Cardiac Glycosides

Cardiac Glycosides

The English botanist, chemist, and physician Sir William Withering is credited with the first published observation in 1785 that digitalis purpurea, a derivative of the purple foxglove flower, could be used for the treatment of "cardiac dropsy," or congestive heart failure. The benefits of cardiac glycosides in CHF have been extensively studied (Eichhorn and Gheorghiade, 2002) and are generally attributed to:

• Inhibition of the plasma membrane Na⁺, K⁺-ATPase in myocytes
• A positive inotropic effect on the failing myocardium
• Suppression of rapid ventricular rate response in CHF-associated atrial fibrillation
• Regulation of downstream deleterious effects of sympathetic nervous system overactivation

Mechanism of the Positive Inotropic Effect

With each cardiac myocyte depolarization, Na⁺ and Ca²⁺ ions shift into the intracellular space (Figure 28–5). Ca²⁺ that enters the cell via the L-type Ca²⁺ channel during depolarization triggers the release of stored intracellular Ca²⁺ from the sarcoplasmic reticulum via the ryanodine receptor (RyR). This Ca²⁺-induced Ca²⁺ release increases the level of cytosolic Ca²⁺ available for interaction with myocyte contractile proteins, ultimately increasing myocardial contraction force. During myocyte repolarization and relaxation, cellular Ca²⁺ is re-sequestered by the sarcoplasmic reticular Ca²⁺-ATPase and is removed from the cell by the Na⁺Ca²⁺ exchanger and, to a much lesser extent, by the sarcolemmal Ca²⁺-ATPase

Cardiac glycosides bind and inhibit the phosphorylated ( subunit of the sarcolemmal Na⁺,K⁺-ATPase and thereby decreasing Na⁺ extrusion and increasing cytosolic [Na⁺]. This decreases the transmembrane Na⁺ gradient that drives Na⁺–Ca²⁺ exchange during myocyte repolarization. As a consequence, less Ca²⁺ is removed from the cell and more Ca²⁺ is accumulated in the sarcoplasmic reticulum (SR) by SERCA2. This increase in releasable Ca²⁺ (from the SR) is the mechanism by which cardiac glycosides enhance myocardial contractility. Elevated extracellular K⁺ levels (i.e., hyperkalemia) cause dephosphorylation of the ATPase subunit, altering the site of action of the most commonly used cardiac glycoside, digoxin, and thereby reducing the drug's binding and effect.

Electrophysiologic Actions

At therapeutic serum or plasma concentrations (i.e., 1-2 ng/mL), digoxin decreases automaticity and increases the maximal diastolic resting membrane potential in atrial and atrioventricular (AV) nodal tissues. This occurs via increases in vagal tone and sympathetic nervous system activity inhibition. In addition, digoxin prolongs the effective refractory period and decreases conduction velocity in AV nodal tissue. Collectively, these may contribute to sinus bradycardia, sinus arrest, prolongation of AV conduction, or high-grade AV block. At higher concentrations, cardiac glycosides may increase sympathetic nervous system activity that influences cardiac tissue automaticity, change associated with the genesis of atrial and ventricular arrhythmias. Increased intracellular Ca²⁺ loading and sympathetic tone increases the spontaneous (phase 4) rate of diastolic depolarization as well as promoting delayed afterdepolarization; together, these decrease the threshold for generation of a propagated action potential and predisposes to malignant ventricular arrhythmias (see Chapter 29).

Pharmacokinetics

The elimination t_1/2 for digoxin is 36-48 hours in patients with normal or near-normal renal function, permitting once-daily dosing. Near steady-state blood levels are achieved ~7 days after initiation of maintenance therapy. Digoxin is excreted by the kidney, and increases in cardiac output or renal blood flow from vasodilator therapy or sympathomimetic agents may increase renal digoxin clearance, necessitating adjustment of daily maintenance doses. The volume of distribution and drug clearance rate are both decreased in elderly patients.

