Class IA Drugs

Class 1 A drugs increase the threshold for excitability and decrease automaticity, reduce the rate of phase 0 depolarization and thus slow conduction, prolong both the effective refractory period and the action potential duration, and delay repolarization. A shared arrythmogenic effect of sodium channel blockers with atrial flutter reflects slowed conduction. Subsequent slowing of atrial flutter may allow more signals to be transmitted through the atrioventricular node, causing the heart rate to increase.

Quinidine

Quinidine, derived from the bark of the cinchona plant, is a diastereomer of the antimalarial drug quinine. Quindine affects most types of cardiac muscles.^5,112 Its efficacy against supraventricular and ventricular arrhythmias facilitates its classification as a broad-spectrum antiarrhythmic. Quinidine has both direct and indirect effects. For direct effects, quinidine blocks open Na⁺ channels, increasing the threshold for excitability and decreasing automaticity, thus suppressing ectopic pacemakers. Blockade of multiple K⁺ currents prolongs action potentials, particularly at slow heart rates. Electrophysiologically, quinidine increases the QRS complex; the QT interval may also be prolonged, causing torsades de pointes at therapeutic or subtherapeutic concentrations in some patients.⁵ Because it also prolongs the effective refractory period, especially in the atria, quinidine is particularly useful for treatment of reentrant arrhythmias such as atrial fibrillation.^{112,113,2,115} In the atria quinidine also has an indirect effect through antivagal (“atropine-like”) actions, contributing to undesirable side effects, and specifically, tachycardia.

Although given intravenously (which markedly increases the risk of cardiotoxicity) and intramuscularly, quinidine is most practically administered orally. Intramuscular injection is painful. Quninidine has been prepared as different salts to manipulate (prolong) oral absorption. Quinidine sulfate is absorbed rapidly after oral administration,^5,112 whereas the gluconate form is absorbed more slowly. Despite marked (90%) binding to α glycoproteins, quinidine distributes rapidly to most tissues, resulting in a large volume of distribution. In states of high stress, it may be necessary to increase doses of quinidine to overcome increased binding associated with increased inflammatory and other α glycoproteins, although this may be an issue more commonly encountered in humans with myocardial infarction. Quinidine binds to tissue, including cardiac proteins. Hepatic metabolism is mediated by CYP3A and is extensive, with excretion of parent compound or metabolites in the urine. Variability in metabolism is marked among patients and can be influenced by other drugs, necessitating individualized therapy. The duration of action of quinidine may be shortened or lengthened by drugs that target CYP3A4. The half-life is about 6 hours, but the dosing interval may be prolonged with slow-release preparations.

Quindine disposition has been studied in Beagle dogs (n=4). An intravenous dose of 1 mg/kg distributed to a volume of 1.17 ± 0.40 L/kg and was cleared at a rate of 5.90 ± 0.40 mL/min/kg, yielding an elimination half-life of 3.46 ± 1.44 h and mean residence time (MRT) of 3.34 ± 1.25 h. After oral administration of the sulfate salt (100 mg orally), C_max was 2162 ± 598 ng/mL and oral bioavailability was 73%.¹¹⁶

Quindine can cause or be affected by drug interactions, particularly by drugs that affect CYP 2D6 and 3A. It is a potent inhibitor of CYP 2D6, prolonging the elimination of selected drugs or preventing the formation of active drug (e.g., morphine from codeine).⁵ Its clearance is affected by other drugs that impair (e.g., cimetidine, verapamil) or induce (e.g., phenobarbital, phenytoin, rifampin) CYP 2D6. Clearance of quinidine was decreased in normal Beagles (n=4) by 50% after treatment with the CYP3A substrate inhibitor ketoconazole. The elimination half-life (hr) increased from 3.46 ± 1.44 to 6.78 ± 1.98; C_max increased from 2162 ± 598 to 3295 ± 636 ng/mL.¹¹⁶ Quindine clearance also is prolonged by drugs that alkalinize the urine (e.g., carbonic anhydrase inhibitors, thiazide diuretics). Quindine decreases digoxin clearance and may compete with it for P-glycoprotein–mediated efflux. Competition at cardiac binding sites also may displace digoxin, further increasing plasma digoxin concentrations, which may exacerbate digoxin-induced cardiac arrhythmias.¹¹⁷

Quinidine is associated with cardiotoxicity-induced arrhythmias such as atrioventricular blockade or ventricular arrhythmias. Sudden death caused by syncope has been reported. The atropine-like (antivagal) effects of quinidine probably account for some potentially serious side effects. Loss of vagal tone, important to the control of conduction in the atrioventricular node, may increase impulse conduction to the ventricles, resulting in paradoxical acceleration, an undesirable increase in heart rate in the patient with supraventricular tachycardias (including atrial fibrillation). This loss of vagal tone also impacts drugs whose cardiac effect is based on enhanced vagal tone. In humans, digitalization prior to therapy is indicated. Quinidine is also an α-adrenergic blocking agent and can cause vasodilation and potential hypotension. Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) may occur, particularly with the sulfate form.

As a broad-spectrum drug, quinidine may be effective for acute or chronic management of supraventricular and ventricular arrhythmias. However, its efficacy particularly targets atrial arrhythmias. Quinidine is contraindicated in the presence of complete A-V heart block. Daily doses range from 5 to 15 mg/kg; therapeutic concentrations are 2 to 6 μg/mL. The drug can be given intravenously, but only with extreme caution.

Procainamide

Procainamide differs from the local anesthetic procaine only by replacement of an ester with an amide (see Figure 14-9). Like quinidine, procainamide blocks open Na⁺ channels and outward K⁺ channels. Thus it decreases automaticity, increases refractory periods, and slows conduction as well as prolongs the action potential duration. Its N-acetyl metabolite (in which the dog is deficient) is active and accounts for a major proportion of activity in humans. Although the metabolite does not block Na⁺ channels, it does prolong the action potential duration (a K⁺-blocking effect).⁵ The metabolite is equal in efficacy but less potent than the parent compound in the control of ventricular arrhythmias.¹¹⁸ The effects of procainamide on automaticity, excitability, responsiveness, and conduction are similar to those produced by quinidine. Indirect effects (those affecting the autonomic nervous system) are significantly weaker, with no α-adrenergic blockade or paradoxical acceleration.⁵

Procainamide is rapidly and almost completely absorbed after oral administration, although the rate varies with the preparation. Peak concentrations occur within 45 to 75 minutes with a capsule but take longer with tablets. Bioavailability in the dog approximates 85%.¹¹⁹ Only about 20% of the drug is protein bound to glycoproteins in humans.⁵ Distribution occurs to most tissues except the brain,⁵ yielding a large (1.44 L/kg in dogs) volume of distribution.¹¹⁹ Procainamide is extensively biotransformed by the liver to metabolites. In humans, N-acetylprocainamide is a major active metabolite, contributing significantly to antiarrhythmic effects. In dogs acetylation is deficient and therapeutic concentrations reflect principally the parent drug whereas for humans, it reflects both parent and metabolite. In dogs the mean concentration necessary to control arrhythmias in ouabain (a cardiac glycoside)-intoxicated dogs was 33.8 μg/mL, with a range of 25 to 48.5 μg/mL.¹²⁰ This compares with a therapeutic range of concentration of 5 to 30 μg/mL for the combined parent and metabolite in humans. The elimination half-life of procainamide in the normal dog is 2.5 to 2.8 hours.

