Digoxin Overdose

Chapter 85 Digoxin Overdose

Meredith L. Daly, VMD, Deborah Silverstein, DVM, DACVECC

• Cardiac glycoside toxicity is not uncommon because of the narrow therapeutic index, variability in patient sensitivities to the medications, and alterations in pharmacodynamics due to comorbid disease.

• Cardiac glycosides cause positive inotropy through inhibition of membrane-bound sodium and potassium-activated adenosine triphosphatase (Na⁺,K⁺-ATPase).

• Noncardiac manifestations of digoxin overdose include gastrointestinal disturbances and neurologic abnormalities.

• Cardiac manifestations of digoxin overdose are extremely variable but classically include arrhythmias characterized by increased automaticity with or without conduction delays.

• Patients with alterations in serum electrolytes, renal disease, endocrine disease, increased sympathetic nervous system activity, or concurrent drug administration may be more susceptible to digoxin toxicosis.

• Treatment of digoxin toxicosis involves gastrointestinal decontamination, recognition and treatment of life-threatening arrhythmias, normalization of serum electrolyte concentrations and, in severe cases, administration of Fab fragments of digoxin-specific antibodies.

INTRODUCTION

Cardiac glycosides, the most common of which is digoxin, have an extremely narrow therapeutic index. In addition, there is marked variability in the sensitivity of individual patients to the toxic effects of cardiac glycosides. Therefore, it is not uncommon for both human and veterinary patients to exhibit clinical evidence of toxicity. Although information on the incidence of toxicosis in veterinary patients is not available, it has been reported in up to 35% of digitalized human patients.¹

Several mechanisms may contribute to toxicosis. Digoxin is excreted primarily by the kidneys. Renal insufficiency may therefore increase serum concentrations. Congestive heart failure, renal disease, and hepatic disease may alter the metabolism or volume of distribution of digoxin, as can other medications used for cardiac or other concurrent diseases.² Serum electrolyte abnormalities, particularly alterations in potassium, calcium, and magnesium, can potentiate cardiac glycoside toxicity.² Although there is a clinical assay for serum digoxin concentrations, toxicity is still common because serum concentrations do not correlate directly with clinical evidence of toxicity.

The most important aspect of digoxin toxicosis management is early recognition. Some patients with signs of mild toxicosis may respond to withdrawal of the medication. Therapy of the patient suffering from severe toxicosis includes, but is not limited to, gastrointestinal decontamination, fluid therapy, correction of serum electrolyte and acid-base abnormalities, treatment of congestive heart failure, antiarrhythmic or pacemaker therapy, and in severely affected animals, the administration of Fab fragments of digoxin-specific antibodies. The incidence and severity of digoxin toxicity has declined since the development of alternative drugs for treating supraventricular arrhythmias, the widespread availability of assays for serum digoxin levels, the identification of interactions between digoxin and other medications, and the increased vigilance of clinicians.¹ Although the human literature still suggests a role for digoxin for patients with congestive heart failure,³ it is likely that digoxin use will wane as newer and safer drugs become available.

MECHANISM OF ACTION

An understanding of digoxin’s mechanism of action is essential to comprehend the toxicologic features of this medication. The beneficial effects of the cardiac glycosides in animals with congestive heart failure can be attributed primarily to their positive inotropic and negative chronotropic effects. Their positive inotropic effect is caused by the inhibition of the membrane-bound Na⁺,K⁺-ATPase on the myocardial cell membranes. Digoxin competitively binds to the site that potassium typically occupies and therefore stops activity of approximately 30% of these pumps when given at therapeutic levels. As the activity of this enzyme is impaired, there is an accumulation of intracellular sodium and an increase in intracellular osmolality. The cell attempts to counter these changes by increasing the efflux of sodium and influx of calcium through the sodium-calcium cation exchanger. The increased intracellular sodium concentration also reduces the transmembrane gradient that drives calcium outside of the cell during repolarization, decreasing calcium efflux. The subsequent increase in intracellular calcium further triggers the release of stored intracellular calcium from the sarcoplasmic reticulum during systole, thus increas-ing the amount of cytosolic calcium available to interact with the contractile proteins. This ultimately results in an increase in myocardial contractility.⁴

Cardiac glycosides exhibit both direct and neurally mediated actions on the atrial and ventricular myocytes, as well as on the specialized conduction tissues within the myocardium. At therapeutic serum levels, digoxin indirectly depresses the rate of sinoatrial node depolarization by increasing vagal tone. In addition, the drug decreases atrial fiber automaticity and increases maximal diastolic resting potential in both atrial and atrioventricular (AV) nodal tissues.^4,5 These effects are due, at least in part, to an increase in vagal tone as well because they are blocked by atropine administration.⁶ In addition, at therapeutic levels digitalis causes a predominantly vagally mediated prolongation of the effective refractory period in these tissues, which results in decreased conduction velocity in AV nodal tissue. This action accounts for the utility of digitalis in terminating reentrant arrhythmias involving the AV node, and in controlling the ventricular response rate to atrial fibrillation.⁴ At higher concentrations, however, digoxin may increase resting membrane potential, increase automaticity, and increase sympathetic nervous system activity.⁶ These effects, in conjunction with increases in intracellular calcium and altered impulse conduction velocities, may result in severe and life-threatening arrhythmias.

The cardiac glycosides have an important role in the modulation of abnormal autonomic tone that is classically seen in moderate to severe heart failure. Patients in congestive heart failure develop increased sympathetic tone in response to alterations in cardiac output. Mitigation of this excessive sympathetic tone is thought to contribute to the efficacy of digoxin for the treatment of heart failure. In patients with moderate to severe heart failure, infusion of a cardiac glycoside increases forearm blood flow and cardiac index and decreases heart rate and skeletal muscle sympathetic activity (a surrogate of the central sympathetic nervous system tone).⁷ In addition, digoxin inhibits the sodium pump in neuronal cells (i.e., baroreceptor cells), resulting in stimulation of parasympathetic and inhibition of sympathetic nerves.⁸ As a result, the cardiac glycosides alter carotid baroreceptor reflex responsiveness to changes in carotid sinus pressure in animals with heart failure.¹⁰ Because cholinergic innervation is more prominent in the atrial and AV nodal tissues, the cholinomimetic actions of digoxin affect these tissues to a greater extent than the Purkinje fibers or the ventricular myocardium.⁴ On the basis of these observations, among others, modulation of neurohormonal activation could be an important mechanism contributing to the efficacy of digoxin in the treatment of heart failure.

NONCARDIAC MANIFESTATIONS OF TOXICOSIS

Noncardiac manifestations of digoxin toxicosis are relatively nonspecific and develop as a result of inhibition of Na⁺,K⁺-ATPase in other excitable tissues, such as smooth muscle cells and the central nervous system. Animals with extracardiac toxicosis most commonly have signs referable to the GI system, including anorexia, nausea, vomiting, or diarrhea. These may be the result of direct effects of cardiac glycosides on the GI tract; however, vomiting may also result from central stimulation of the chemoreceptor trigger zone.¹ Neurologic effects may manifest as depression, fatigue, restlessness, disorientation and, uncommonly, seizures. Visual deficits and convulsions have been documented rarely in human patients.¹ Thrombocytopenia and alterations in follicle-stimulating hormone, leuteinizing hormone, and sex hormone levels have been seen infrequently in human medicine.¹¹

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Tags: Small Animal Critical Care Medicine

Sep 10, 2016 | Posted by admin in SMALL ANIMAL | Comments Off

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