Digitalis glycosides

A. Prototypes and Pharmacokinetics: All cardiac glycosides include a steroid nucleus and a lactone ring; most also have one or more sugar residues. The sugar residues constitute the glycoside portion of the molecule, and the steroid nucleus plus lactone ring comprise the "genin" portion. The cardiac glycosides are often called "digitalis" because several come-from the digitalis (foxglove) plant. Digoxin is the prototype agent and the one most commonly used in the USA. A very similar molecule, digitoxin, now rarely used, also comes from the foxglove. Digitalis-like drugs come from many other plants, and a few come from animals. Ouabain, a shorter-acting glycoside, is derived from a tropical plant, though some evidence suggests that ouabain is synthesized in mammals as well. The pharmacokinetics of digoxin, digitoxin, and ouabain are summarized in Table 13-2.

Table 13-2. Pharmacokinetic parameters of typical cardiac glycosides in adults. Digoxin is the cardiac glycoside most commonly used in the USA.
Properties	Digoxin	Digitoxin	Ouabain
Oral bioavailability (%)	60-85	90-100
Half-life (hours)	36-40
Primary organ of elimination	Kidney	Liver	Kidney
Volume of distribution (L/kg)	6-8	0.6
Protein bound in plasma (%)	20-40	>90

B. Mechanism of Action: Inhibition of Na+/K+ ATPase of the cell membrane by digitalis is well documented and is considered to be the primary biochemical mechanism of action of digitalis (Figure 13-3). The translation of this effect into an increase in cardiac contractility involves the Na+/Ca++ exchange mechanism. Inhibition of Na+/K+ ATPase results in an increase in intracellular sodium. The increased sodium alters the driving force for sodium-calcium exchange so that less calcium is removed from the cell. The increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release increases contractile force. Other mechanisms of action for digitalis have been proposed, but they are probably not as important as the ATPase effect. The consequences of Na+/K+ ATPase inhibition are seen in both the mechanical and the electrical function of the heart. Digitalis also modifies autonomic outflow, and this action has effects on the electrical properties of the heart.

C. Cardiac Effects:

1. Mechanical effects: The increase in contractility evoked by digitalis results in increased ventricular ejection, decreased end-systolic and end-diastolic size, increased cardiac output, and increased renal perfusion. These beneficial effects permit a decrease in the compensatory sympathetic and renal responses previously described. The decrease in sympathetic tone is especially beneficial: reduced heart rate, preload, and afterload permit the heart to function more efficiently (point C in Figure 13-1).

2. Electrical effects: Electrical effects include early cardiac parasympathomimetic responses and later arrhythmogenic responses. They are summarized in Table 13-3.

a. Early responses: Increased PR interval, caused by the decrease in atrioventricular conduction velocity, and flattening of the T wave are often seen. The effects on the atria and AV node are largely parasympathetic in origin and can be partially blocked by atropine. The increase in the atrioventricular nodal refractory period is particularly important when atrial flutter or fibrillation is present because the refractoriness of the AV node determines the ventricular rate in these arrhythmias. The effect of digitalis is to slow ventricular rate. Inversion of the T wave and ST depression may occur later.

b. Toxic responses: Increased automaticity caused by intracellular calcium overload, is the most important manifestation of toxicity. It results from delayed afterdepolarizations, which may evoke extrasystoles, tachycardia, or fibrillation in any part of the heart. In the ventricles, the extrasystoles are recognized as premature ventricular beats (PVBs). When PVBs are coupled to normal beats in a 1:1 fashion, the rhythm is called bigeminy (Figure 13-4).

Figure 13-3. Schematic diagram of a cardiac sarcomere with the cellular components involved in excitation-contraction coupling. Factors involved in excitation-contraction coupling are numbered. 1, Na+/K+-ATPase; 2, Na+-Ca++-exchanger; 3, voltage-gated calcium channel; 4, calcium pump in the wall of the sarcoplasmic reticulum (SR); 5, calcium release channel in the SR; 6, site of calcium interaction with troponin-tropomyosin system. (Reproduced, with permission, from Katzung BG [editor]: Basic & Clinical Pharmacology, 7th ed. Appleton & Lange. 1998.)