The fluoroquinolones decrease clearance of procainamide or its N-acetyl metabolite in humans. The extent and target (parent versus metabolite) varies with the fluoroquionlone drug. In humans ciprofloxacin decreases clearance of both by nearly 20%; competition appears to be occurring for renal tubular transport proteins.¹²¹ Toxicities of procainamide include cardiotoxicity, similar to that induced by quinidine; hypotension with rapid intravenous administration (bolus); and gastrointestinal signs (anorexia, nausea, vomiting, diarrhea). Cardiac toxicity is indicated by a 50% widening of the QRS complex or by bradyarrhythmias or tachyarrhythmias.

Procainamide is available as oral capsules, tablets, and sustained-release tablets. Intravenous preparations are available for acute or unstable situations. Intravenous infusion is a reasonable approach for the treatment of the acute patient and may be preferred to rapid bolus, which may be associated with hypotension. Procainamide also can be administered intramuscularly (15 to 20 mg every 2 hours [dog] or 8 to 16 mg every 3 to 6 hours [cat]). An advantage to procainamide over other antiarrhythmics is ease of converting from an intravenous to an oral preparation. The transition is best accomplished by stopping an infusion, and, at one elimination half-life, administering the first oral dose (125 to 500 mg every 6 to 8 hours, for a total of 33 mg/kg per day).

Procainamide is a broad-spectrum antiarrhythmic drug. In general, its effectiveness as a ventricular antiarrhythmic drug parallels or exceeds that of quinidine, and it is useful for patients who have failed quinidine therapy. Arrhythmias for which procainamide have proved useful include ventricular¹²² and, to a lesser degree, supraventricular types. Procainamide can suppress digitalis-induced toxicity but fatalities may occur.

Disopyramide

The pharmacologic effects and spectrum of disopyramide are similar to those of procainamide and quinidine. Although it is effective in controlling supraventricular arrhythmias, its primary use is for ventricular tachyarrhythmias. Disopyramide has been studied in the dog.¹²³ It is quickly absorbed after oral administration, but it undergoes rapid metabolism and clearance. Its half-life is less than 2 hours in the dog, necessitating multiple daily administrations. Like quinidine, disopyramide has potent antivagal effects and can therefore increase the ventricular rate dramatically in patients with supraventricular tachycardias. More important, disopyramide also has a negative inotropic effect on the heart and can be lethal for patients with preexisting myocardial disease. Clinical indications for disopyramide are probably limited by its potential adverse affects on the heart.¹²⁴

Class IB Drugs

Class IB drugs include agents such as lidocaine and its congeners and phenytoin. Lidocaine (see Figure 14-9), widely used as a local anesthetic, is the prototypic class IB drug. Increasingly, it is being used for a variety of conditions (discussed later). Lidocaine preferentially binds to open (phase 0) and inactivated (phases 1 through 3) channels. Therefore cardiac tissues with long action potential duration or tissues that are rapidly firing (because more time is spent in the inactivated state), such as ischemic tissues, are more affected by lidocaine. Because atrial tissues have a very short action potential compared with ventricles, lidocaine preferentially targets arrhythmias in the abnormal Purkinje system and ventricles. In contrast, it minimally affects the sinoatrial node, atria, or atrioventricular node, although it has been used to successfully treat supraventricular arrhythmias in a limited number of dogs.¹²⁵ Additionally, abnormal ventricular tissues are preferentially affected compared to normal myocardial tissues. Lidocaine also minimally affects the autonomic system.

Lidocaine suppresses automaticity, increases the threshold, and hyperpolarizes (increases the resting membrane potential) of Purkinje fibers. Increased conduction velocity may facilitate inhibition of reentrant arrhythmias. The action potential duration is either unaffected or shortened. Lidocaine efficacy is dependent on potassium; hypokalemia will minimize its efficacy.

Lidocaine is well absorbed orally, but it is subject to first-pass metabolism, with only one third of the drug reaching systemic circulation. Rectal bioavailability ranges from 32% to 56%, depending on the preparation.¹²⁶ Peak concentrations in dogs after intravenous administration of 6 mg/kg approximate 10 μg/mL, declining to 0.1 μg/mL by 3 hours, with the elimination half-life approximating 50 minutes.¹²⁷ After intramuscular administration, absorption is complete, with peak concentrations at the same dose approximating 1.8 μg/mL at 30 minutes. Distribution is rapid to a volume of approximately 1.4 L/kg.^127,128 About 70% of the drug is bound to protein (glycoprotein). Lidocaine is cleared by hepatic metabolism to active and inactive metabolites. Clearance in female dogs (n=4; dose of 2 mg/kg infused over 5 minutes) was 27.5 ± 6.0 mL/min/kg. As a flow-limited drug, systemic clearance of lidocaine should decrease in proportion with hepatic blood flow. Portosystemic shunting will increase oral bioavailability; experimentally induced portosystemic shunting in dogs increases it from 15% to 80%.¹²⁹ Lidocaine is prepared for intravenous administration. Lidocaine can be administered intravenously as a rapid bolus or as a continuous intravenous infusion. It can also be given intramuscularly in emergency situations. Topical creams, salves, or gels and patches are intended for local anesthetic use only and will not provide antiarrhythmic efficacy.

As an antiarrhythmic, lidocaine is indicated for emergency treatment of ventricular arrhythmias. Pharmacologic effects occur rapidly. Lidocaine has several undesirable effects. Although lidocaine may decrease the risk of acute death associated with ventricular fibrillation, one study demonstrated decreased hospital survival, mitigating its routine use. The primary toxicity in the dog occurs in the central nervous system, with symptoms that range from drowsiness or agitation to muscle twitching and convulsions at higher plasma concentrations. Therapeutic and toxic lidocaine concentrations have been established experimentally. In an study of canine myocardial infarction, inhibition of electrically stimulated ventricular tachycardia responded to mean concentrations of 3.5 μg/mL (1 mg/kg intravenously followed by 80 μg/kg/min).¹³⁰ Wilcke and coworkers¹³¹ compared effective and toxic concentrations in six dogs. Minimum effective concentrations for experimentally induced ouabain toxicity (outcome measure was eradication of ventricular tachycardia) ranged from 3.8 to 7.65 μg/mL (mean 6.25 μg/mL). The time necessary to eradicate the arrhythmia ranged from 0.3 to 1 hour after infusion of 1480 mg/hr. However, neurologic manifestations of toxicity appeared at 6.3 to 10.4 μg/mL (mean 8.21 μg/mL) (tonic extension) and became more exaggerated (cortical seizures) at 7.3 to 11.2 μg/mL (mean 9.58 μg/mL). Other neurologic manifestations of lidocaine toxicity include anxiety, sedation, and disorientation. The risk of toxicity with intravenous administration is greater in the cat compared with the dog; however, the cat s prone to cardiac toxicity. Cardiac suppression will occur at higher doses; exacerbation of heart failure has been reported in human patients with poor left ventricular function.⁵ Lidocaine can worsen first-degree or second-degree atrioventricular block and is contraindicated for patients with third-degree heart block because of suppression of ventricular automaticity. A large intravenous bolus may cause sinus arrest; cats are more prone to this adversity.