Despite renal clearance, digoxin is not removed effectively by hemodialysis due to the drug's large (4-7 L/kg) volume of distribution. The principal tissue reservoir is skeletal muscle and not adipose tissue, and thus dosing should be based on estimated lean body mass. Most digoxin tablets average 70-80% oral bioavailability; however, ~10% of the general population harbors the enteric bacterium Eubacterium lentum, which inactivates digoxin and thus may account for drug tolerance that is observed in some patients. Liquid-filled capsules of digoxin (LANOXICAPS) have a higher bioavailability than do tablets (LANOXIN); thus, the drug requires dosage adjustment if a patient is switched from one delivery form to the other. Digoxin is available for intravenous administration, and maintenance doses can be given intravenously when oral dosing is inappropriate. Digoxin administered intramuscularly is erratically absorbed, causes local discomfort, and usually is unnecessary. A number of clinical conditions may alter the pharmacokinetics of digoxin or patient susceptibility to the toxic manifestations of this drug. For example, chronic renal failure decreases the volume of distribution of digoxin and therefore requires a decrease in maintenance dosage of the drug. In addition, drug interactions that may influence circulating serum digoxin levels include several commonly used cardiovascular medications such as verapamil, amiodarone, propafenone, and spironolactone. The rapid administration of Ca²⁺ increases the risk of inducing malignant arrhythmias in patients already treated with digoxin. Electrolyte disturbances, especially hypokalemia, acid–base imbalances, and one's form of underlying heart disease also may alter a patient's susceptibility to digoxin side effects.

Maximal increase in LV contractility becomes apparent at serum digoxin levels ~1.4 ng/mL (1.8 nmol) (Kelly and Smith, 1992). The neurohormonal benefits of digoxin, however, may occur between 0.5-1 ng/mL. In turn, higher serum concentrations are not associated with incrementally increased clinical benefit. Moreover, there are data to suggest that the risk of death is greater with increasing serum concentrations, even at values within the traditional therapeutic range, and therefore many advocate maintaining digoxin levels <1 ng/mL.

Clinical Use of Digoxin in Heart Failure

Data from contemporary clinical trials have re-characterized the utility of cardiac glycosides, once first-line agents, in CHF, especially in patients with normal sinus rhythm (as opposed to atrial fibrillation).

Digoxin discontinuation in clinically stable patients with mild-to-moderate CHF from LV systolic dysfunction worsened symptoms and decreased maximal treadmill exercise (Uretsky et al., 1993; Packer et al., 1993). However, eventhough digoxin may decrease CHF-associated hospitalizations in patients with severe forms of the disease, drug use does not reduce all-cause mortality. Overall, digoxin use usually is limited to CHF patients with LV systolic dysfunction in atrial fibrillation or to patients in sinus rhythm who remain symptomatic despite maximal therapy with ACE inhibitors and adrenergic receptor antagonists. The latter agents are viewed as first-line therapies because of their proven mortality benefit.

Digoxin Toxicity

The incidence and severity of digoxin toxicity have declined substantially in the past 2 decades as a consequence of alternative drugs available for the treatment of supraventricular arrhythmias in CHF, increased understanding of digoxin pharmacokinetics, improved serum digoxin level monitoring, and identification of important interactions between digoxin and other commonly co-administered drugs. Nevertheless, the recognition of digoxin toxicity remains an important consideration in the differential diagnosis of arrhythmias, and neurologic or gastrointestinal symptoms in patients receiving cardiac glycosides. An antidote, digoxin immune Fab (DIGIBIND, DIGIFAB), is available to treat toxicity.

Among the more common electrophysiologic manifestations of digoxin toxicity are ectopic beats originating from the AV junction or ventricle, first-degree AV block, abnormally slow ventricular rate response to atrial fibrillation, or an accelerated AV junctional pacemaker. When present, only dosage adjustment and appropriate monitoring are usually necessary. Sinus bradycardia, sinoatrial arrest or exit block, and second- or third-degree AV conduction delay requiring atropine or temporary ventricular pacing are uncommon. Unless in the setting of high-degree AV block, potassium administration should be considered for patients with evidence of increased AV junctional or ventricular automaticity even if serum K⁺ levels are in the normal range. Lidocaine or phenytoin, which have minimal effects on AV conduction, may be used for the treatment of digoxin-induced ventricular arrhythmias that threaten hemodynamic compromise (see Chapter 29). Electrical cardioversion carries an increased risk of inducing severe rhythm disturbances in patients with overt digitalis toxicity and should be used with particular caution. Note, too, that inhibition of the Na⁺,K⁺-ATPase activity of skeletal muscle can cause hyperkalemia. An effective antidote for life-threatening digoxin (or digitoxin) toxicity is available in the form of anti-digoxin immunotherapy. Purified Fab fragments from ovine anti-digoxin antisera (DIGIBIND) are usually dosed by the estimated total dose of digoxin ingested in order to achieve a fully neutralizing effect. For a more comprehensive review of the treatment of digitalis toxicity, see Kelly and Smith (1992).

