Cardiac glycosides. Drug interactions of clinical significance.

Several commonly coadministered drugs interfere significantly with the pharmacokinetics or pharmacodynamics of cardiac glycosides. Only a few of these interactions (e.g. amiodarone, propafenone, quinidine) take place consistently, and although their extent may vary in individual patients, digitalis dosage adjustments should be made to avoid underdigitalization or toxicity. In other instances the appearance of clinically significant interactions depends on individual pharmacokinetic/metabolic characteristics (e.g. erythromycin, tetracycline), and the result cannot be anticipated on clinical grounds. Some interactions are controversial, having not been confirmed by all studies; others have been shown only in healthy volunteers but lack the definition of their relevance in the context of disease states. In view of the possible impact on the individual patient, close clinical monitoring (which may be supplemented with evaluation of digitalis plasma concentration) is recommended when prescribing cardiac glycosides with other therapeutic agents for which the possibility of an interaction has been reported.

Digitalis receptors and digoxin sensitivity in renal failure.

The number and the in vitro and in vivo affinity of digitalis receptors for digoxin were measured in patients with normal renal function and in uraemics. In uraemic patients the number of receptors was decreased. Although their in vitro affinity for digoxin was unchanged the in vivo affinity was decreased, probably due to hyperkalaemia. These findings provide a possible pharmacodynamic explanation for decreased activity of cardiac glycosides in chronic renal failure.

Long-term antihypertensive, metabolic and cellular effects of enalapril.

Fifty-three patients with mild to moderate essential hypertension were treated with enalapril (10-40 mg q.d.) alone, in combination with a fixed dose of hydrochlorothiazide (50 mg/day), or in a randomized cross-over study with varying dosages of hydrochlorothiazide (50, 25, 12.5 mg/day). Normalization of blood pressure was obtained in 47% of the patients after enalapril. In the remaining patients, all except four were normalized by the combination with hydrochlorothiazide. The addition of hydrochlorothiazide was required in six patients who had optimally responded to enalapril during the first three months. In the cross-over study, diastolic blood pressure was maintained below 95 mmHg with all the doses of diuretic used in association with 40 mg enalapril. No adverse metabolic (blood glucose, cholesterol, triglycerides), renal (creatinine clearance, urinary lysozyme and gamma-GT) or haematological (total and differential counts) effects were observed after long-term treatment for one year with enalapril alone or in combination with hydrochlorothiazide. Blood uric acid decreased significantly after enalapril and tended to increase after the combination with hydrochlorothiazide. Enalapril increased Na/K ATPase activity on erythrocyte membranes thus reducing intracellular sodium and increasing potassium.

Digitalis: new aspects of pharmacokinetics and clinical implications.

Any evaluation of the efficacy of digoxin therapy must rely upon a precise index of the digitalization status. As the plasma concentrations bear a rather poor relationship with clinical effects of treatment, the occupied fraction of digoxin receptors (Na-K ATPase) on the erythrocytes membranes is proposed as a new index of digitalization status; preliminary data on the value of this approach are discussed.

Erythrocyte Na+-ATPase in obese patients.

Na+-K+-ATPase activity, as measured by erythrocytic 86Rb uptake and number Digoxin Binding Sites were evaluated in 34 obese patients and in 39 control subjects. No differences were found in 86Rb uptake and Digoxin Binding Sites between obese and controls. Likewise no differences were found between obese patients on their spontaneous caloric intake and those studied during various hypocaloric regimens. Finally, no relationship between thyroid hormone serum concentrations and ATPase activity was found in the group of obese patients.

Digitalis 'receptors' during chronic digoxin treatment.

The effect of digoxin treatment on Mg-dependent [Na+-K+]-ATPase (the receptor for cardiac glycosides) was assessed by comparison of intracellular Na+-K+, 86Rb uptake and number of digoxin binding sites in the erythrocytes of 138 patients on long term digoxin and of 133 control subjects. The parameters were also assessed in thirty-two patients followed longitudinally for 1 y. The results indicate that the cells adapt to chronic exposure to 'therapeutic' dosage of digoxin with an overcompensatory synthesis of new receptors, a possible mechanism through which the normal intraerythrocytic ionic equilibrium is re-established. The process of synthesis of new receptors appears to be completed in erythrocytes in a period of 4 months after the start of digoxin treatment.

[Hemodynamic effects of disopyramide and procainamide in open-chest animals]. / Effetti emodinamici della diisopiramide e della procainamide nell'animale a torace aperto.

Hemodynamic effects of two antiarrhythmic agents, disopyramide and procainamide, have been evaluated in anesthetized open-chest healthy pigs after random administration. At therapeutic plasma concentrations none of these agents proved to have deleterious hemodynamic effects. The most important action was observed after disopyramide infusion and consisted in significant bradycardia which confirmed the known effect on sinus node automaticity of the drug. Left ventricular dp/dt, an index of cardiac contractility, was unchanged after infusion of both drugs. On the ECG intervals, only procainamide provoked a significant prolongation of QTc. It is concluded that at therapeutic dosage disopyramide does not present deleterious hemodynamic effects in animals and proves to be a valid alternative to other traditional antiarrhythmic agents.