Drug interactions involving lidocaine are limited. Care should be taken when mixing lidocaine solution with other drugs to avoid pharmaceutic direct drug-drug interactions. Selected drug interactions reflect competition with other basic drugs for binding sites on glycoproteins, although their clinical relevance is not clear. Lidocaine increases hepatic blood flow: a 12-hour infusion of 76 μg/kg/min increased hepatic arterial blood flow 1.6- to 9.2-fold.¹²⁸ Despite its flow-limited behavior, lidocaine appears to decrease its own clearance, with the impact being demonstrable following longer infusions compared with bolus administration.^128,132 Changes were more profound in one study following a 24-hour compared with a 90-minute infusion period.¹³² Another study found that multiple administration of lidocaine (once daily) was associated with a decrease in hepatic intrinsic clearance from 1224 ± 859 to 285 ± 104 mL/min/kg.¹²⁸ Lidocaine metabolism is inhibited by a number of drugs, including midazolam and thiamylal.¹³³

Tocainide (no longer marketed in the United States) and mexiletine are class IB antiarrhythmic drugs that are similar in chemistry and mechanism of action to lidocaine but modified to reduce first-pass metabolism, thus allowing oral administration. For example, tocainide is 100% orally bioavailable. Using a model of canine myocardial infarction, tocainide prolonged conduction intervals and the effective refractory period by 26% to 31% in damaged tissue compared with 6% to 8% in the noninfarcted zone.¹³⁴ Tocainamide has been used for long-term management of ventricular arrhythmias, particularly those that respond to lidocaine or fail to respond to procainamide. Arrhythmias that are refractory to lidocaine are not likely to respond to tocainide. Tocainide is prepared as a racemic mixture. Both the R and S enantiomers appear to have greater antiarrhythmic activity alone compared with the racemic mixture, whereas the racemic mixture appears more toxic than either enantiomer alone. Consequently, safety and efficacy might be improved if single enantiomer preparations become available.¹³⁵ Tocainaide may be more likely than lidocaine to cause CNS and gastrointestinal adverse reactions. Bone marrow dyscrasias and pulmonary fibrosis have limited use of tocainide. Blood dyscrasias have occurred in dogs.¹¹⁰ Contraindications to lidocaine should be followed for tocainide.

After intravenous administration of tocainide, spontaneous premature ventricular complexes were reduced in dogs with experimentally induced myocardial infarction.¹³⁶ In Doberman Pinschers (n=23) with cardiomyopathy, tocainide at 15 to 25 mg/kg every 8 hours reduced the number of ventricular premature complexes short term by at least 70% in 80% of treated dogs; ventricular tachycardia was corrected in 90% of affected dogs. Serum concentrations at 2 hours and 8 hours were 6.2 to 19.1 mg/L and 2.3 to 11.1 mg/L, respectively. Long-term control was more difficult in animals whose left ventricular shortening fraction was less than 17%. Although efficacious, tocainide therapy may be limited by side effects. Anorexia and gastrointestinal disturbances occurred in 35% of dogs, with peak concentrations being higher in afflicted dogs (14 μg/mL) compared with dogs not exhibiting toxicity (11 μg/mL). Serious adverse effects occurred in 58% of dogs treated longer than 4 consecutive months and included progressive corneal endothelial dystrophy; renal dysfunction occurred in 25% of the dogs.¹³⁷

Mexiletine, like tocainide, is a structural analog of lidocaine, indicated for oral management of life-threatening ventricular arrhythmias. Like lidocaine, it decreases the the APD more than the ERP such that the ratio of ERP/APD increases (package insert). Normal cardiac tissue is minimally impacted. In humans and dogs, mexiletine is characterized by high oral bioavailability, low first pass metabolism, 50-60% bound to plasma protein, and a volume of distribution of 5-7 liters/kg. Clearance in humans is primarily hepatic via CYP2D6 metabolism (hence, major differences in metabolizer phenotypes may occur), with some CYP1A2; metabolites are largely inactive. extensive metabolizer phenotypes. In dogs, most of the drug may be renally excreted, although its plasma elimination half-life approximates 10-12 hours; liver disease may prolong clearance. Mexiletine exists as a racemic mixture; in humans, the S isomer is characterized by a higher area under the curve (mean R/S ration = 0.8). ^137a In dogs, mexiletine has demonstrated stereoselective effects, with R-(-)-mexiletine being more potent in the prevention of ventricular tachycardia than S-(+)- mexiletine. ^137b

In human clinical trials involving mexiletine, approximately 40% of study participants withdrew from studies because of adverse effects; this rate was similar to treatment groups receiving quinidine or procainamide. Rarely, mexiletine has been associated with liver disease, warranting monitoring in patients with abnormal tests indicative of liver disease. Although mexiletine does not cause heart block in normal animals, it occasionally exacerbates pre-existing conduction disturbances; its use is contraindicated in the presence of 2^nd or 3^rd degree heart block. Mexiletine is arrhythmogenic: sustained ventricular arrhythmias worsened in approximately 10% of human patients receiving mexiletine. Minimum therapeutic plasma concentrations appear to approximate 0.5 mcg/ml in humans (range 0.05 to 2 mcg/ml). Dosing intervals are designed to minimize fluctuation.

Studies of mexiletine in dogs are largely experimental in nature, supporting use in humans. Experimentally, including studies using canine models, it suppresses induced ventricular arrhythmias. Mexiletine (5 mg/kg) (or esmolol at 1.25 mg/kg or verapamil at 0.4 mg/kg) was limited in its success in preventing torsades de pointes in a canine model involving blockade of delayed rectifying current and β-adrenergic stimulation. ^110a However, mexiletine (4.5 mg/kg load followed by 1.5 mg/kg/hr infusion) was able to partially prevent the proarrhythmic effects of β-adrenergic A-V blockade (sotalol 4.5 mg/kg load followed by 1.5 mg/kg/hr infusion) in diuretic (furosemide and hydrochlorthiazide)-induced hyopkalemic dogs. Mexiletine prevented sotalol-associated torsades de pointes that was electrically induced in the dogs. ^110b Pharmacodynamic effects of melixetine were determined in three canine models of arrhythmias. The minimum effective plasma concentrations (μg/ml) of mexiletine necessary to suppress arrhythmias were 1.8 ± 0.6 when induced by digitalis, 3.7+0.9 for adrenaline, and 2.2 ± 0.4 for coronary ligation μg/mL.^110c The plasma elimination half-life in dogs is 3 to 4 hr. Mexiletine may be more effective when used in combination with other drugs. For example, it was more effective at in preventing experimentally induced ventricular arrhythmias in dog myocardium when combined with quinidine. ^110d

Like tocainide, mexiletine is more likely than lidocaine to cause central nervous system and gastrointestinal toxicity. Mexiletine induces seizures in dogs at 25 mg/kg; vomiting occurs at 15 to 30 mg/kg. However, the drug was well tolerated at 15 mg/kg for 13 weeks in normal dogs. ^138b

Contraindications to lidocaine should be followed for mexiletine.

