THE MERCK VETERINARY MANUAL
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Positive Inotropes

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Positive inotropes increase the strength of cardiac muscle contraction by increasing the quantity of intracellular calcium available for binding by muscle proteins or by increasing the sensitivity of contractile proteins to calcium. This, in turn, augments contractile protein interaction in the myocardial cell. Intracellular calcium can be increased by altering the Na+/Ca2+ exchange pump, by increasing production of cyclic adenosine monophosphate (cAMP) via stimulation of adenylate cyclase, or by decreasing degradation of cAMP via inhibition of phosphodiesterases.

Cardiac Glycosides

The probable mechanism of action for the inotropic effect of digitalis is inhibition of the membrane-bound Na+/K+-ATPase pump; when this occurs, Na+ increases in the cell, the exchange of Na+ for Ca2+ is augmented, and calcium influx is increased. The increased intracellular calcium in turn leads to increased release of Ca2+ from the sarcoplasmic reticulum and increased contractility of the cardiac muscle. Changes in the ratio of intracellular and extracellular electrolytes can result in increased automaticity and cardiac arrhythmias.

Digitalis also has a negative chronotropic effect due to decreased conduction velocity in the atrioventricular (AV) node. In addition, digitalis potentiates vagal (cholinergic) activity in the heart. Changes in conduction can ultimately result in AV nodal blockade. At toxic levels, digitalis also can directly slow sinus nodal activity due to increased sensitivity to acetylcholine. Because the atria are sensitive to acetylcholine, atrial conduction is also enhanced in the diseased heart, which can then lead to atrial arrhythmias. Digitalis may also improve vascular baroreceptor responsiveness, thereby minimizing sympathetic activation in heart failure states.

Digoxin and digitoxin are the 2 most widely used preparations. Digoxin is available for administration IV or PO. Administration IV results in pharmacologic effects in 5–30 min with a maximal effect in 2 hr. However, toxic drug concentrations are more difficult to avoid with this route. Digoxin should not be given IM because it causes pain and muscle necrosis. Administration PO results in pharmacologic effects in 1–2 hr.

Absorption of digoxin varies with the preparation. Absorption of the alcohol (elixir) form is best. Variation in bioavailability of tablets results from differences in dissolution between products. Absorption is slowed by food, but the absorption of digitoxin is more complete because it is more lipid soluble. Both drugs are distributed slowly and are concentrated in cardiac tissues. Only 25% of digoxin is bound to plasma proteins, while ∼90% of digitoxin is protein bound. Digoxin is primarily eliminated unchanged by the kidneys; its half-life (∼1.7 days in dogs) is strongly influenced by renal function. Digitoxin is metabolized by the liver (one of the metabolites is digoxin); its half-life in dogs is 8–12 hr.

The concurrent administration of quinidine increases plasma concentrations of digoxin, probably due to displacement from tissue-binding sites. Verapamil, spironolactone, and captopril also may increase plasma digoxin concentrations. Interactions between digitalis and diuretics (eg, furosemide) stem primarily from the effects on potassium (hypokalemia). Administration of β-adrenergic agonists increases the likelihood of arrhythmias. Amphotericin B and glucocorticoids deplete body K+ and thus potentiate digitalis intoxication.

Toxic effects with digitalis glycosides are frequent and can be lethal. Cats are more sensitive to digoxin than dogs. Probably the most frequent cause of toxicity is overdosing. The potential for toxicity is increased with hypokalemia. The likelihood and severity of toxicity are related to the severity of cardiac disease. Any type of cardiac arrhythmia can be induced by digitalis. Other signs of toxicity include diarrhea, anorexia, and nausea and vomiting due to direct stimulation of the chemoreceptor trigger zone. Frequently, these are the earliest indications of toxicity. Neurologic effects include malaise and drowsiness. Digitalis toxicity can be diagnosed (and avoided) by monitoring plasma drug concentrations. Treatment of intoxication includes discontinuing therapy with digitalis and potassium-depleting diuretics and administering phenytoin (blocks AV nodal effects of digitalis), lidocaine (for ventricular arrhythmias), and if indicated, potassium (preferably PO). Atropine may be useful to treat both sinus bradycardia and second- or third-degree heart block induced by cholinergic augmentation.

Digitalis is used for restoring adequate circulation in animals with congestive heart failure (CHF) due to poor systolic (ie, contractile) function or for slowing the ventricular rate during supra-ventricular tachyarrhythmias, such as atrial fibrillation or flutter. Both syndromes require longterm treatment. Digoxin is the cardiac glycoside more commonly used except in animals with renal disease, in which digitoxin is preferred. The maintenance dosage schedules are 0.0055–0.011 mg/kg, PO, bid for dogs, and 0.005–0.01 mg/kg, PO, every 24–48 hr for cats. Calculation of digoxin doses should be based on lean body weight, and dosages should be reduced in obese or cachectic animals and in the presence of ascites. The calculated dose should be multiplied by 0.75 for elixir and by 0.85 for tablet formulations of digoxin. Alternatively, dosing of digoxin on the basis of body surface area (0.22 mg/m2, bid) is best for large and giant breeds of dogs. see Weight to Body Surface Area ConversionTables, for weight to body surface area (in m2) conversion. Electrolyte disorders should be corrected before digitalis glycosides are administered.

Phosphodiesterase Inhibitors

Phosphodiesterase (PDE) inhibitors block the breakdown of cAMP and therefore increase intracellular cAMP concentrations. The result is an increase in myocardial contractility. Methylxanthine derivatives have been classified as PDE inhibitors, but this is controversial. Of the methylxanthines, theophylline is the most cardiopotent. In addition to their cardiac effects, these drugs have significant CNS, renal, and smooth muscle effects, including bronchial smooth muscle. Their use for cardiac disease is limited to conditions that would benefit from bronchodilation.

