Pharmacology of Cardiac Glycosides and Inotropes

Introduction/Overview

The pharmacological modulation of cardiac contractility represents a cornerstone in the management of heart failure and certain arrhythmias. Agents that increase the force of myocardial contraction, known as positive inotropes, have been utilized for centuries, with cardiac glycosides holding a particularly storied position in medical history. Despite the evolution of heart failure management towards neurohormonal blockade, these agents retain specific, albeit more narrowly defined, clinical roles. This chapter provides a systematic examination of the pharmacology of cardiac glycosides and other clinically relevant inotropic drugs, detailing their mechanisms, therapeutic applications, and significant limitations.

The clinical relevance of these drugs persists, primarily in the treatment of symptomatic heart failure with reduced ejection fraction, particularly when accompanied by atrial fibrillation, and in specific acute care settings. Their importance is underscored by their potent effects and narrow therapeutic index, necessitating a precise understanding of their pharmacology to ensure safe and effective use. The historical context of digitalis, derived from the foxglove plant (Digitalis purpurea), highlights the transition from herbal remedy to a molecule with a well-characterized, albeit complex, mechanism of action.

Learning Objectives

• Describe the molecular and cellular mechanism of action of cardiac glycosides, focusing on inhibition of the Na⁺/K⁺-ATPase pump and its downstream effects on intracellular calcium.
• Compare and contrast the pharmacokinetic profiles of digoxin and digitoxin, including absorption, distribution, metabolism, and elimination pathways.
• Identify the primary therapeutic indications for cardiac glycosides and other positive inotropic agents, distinguishing between chronic and acute clinical scenarios.
• Analyze the major adverse effects, toxicity manifestations, and life-threatening drug interactions associated with cardiac glycoside therapy.
• Apply knowledge of pharmacodynamic and pharmacokinetic principles to develop monitoring strategies and dosing adjustments for special populations, including those with renal impairment or electrolyte disturbances.

Classification

Positive inotropic agents can be classified based on their primary mechanism of action. This classification is clinically useful as it predicts not only the hemodynamic effects but also the potential adverse effect profiles and appropriate clinical contexts for use.

Cardiac Glycosides (Digitalis Compounds)

This class includes drugs derived from plant sources, characterized by a steroid nucleus (aglycone or genin) attached to one or more sugar molecules. The chemical structure is essential for activity.

• Digoxin: The most commonly used cardiac glycoside in contemporary practice. It is derived from Digitalis lanata.
• Digitoxin: Now rarely used, it is derived from Digitalis purpurea and differs from digoxin primarily in its pharmacokinetic properties, notably hepatic metabolism and a longer half-life.
• Ouabain: A rapid-acting glycoside used primarily in research; it is also an endogenous substance found in human plasma.

Beta-Adrenergic Receptor Agonists

These agents act as catecholamines or catecholamine analogs to stimulate cardiac β₁-adrenergic receptors.

• Dobutamine: A synthetic catecholamine with relative selectivity for β₁-receptors, producing a potent inotropic effect with less chronotropic and peripheral vascular activity compared to other agents.
• Dopamine: An endogenous catecholamine precursor whose effects are dose-dependent, involving dopamine receptor agonism at low doses and increasing β and α-adrenergic effects at higher doses.
• Epinephrine/Norepinephrine: Primarily used as vasopressors in shock, but possess significant inotropic properties mediated through β₁-adrenergic stimulation.

Phosphodiesterase (PDE) III Inhibitors

These agents inhibit the breakdown of cyclic adenosine monophosphate (cAMP), leading to increased intracellular calcium availability.

• Milrinone: A bipyridine derivative used for short-term management of acute decompensated heart failure.
• Inamrinone (formerly amrinone): Less commonly used due to potential thrombocytopenia and other adverse effects.

Calcium Sensitizers

This newer class enhances myocardial contractility by increasing the sensitivity of the cardiac myofilaments to calcium, rather than increasing intracellular calcium concentration.

• Levosimendan: Binds to cardiac troponin C, stabilizing its calcium-bound conformation. It also has vasodilatory properties via opening of ATP-sensitive potassium channels. Its use varies by region.

Mechanism of Action

The primary mechanism by which these drugs increase cardiac contractility differs significantly between classes, leading to distinct pharmacodynamic profiles.

