Mechanism of Action and Indications

Digitalis refers to a class of cardioactive drugs called glycosides which exert both mechanical and electrical effects on the heart. The most commonly used digitalis preparation in current practice is digoxin.

The mechanical action of digitalis glycosides is to increase the strength of myocardial contractions in selected patients with dilated hearts and systolic chronic heart failure (CHF). Their therapeutic electrical effects relate primarily to decreasing automaticity and conductivity in the sinoatrial (SA) and atrioventricular (AV) nodes, in large part by increasing parasympathetic (vagal) tone. Consequently, digitalis is used for controlling the ventricular response in atrial fibrillation (AF) and atrial flutter, which are characterized by the excessive transmission of stimuli from the atria to the ventricles through the AV junction.

Since a number of more efficacious and safer medications have become available, the use of digitalis is mostly limited to the patients with AF, systolic CHF, and hypotension who cannot tolerate beta blockers or calcium channel blockers, or it is used as an adjunct to therapy. More rarely, digoxin is still used in the treatment of certain reentrant types of paroxysmal supraventricular tachycardia (PSVT), for example, during pregnancy, when other drugs might be contraindicated.

Although digitalis has indications in the treatment of certain forms of chronic systolic heart failure and selected supraventricular arrhythmias, it also has a relatively low margin of safety. The difference between therapeutic and toxic concentrations is narrow.

Digitalis Toxicity Vs. Digitalis Effect

Digitalis toxicity refers to the arrhythmias and conduction disturbances (as well as the toxic systemic effects described later) produced by this class of drug. Digitalis toxicity should not be confused with digitalis effect. Digitalis effect (Figs. 18-1 and 18-2) refers to the distinct scooping (“thumbprinting” sign) of the ST-T complex (associated with shortening of the QT interval) typically seen in patients taking digitalis glycosides.

Figure 18-1 Characteristic scooping of the ST-T complex produced by digitalis. (Not all patients taking digitalis exhibit these changes.)

Figure 18-2 The characteristic scooping of the ST-T complex produced by digitalis is best seen in leads V₅ and V₆. (Low voltage is also present, with total QRS amplitude of 5 mm or less in all six limb leads.)

Note: The presence of digitalis effect, by itself, does not imply digitalis toxicity and may be seen with therapeutic drug concentrations. However, most patients with digitalis toxicity manifest ST-T changes of digitalis effect on their ECG.

Symptoms and Signs of Digitalis Toxicity

Digitalis toxicity can produce general systemic symptoms as well as specific cardiac arrhythmias and conduction disturbances. Common extracardiac symptoms include weakness, anorexia, nausea, and vomiting. Visual effects (altered color perception) and mental changes may occur.

As a general clinical rule virtually any arrhythmia and all degrees of AV heart block can be produced by digitalis. However, a number of arrhythmias and conduction disturbances are commonly seen with digitalis toxicity (Box 18-1). In some cases, combinations of arrhythmias will occur, such as AF with a relatively slow ventricular response and frequent ventricular ectopy (Fig. 18-3).

Figure 18-3 Ventricular bigeminy caused by digitalis toxicity. Ventricular ectopy is one of the most common signs of digitalis toxicity. A, The underlying rhythm is atrial fibrillation. B, Each normal QRS complex is followed by a ventricular premature beat.

Two distinctive arrhythmias, when encountered, should raise concern for digitalis toxicity. The first is bidirectional ventricular tachycardia (VT) (Fig. 18-4), a rare type of VT in which each successive beat in any lead alternates in direction. However, this rare arrhythmia may also be seen in the absence of digitalis excess (e.g., with catecholaminergic polymorphic VT; see Chapters 16 and 19).

Figure 18-4 This digitalis toxic arrhythmia is a special type of ventricular tachycardia with QRS complexes that alternate in direction from beat to beat. No P waves are present.

The second arrhythmia suggestive of digitalis toxicity is atrial tachycardia (AT) with AV block (Fig. 18-5). Not uncommonly, 2:1 AV block is present so that the ventricular rate is half the atrial rate. AV block is usually characterized by regular, rapid P waves occurring at a rate between 150 and 250 beats/min (due to increased automaticity) and a slower ventricular rate (due to increased AV block). Superficially, AT with block may resemble atrial flutter; however, when atrial flutter is present, the atrial rate is faster (usually 250 to 350 beats/min). Furthermore, in AT with block the baseline between P waves is isoelectric. Note: Most cases of AT with block encountered clinically are not due to digitalis excess, but it is always worth checking to rule out this possibility.

Figure 18-5 This rhythm strip shows atrial tachycardia (about 200 beats/min) with 2:1 block producing a ventricular rate of about 100 beats/min.

Digitalis toxicity is not a primary cause of AF or of atrial flutter with a rapid ventricular response. However, digitalis toxicity may occur in patients with these arrhythmias. In such cases the toxicity may be evidenced by marked slowing of the ventricular rate to less than 50 beats/min (Fig. 18-6) or the appearance of ventricular premature beats (VPBs). In some cases, the earliest sign of digitalis toxicity in a patient with AF may be a subtle regularization of the ventricular rate at the slower heart rate (Fig. 18-7).

