Robert H. Seller

Digitalis toxicity and hypomagnesemia.

Abstract Four patients with digitalis toxicity were found to be hypomagnesemic and normokalemic. A significantly lower mean serum magnesium was noted in a group of digitalized heart failure patients (1.40 mEq./L.) than in matched normal subjects (1.93 mEq./L.). These observations, coupled with the fact that both digitalis and magnesium deficiency lead to a decrease in intracellular potassium, suggested that hypomagnesemia might contribute to the development of digitalis toxicity. To determine whether hypomagnesemia facilitates the development of digitalis toxicity, serial acetyl strophanthidin infusions were performed in 19 adult mongrel dogs. Hypomagnesemia was achieved by Kiil kidney dialysis. While dialysate electrolyte concentration corresponded to normal canine plasma, acetyl strophanthidin was infused (100 μg per minute) three times at three hour intervals. Hypomagnesemia was then induced by three hours of magnesium-free dialysis and acetyl strophanthidin was again infused. Mean serum magnesium was reduced 44 per cent (1.67 to 0.93 mEq./L.). This was accompanied by a 26 per cent reduction in the amount of acetyl strophanthidin needed to produce a toxic arrhythmia (42.4 to 31.4 μg per kilogram). Restitution of sinus rhythm was observed in 13 dogs immediately after the intravenous infusion of 2 to 7 c.c. of 25 per cent magnesium sulfate. These studies have shown that hypomagnesemia facilitates digitalis toxicity which can be promptly terminated with magnesium sulfate. Since diuretic drugs may produce hypomagnesemia as well as hypokalemia and both may predispose to digitalis toxicity, it is suggested that serum magnesium as well as potassium levels be determined in patients with digitalis toxicity.

Magnesium sulfate in digitalis toxicity

Abstract This study was undertaken to evaluate the mechanism of the antiarrhythmic effect of magnesium sulfate in digitalis toxicity. The egress of potassium from the myocardium after the administration of 1 mg of acetyl strophanthidin into the right atrium was determined in 16 dogs by measurement of the coronary sinus-femoral artery potassium concentration difference. Three infusions of acetyl strophanthidin were given at 2 1 2 hour intervals. Twenty-five percent magnesium sulfate was given simultaneously with the third infusion. Arterial and coronary sinus samples were collected at 2 minute intervals after each infusion. The mean maximal arteriovenous potassium concentration difference was 0.47 mEq/liter after the first dose of acetyl strophanthidin and 0.80 mEq/liter after the second dose. When magnesium sulfate was given with acetyl strophanthidin, the arteriovenous difference was not significantly different from that of control subjects (0.15 mEq/ liter). A high level of magnesium concentration may overcome the acetyl strophanthidin-induced inhibition of transport adenosine triphosphatase. This may explain the efficacy of magnesium sulfate in the treatment of the arrhythmias of digitalis toxicity associated with hypomagnesemia. Although magnesium sulfate blocked myocardial egress of potassium in all studies, arrhythmias still occurred in 60 percent of the animals. This suggests that factors independent of potassium loss from the myocardium underlie the development of some digitoxic arrhythmias.

Serum and erythrocytic magnesium levels in congestive heart failure

Abstract Pretreatment serum and erythrocytic magnesium levels were found to be significantly lower in patients with congestive heart failure than in control subjects. The erythrocytic sodium level also was lower. The low magnesium and sodium values may be the result of a dilutional intracellular effect or may reflect long term diuretic therapy and possibly diets low in magnesium and sodium. The administration of hydrochlorothiazide did not significantly affect serum or erythrocytic cation levels. Absence of the expected decrease in serum magnesium subsequent to the administration of hydrochlorothiazide may be due to the fact that the pretreatment serum levels were significantly lower than in normal subjects. It is suggested that, in patients with congestive heart failure, low serum and intracellular magnesium levels may contribute to the development of digitalis toxicity, even in the presence of normal serum potassium levels. Although the patients with congestive heart failure were normotensive, changes in diastolic blood pressure induced by hydrochlorothiazide correlated with changes in serum magnesium as well as with changes in the ratio of erythrocytic potassium to serum magnesium.