Cardiac Glycosides: Molecular and Cellular Basis

The fundamental action of digitalis compounds is specific, reversible inhibition of the membrane-bound sodium-potassium adenosine triphosphatase pump (Na⁺/K⁺-ATPase). This enzyme is responsible for maintaining the trans-sarcolemmal ionic gradient by extruding three sodium ions from the cell in exchange for importing two potassium ions, utilizing energy from ATP hydrolysis.

Inhibition of this pump has two principal direct consequences. First, intracellular sodium concentration rises. This elevated intracellular sodium reduces the efficiency of the sodium-calcium exchanger (NCX), a secondary active transport system that normally extrudes one calcium ion from the cell in exchange for the entry of three sodium ions. With a diminished trans-sarcolemmal sodium gradient, calcium extrusion is impaired, leading to a net increase in intracellular calcium concentration. The increased intracellular calcium is sequestered into the sarcoplasmic reticulum (SR) via the SR calcium ATPase (SERCA). During subsequent action potentials, this larger SR calcium store is released via ryanodine receptors, resulting in a greater amount of calcium available to bind to troponin C and enhance the force of myocardial contraction (positive inotropy).

Beyond inotropy, cardiac glycosides exert significant electrophysiological effects. In the atria and atrioventricular (AV) node, they enhance parasympathetic (vagal) tone and decrease sympathetic outflow. This is mediated through direct sensitization of baroreceptors and central vagal stimulation. The increased vagal activity decreases conduction velocity and increases the refractory period of the AV node, making it a primary site of action for controlling ventricular rate in atrial fibrillation. At higher concentrations, digitalis can increase automaticity (particularly in Purkinje fibers) and slow conduction, which can precipitate serious ventricular arrhythmias. This pro-arrhythmic potential is linked to excessive intracellular calcium, which can lead to delayed afterdepolarizations and triggered activity.

Beta-Adrenergic Agonists

These agents act as sympathomimetics. Dobutamine, for instance, is a relatively selective β₁-adrenergic receptor agonist. Binding to the β₁-receptor activates the stimulatory G-protein (G_s), which in turn activates adenylate cyclase. This enzyme catalyzes the conversion of ATP to cyclic AMP (cAMP). Elevated cAMP levels activate protein kinase A (PKA), which phosphorylates several key proteins: L-type calcium channels, phospholamban, and troponin I. Phosphorylation of L-type channels increases calcium influx during the action potential plateau. Phosphorylation of phospholamban relieves its inhibition on SERCA, enhancing calcium re-uptake into the SR, which allows for more calcium to be available for release in subsequent cycles. Phosphorylation of troponin I reduces the affinity of troponin C for calcium, facilitating diastolic relaxation (positive lusitropy). The net effect is a rapid and potent increase in contractile force and heart rate (positive chronotropy).

Phosphodiesterase III Inhibitors

Milrinone produces inotropic and vasodilatory effects via a mechanism that is synergistic with, but independent of, β-adrenergic stimulation. It selectively inhibits the type III isoform of phosphodiesterase (PDE-III), an enzyme predominantly found in cardiac and vascular smooth muscle that degrades cAMP. By inhibiting cAMP breakdown, milrinone increases intracellular cAMP levels, activating PKA and producing effects similar to β-agonists: increased contractility and enhanced relaxation. Importantly, in vascular smooth muscle, increased cAMP leads to PKA-mediated phosphorylation and inhibition of myosin light-chain kinase, resulting in vasodilation. This combination of inotropy and vasodilation is termed “inodilator” therapy.

Calcium Sensitizers

Levosimendan enhances cardiac contractility through a calcium-dependent binding to cardiac troponin C. This binding stabilizes the calcium-induced conformational change of troponin C, thereby increasing the force generated by the actin-myosin cross-bridge at any given intracellular calcium concentration. This mechanism is fundamentally different from other inotropes as it does not increase intracellular calcium transients or myocardial oxygen demand proportionally to the increase in contractility. Its additional vasodilatory effect is mediated by opening ATP-sensitive potassium channels in vascular smooth muscle, leading to hyperpolarization and vasodilation.

Pharmacokinetics

The pharmacokinetic properties of these agents vary widely, influencing their route of administration, dosing frequency, onset and duration of action, and need for therapeutic drug monitoring.