Figure 18-6 Atrial fibrillation with an excessively slow ventricular rate because of digitalis toxicity. Atrial fibrillation with a rapid ventricular rate is rarely caused by digitalis toxicity. However, in patients with underlying atrial fibrillation, digitalis toxicity is often manifested by excessive slowing or regularization of the QRS rate.

Figure 18-7 Digitalis (digoxin) excess in a patient with underlying atrial fibrillation. Note the slow (about 60 beats/min) and relatively regularized ventricular response. A single ventricular premature beat (VPB) (beat 4) is also present. The “scooping” of the ST-T in lead II and the lateral chest leads is consistent with digitalis effect, although other factors, including ischemia or left ventricular hypertrophy (LVH), cannot be excluded. The borderline prominent chest lead voltage raises consideration of LVH, but is not diagnostic. The relatively vertical QRS axis (about +75°) also raises consideration of biventricular hypertrophy given the possible LVH.

In summary, digitalis toxicity causes a number of important arrhythmias and conduction disturbances. You should suspect digitalis toxicity in any patient taking a digitalis preparation who has an unexplained arrhythmia until you can prove otherwise.

Factors Predisposing to Digitalis Toxicity

A number of factors significantly increase the hazard of digitalis intoxication (Box 18-2).

Prevention of Digitalis Toxicity

The first step in treatment is always prevention. Before any patient is started on digoxin or a related drug, the indications should be carefully reviewed. Some patients continue to receive digoxin or related drugs for inappropriate reasons, e.g., diastolic heart failure. The patient should have a baseline ECG, serum electrolytes, and BUN and creatinine measurements. Serum magnesium blood levels should also be considered, particularly if indicated by diuretic therapy, malabsorption, etc. Other considerations include the patient’s age and pulmonary status, as well as whether the patient is having an acute MI.

Early signs of digitalis toxicity (e.g., increased frequency of VPBs, sinus bradycardia, or increasing AV block) should be carefully checked.

Furthermore, digoxin dosages should be lowered in advance of starting medications that routinely increase digoxin levels.

Treatment of Digitalis Toxicity

Definitive treatment of digitalis toxicity depends on the particular arrhythmia. With minor arrhythmias (e.g., isolated VPBs, sinus bradycardia, prolonged PR interval, Wenckebach AV block, or AV junctional rhythms), discontinuation of digitalis and careful observation are usually adequate. More serious arrhythmias (e.g., sustained VT) may require suppression with an intravenous (IV) drug such as lidocaine. For tachycardias, potassium supplements should be given to raise the serum potassium level to well within normal limits.

Patients with complete heart block from digitalis toxicity may require a temporary pacemaker while the effect of the digitalis dissipates, particularly if they have symptoms of syncope, hypotension, or CHF. In other cases, complete heart block can be managed conservatively while the digitalis wears off.

Occasionally patients present with a large overdose of digitalis taken inadvertently or in a suicide attempt. In such cases the serum digoxin level is markedly elevated, and severe brady- or tachyarrhythmias may develop. In addition, massive digitalis toxicity may cause life-threatening hyperkalemia because the drug blocks the cell membrane mechanism that pumps potassium into the cells in exchange for sodium. Patients with a potentially lethal overdose of digitalis can be treated with a special digitalis-binding antibody given intravenously (digoxin immune Fab [antigen-binding fragment]). Of note, when hyperkalemia is present in a patient with digitalis toxicity, do not give IV calcium as a means of treatment.

Finally, clinicians should be aware that direct current electrical cardioversion of arrhythmias in patients who have digitalis toxicity is extremely hazardous and may precipitate fatal VT and fibrillation. Therefore, you should not electrically cardiovert patients suspected of having digitalis toxicity (e.g., AF with a slow ventricular response, AT with block, etc.).

Serum Digoxin Concentrations (Levels)

The concentration of digoxin in the serum can be measured by means of radioimmunoassay. “Therapeutic concentrations” are still widely reported in the range from about 0.5 to 2 ng/mL in many laboratories.

Concentrations exceeding 2.0 ng/mL are associated with a high incidence of digitalis toxicity. However, when ordering a test of digoxin level in a patient, you must be aware that “therapeutic levels” do not rule out the possibility of digitalis toxicity. As previously mentioned some patients are more sensitive to digitalis and may show signs of toxicity with “therapeutic” levels. In other patients, factors such as hypokalemia or hypomagnesemia may potentiate digitalis toxicity despite a “therapeutic” serum drug level. Although a “high” digoxin level does not necessarily indicate overt toxicity, these patients should be examined for early evidence of digitalis excess, including systemic symptoms (e.g., gastrointestinal symptoms) and all cardiac effects that have been discussed. Efforts should be made to keep the digoxin level well within therapeutic bounds, and lower levels appear to be as efficacious as (and safer than) higher ones in the treatment of heart failure. A spuriously high digoxin level may be obtained if blood is drawn within a few hours of the administration digoxin.

For most patients being treated for systolic heart failure or AF, it is safest to maintain the digoxin levels at the low end of the therapeutic range, around 0.4 to 0.8 ng/mL.