Adrenergic and Dopaminergic Agonists

In the setting of severely decompensated CHF from reduced cardiac output, the principal focus of initial therapy is to increase myocardial contractility. Dopamine and dobutamine are positive inotropic agents most often used to accomplish this. These drugs provide short-term circulatory support in advanced CHF via stimulation of cardiac myocyte dopamine (D₁) and adrenergic receptors that stimulate the G_s-adenylyl cyclase-cyclic AMP–PKA pathway. The catalytic subunit of PKA phosphorylates a number of substrates that enhance Ca⁺²-dependent myocardial contraction and accelerate relaxation (Figure 28–5). Isoproterenol, epinephrine, and norepinephrine are useful in certain circumstances but have little role in routine CHF management. Indeed, inotropic agents that elevate cardiac cell cyclic AMP are consistently associated with increased risks of hospitalization and death, particularly in patients with NYHA class IV. At the cellular level, enhanced cyclic AMP levels have been associated with apoptosis (Brunton, 2005; Yan et al., 2007). The basic pharmacology of adrenergic agonists is discussed in Chapter 12.

Dopamine

Dopamine is an endogenous catecholamine with only limited utility in the treatment of most patients with cardiogenic circulatory failure. The pharmacologic and hemodynamic effects of dopamine are concentration dependent. Low doses (2 g/kg lean body mass/min) induces cyclic AMP–dependent vascular smooth muscle vasodilation. In addition, activation of D₂ receptors on sympathetic nerves in the peripheral circulation at these concentrations also inhibits NE release and reduces adrenergic stimulation of vascular smooth muscle, particularly in splanchnic and renal arterial beds. Therefore, low-dose dopamine infusion often is used to increase renal blood flow and thereby maintain an adequate glomerular filtration rate in hospitalized CHF patients with impaired renal function refractory to diuretics. Dopamine also exhibits a pro-diuretic effect directly on renal tubular epithelial cells that contributes to volume reduction.

At intermediate infusion rates (2-5 g/kg/min), dopamine directly stimulates cardiac receptors and vascular sympathetic neurons that enhance myocardial contractility and neural NE release. At higher infusion rates (5-15 g/kg/min), adrenergic receptor stimulation–mediated peripheral arterial and venous constriction occurs. This may be desirable in patients with critically reduced arterial pressure or in those with circulatory failure from severe vasodilation (e.g., sepsis, anaphylaxis). However, high-dose dopamine infusion has little role in the treatment of patients with primary cardiac contractile dysfunction; in this setting, increased vasoconstriction will lead to increased afterload and worsening of LV performance. Tachycardia, which is more pronounced with dopamine than with dobutamine, may actually provoke ischemia (and ischemia-induced malignant arrhythmias) in patients with coronary artery disease.

Dobutamine

Dobutamine is the agonist of choice for the management of CHF patients with systolic dysfunction. In the formulation available for clinical use, dobutamine is a racemic mixture that stimulates both ₁ and ₂ receptor subtypes. In addition, the (–) enantiomer is an agonist for adrenergic receptors, whereas the (+) enantiomer is a weak, partial agonist. At infusion rates that result in a positive inotropic effect in humans, the ₁ adrenergic effect in the myocardium predominates. In the vasculature, the adrenergic agonist effect of the (–) enantiomer appears to be offset by the (+) enantiomer and vasodilating effects of ₂ receptor stimulation. Thus, the principal hemodynamic effect of dobutamine is an increase in stroke volume from positive inotropy, although ₂ receptor activation may cause a decrease in systemic vascular resistance and, therefore, mean arterial pressure. Despite increases in cardiac output, there is relatively little chronotropic effect.

Continuous dobutamine infusions are typically initiated at 2-3 g/kg/min without a loading dose and uptitrated until the desired hemodynamic response is achieved. Pharmacologic tolerance may limit infusion efficacy beyond 4 days, and, therefore, addition or substitution with a class III PDE inhibitor may be necessary to maintain adequate circulatory support. The major side effects of dobutamine are tachycardia and supraventricular or ventricular arrhythmias, which may require a reduction in dosage. Recent receptor antagonist use is a common cause of blunted clinical responsiveness to dobutamine.

Phosphodiesterase Inhibitors

The cyclic AMP–PDE inhibitors decrease cellular cyclic AMP degradation, resulting in elevated levels of cyclic AMP in cardiac and smooth muscle myocytes. The physiologic effects of this are positive myocardial inotropism and dilation of resistance and capacitance vessels. Collectively, therefore, PDE inhibition improves cardiac output through ionotropy and by decreasing preload and afterload (thus giving rise to the term inodilator). The clinical application of early-generation PDE inhibitors (e.g., theophylline, caffeine) is limited by low cardiovascular specificity and an unfavorable side-effect profile, whereas inamrinone, milrinone, and other more recently developed PDE inhibitors are preferred