Pimobendan is a benzimidazole pyridazinone derivative approved for treatment of CHF due to dilated cardiomyopathy and atrioventricular valvular insufficiency in dogs. Pimobendan is a type III PDE inhibitor and has both positive inotropic and vasodilating properties. In addition, pimobendan increases myocardial contractility by increasing the sensitivity of contractile proteins to calcium. Calcium-sensitizing agents may increase contractility without increasing myocardial oxygen consumption. Pimobendan should only be used in patients with clinical evidence of heart failure, and it is contraindicated in cases of hypertrophic cardiomyopathy. The dose of pimobendan for treating CHF in dogs is 0.5 mg/kg, PO, daily, divided bid.

In clinical trials in dogs with dilated cardiomyopathy or atrioventricular valvular insufficiency, common adverse events of treatment included poor appetite, lethargy, diarrhea, dyspnea, azotemia, weakness and ataxia, pleural effusion, syncopy, cough, sudden death, ascites, and heart murmur.

In dogs, pimobendan is oxidatively demethylated to an active metabolite. Both parent drug and active metabolite are >90% bound to plasma protein in the dog. The steady state volume of distribution of pimobendan is 2.6 L/kg, and the terminal elimination half-lives of pimobendan and active metabolite are 0.5 and 2 hr, respectively.

Limited clinical data suggest that pimobendan is safe when administered concomitantly with furosemide, digoxin, enalapril, atenolol, spironolactone, nitroglycerin, hydralazine, and diltiazem. Digoxin or β-adrenergic blockers may be administered concomitantly with pimobendan for treating supraventricular tachyarrhythmia in dogs with dilated cardiomyopathy or atrioventricular valvular insufficiency. Pimobendan is not approved for use in cats, and safety and efficacy data are generally lacking. However, a suggested dosage of pimobendan for idiopathic dilated cardiomyopathy in cats is 0.625 mg/kg, PO, sid-bid.

The mechanism of action of the bipyridine derivatives amrinone and milrinone is probably inhibition of PDE and increased levels of intracellular cAMP. These effects appear to occur without a dramatic rise in myocardial oxygen consumption. Peripheral vasodilation is another therapeutic benefit of these drugs. Arrhythmias may be exacerbated in some animals, and milrinone has been associated with decreased longterm survival in chronic heart failure in humans. Both amrinone and milrinone are available for IV administration and are suitable only for short-term management of CHF. Experience is limited with both drugs in dogs and cats, particularly with the IV administration of milrinone. Amrinone can be diluted for administration in normal or half-strength saline, but not dextrose; a loading dose of 1–3 mg/kg is followed by constant rate infusion of 30–100 μg/kg/min, starting at the low end of the range and titrating upward as needed.

B-Adrenergic Agonists

These drugs cause their positive inotropic effect by activating β-receptors with subsequent stimulation of adenylate cyclase and increased cAMP.

Dopamine is an endogenous catecholamine precursor with selective β1 activity. However, it also stimulates the release of norepinephrine. At low doses, it stimulates renal dopaminergic receptors, which causes increased renal blood flow and diuresis. Dopamine is not effectively absorbed if given PO. It is rapidly metabolized by the body and has a half-life of <2 min. Dopamine is available as a solution, which is further diluted with saline or dextrose. It is administered IV, usually by constant infusion (1–15 μg/kg/min). Cardiac arrhythmias may develop due to β-adrenergic activity. Indications include cardiogenic or endotoxic shock and oliguria.

Dobutamine is a synthetic drug similar to dopamine, but it does not cause release of norepinephrine and therefore has minimal effects other than β1 activity. Dobutamine is a more effective positive inotrope than dopamine with less chronotropic effects, although it does not dilate the renal vascular bed. Like dopamine, dobutamine is not effective if given PO and has a plasma half-life of ∼2 min. Dobutamine is also prepared as a solution to be diluted with 5% dextrose or normal saline. It is the preferred drug for short-term therapy of refractory CHF. Dobutamine causes an immediate increase in blood pressure due to increased cardiac output. It is given as a constant rate IV infusion at 2–20 μg/kg/min; heart rate, blood pressure, and cardiac output should be monitored. In cats, dobutamine has a longer half-life and causes CNS stimulation, so lower infusion rates (0.5–10 μg/kg/min) should be used.

Compared with other inotropic drugs, epinephrine causes the greatest increase in the rate of energy usage and myocardial oxygen demand. This increase in oxygen need may be detrimental to the failing heart. Epinephrine also causes vasoconstriction and bronchodilation. Epinephrine is rapidly metabolized in the GI tract and is not effective after administration PO. Absorption is more rapid after IM versus SC administration. Epinephrine is available in several preparations and is effective after IV, pulmonary, and nasal administration. However, because of the decreased efficiency of cardiac work, epinephrine is not used as a positive inotropic agent but rather for emergency therapy of cardiac arrest and anaphylactic shock. Ventricular arrhythmias can be expected.

Isoproterenol is a nonspecific β-agonist that, like epinephrine, increases myocardial oxygen demand. Tachycardia and the potential for other arrhythmias excludes its use in the cardiac patient except for short-term therapy of bradyarrhythmias or AV block.

Calcium is also a positive inotrope but must be given as a slow IV injection or infusion. Calcium must be administered carefully because it can cause cardiac rigor and standstill at high doses. The gluconate form is preferred to calcium chloride.

Last full review/revision March 2012 by Mark J. Novotny, DVM, MS, PhD, DACVCP

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