Table 13-3. Major actions of cardiac glycosides on cardiac electrical functions. (PANS, parasympathomimetic actions; direct, direct membrane actions.)
Variable	Tissue
Atrial Muscle	AV Node	Purkinje System, Ventricles
Effective refractory period	(PANS)	(PANS)	(Direct)
Conduction velocity	(PANS)	(PANS)	Negligible
Automaticity	(Direct)	(Direct)	(Direct)
Electrocardiogram Before arrhythmias	Negligible	PR interval	QT interval; T wave inversion; ST segment depression
Electrocardiogram Arrhythmias	Atrial tachycardia, fibrillation	AV nodal tachycardia; AV blockade	Premature ventricular contractions, ventricular tachycardia, ventricular fibrillation

D. Clinical, Uses:

1. Congestive heart failure: Digitalis is the traditional positive inotropic agent used in the treatment of congestive heart failure. However, other agents (diuretics, ACE inhibitors, vasodilators) may be equally effective and less toxic in some patients. Because the half-lives of both digoxin and digitoxin are long, the drugs accumulate significantly in the body, and dosing regimens must be carefully designed and monitored.

2. Atrial fibrillation: In atrial flutter and fibrillation, it is desirable to reduce the conduction velocity or increase the refractory period of the atrioventricular node so that ventricular rate is decreased. The parasympathomimetic action of digitalis effectively accomplishes this therapeutic objective.

E. Interactions: Quinidine causes a well-documented reduction in digoxin clearance and often increases the serum digoxin level if digoxin dosage is not adjusted. Several other drugs (amiodarone, verapamil, others) have been shown to have the same effect, but the interactions with these drugs are not clinically significant. Digitalis effects are inhibited by extracellular potassium and magnesium and facilitated by extracellular calcium. Loop diuretics and thiazides, often used in treating heart failure, may significantly reduce serum potassium and thus precipitate digitalis toxicity. Digitalis-induced vomiting may deplete serum magnesium and similarly facilitate toxicity. These ion interactions are important in treating digitalis toxicity (see below).

F. Digitalis Toxicity: The major signs of digitalis toxicity are arrhythmias, nausea, vomiting, and diarrhea. Rarely, confusion or hallucinations and visual aberrations may occur. The treatment of digitalis arrhythmias is important because this manifestation of digitalis toxicity is common and dangerous. Chronic intoxication is an extension of the therapeutic effect of the drug and is caused by excessive calcium accumulation in cardiac cells (calcium overload). This overload triggers abnormal automaticity and the arrhythmias noted in Table 13-3. Digitalis arrhythmia is more likely if serum potassium or magnesium is lower than normal or if serum calcium is higher than normal.

Severe acute intoxication is caused by suicidal or accidental extreme overdose and results in cardiac depression leading to cardiac arrest rather than tachycardia or fibrillation. A case of severe intoxication is described in Case 2 (Appendix IV).

Treatment of digitalis toxicity includes the following:

1. Correction of potassium or magnesium deficiency: Correction of potassium deficiency (caused for example, by diuretics) is useful in chronic digitalis intoxication. Mild toxicity may often be managed by omitting one or two doses of digitalis and giving oral or parenteral K + supplements. Similarly, if hypomagnesaemia is present, it should be treated by normalizing serum magnesium. Severe acute intoxication (as in suicidal overdoses) usually causes marked hypokalemia and should not be treated with supplemental potassium.

2. Antiarrhythmic drugs: Antiarrhythmic drugs may be useful if increased automaticity is prominent and does not respond to normalization of serum potassium. Agents that do not severely impair cardiac contractility (eg, lidocaine) are favored. Severe acute digitalis overdose usually causes suppression of all pacemaker cells. Antiarrhythmic drugs would be dangerous in such patients.

3. Digoxin antibodies: Digoxin antibodies (FAB fragments, Digibind) are extremely effective and should always be used if other therapies appear to be failing. They are effective for both digoxin and digitoxin overdose and may save severely poisoned patients who would otherwise die.

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