Positive Inotropes

By | 2011-12-12

Agents capable of increasing cardiac contractility can improve a patient’s strength and exercise capacity, thereby potentially enhancing the pet’s quality of life. Ideally, these compounds would concurrently promote mortality benefits by improving cardiac efficiency and limiting the activation of endogenous compensatory mechanisms (with their detrimental long-term consequences). Unfortunately, to date most of the potent agents available to augment systolic function act by means of “upstream,” cAMP-dependent mechanisms that have shown negative effects on survival.

Membrane-associated adenylate cyclase is the enzyme responsible for cyclic adenosine monophosphate production, and phosphodiesterase III is responsible for its degradation. Therefore mechanisms to increase cyclic adenosine monophosphate concentrations may take one of two pathways: beta agonists increase production of cAMP, and phosphodiesterase inhibitors increase cytosolic cyclic adenosine monophosphate by inhibiting its breakdown. Acting through protein kinase A, cyclic adenosine monophosphate promotes phosphorylation of the L-type calcium channel to increase calcium release from the sarcoplasmic reticulum (SR). The increased systolic Ca2+ concentration (1) deinhibits the troponin complex to promote actin and myosin interaction and (2) increases the activity of myosin ATPase. These mechanisms serve to increase both the total force developed and the rate at which the force is developed. Protein kinase A also exerts beneficial lusitropic effects by promoting phosphorylation of (1) the regulatory SR membrane phosphoprotein, phospholamban, to enhance diastolic calcium uptake and (2) troponin I, to increase the rate of cross-bridge detachment and relaxation. Paradoxically, despite these beneficial properties, long-term administration of agents capable of increasing cyclic adenosine monophosphate has been linked to increased mortality rates in patients with heart failure. The increased Ca2+ concentrations are believed to contribute to the development of arrhythmias and to increase myocardial energy consumption and oxygen demand, thereby worsening the outcome. These findings lend support to the premise that downregulation and uncoupling of beta receptors, along with upregulation of adenylate cyclase inhibitory proteins, serve as compensatory protective mechanisms rather than primary biochemical abnormalities. Current investigations are evaluating agents capable of enhancing systolic performance “downstream” from cytosolic Ca2+ in the hopes of avoiding excessive mortality.

Digitalis glycosides The digitalis glycosides are the only readily available class of inotropic agents that act independendy of the cyclic adenosine monophosphate second-messenger system. This characteristic imparts a degree of safety to the glycosides, with regard to their neutral effect on mortality, but simultaneously limits their inotropic potency. Because of digoxin’s potential positive inotropic effects and rate-controlling properties for atrial fibrillation, there is litde debate that it is indicated in the treatment of dilated cardiomyopathy; however, there is substantial debate over its role in the management of mitral valve insufficiency. The authors’ rationale for the use of digoxin (0.003 mg/kg given orally twice daily) in dogs with mitral valve insufficiency is primarily its neurohormonal antagonism effect rather than pump support. Inhibition of the Na+/K+ ATPase pump in the vagal afferents sensitizes the baroreceptors to the prevailing blood pressure, which may decrease sympathetic outflow and renin-angiotensin activity. Although the findings are purely anecdotal, the authors have had and continue to have cases in which the addition of digoxin to background therapy of furosemide and enalapril has produced clear symptomatic improvement.

The cardiac glycosides inhibit the action of the Na+/K+ ATPase pump by competitively binding to the extracellular potassium site. This antagonism promotes an increase in the intracellular sodium concentration, with its subsequent exchange for calcium via the reversible Na+/Ca2+ pump. The net result is an increase in cytosolic calcium levels and enhanced cardiac contractility. Inhibition of the Na+/K+ ATPase pump further sensitizes the baroreceptors (blunting sympathetic discharge), inhibits renal tubular resorption of sodium (promoting mild diuresis), and increases the delivery of sodium to the distal tubules (inhibiting renin release).

