Cardiac Glycosides

Cardiac glycosides represent a group of naturally derived compounds isolated from several plants and animal species. It is generally used in the treatment of cardiac congestion and various types of cardiac arrhythmias. The compounds of the cardiac glycoside group have been well characterised in inhibiting Na+/K+- ATPase pump and are responsible for the Na+, K+ and Ca2+ ion level exchange that resulted in the ionotropic activity that is useful for the treatment of various heart conditions. The therapeutic effect of cardiac glycosides as anticancer agents was revealed in the eighth century; however, the mechanisms of action by cardiac glycosides remain largely unknown.
Cardiac glycosides (CG) are secondary metabolites that are naturally derived from plant species and also from the venom of a toad species (Steyn and Heerden 1998). A few examples of CG such as digitoxin, digoxin, oleandrin, neriifolin, cerberin, ouabain, thevetin and proscillaridin can be found in the plant families of Scrophulariaceae, Liliaceae, Apocynaceae and Asparagaceae (e.g. Digitalis purpurea, D. lanata, Nerium oleander, Strophanthus gratus and Urginea maritima); some of them can also be found in few amphibians and mammals, for instance, digoxin, ouabain, bufalin, marinobufagenin and telecinobufagin (Steyn and Heerden 1998; Lòpez-Lázaro 2007).

The understanding on the mechanisms of the pharmacological activities of CG has increased significantly ever since the discovery of its antiarrhythmic effects. Members of CG family have been well characterised in inhibiting Na⁺/K⁺-ATPase pump and are responsible for the Na⁺, K⁺ and Ca²⁺ ion level exchange. These resulted in the ionotropic activity that is useful in the treatment of various heart conditions which eventually increases the force of the myocardial contraction in congestive heart failure. The pump is involved in transporting potassium ions inside and sodium ions outside of cells in a 2:3 stoichiometry (Kaplan 2002). Such activity plays an important role in keeping the intracellular sodium levels low, thus initiating and sustaining adequate electrochemical gradient in the plasma membrane of all mammalian cells. This pump is important in regulating cell volume, cytoplasmic pH and Ca2+ levels through the Na+/H+ and Na+/Ca2+ exchangers, respectively, and in driving a variety of secondary transport process such as Na+-dependent glucose and amino acid transport (Scheiner-Bobis 2002). CG is also involved in the regulation of major cell signalling pathways that contribute to the prevention and/or treatment of cancers. CG was found to exhibit anticancer effects through apoptotic cell death mechanisms. However, the detailed information on the mechanisms of actions remains largely unknown. CG at low doses may activate the downstream proapoptotic pathways in few types of cancer cells. Several reported mechanisms showed that the proapoptotic effects might cause the preferential cytotoxicity in cancer cells, including the cancer-specific overexpression of Na+/K+-ATPase pump subunits, inhibition of glycolysis and inhibition of N-glycan expression. Details on these mechanisms of action by CG will be discussed in the following paragraphs.

The mechanism whereby cardiac glycosides cause a positive inotropic effect and electrophysiological changes is still not completely known despite years of active investigation. Several mechanisms have been proposed, but the most widely accepted mechanism involves the ability of cardiac glycosides to inhibit the membrane-bound Na+/K+–adenosine triphosphatase (Na+/K+-ATPase) pump responsible for sodium/potassium exchange. To understand better the correlation between the pump and the mechanism of action of cardiac glycosides on the heart muscle contraction, one has to consider the sequence of events associated with cardiac action potential that ultimately leads to muscular contraction. The process of membrane depolarization/repolarization is controlled mainly by the movement of the three ions, Na+, K+, Ca2+,in and out of the cell. At the resting state (no contraction), the concentration of sodium is high outside the cell. On membrane depolarization, Na+fluxes in, leading to an immediate elevation of the action potential. Elevated intracellular sodium triggers the influx of Ca2+, which occurs slowly and is represented by the plateau region of the cardiac action potential. The influx of calcium results in efflux of potassium out of the myocardium. The Na1/K+exchange occurs at a later stage of the action potential to restore the membrane potential to its normal level. The Na1/K+exchange requires energy and is catalyzed by the enzyme Na+/K+-ATPase. Cardiac glycosides are proposed to inhibit this enzyme, with a net result of reduced sodium exchange with potassium (i.e., increased intracellular sodium), which in turn results in increased intracellular calcium. Elevated intracellular calcium concentration triggers a series of intracellular biochemical events that ultimately result in an increase in the force of the myocardial contraction, or a positive inotropic effect. This mechanism of the cardiac glycosides via inhibiting the Na+/K+-ATPase pump is in agreement with the fact that the action of the cardiac glycosides is enhanced by low extracellular potassium and inhibited by high extracellular potassium. The cardiac glycosides–induced changes in the electrophysiology of the heart also can be explained based on the inhibition of Na+/K+-ATPase. It has been suggested that the intracellular loss of potassium because of inhibition of the pump causes a decrease in the cellular transmembrane potential approaching zero. This decrease in the membrane potential is sufficient to explain the increased excitability and other electrophysiological effects observed following cardiac glycosides administration.