Cardiac Glycosides

Digoxin is typically administered orally as tablets or an elixir, with bioavailability ranging from 60% to 80% for standard tablets and nearly 100% for the elixir and capsule formulations. Absorption can be slowed by high-fiber meals but the total amount absorbed is generally not affected. Following absorption, digoxin distributes widely throughout body tissues, with a large volume of distribution (approximately 5-8 L/kg). It does not distribute extensively into body fat. Steady-state concentrations are typically achieved after 4 to 5 half-lives (approximately one week with normal renal function). Digoxin is primarily eliminated unchanged by the kidneys via glomerular filtration and active tubular secretion. Its elimination half-life (t_1/2) is normally 36 to 48 hours in adults with normal renal function, but this can extend to 3.5 to 5 days in anuric patients. Clearance is proportional to creatinine clearance, necessitating dose reduction in renal impairment. Only a small fraction (approximately 10-20%) is metabolized hepatically, and it is not significantly removed by dialysis.

Digitoxin, in contrast, is nearly completely absorbed orally and undergoes extensive hepatic metabolism via the cytochrome P450 system (primarily CYP3A4) to inactive metabolites. It is also subject to enterohepatic recirculation. Its elimination is primarily hepatic, with a half-life of approximately 5 to 7 days, making it less dependent on renal function but susceptible to interactions with hepatic enzyme inducers and inhibitors.

Beta-Adrenergic Agonists

Dobutamine and dopamine are not effective orally due to extensive first-pass metabolism. They are administered exclusively by continuous intravenous infusion. Dobutamine has a very short onset of action (1-2 minutes) and a plasma half-life of approximately 2 minutes, requiring continuous infusion. It is rapidly metabolized by catechol-O-methyltransferase (COMT) in the liver and other tissues to inactive metabolites. Dopamine is also rapidly metabolized by both MAO and COMT, with a half-life of about 1-2 minutes. The effects of both drugs cease shortly after infusion discontinuation.

Phosphodiesterase Inhibitors

Milrinone is administered intravenously, with a bioavailability of approximately 85% if given orally, but oral formulations are not used clinically due to adverse effects. It has a distribution half-life of about 5-15 minutes and an elimination half-life of 1.5 to 2.5 hours in patients with normal renal function. Approximately 80-90% of a dose is excreted unchanged in the urine, mandating significant dose reduction in renal impairment. Its hemodynamic effects are apparent within 5-15 minutes of starting an infusion.

Calcium Sensitizers

Levosimendan is administered as an intravenous loading dose followed by a continuous infusion. It has a relatively short half-life for the parent drug (about 1 hour), but it forms an active metabolite, OR-1896, via acetylation in the gut. This metabolite has a very long half-life (up to 80 hours) and is responsible for sustained hemodynamic effects for up to a week after a 24-hour infusion.

Therapeutic Uses/Clinical Applications

The clinical application of positive inotropes is guided by the acuity of the condition, the underlying pathophysiology, and the risk-benefit profile of the specific agent.

Cardiac Glycosides

The principal approved indications for digoxin are twofold. First, it is used for the treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF) to reduce hospitalizations, typically as an adjunct to guideline-directed medical therapy including ACE inhibitors/ARBs/ARNIs, beta-blockers, and MRAs. Its benefit is most pronounced in patients with severe symptoms. Second, it is a cornerstone for rate control in patients with atrial fibrillation and flutter, particularly in those with concomitant heart failure, where other rate-controlling agents like beta-blockers or non-dihydropyridine calcium channel blockers may be poorly tolerated. Its role in converting atrial fibrillation to sinus rhythm or maintaining sinus rhythm is minimal.

Beta-Adrenergic Agonists and PDE Inhibitors

These agents are reserved for acute, inpatient settings due to their intravenous administration and potential to increase mortality with long-term use. Dobutamine infusion is used for short-term support in acute decompensated heart failure, particularly in patients with systolic dysfunction and low cardiac output, often as a “bridge” to definitive therapy or decision. It is also used in pharmacologic stress testing. Dopamine at low “renal” doses was historically used for presumed renal protection, but this practice is no longer supported by evidence. Higher doses are used for inotropic and vasopressor support in shock. Milrinone is used in the management of acute decompensated heart failure, especially in patients with high systemic vascular resistance or those who are on chronic beta-blocker therapy, as its mechanism is “downstream” of the beta-receptor. It is also used for inotropic support after cardiac surgery.

Calcium Sensitizers

Levosimendan is used in some countries for the short-term treatment of acutely decompensated chronic heart failure, especially when conventional therapy is insufficient, and in low cardiac output syndrome following cardiac surgery. Its use is predicated on its unique mechanism which may not increase myocardial oxygen demand or arrhythmogenicity to the same degree as other inotropes.