Phenytoin is an anticonvulsant with a limited spectrum of cardiac antiarrhythmic activity. Its mechanism and impact are similar to those of lidocaine. Its primary use in veterinary medicine has historically been management of digitalis-induced arrhythmias; phenytoin will shorten atrioventricular nodal and Purkinje refractory period in digitalized patients.

Class IC Drugs

Class IC drugs cause effects similar to those of the class IB drugs except that they do not prolong the refractory period. Examples include encainide, flecainide, lorcainide, and propafenone. Conduction velocity is depressed. In addition to sodium channel blockade, flecainide also blocks (in vitro) delayed rectifier potassium channels and calcium channels. Action potential duration is shortened in Purkinje cells (as a result of blockade of late-opening sodium channels) but prolonged in ventricular tissues (because of potassium channel blockade). In contrast to most class 1B drugs, flecainamide affects atrial tissues, prolonging the action potentials proportionately with rates, rendering it effective for atrial arrhythmias. However, it affects normal as well as abnormal tissues. Flecainide studies in dogs have been largely experimental. In one study concentrations of 610 ± 111 ng/mL increased the electrically induced defibrillation threshold in dogs.¹³⁸ The arrhythmogenicity of flecainamide can be lethal. Reentrant ventricular tachycardia may emerge when treating atrial arrhythmias, heart block may occur in conduction disturbances, and congestive heart failure can be exacerbated if ventricular performance is poor.⁵

Propafenone is a Na⁺ channel blocker that is similar to flecainide, including K⁺ channel blockade. It is prepared as a racemic mixture with the S-(+) isomer also exhibiting β-adrenergic antagonism in some (human) patients at concentrations at or above 1 μg/mL. Its efficacy is greater with atrial than with ventricular arrhythmias. It is eliminated through CYP2D6 metabolism as well as renal excretion, generally undergoing first-pass metabolism to an equipotent active metabolite. At least one other metabolite is active. Metabolism can be saturated with only small dose increases, resulting in disproportionately high plasma drug concentrations. Inhibitors of CYPD26 will contribute to high drug concentrations. It is available in slow-release preparations. Dosing is modified in human patients with liver disease.

Nonselective B Blockers

Propranolol is the prototype β blocker. It is a competitive, nonselective β blocker of both β-1 and β-2 receptors. Like all β blockers, propranolol is most effective in the presence of elevated sympathetic tone. Its negative chronotropic effect is less likely in conditions not associated with elevated levels of catecholamines (e.g., less effective if associated with hypokalemia, fever, some heart diseases). It will slow ventricular rates in patients suffering from supraventricular arrhythmias, including those induced by digitalis toxicity, but is rarely able to convert a supraventricular arrhythmia to a normal sinus rhythm. As a β-1 blocker, propranolol is also a negative inotrope. This pharmacologic effect might be detrimental in the patient with small cardiac reserve (e.g., the patient with decompensated CHF) during acute treatment. Propranolol has been studied in euthryoid and hyperthyroid cats.¹⁴⁶ Changes in disposition induced by hyperthyroidism suggest that a lower dose is indicated for oral administration because of increased bioavailability. Clinical indications of propranolol (β blockers) as an antiarrhythmic include reduction of ventricular rate in cases of supraventricular tachycardias, hypertrophic and other forms of obstructive heart disease, and hyperthyroidism. The effects of propranolol are dose, time, duration and route dependent; although oral administration may be associated with decreased bioavailability of the parent drug, formation of a more effective metabolite may cause better response with oral administration.^146b

The toxic effects of propranolol are the result of nonselective β blockade and include bradyarrhythmias, hypotension, heart failure, bronchospasm, and hypoglycemia, particularly in diabetics. In an intact experimental canine model, insulin (4 IU/min intravenously with glucose) was shown to be superior to epinephrine for treatment of acute propranolol toxicity.¹⁴⁷

Nadolol (5 to 10 mg orally every 6 to 12 hours [cat]; 40 to 60 mg orally every 6 to 12 hours [dog]) also is a nonspecific β blocker that is renally excreted. Side effects and contraindications typical of propranolol occur for nadolol.¹¹⁰ Sotalol is another non-specific β-blocker that also prolongs the APD and ERP of atrial and ventricular fibers (Class III).

Selective Beta Blockers

Metoprolol is a relatively selective, lipophilic β-1 blocker. It is marketed as a racemic mixture, although the (−) isomer provides the predominant β blockade effect. The clinical pharmacology of metoprolol exemplifies the complexities associated with therapeutic use. Metoprolol undergoes hepatic clearance to several metabolites, of which the α-hydroxyl metabolite, the product of metabolism steroselective for the S(−) isomer is active. However, the proportion of this metabolite formed from the parent compound may not be clinically significant. O-Demethylation and N-dealkylation appear to be the major metabolites formed in dogs.¹⁴⁸

The β-blocking effect of α-hydroxymetoprolol has been compared with that of metoprolol after intravenous administration in the dog. The dose–response relationship was linear for both compounds, but the metabolite required 10 times the plasma concentration of the metoprolol (5 times the dose) for therapeutic equivalence. The volume of distribution for the metabolite was 2 liters/kg compared with 3.5 liters/kg for metoprolol, whereas clearance was 3.5 mL/kg/min for the metabolite compared with 20 mL/kg/min for metoprolol. The net effect of these differences resulted in an elimination half-life for the α-hydroxy metabolite of 7 hours compared with 2 hours for the parent compound. Approximately 5% of an intravenous dose of metoprolol was metabolized to the active metabolite.¹⁴⁴ In Beagles (n=4, 8 years old, all female) receiving 1.37 mg/kg metoprolol orally, the area under the curve (0-48 hours; μg/mL/hr) was 2 for α-hydroxymetoprolol, compared with 4.39 for metoprolol acid and 1.89 for metoprolol. Peak plasma concentrations (estimated from concentration versus time curve) of metoprolol and its metabolites were 400 ng/mL at 0.5 hour for metoprolol, compared with 100 ng/mL at 3 hours for α-hydroxymetoprolol. An intravenous dose of 2 mg/kg resulted in a decrease in heart rate in normal dogs by 35% at a concentration of 379 ± 24 ng/mL; the concentration of the α-hydroxyl metabolite was approximately 38 ng/mL. A similar intravenous dose of the metabolite (2 mg/kg) resulted in a 25% reduction in heart rate. These studies suggest that the active metabolite of metoprolol may not play a major role in cardiac response, although the impact on other effects (i.e., antiarrhythmic, cardioprotective) is not clear.