Cardiac glycosides affect the heart in a dual fashion, both directly (on the cardiac muscle and the specialized conduction system of sinoatrial [SA] node, atrioventricular [AV] node, and His-Purkinje system) and indirectly (on the cardiovascular system mediated by the autonomic nervous reflexes). The combined direct and indirect effects of the cardiac glycosides lead to changes in the electrophysiological properties of the heart, including alteration of the contractility; heart rate; excitability; conductivity; refractory period; and automaticity of the atrium, ventricle, Purkinje fibers, AV node, and SA node. The heart response to the cardiac glycosides is a dose-dependent process and varies considerably between the normal hear and the heart with CHF. The effects observed after the administration of low doses (therapeutic doses) differ considerably from those observed at high doses (cardiotoxic doses). The effects of cardiac glycosides on the The increased force and rate of myocardial contraction (positive inotropic effect) and the prolongation of the refractory period of the AV node are the effects most relevant to the CHF problem. Both of these effects result from the direct action of the cardiac glycosides on the heart. The indirect effects are manifested as increased vagal nerve activity, which probably results from the glycoside-induced sensitization of the baroreceptors of the carotid sinus to changes in the arterial pressure; in other words, any given increase in the arterial blood pressure results in an increase in the vagal activity (parasympathetic) coupled with a greater decrease in the sympathetic activity. The vagal effect with uncompensated sympathetic response results in decreased heart rate and decreased peripheral vascular resistance (afterload). Therefore, cardiac glycosides reverse most of the symptoms associated with CHF as a result of increased sympathetic system activity, including increased heart rate, vascular resistance, and afterload. The administration of cardiac glycosides to a patient with CHF increases cardiac muscle contraction, reduces heart rate, and decreases both edema and the heart size.

Although the primary clinical use for digoxin is in the treatment of CHF, this agent also is used in cases of atrial flutter or fibrillation and paroxysmal atrial tachycardia.
The therapeutic effects of all cardiac glycosides on the heart are qualitatively similar; however, the glycosides largely differ in their pharmacokinetic properties. The latter are greatly influenced by the lipophilic character of each glycoside. In general, cardiac glycosides with more lipophilic character are absorbed faster and exhibit longer duration of action as a result of a slower urinary excretion rate. The lipophilicity of a cardiac glycoside is measured by its partitioning between chloroform and water mixed with methanol: The higher the concentration of the cardiac glycoside in the chloroform phase, the higher its partition coefficient, and the more lipophilic it is. It is evident from a comparison of the coefficients that their lipophilicity is markedly influenced by the number of sugar molecules and the number of hydroxyl groups on the aglycone part of a given glycoside. Lanatoside C, with a partition coefficient of 16.2, is far less lipophilic than that of acetyldigoxin (partition coefficient, 98), which structurally differs only in lacking the terminal glucose molecule. Likewise, a comparison of digitoxin and digoxin structures reveals that they only differ by an extra hydroxyl in digoxin at C-12. This seemingly minor difference in their partition coefficients from 96.5 to 81.5 for digitoxin and digoxin, respectively, results in significant differences in their pharmacokinetic behavior.The glycoside G-strophanthin (ouabain) possesses a very low lipophilic character because of the presence of five free hydroxyl groups on the steroid nucleus of the aglycone ouabagenin.

The most common and severe side effect of PDE3 inhibitors is ventricular arrhythmias, some of which may be life-threatening. Other side effects included headaches and hypotension, which are not uncommon for drugs that increase cAMP in cardiac and vascular tissues, with other examples being β-agonists.

