Digoxin exerts a positive inotropic effect, thereby enhancing the force of myocardial contraction. Direct effects of digoxin
include prolongation of the effective refractory period in the atria and the atrioventricular (AV) node, which diminishes the conduction velocity through those regions. CGs are readily absorbed through the gastrointestinal tract; digoxin has up to 80% bioavailability [6]. Digoxin has a volume of distribution (V_d) of 5.1 to 7.4 L per kg [7] and a half-life of 36 to 48 hours [2]. The generally accepted therapeutic serum concentration range for digoxin is 0.8 to 2.0 ng per mL for inotropic support in patients with left ventricular dysfunction. Higher concentrations (1.5 to 2.0 ng per mL) may be needed for ventricular rate control in patients with atrial dysrhythmias. Digoxin is primarily eliminated by the kidneys. In patients with renal dysfunction, digoxin clearance is reduced. Serum digoxin concentrations can be altered by numerous drug interactions [8,9,10].

Toxicity results from an exaggeration of therapeutic effects [6]. Cardiac glycosides bind to and inactivate the sodium–potassium adenosine triphosphatase pump (Na⁺–K⁺-ATPase) on cardiac cell membranes. This pump maintains the electrochemical membrane potential, vital to conduction tissues, by concentrating Na⁺ extracellularly and K⁺ intracellularly. When Na⁺–K⁺-ATPase is inhibited, the Na⁺–calcium exchanger removes accumulated intracellular sodium in exchange for calcium. This exchange increases sarcoplasmic calcium and is the mechanism responsible for the positive inotropic effect of digitalis. Intracellular calcium overload causes delayed after depolarizations and gives rise to triggered dysrhythmias. Increased vagal tone and direct AV depression may produce conduction disturbances. The decreased refractory period of the myocardium increases automaticity.

Differences between the presentations of patients with CG poisoning due to a single acute ingestion and those with chronic toxicity resulting from excessive therapeutic doses are illustrated in Table 127.1. Diagnosing chronic CG toxicity is more difficult because the presentation may mimic more common illnesses, such as influenza or gastroenteritis. Patients with chronic CG toxicity may present with constitutional, gastrointestinal, psychiatric, or visual complaints that may not be recognized as signs of digitalis toxicity. Symptoms most commonly reported include fatigue, weakness, nausea, anorexia, and dizziness [11]. Neuropsychiatric signs and symptoms include headache, weakness, vertigo, syncope, seizures, memory loss, confusion, disorientation, delirium, depression, and hallucinations [12]. The most frequently reported visual disturbances are cloudy or blurred vision, loss of vision, and yellow-green halos or everything appearing “washed in yellow” (xanthopsia) [13].

Cardiac manifestations of CG toxicity are common and potentially life threatening. An extremely wide variety of dysrhythmias has been reported [14,15]. Dysrhythmias frequently associated with CG toxicity include premature ventricular contractions, paroxysmal atrial tachycardia or atrial fibrillation with a conduction block, junctional tachycardia, sinus bradycardia, AV nodal blocks, ventricular tachycardia, and ventricular fibrillation. Atrial tachycardia (enhanced automaticity) with variable AV block (impaired conduction), atrial fibrillation with an accelerated or slow junctional rhythm (regularization of atrial fibrillation), and fascicular tachycardia are highly suggestive of CG toxicity [16,17]. Bidirectional ventricular tachycardia, a narrow-complex tachycardia with right bundle-branch morphology, is highly specific, but not pathognomonic for digitalis toxicity [14].

True end-organ digoxin sensitivity is seen with myocardial disease, myocardial ischemia, and metabolic or electrolyte disturbances [18]. Hypokalemia, hypomagnesemia, and hypercalcemia predispose to toxicity [2]. The elderly are at increased risk, whereas renal impairment, hepatic disease, hypothyroidism, chronic obstructive pulmonary disease, and drug interactions alter sensitivity to CGs [1].

Essential laboratory tests include serum digoxin concentrations, electrolytes, blood urea nitrogen, creatinine, calcium, magnesium, and electrocardiogram. Additional laboratory tests should be obtained as clinically indicated. Serum digoxin concentrations can assist in the diagnosis of CG poisoning but often are unreliable indicators of toxicity [17]. A therapeutic concentration does not exclude poisoning, as predisposing factors can cause an individual to become poisoned despite a concentration within the therapeutic range. Conversely, high serum
digoxin concentrations after an acute ingestion are not always indicative of toxicity [19]. Digoxin follows a two-compartment model of distribution, with relatively rapid absorption into the plasma compartment and then slow redistribution into the tissue compartment [2]. Serum digoxin concentrations most reliably correlate with toxicity when obtained after distribution is complete, which occurs 6 hours or more after oral or intravenous digoxin administration.

Naturally occurring digitalis glycosides from plants and animals can cross-react with the digoxin assay. The degree of cross-reactivity is unknown, and no good correlation has been established between serum concentrations of these glycosides and toxicity [5]. A false-positive digoxin assay (usually less than 3 ng per mL), may occur in neonates and patients with renal insufficiency, liver disease, and pregnancy [20,21,22] because of endogenous digoxin-like immunoreactive factors.