Stereoselective pharmacodynamic effects of metoprolol also have been described in dogs. The concentration (μg/mL) necessary to achieve 50% of the inhibitory effect for each isomer were as follows: for V_max 250 ± 80 (R) versus 70 ± 30 (S), dP/dtmax: 450 ± 210 (R) versus 70 ± 40 (S) and heart rate, 520 ± 210 (R) versus 82 ± 27 (S). As such, the (S) isomer was more potent than the (R) isomer at a ratio of 3.7, 6.8, and 6.3 for V_max, dp/dt_max, and heart rate, respectively.¹⁴⁵ Stereoselectivity has also been reported for the disposition of metoprolol in anesthetized dogs, (although applicability to awake dogs is not clear). The peak times to maximum inhibitory effect of either metoprolol isomer occurred at 90 to 120 minutesBecause the isomers were not given intravenously, volume of distribution(Vd) and CLs could not be corrected for bioavailability (F); however, differences occurred in Vd/F, CLs/F, and area under the curve between the isomers;.¹⁴⁵ Another investigator¹⁴⁹ documented that hepatic clearance of metoprolol in dogs is slightly selective for the (S) isomer.

Metoprolol is prepared as an oral tartrate (Lopressor®), and slow-release succinate salt (Toprol XI®); the latter allows once-daily dosing in humans. The slow-release preparation does not appear to have been studied in dogs or cats. Indications of the slow-release preparation in humans include hypertension as well as treatment of stable CHF.

Verapamil (3 mg/kg) inhibited clearance of metoprolol in dogs approximately 50% to 70%. The effect is profound after oral administration, abolishing first-pass metabolism, with inhibition selective toward O-demethylation of the (S) isomer.¹⁴⁹

A large multicenter clinical trial studied the use of metoprolol for treatment of acquired heart disease and particularly DCM compared with a placebo in dog.^149a The drug did not appear to decrease mortality rates but did improve ventricular function as well as quality of life.

Carvedilol represents one of the more recently (third) generation of β blockers associated with potential antiarrhythmic, antihypertensive, and antiremodeling effects.^150-152 Carvedilol is specifically approved to reduce cardiovascular mortality in human patients. Although it is characterized by β₁ and β₂ as well as α-adrenergic blockade, it is relatively (mildly) β₁-selective in human patients. Vascular endothelium contains β1 and β2 receptors as well as α-1 receptors, each targeted by carvedilol. As such, it decreases total peripheral resistance and preload without compromise of cardiac output or causing reflex tachycardia. This advantage however, might be minimized by low-dose therapy of other (i.e., not carvedilol) β blockers.¹⁵³Advantages compared with traditional selective β blockers such as metoprolol include reduced mortality in human patients with left ventricular failure, perhaps resulting from a more complete antagonism of sympathetic activation.^{140,142,154,155} Carvedilol benefits do not reflect a reduction in heart rate as much as improvement in left ventricular function. Additional advantages may include antioxidant and antiproliferative properties and inhibition of apoptosis in the heart.^150-152,156 Finally, carvedilol may inhibit the synthesis of endothelin in coronary arteries.¹⁵⁷ Carvedilol appears to protect against doxorubicin-induced cardiomyopathy.¹⁵⁸ In a rabbit model of ischemia, carvedilol provided superior cardioprotection, probably because of antioxidant and antineutrophil effects.¹⁵⁹ Similar effects were reported in a human patient receiving doxorubicin.¹⁶⁰

Carvedilol has been relatively well studied in dogs, It is well absorbed and undergoes extensive hepatic metabolism, including glucuronidation and subsequent biliary excretion.¹⁶¹ The kinetics and selected pharmacodynamics have been studied in anesthetized¹⁶² and awake^163,164 dogs. In anesthetized dogs the elimination half-life was 54 minutes (compared with 2.4 hours in humans), and the volume of distribution was 2 L/kg. When studied at doses ranging from 10 μg to 630 μg/kg, heart rate did not decrease, although reports in awake dogs indicate otherwise. Pulmonary and systemic pressures decreased in treated animals but increased in control animals, consistent with the β blockade effect of the drug. The authors recommend an optimal plasma drug concentration of 100 ng/mL, achieved after intravenous infusion of 150 to 310 μg/mL. Disposition was characterized by marked variability. The median peak concentration (extrapolated) of carvedilol after intravenous administration of 1.75 μg/mL was 476 ng/mL (range 203 to 1920 ng/mL), elimination half-life (t_1/2) was 282 minutes (range 19 to 1021 minutes), and MRT was 360 minutes (range 19 to 819 minutes). Volume of distribution at steady state was 2 L/kg (range 0.7 to 4.3 L/kg). After oral administration of 1.5 mg/kg, the median peak concentration was 24 μg/mL (range 9 to 173 μg/mL), time to maximum concentration was 90 minutes (range 60 to 180 minutes), t_1/2 was 82 minutes (range 64 to 138 minutes), and MRT was 182 minutes (range 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range 0.4% to 54%). However, the bioavailability of active metabolites (M4 and M5, which are equipotent to parent drug in humans) was not determined, and it is not clear whether these metabolites are produced in dogs. On the basis of these data, monitoring should be considered to adjust dose. The half-life of 3 hours suggests 8-hour dosing. However, pharmacodynamic studies were also performed.¹⁶⁴ Normal dogs were studied at baseline and after multiple-dose (>5 days) oral administration of carvedilol (1.5 mg/kg of body weight orally every 12 hours). Dogs were challenged with isoproterenol. Carvedilol had no effect on heart rate or blood pressure in six of eight dogs at baseline or study end, but heart rate reduced after multiple dosing in two of eight dogs. Carvedilol attenuated isoproterenol-induced changes in heart rate by 54% to 76% through 12 hours and by 30% at 24 hours. The effects of isoproterenol on blood pressure was attenuated by 80% to 100% through 12 hours. Based on normal dogs, an oral dose of 1.5 mg/kg was recommended every 12 hours. The magnitude of β-blockade response correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful. Carvedilol also has been compared to bisopropol (see later discussion).

The efficacy of carvedilol and metoprolol for the treatment of chronic heart failure has been compared in humans. The efficacy of these drugs has also been compared with that of standard therapy in humans.^154,165 No difference could be demonstrated in most outcome measures between carvedilol versus metoprolol treatment, although blood pressures were lower in carvedilol compared with metoprolol patients. Patients receiving either carvedilol or metoprolol significantly improved compared with those receiving standard therapy.¹⁵⁴ More recently, the results of the COMET study, which compared carvedilol with metoprolol, have been reported. The COMET study was a randomized, double-blind, parallel comparison of carvedilol at approximately 0.3 mg/kg twice a day and metoprolol tartrate at approximately 0.7 mg/kg twice a day. Patients (n=3000) were studied for 58 weeks and had stable chronic heart failure, New York Heart Association (NYHA) functional class II to IV, with left ventricular dysfunction. Patients continued ACE inhibition and diuretics. Patients were randomly assigned to receive either carvedilol or metoprolol and followed for 58 months. Endpoints were cardiovascular events (which may be less relevant in dogs or cats), and the proportion of such events in each group (584 for carvedilol versus 667 for metoprolol), although statistically significant, may not be as clinically relevant.