The mechanism of cardiac contraction involves a G-protein signal transduction pathway, which regulates intracellular calcium concentrations. Activation of the Gs -protein involves the formation of intracellular cAMP, which thereby increases intracellular calcium, stimulating cardiac muscle contraction. Relaxation occurs when the released cAMP is hydrolyzed by cytosolic cAMP-dependent PDE3, one of the phosphodiesterase isofoms. Therefore, inhibition of PDE3 increases intracellular cAMP, promoting cardiac muscle contraction but vasodilation of vascular smooth muscle.
The overall cardiostimulatory and vasodilatory actions of PDE3 inhibitors make them suitable for the treatment of heart failure, because vascular smooth muscle relaxation reduces ventricular wall stress and the oxygen demands placed on the failing heart. The cardiostimulatory effects of the PDE3 inhibitors increases inotropy, which further enhances stroke volume and ejection fraction. Clinical trials have shown that long-term therapy with PDE3 inhibitors increases mortality in heart failure patients. Therefore, these PDE3 inhibitors are not used for the long-term, chronic therapy of CHF. They are very useful, however, in treating acute, decompensated heart failure or temporary bouts of decompensated chronic failure. They are not used as a monotherapy. Instead, they are used in conjunction with other treatment modalities, such as diuretics, angiotensin-converting enzyme inhibitors, β-blockers, or cardiac glycosides. The PDE3 inhibitors contract cardiac muscle and are used for treating heart failure, whereas the phosphodiesterase 5 (PDE5) inhibitors are vasodilators and are used for treating male erectile dysfunction. Note that the generic names for PDE3 inhibitors end in “ one,” and those for the PDE5 inhibitors end in “fil.”

Digoxin–drug interactions are common causes of digitalis toxicity. Recently, the clinical significance of the P-gp–dependent renal tubular secretion of digoxin associated with the well-documented digoxin–quinidine interaction has been reported. The discovery that digoxin is actively secreted into the urine by the renal tubular cell via the P-gp efflux pump has led to the conclusion that the digoxin–quinidine interaction can be attributed to inhibition of renal tubular secretion of digoxin by quinidine (a P-gp substrate). Quinidine competitively binds to P-gp in the renal tubule reducing the renal secretion of digoxin by as much as 60%, raising digoxin's plasma concentration to toxic levels. Other drugs that are substrates for renal P-gp also are likely to be associated with digoxin–drug interactions. Another documented digoxin–drug interaction associated with increased digoxin blood levels and toxicity is with verapamil. Unlike quinidine, verapamil inhibits intestinal P-gp efflux of digoxin, thereby blocking the intestinal secretion of digoxin into the lumen of the intestine and raising digoxin blood levels to toxic levels. On the other hand, the rifampin–digoxin interaction involves the rifampin induction of intestinal P-gp expression, thereby increasing the P-gp–mediated secretion of digoxin. This results in the lowering of digoxin blood levels to subtherapeutic concentrations. The P-gp transporters and their substrates, inhibitors, or inducers appear to play an important role in controlling the digoxin area under the curve (AUC) values through the renal tubular and intestinal secretion of digoxin and, subsequently, to digoxin–drug interactions and digitalis toxicity. Concurrent use of the cardiac glycosides with antiarrhythmics, sympathomimetics, β-adrenergic blockers, and calcium channel blockers that are substrates for P-gp may alter control of arrhythmias.
The absorption of digoxin after oral administration also can be significantly altered by other drugs concurrently present in the gastrointestinal tract. For example, laxatives may interfere with the absorption of digoxin because of increased intestinal motility. The presence of the drug cholestyramine, an agent used to treat hyperlipoproteinemia, decreases the absorption of digoxin by binding to and retaining digoxin in the gastrointestinal tract. Antacids, especially magnesium trisilicate, and antidiarrheal adsorbent suspensions also may inhibit the absorption of the digoxin. Potassium-depleting diuretics, such as thiazides, may increase the possibility of digitalis toxicity because of the additive hypokalemia. Several other drugs that are known to bind to plasma proteins, such as thyroid hormones, have the potential to displace digoxin from its plasma-binding sites, thereby increasing its free drug concentration to a toxic level.