Adverse Effects

The adverse effect profiles are class-specific and often related to the extension of their pharmacological actions.

Cardiac Glycosides Toxicity

Digitalis toxicity is a serious condition due to its narrow therapeutic index. Toxicity can be precipitated by factors that increase drug concentration (e.g., renal impairment, drug interactions) or increase myocardial sensitivity (e.g., hypokalemia, hypomagnesemia, hypercalcemia, hypoxia, acidosis).

• Cardiac Effects: These are the most dangerous. They include a wide variety of arrhythmias. Bradyarrhythmias such as sinus bradycardia, sinoatrial block, and high-grade AV block can occur due to enhanced vagal effects. Tachyarrhythmias, including atrial tachycardia with block, accelerated junctional rhythms, bidirectional ventricular tachycardia, and ventricular fibrillation, result from increased automaticity and triggered activity. The classic description of “regularization of atrial fibrillation” (i.e., the ventricular rhythm becoming regular despite underlying AF) is a sign of advanced toxicity.
• Gastrointestinal Effects: Anorexia, nausea, vomiting, and abdominal pain are often early, non-cardiac signs of toxicity.
• Central Nervous System Effects: Fatigue, malaise, headache, dizziness, confusion, and visual disturbances (e.g., xanthopsia – yellow-green halos around lights) may occur.
• Endocrine Effects: Digoxin can weakly bind to estrogen receptors and has been associated with gynecomastia in men with chronic use.

Beta-Adrenergic Agonists and PDE Inhibitors

Adverse effects are largely predictable from their pharmacodynamic profiles.

• Tachycardia and Arrhythmias: Increased myocardial oxygen demand can provoke ischemia, and increased automaticity can cause atrial and ventricular arrhythmias.
• Hypotension: Particularly with milrinone and higher doses of dobutamine, due to vasodilation.
• Other: Tremor, anxiety, and hypokalemia (due to intracellular shift of potassium stimulated by β₂ activity) can occur with catecholamines. Milrinone has been associated with thrombocytopenia.

A critical consideration for both dobutamine and milrinone is the consistent finding from clinical trials that long-term oral therapy with positive inotropes increases mortality in patients with chronic heart failure. This has confined their use to short-term, carefully monitored inpatient settings.

Drug Interactions

Drug interactions are particularly significant for cardiac glycosides due to their narrow therapeutic index.

Major Interactions with Digoxin

• Drugs that Reduce Renal Clearance: Concomitant use with drugs that inhibit renal tubular secretion, such as verapamil, diltiazem, amiodarone, quinidine, spironolactone, and cyclosporine, can significantly increase serum digoxin concentrations, sometimes doubling or tripling them. These interactions often necessitate a 25-50% reduction in digoxin dose and close monitoring.
• Diuretics: Loop and thiazide diuretics can cause hypokalemia and hypomagnesemia, which increase myocardial sensitivity to digoxin and predispose to toxicity even at normal serum levels.
• Other Inotropes/Antiarrhythmics: Concurrent use with other drugs that affect cardiac conduction (e.g., beta-blockers, calcium channel blockers) or automaticity (e.g., class IA/III antiarrhythmics) can have additive effects on heart rate and rhythm, increasing the risk of bradycardia or heart block.
• Antibiotics: Certain broad-spectrum antibiotics (e.g., tetracyclines, erythromycin) may alter gut flora and reduce the metabolism of digoxin in the approximately 10% of patients who have significant metabolism by intestinal bacteria, leading to increased absorption.

Contraindications

Absolute contraindications to cardiac glycosides include known hypersensitivity, ventricular fibrillation, and certain types of dynamic outflow obstruction (e.g., hypertrophic obstructive cardiomyopathy) where increased contractility can worsen the obstruction. They are relatively contraindicated in second- or third-degree AV block (unless a pacemaker is present), Wolff-Parkinson-White syndrome with atrial fibrillation (can accelerate conduction down the accessory pathway), and severe hypokalemia.

For other inotropes, contraindications include severe hypotension (for vasodilating inotropes like milrinone), tachyarrhythmias, and severe aortic or pulmonic stenosis.

Special Considerations

Pregnancy and Lactation

Digoxin is classified as Pregnancy Category C. It crosses the placenta, and fetal serum concentrations are similar to maternal levels. It has been used to treat fetal supraventricular tachycardias and heart failure in utero. During lactation, digoxin is excreted in breast milk, but the infant dose is estimated to be less than 4% of the maternal weight-adjusted dose, which is generally considered acceptable for breastfeeding. Other inotropes (dobutamine, milrinone) are used in pregnancy only if the potential benefit justifies the potential fetal risk, typically in critical care scenarios.