In a study of myocardial perfusion in dogs receiving either carvedilol (2 mg/kg) or metoprolol (4 mg/kg) orally, carvedilol was associated with greater increase in myocardial perfusion and decrease in blood pressure, whereas metoprolol was associated with greater decrease in heart rate.¹⁶⁶ Carvedilol appears to be an inhibitor of P-glycoprotein, at least as was demonstrated in vitro in cancer cells: the LD₅₀ of doxorubicin in breast cancer cells increased by twentyfold (200 to 10 ng/mL)¹⁶⁷ despite doxorubicin cardioprotection.¹⁶⁰

Oyama and coworkers¹⁶⁸prospectively failed to find a significant impact of carvedilol (0.3 mg/kg twice daily) in dogs with DCM (n=16; n=7 placebo) using a placebo-controlled, double-blinded randomized design. Endpoints for which significant differences were not documented included changes in ventricular function, activation of neurohumoral compensatory responses, or owner-perceived quality of life. However, animal death reduced sample size and the power of the study to detect a significant difference was not reported. Marcondes-Santos and coworkers¹⁶⁹ found some beneficial effect of carvedilol when added to traditional therapy (digoxin, benazepril, codeine) in dogs (n=13) with chronic mitral valvular disease; 12 control dogs with disease did not receive carvedilol. Dogs were studied using a prospective blinded parallel study. A tendency for improvement occurred for quality of life and a reduction in SBP, and improved disease classification during the 3-month study period.

Atenolol (see Figure 14-9) is a selective β₂ blocker. In humans its use is associated with greater mortality compared to non-atenolol β blockers. The difference presumably reflects a risk of ventricular fibrillation that is greater with atenolol compared to others. Compared to most other clinically used selective β blockers, atenolol is much less lipid soluble and thus less likely to penetrate the central nervous system; increased mortality may be related to the lack of centrally mediated vagal tone, which would otherwise counteract the risk of fibrillation.¹⁷⁰ The implications of this difference among β blockers is not clear for dogs or cats. Little information is available regarding active metabolites or stereoisomers.

Atenolol is 90% bioavailable after oral administration in normal adult cats.¹⁷¹ Elimination half-life in normal adult cats is 3.44 ± 0.5 and 3.65 ± 0.39 hours after intravenous and oral administration, respectively. A dose of 3 mg/kg orally generates a peak plasma concentration of 0.48 ± 0.16 μg/mL and will block cardioresponsiveness to isoproterenol for 12, but not 24, hours, suggesting a 12-hour dosing interval. Using a prospective, randomized, crossover, blinded study, atenolol (6.25 mg every 12 hours) was studied in healthy cats as either an oral or transdermal preparation.¹⁷² Peak (2-hour) and trough (12-hour) concentrations were measured after 1 week of administration.Therapeutic concentrations (250 ng/mL) were reached in six of seven cats (579 ± 212 ng/mL) 2 hours after oral administration, but in only two of seven cats (177 ± 123 ng/mL) following transdermal administration. Trough plasma atenolol concentrations were 258 ± 142 ng/mL following oral administration and 62.4 ± 17 ng/mL following transdermal administration. The authors concluded Monitoring might be considered in animals that must receive atenolol transdermally. Atenolol is indicated for cats with HCM associated with outflow obstruction and respiratory distress. Henik and coworkers¹⁷³ reported the efficacy of atenolol (1 to 2 mg/kg PO every 12 hours) for control of hypertension in hyperthyroid cats (n=20). Although heart rate was decreased, SPB was not well controlled, indicating the need for an additional vasodilator. Crandell and Ware¹⁷⁴ described the successful use of atenolol for treatment of cardiac toxicity associated with phenylpropanolamine overdose in a dog.

Esmolol is a β₁-selective blocker (S enantiomer) characterized by a very (ultra) short half-life owing to metabolism by erythrocyte esterases. Methanol is a metabolite of esmolol in humans, but its formation does not appear to be clinically relevant. Duration of effect is about 10 minutes; therefore its effects will rapidly dissipate once the drug is discontinued.⁵ It is administered intravenously and has proved useful in dogs for acute ventricular arrhythmias associated with inhalation anesthesia and surgical removal of hyperactive thyroid glands.¹¹⁰ In anesthetized dogs receiving a constant-rate infusion, steady-state concentrations occurred in 10 minutes, with duration of β blockade paralleling drug concentrations.¹⁷⁵ Peak β blockade occurred within 15 seconds after loading with a 500 μg/kg constant-rate infusion and at 30 to 45 seconds after switching to a maintenance dose of 12.5, 25, or 50 μg/kg/min. Duration of β blockade was less than 15 minutes once drug was discontinued. Esmolol has been proved to be effective for treatment of cats with HCM and left ventricular outflow tract obstruction.¹⁷⁶

Bisoprolol is among the β-1 selective blockers that have prolonged the life span of humans with cardiac disease. Among its distinguishing characteristics is less lipophilicity than other drugs; consequently, the parent drug is eliminated by both hepatic metabolism and renal excretion (approximately 50% each) in dogs.¹⁷⁷ Bisoprolol is less lipophilic than other β blockers, including carvedilol; the implication is not clear, but pharmacodynamic data for bisoprolol apparently are not yet available in dogs. However, Beddies and coworkers¹⁷⁷ compared the pharmacokinetics of carvedilol and bisoprolol (1 mg/kg either drug) after both intravenous and oral administration in 12 Beagles using a parallel nonrandomized study design (six dogs per group; oral drug was followed by intravenous drug). Intravenous administration of bisoprolol resulted in a C_max (presumed to be extrapolated) of 408 ± 75 (presumed to be ng/mL) with a 3.9 ± 0.3 hour half-life. Volume of distribution was 2.4 ± 0.6 L/Kg, and clearance 0.42 ± 0.08 L/h/kg). After oral administration of bisoprolol, the C_max was 322 ± 261 at 1.1 ± 0.7 hr. Oral bioavailability of bisoprolol was 91.4% compared with 14.3% for carvedilol. For carvedilol, after intravenous administration, C_max (presumed to be extrapolated) for carvedilol was 788 ± 348 (presumed to be ng/mL) and half-life 1 ± 0.2 hour. Volume of distribution was 2.9 ± 0.6, and clearance 2.1 ± 0.5 L/hr/kg. After oral administration the C_max of carvediolol was 51 ± 42 at 1.1 ± 07 hours.