Despite these theoretical benefits, digitalis has been unable to alter the natural course of heart failure. The Digitalis Investigation Group (DIG) enrolled 6800 human patients in a placebo-controlled study to evaluate whether digoxin administration affected mortality or morbidity. Digoxin did not reduce overall mortality but did reduce the rate of hospitalization for worsening heart failure (26.8% versus 34.7%, P < 0.001). Subgroup analysis revealed that patients in class III or class IV heart failure showed the greatest benefit from digoxin administration. Compared with results from agents not related to glycosides, including dobutamine and milrinone, the findings of this investigation did not demonstrate excess mortality. It is unlikely that a similar study evaluating the efficacy of digoxin will ever be performed in dogs because of the extreme sample size needed to detect these small differences. One study reported that four of 10 dogs with dilated cardiomyopathy showed echocardiographically identifiable improvements in cardiac contractility after treatment with digoxin. Whether the 7% increase in fractional shortening was a true increase in contractility or merely occurred subsequent to rate control (250 beats per minute (bpm] pretreatment versus 145 bpm post-treatment) is uncertain, but digoxin appears to be a relatively weak inotropic agent in dogs with heart failure. Nonetheless, it is the only oral inotropic agent that is readily available in the United States.

Therapeutic levels of digitalis increase parasympathetic tone, while blunting sympathetic activation, to promote slowing of the sinus node and increased atrioventricular (AV) node refractoriness with decreased conduction velocity. This property makes them useful in the management of dilated cardiomyopathy complicated by atrial fibrillation, because the other negative chronotropes (e.g., beta blockers, Ca2+ channel Mockers) acutely depress systolic function. Digitalis is further indicated for the management of symptomatic dilated cardiomyopathy with sinus rhythm or left to right shunting lesions complicated by myocardial failure. Although digoxin is not always considered a mainstay of therapy for the management of mitral insufficiency, the authors continue to use it in cases of heart failure subsequent to chronic degenerative valve disease (CDVD). Although some of these mitral insufficiency patients fail to attain symptomatic benefit from digoxin therapy, the drug’s low cost and safety when used appropriately continue to make it a useful agent. Digoxin is an inappropriate agent to use for rate control in cases of hyper-trophic cardiomyopathy in which the primary abnormality is diastolic rather than systolic dysfunction. Any positive inotropic response predisposes HCM patients to the development or worsening of systolic anterior motion of the mitral valve.

Digoxin Digoxin is the digitalis glycoside most commonly used in dogs, and it appears to be the most suitable glycoside for cats with systolic dysfunction. The bioavailability of digoxin after oral administration of the tablet form is approximately 60%. The digoxin elixir shows better bioavailability after oral administration (about 75%) and is easier to dose appropriately for small dogs. After absorption, digoxin has a relatively long and variable serum half-life in dogs, with reports ranging from 23 to 39 hours. In cats the duration is even more uncertain, with reports of mean half-lives ranging from 33.5 hours to 57.8 hours, with even longer half-lives during prolonged administration. Because approximately five half-lives are required to attain steady-state concentrations of a drug, digoxin cannot be expected to produce rapid symptomatic or rate-controlling benefits. Digoxin predominately undergoes renal excretion, although a small amount (approximately 15%) is metabolized by the liver. Renal failure significantly reduces the clearance of digoxin and profoundly increases the serum concentration, often to the point of intoxication. Patients with renal failure that require a cardiac glycoside should be given digitoxin because it undergoes hepatic elimination.

Determining the appropriate dose of digoxin to attain therapeutic levels yet avoid digitalis intoxication can be a frustrating endeavor. Traditionally, small dogs (less than 20 kg) have been treated with 0.005 to 0.008 mg/kg given orally twice daily, and larger dogs have been treated based on body surface area, with 0.22 mg/m given orally twice daily. The intent with these doses was to attain a therapeutic digoxin level of 1 to 2 µg/mL. The DIG trial found that human mortality varied direcdy with serum digoxin levels, even within this “therapeutic” range. A new trend has emerged from that data whereby the human medical profession has aimed to keep trough levels of digoxin at 0.5 to 1 µg/ml. Whether these recommendations hold true for dogs is uncertain, but aiming for the low end of the reference range appears to be appropriate. The authors currently institute digoxin therapy at a dosage of 0.003 mg/kg given orally twice daily. If the digoxin level is subtherapeutic 5 to 7 days after initiation of therapy, the dosage is increased by 25%, and the serum level is rechecked a week later. This regimen is continued until therapeutic levels have been attained.