Cardiac effect of diuretic drugs

Triamterene, amiloride, ethacrynic acid, and furosemide were studied to determine whether they modified the digitalis-induced egress of myocardial potassium which is thought to facilitate the development of digitalis arrhythmias. In a control group of 15 dogs, potassium was measured in samples obtained simultaneously from the femoral artery (FA) and the coronary sinus (CS) in a control period and at intervals after the administration of 1 mg. of acetylstrophanthidin. Acetylstrophanthidin caused a significant increase in cardiac A-V difference in the potassium concentration (CS-FA) averaging 0.47 mEq. per liter. In a group of 10 dogs, when 175 mg. of triamterene was infused prior to the acetylstrophanthidin, the rise in A-V differnece was abolished and the arrhythmias often aborted. In contrast, the infusion of potent diuretics (40 mg. of furosemide in five dogs and 100 mg. of ethacrynic acid in another five dogs) prior to acetylstrophanthidin, caused a doubling of the maximal A-V potassium difference. This study suggests that the clinical administration of antikaliuretic drugs may prevent the arrhythmias of digitalis toxicity not only by reducing kaliuresis and subsequent hypokalemia, but by a myocardial effect which antagonized the digitalis-induced loss of myocardial potassium. Contrariwise, potent diuretics may facilitate digitalis arrhythmias through a myocardial action causing a greater egress of myocardial potassium, thus explaining the development of arrhythmias despite normal serum potassium levels. These potent diuretics should be used cautiously, especially when given intravenously to patients receiving digitalis.

Increasing the inotropic effect and toxic dose of digitalis by the administration of antikaliuretic drugs—further evidence for a cardiac effect of diuretic agents

In prior studies, we have shown that the antikaliuretic drugs, triamterene and amiloride, through a direct cardiac effect reduce the loss of cardiac potassium induced by the administration of digitalis. Since loss of myocardial potassium is thought to underlie digitalis arrhythmias, this study was performed to determine whether triamterene and amiloride also extend the toxic dose and thus the therapeutic effect of digitalis. In twelve dogs, acetylstrophanthidin was infused (100 ug per minute) serially at 2.5-hour intervals. Trimterene (400 mg. in divided doses) was infused before the third acetylstrophanthidin infusion. This extended the dose required to produce a toxic arrhythmia by 110 per cent. In fourteen additional studies, nine dogs received 400 mg. of triamterene prior to the third acetylstrophanthidin infusion and five animals received 100 mg. of amiloride during the same period. In these fourteen studies, not only was the toxic dose of digitalis extended, but its inotropic effect (see article) (common peak developed isovolumic ventricular pressure) was also increased. These studies have demonstrated that through a cardiac effect, by reducing the digitalis-induced loss of cardiac potassium, the potassium-sparing drugs, triameterene and amiloride, extend the toxic dose of digitalis and thus permit txtension of its inotropic activity.

Pharmacodynamic effects of a new diuretic drug, ethacrynic acid∗

Abstract Ethacrynic acid is an extremely potent diuretic and natriuretic agent. Its rapid onset of action following intravenous administration suggests particular usefulness in patients with severe cardiac decompensation, e.g., acute pulmonary edema. Furthermore, the parenteral drug appears to be effective despite reduced glomerular filtration rates, and, therefore, may be useful in the treatment of edema associated with advanced renal functional impairment. Oral administration of ethacrynic acid also results in potent diuretic activity, with substantial antihypertensive effectiveness as well. The oral compound compares favorably with other potent oral diuretics and with parenteral meralluride.

Clinical selection of diuretic drugs in the management of cardiac edema

Abstract Mild cardiac edema can usually be controlled with a thiazide diuretic or a related sulfonamide compound. Successful treatment of moderate or severe heart failure generally requires (1) more potent diuretic drugs used alone, or (2) a combination of diuretic agents, such as ethacrynic acid or furosemide combined with a potassium-sparing drug or thiazide diuretic, or both. Regardless of the regimen employed, the efficient use of these various diuretic agents requires an intimate familiarity with their clinical pharmacology.

Five Years' Experience with the Evaluation of Diuretic Agents

Twelve diuretics and 2 combinations of diuretics were evaluated by a standard methodology. Electrolyte excretion patterns were evaluated in “normal” hospitalized patients, and acute weight loss was evaluated in out-patients in congestive failure. The large standard errors of the means for natriuresis, kaluresis, and acute weight loss reflect the inherent biologic variation of such assays and permit separation of drugs into only a few overlapping categories of potency. The combination of a mercurial and a thiazide caused significantly greater sodium excretion than any other drug used alone. No single diuretic was significantly more potent than all others.

Idiopathic orthostatic hypotension: Report of successful treatment with a new form of therapy

Abstract A case of severe idiopathic orthostatic hypotension is described. The patient had only temporary relief of symptoms with conventional therapy of hydroxyamphetamine (Paredrine) and fludrocortisone (Florinef). Subsequently, while closely observed in the hospital, his condition responded satisfactorily to a new form of therapy: the combined administration of hydroxyamphetamine with a monamine oxidase inhibitor, tranylcypromine (Parnate). The pathophysiology of idiopathic orthostatic hypotension is reviewed and the rationale of this new form of therapy is discussed.

Digitalis Toxicity and Hypomagnesemia.

Excerpt Four patients with digitalis toxicity were found to be hypomagnesemic and normokalemic. Subsequently we observed a significantly lower mean serum magnesium in a group of digitalized heart f...