Diltiazem

Diltiazem (see Figure 14-9) is the most commonly used CCB in veterinary medicine, in part because it has been studied in both dogs and cats. It exerts its greatest effects in the sinoatrial and atrioventricular nodes, tissues in which slow Ca²⁺ influx is largely responsible for phase 0 depolarization. Diltiazem slows sinus rate and atrioventricular conduction. The ventricular rate is reduced in patients with atrial fibrillation or flutter, but primary ventricular arrhythmias are generally unresponsive to diltiazem. Myocardial oxygen demand decreases in response to the effects of diltiazem. Cardiac side effects include hypotension, bradycardia, and various degrees of heart block. In human patients a therapeutic range of 50 to 300 ng/mL has been identified and can be used as a target for clinical response in animals.

The magnitude of the hemodynamic affects of the CCB reflects the route of administration. Bioavailability is reduced as a result of first-pass metabolism for nifedipine > verapamil > diltiazem, with bioavailability of diltiazem only 50% after oral administration. However, the extent of metabolism decreases with chronic administration, facilitating chronic oral therapy. Diltiazem is metabolized by acetylation, which is deficient in the dog but not in the cat; the impact of acetylation deficiencies in the dog on diltiazem disposition has not been studied.

In an attempt to identify a product that allows convenient (once to twice daily) dosing intervals, the disposition of several diltiazem products has been studied in cats. Comparison of intravenous, standard, and slow-release (CD) diltiazem preparations reveals a disappearance half-life of 120 minutes for the intravenous and oral preparations, but 460 minutes (7 hours) for the CD preparation. The bioavailabilities of the oral preparations are 71% (standard) and 36% (CD). The higher bioavailability of the standard preparation for cats compared with humans (30%) may reflect less first-pass metabolism, despite the fact that cats are efficient acetylators. Peak plasma concentrations for the standard preparation occurred at 45 minutes; peak steady-state concentrations of CD should occur at 1 to 2 days. Diltiazem is approximately 55% to 65% bound to serum proteins in cats. Maximum prolongation of the PR interval is less than 20% for either preparation, occurring at approximately 18 hours, when plasma diltiazem concentrations are between 50 and 100 ng/mL. The pharmacodynamic effects have not been studied in cats with HCM. However, on the basis of the pharmacokinetic data, the standard diltiazem product is administered at 1 mg/kg every 8 hours, but the CD product (prepared in gelatin as either 60-mg or 90-mg capsules) can be administered at 10 mg/kg every 24 hours. An extended-release diltiazem (Dilacor XR) also was studied in cats (n=13; 10 normal and 3 with HCM) after oral administration of either 30 or 60 mg (9.3 to 14.8 mg/kg, obtained as 60-mg tablets in 120-mg capsules; tablets were halved [with difficulty] to yield 30 mg fractions). Peak serum concentrations following 60 mg (8 cats; concentrations not measured until 6 hours) were markedly variable, ranging from approximately 71 to 1500 ng/mL (mean 787 ± 488 ng/mL); by 24 hours, concentrations were 196 ± 232 (range 5 to 920) ng/mL. At 30 mg (5 cats), peak concentrations were 448 ± 370 (20 to 800) at 6 hours and 43 ± 24 (20 to 88 ng/mL) at 24 hours. Variability in absorption indicates that monitoring, if available, would be a useful tool for targeting effective concentrations.¹⁸⁵ The recommended dose is one half of one of the pellets given once or twice daily.

Diltiazem appears to be relatively safe in cats. A retrospective study of client-owned cats (n=25) with HCM treated with 60 mg diltiazem once daily, reported side effects evident at 60 mg per cat included lethargy, gastrointestinal disturbances (vomiting, diarrhea), and weight loss (36%). Clinical signs appeared in 1 to 7 days.¹⁸⁵ Diltiazem has been studied in cats after single-dose transdermal administration. Therapeutic concentrations (50 to 200 ng/mL) were not acheived in any cat (n = 6).^185a Administration as a transdermal gel is not recommended until multiple dosing has been documented to predictably achieve therapeutic concentrations.

Diltiazem has been studied in dogs.^186,187 The PR interval is prolonged approximately 20% at plasma concentrations of 60 ng/mL. In dogs suffering from atrial fibrillation or CHF, diltiazem (0.5 to 1 mg/kg every 8 hours) can be used for its negative chronotropic effects to reduce heart rate in the presence of sustained supraventricular arrhythmias. Diltiazem can be used either alone or in combination with digoxin. Because of its negative inotropic effects, however, it must be used cautiously in patients with myocardial failure, and digitalization may be indicated before diltiazem therapy is begun. The drug can be used intravenously (0.2 to 0.4 mg/kg, followed by infusion of 4 to 8 μg/kg per minute), although extreme caution is recommended.

A single case of diltiazem toxicity has been reported in a dog that accidentally ingested between 95 and 109 mg/kg of a slow-release product.¹⁸⁸ Clinical signs included cardiac arrhythmias, bradycardia, hypotension, mental depression, and gastrointestinal upset. The patient was treated with a temporary pacemaker. Costello and Syring¹⁸⁹ reviewed the toxicity associated with CCBs in general. Therapeutic strategies discussed for treatment included calcium as the initial therapy to increase availability to cells. Response should be monitored by electrocardiogram and heart rate. Glucagon may improve or reverse bradycardia and hypotension through unclear mechanisms that increase cAMP. Experimental doses used in dogs were 0.2 to 0.25 mg/kg bolus followed by 150 μg/kg/min constant-rate infusion. Because calcium blockade may cause hypoinsulinemia (and hyperglycemia) at the level of insulin release from pancreatic β cells, insulin and dextrose may be indicated (4 U/min in 20% dextrose and potassium supplementation as needed), as is a pacemaker. Finally, drugs that act as direct agonists at calcium channels may be beneficial, although no drug is clinically available or described with this effect. Among the drugs studied is 4-aminopyridine.

Verapamil

Verapamil is similar to diltiazem in its actions. It undergoes first-pass metabolism after oral administration in humans. Although it is available in both intravenous and oral preparations, caution is recommended with intravenous use. It has been studied for the treatment of acute supraventricular tachycardia in the dog at a dose of 0.05 to 0.15 mg/kg up to 0.2 to 5 mg/kg.^110,190 Supraventricular arrhythmias that do not respond to class IA drugs often respond to oral verapamil therapy.¹¹⁰ Among the CCBs used in small animals, verapamil is associated with the greatest negative inotropic effects and as such should be used cautiously in animals with ventricular myocardial dysfunction. Further, verapamil may be associated with more drug interactions than diltiazem.

Structure–Activity Relationship

Digitalis refers to both digoxin and digitoxin. Digitalis is obtained from the dried leaf of the foxglove plant (Digitalis purpurea). The active component of cardiac glycosides is an aglycone, which is released from attached sugars by hydrolysis (Figure 14-10).^3,6 Cardiac glycosides contain a steroidal nucleus containing a lactone ring (at C17) and one or more glycosidic residues (C3). Although the term digitalis has been used interchangeably with the term cardiac glycosides, current use is largely limited to digoxin in humans.