A number of factors may influence the distribution of digoxin, creating a need for special consideration and monitoring. The principal reservoir for digoxin is skeletal muscle, therefore dosing recommendations should be based on lean body mass. Obese dogs require lower doses of digoxin than thin dogs, and the dosing requirement for dogs that experience marked muscle loss tends to decline. Patients with right-sided heart failure and large volumes of ascites need dosage reductions because digoxin does not distribute into free abdominal fluid. After institution of digoxin therapy, it is most appropriate to alter the dosing scheme based on the serum digoxin level, the response to therapy, and evidence of intoxication.

A number of drug interactions also are possible with digoxin. The best recognized interaction is between digoxin and the class la antiarrhythmic quinidine. When these drugs are combined, serum digoxin levels increase because quinidine displaces digoxin from the Na+/K+ ATPase pump and reduces its renal clearance through inhibition of P-glycoprotein.The binding of digoxin with myocardial Na+/K+ ATPase is “tighter” than that with skeletal muscle, therefore the net effect of this drug combination is an increase in the likelihood of digitalis intoxication. It is recommended that these agents not be used together. Fortunately, no interactions have been reported between digoxin and the more frequently used class I anti-arrhythmics procainamide and mexiletine. Most of the other reported drug interactions, with amiodarone, verapamil, nifedipine, propafenone and, to a lesser extent diltiazem, occur because of inhibition of P-glycoprotein. Any agent that alters renal blood flow or hepatic microsomal enzymes has the potential to disturb digoxin’s pharmacokinetics.

Similar to quinidine, the extracellular potassium concentration can influence digoxin binding to the Na+/K+ ATPase pump. The hypokalemia often associated with anorexia or large doses of a diuretic leaves more receptors exposed for digoxin attachment, thereby increasing the likelihood of digitalis intoxication. With hyperkalemia, more receptors are bound, and digoxin is displaced from the Na+/K+ ATPase. Hypercalcemia and hypernatremia promote digoxin’s inotropic and toxic properties, whereas decreased calcium and sodium concentrations have the opposite effects.

Since it was recognized that taurine deficiency was responsible for most cases of feline DCM, the number of cats receiving digoxin has declined over the past decade. The authors still encounter an infrequent case of dilated cardiomyopathy unrelated to taurine deficiency, and some cases of restrictive cardiomyopathy have such poor systolic function that digoxin is indicated. Cats appear to tolerate the tablet form of digoxin better than the alcohol-based elixir. The recommended dose is one fourth of a 0.125 mg tablet given orally. Dosing intervals are as follows: (1) cats weighing 3 kg or less: every 48 hours; (2) cats weighing 4 to 5 kg: every 24 to 48 hours; (3) cats weighing 6 kg or greater: every 24 hours. Because of the variable half-life of digoxin in cats, the authors typically monitor serum levels 7 to 10 days after initiation of therapy.

Digitalis toxicity Without a doubt, digoxin is a toxic substance when excessive amounts accumulate. This narrow therapeutic index highlights the need for careful client and veterinary attention when digoxin is part of a treatment regimen. In the authors’ experience, when digoxin therapy is instituted at a dosage of 0.003 mg/kg given orally twice daily, with uptitration based on serum digoxin concentrations, the incidence of digitalis toxicity is low both clinically and biochemically.

