, 0. J., Kim, K. E., Mendels- sohn, S., Brest, A. N., and Swartz, C.: Digitalis toxicity and hypomagnesemia, AMER. HEART J. 79:57, 1970.

13. Post, R. L., Merritt, C. R., Kinsolving, C. R., and Albright, C. D.: Membrane adenosine triphosphatase as a participant in the active transport of sodium and potassium in the human erythrocyte, J. Biol. Chem. 235:1796, 1960.

14, Whang, R., and Welt, L. C.: Observations in experimental magnesium depletion, J. Clin. Invest. 42:305, 1963.

15. Seller, R. H., Neff, M., Mendelssohn, S., Kim, K. E., and Swartz, C.: Magnesium sulfate in digitalis toxicity, Ann. Intern. Med. 72:785, 1970.

16. Grupp, G., and Charles, A.: Effect of ouabain and 3-acetylstrophanthidin on potassium ex- change in the dog heart in situ, J. Pharmacol. Exp.-Ther. 143:%6, 1964.

17. Levitt. B.. and Roberts. 1.: The caoacitv of different digitalis materials” to induce ventiicu- lar rhythm disturbances in the reserpine- pretreated cat, J. Pharmacol. Exp. Ther. 156:159, 1967.

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The role of magnesium in digitalis toxicity