Pediatric and Geriatric Considerations

In pediatrics, digoxin remains a mainstay for treating heart failure and supraventricular arrhythmias. Dosing is weight-based, and neonates and infants may require higher weight-adjusted doses due to larger renal clearance and volume of distribution, but they are also more susceptible to toxicity. Close monitoring is essential.

Geriatric patients present unique challenges. Age-related decline in renal function, lean body mass, and concomitant polypharmacy increase the risk of digoxin toxicity. Serum digoxin concentrations above 1.2 ng/mL have been associated with increased mortality in older adults with heart failure. Therefore, lower maintenance doses (e.g., 0.125 mg daily or every other day) are typically initiated, with a target serum concentration of 0.5-0.9 ng/mL for heart failure.

Renal and Hepatic Impairment

Renal Impairment: This is the single most important factor requiring adjustment for digoxin and milrinone. For digoxin, the maintenance dose must be reduced proportionally to the reduction in creatinine clearance. The loading dose may also need reduction if the volume of distribution is decreased (e.g., in advanced renal disease). Serum level monitoring is mandatory. Milrinone infusion rates must be reduced in renal failure to avoid accumulation. Digitoxin and levosimendan (via its metabolite) may be preferable in severe renal impairment, but their own profiles must be considered.

Hepatic Impairment: Digitoxin and the metabolism of levosimendan to its active metabolite may be affected by severe liver disease. Digoxin dosing is not primarily altered for hepatic dysfunction alone, but conditions like right-sided heart failure causing hepatic congestion can alter drug disposition.

Electrolyte Disturbances

Hypokalemia, hypomagnesemia, and hypercalcemia potentiate the toxic effects of cardiac glycosides on automaticity and conduction. Maintaining normal serum potassium and magnesium levels is a critical component of therapy. Conversely, hyperkalemia can be seen in severe acute digoxin overdose due to profound Na⁺/K⁺-ATPase inhibition.

Summary/Key Points

• Cardiac glycosides, primarily digoxin, exert positive inotropy by inhibiting Na⁺/K⁺-ATPase, leading to increased intracellular sodium, decreased calcium extrusion via NCX, and enhanced SR calcium stores. They also increase vagal tone at the AV node.
• Digoxin pharmacokinetics are characterized by oral bioavailability, wide distribution, and predominantly renal elimination, with a half-life of 36-48 hours. Its clearance is directly proportional to creatinine clearance.
• The primary therapeutic roles for digoxin are as an adjunct to reduce hospitalizations in symptomatic chronic HFrEF and for rate control in atrial fibrillation, especially with concomitant heart failure.
• Digitalis toxicity is a life-threatening condition manifesting with a wide array of cardiac arrhythmias (both brady- and tachyarrhythmias), gastrointestinal upset, and neurological symptoms. It is potentiated by renal impairment, electrolyte disturbances (hypokalemia, hypomagnesemia), and numerous drug interactions.
• Intravenous inotropes like dobutamine (β₁-agonist) and milrinone (PDE-III inhibitor) are reserved for short-term support in acute decompensated heart failure or cardiogenic shock. Long-term oral therapy with positive inotropes increases mortality.
• Dosing of digoxin requires careful consideration of renal function, age, lean body mass, and concomitant medications. Therapeutic drug monitoring is used to guide therapy, with a target serum concentration generally between 0.5 and 0.9 ng/mL for heart failure.

Clinical Pearls

• In patients with atrial fibrillation, the development of a regularized ventricular rhythm may be a sign of digoxin toxicity, not therapeutic success.
• When initiating digoxin in a patient on amiodarone, verapamil, or diltiazem, empirically reduce the digoxin maintenance dose by 50% and monitor serum levels.
• Always assess renal function and serum potassium and magnesium levels before initiating digoxin and during episodes of suspected toxicity.
• The benefits of digoxin in heart failure are achieved at lower serum concentrations (0.5-0.8 ng/mL); higher levels provide no additional efficacy but increase toxicity risk.
• For acute inotropic support in a patient on chronic beta-blocker therapy, a PDE inhibitor like milrinone may be more effective than a beta-agonist, as its action is distal to the receptor blockade.

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