Clients should be informed of the most common manifestations of digoxin intoxication and given concise instructions on what to do if clinical signs develop. Continuing drug administration and waiting until the next recheck is not an appropriate step; the authors recommend discontinuation of all drugs followed by an immediate veterinary evaluation. It should be emphasized that the three regions frequently affected by excessive digoxin accumulation are the myocardial, gastrointestinal, and central nervous systems. Gastrointestinal manifestations, which often precede central nervous system (CNS) and myocardial toxicity, commonly include anorexia and vomiting, presumably from a direct chemoreceptor triggering effect exerted by digoxin. The serum concentration at which gastrointestinal signs develop is extremely variable. Some dogs have digoxin-associated anorexia at subtherapeutic drug concentrations, whereas others do not show any evidence of toxicity even with serum concentrations well above the therapeutic range. It can be difficult to determine whether the anorexia is associated with digoxin administration, azotemia secondary to a decreased glomerular filtration rate or renal insufficiency, poor diet palatability, or worsening heart failure. A biochemical profile, serum digoxin determination, and thoracic radiographs should be obtained in any digoxin-treated dog with heart failure that suddenly develops anorexia. In the absence of complicating factors such as azotemia or pulmonary edema, the authors temporarily discontinue digoxin administration even if the serum level is within the therapeutic range. If the pet’s appetite returns (suggesting digoxin-associated anorexia), a lower digoxin dose may be instituted or the drug may be discontinued all together. Digoxin does not provide enough mortality benefit or positive inotropic response to warrant administration in the face of profound anorexia or other complications.

Although the myocardial complications may be more difficult for owners to recognize, they often are the most serious. Digoxin toxicity may induce almost every known cardiac arrhythmia, including both bradyarrhythmias and tachyarrhythmias. First- and second-degree AV block, sinus bradycardia, and sinus arrest are presumably influenced by digoxin’s parasympathomimetic properties. Life-threatening ventricular tachyarrhythmias may develop as a consequence of cellular calcium overload. Excessive calcium precipitates late afterdepolarizations, whereby oscillations within the diastolic membrane potential periodically reach threshold and produce a premature complex. The slowed conduction and altered refractory period may then precipitate re-entry, yielding ventricular tachycardia. Obviously, determining whether the ventricular arrhythmia is associated with digoxin administration or is a manifestation of the underlying disease process may be difficult, but in general, discontinuation of digitalis is indicated.

The central nervous system alterations mediated by digoxin toxicity may include depression, disorientation, or delirium. Again, determining whether such clinical signs are attributable to digitalis intoxication or progression of the underlying disease process often is difficult. These patients should be evaluated for hypotension, in addition to having their serum digoxin levels measured.

Treatment of digitalis toxicity The aggressiveness with which digoxin toxicity is treated depends on the manifestation of intoxication rather than the serum digoxin level. Gastrointestinal disturbances can frequendy be managed by discontinuation of the drug. Dogs with bradyarrhythmias are often asymptomatic, and withdrawal of digoxin is the only therapeutic alteration required. In the rare case of symptomatic patients, short-term administration of atropine may be required while the toxic digoxin concentrations expire. The most aggressively managed complication of digitalis intoxication is ventricular tachyarrhythmias.

The class Ib antiarrhythmic drug lidocaine is the first-choice agent for acute management of digitalis-induced ventricular tachycardia. It is effective at targeting late afterdepolarizations without substantially affecting the sinus rate or AV nodal conduction. An initial bolus of 2 to 4 mg/kg is administered intravenously over 1 to 2 minutes, followed by a constant-rate infusion to suppress the arrhythmias. Lidocaine should be administered conservatively to cats because they are more sensitive to the neurotoxic side effects. Although infrequently used, phenytoin also appears efficacious for the treatment of digoxin-induced arrhythmias.

Because hypokalemia may precipitate digoxin toxicity and limit the efficacy of antiarrhythmic agents, it is important to evaluate the serum potassium concentration and to correct underlying deficits. Because of its ability to bind competitively the Na+/K+ ATPase pump, potassium can displace digoxin from the myocardium, thereby decreasing the likelihood of toxicity.

The development of a specific antibody fragment for cardiac glycosides has enabled production of an “antidote” for severe digoxin intoxication. Digibind® (GlaxoSmith Kline, Durham NC) complexes with the digoxin molecule and inhibits binding to the Na+/K+ ATPase pump, quickly resolving drug intoxication. Unfortunately, this drug is expensive, and its use in clinical practice therefore is limited.