Mechanism of Action and Pharmacodynamic Responses

Cardiac glycosides are potent but reversible inhibitors of the α subunit of cell membrane–bound Na⁺,K⁺-activated adenosine triphosphate (Na⁺,K⁺-ATPase) “pump” (see Figures 14-1 and 14-11). The enzymatic activity is impaired, leading to like impairment of active transport, or exchange of sodium for potassium and a gradual increase in intracellular sodium. Cardiac fibers (both cell membrane and sarcoplasmic membrane) possess a second ATPase pump that exchanges Na⁺ for Ca²⁺; this pump is one of two ATP-ase pumps that extrude intracellular calcium after contraction (the second being a Ca²⁺-ATPase pump). As sodium increases in the cell in response to glycoside inhibition of the Na⁺,K⁺-ATPase pump, exchange of Na⁺ for Ca²⁺ is augmented, increasing calcium influx. Only a small increase in intracellular calcium occurs, but it is sufficient to cause a marked increased in Ca²⁺ release from the sarcoplasmic reticulum during systole (see Figures 14-1 and 14-2). Myocardial contractility improves, resulting in an increase in left ventricular function in both the normal and failing myocardium.⁶ In humans the increased contractility occurs at serum concentrations of 1.4 ng/mL.⁶

At 1 to 2 ng/mL, digoxin also indirectly increases efferent vagal (cholinergic) tone and decreases sympathetic nervous activity. Increased vagal tone is associated with inhibiting Ca²⁺ currents; decreasing automaticity; increasing the diastolic RMP; increasing the ERP, and decreasing conduction velocity, particularly in atrial and atrioventricular nodal tissues. Paradoxically, in nonconducting atrial fibers, acetylcholine-mediated potassium currents are increased, which shortens atrial action potentials. Therefore digoxin may contribute to or cause atrial tachycardias, including reentrant arrhythmias such as atrial fibrillation. The risk is greater in the diseased heart. However, although more impulses are transmitted to the AV node by fluttering or fibrillating atrial tissues, the vagal effects of digitalis decrease the number of atrial impulses that are transmitted by the atrioventricular node to the ventricles. Consequently, digoxin is indicated for slowing of ventricular rates in patients with supraventricular tachycardias such as atrial fibrillation. Electrocardiographically, digoxin prolongs the PR interval and depresses the ST segment (the latter mechanism is not understood).⁶

In addition to increased vagal tone, the indirect effects of digoxin on heart rate also reflect decreased sympathetic nervous system activity.⁶ Digoxin decreases neurohumoral activation associated with heart failure.⁶ Inhibition of the sodium pump in neuronal cells, particularly in the baroreceptor, results in stimulation of parasympathetic and inhibition of sympathetic nerves. Digoxin appears to directly alter carotid baroreflex responsiveness to changes in carotid sinus pressure in animals with heart failure.⁶ Digoxin is less effective as a negative chronotrope for tachycardias associated with marked sympathetic drive such as occurs with CHF. However, even minor reductions in heart rate may markedly improve myocardial function. Heart rate will be slowed, particularly in patients with a rapid heart rate, with effects generally occurring at serum digoxin concentrations of 1.3 ng/mL.⁶ Digitalis has only minor indirect effects in ventricular tissue.

The effects of cardiac glycosides on myocardial oxygen demand depend on the net effect on cardiac function. Mechanistically, energy utilization shifts from one ATPase pump to another, which might minimize the increase in oxygen needs. In normal hearts oxygen demand increases proportionately with increased contraction.³ If ventricular volume decreases and systolic wall stress declines, however, as would be expected in an animal with myocardial failure, improved cardiac function and subsequent decreased fiber length will compensate for the increased oxygen demand caused by improved contractility.^3,191

Cardiac glycosides can cause peripheral arterial and venous vasoconstriction, but these effects are more likely in the normal animal.⁶ Pulmonary vasoconstriction is induced by all cardiac glycosides except digoxin. Effects in the vasculature are more common after intravenous administration and occur in less than 15 minutes; indeed, with oral administration vasodilation predominates. Thus oral digitalization with digoxin will minimize the risk of adverse effects caused by cardiac glycoside–induced vasoconstriction.¹⁹¹

Detrimental effects on myocardial remodeling are a potentially important deterrent to cardiac glycoside therapy. Ouabain (a largely experimental cardiac glycoside) induces mRNA and subsequent production of IL-1b, IL-6, and TNF-α in human peripheral blood mononuclear cells. In an experimental model of myocardial failure, high doses of digoxin increased myocardial necrosis, cellular infiltration, intracardiac IL-1b, TNF-α, and mortality. However, no death occurred among control animals treated with 10 mg/kg.³⁵

Clinical Pharmacology

Digoxin and digitoxin are the two most widely used cardiac glycoside preparations. The disposition of both drugs have been studied in dogs^194-197 and is variable among animals and preparations. Oral bioavailability of digoxin varies from 40% to 90%, depending on the preparation. Up to 90% of the alcohol (i.e., elixir) is absorbed, with peak concentrations occurring in 45 to 60 minutes.³ Variation in bioavailability of tablets is affected by differences in dissolution between products. Absorption is retarded by food. Compared with digoxin, oral absorption of the more lipid-soluble glycoside, digitoxin, is much more complete and thus predictable. Interestingly, in humans Eubacterium lentum, a normal microbial inhabitant, metabolizes digoxin to inactive metabolites in a small percentage of the population, leading to unexpected decreased bioavailability. Both digoxin and digitoxin are distributed slowly, in part because of a large volume of distribution that includes most body tissues but also reflects concentration in cardiac tissues. Although the volume of distribution of digoxin is large, it is distributed primarily to cardiac and skeletal muscle, indicating that dosing should be based on lean body weight.⁶ Only 25% of digoxin is protein bound, whereas most of digitoxin (90%) is protein bound. Accordingly, response to digoxin should be faster and the dose of digitoxin should be higher (to compensate for high protein binding). Digoxin is primarily eliminated unchanged in the kidneys. The half-life varies from 21 to 60 hours,³ with a working average of 1.7 days. Half-life is variable in the same animal, ranging from 46 to 154 hours in one study.³ Elimination half-life is strongly influenced by renal function. Because variability increases as renal function changes with the progression of cardiac disease or response to therapy, monitoring of both a peak and a trough is strongly recommended. For example, our laboratory has demonstrated an elimination half-life for digoxin to be as short as 9 hours in animals concurrently receiving an ACE inhibitor and diuretic therapy but longer than 48 hours in animals with presumed renal dysfunction.

In contrast to digoxin, digitoxin is metabolized by the liver to digoxin and other metabolites. Its metabolism is affected by factors that alter the microsomal system but generally not hepatic disease. Despite binding to serum proteins and hepatic metabolism, a half-life of 8 to 12 hours in dogs (parent compound) is shorter than that of digoxin, which may necessitate more frequent dosing. Digitoxin undergoes a small enterohepatic cycle.

Population kinetic analysis has been used to describe the disposition of digoxin in a population (n=161; 32 studied prospectively) of dogs with naturally occurring heart disease.¹⁹⁸ Covariable data collected included serum creatitine and potassium, body weight and body surface area, and formulation of digoxin administered. Dosing regimens (dose, intervals), formulation of digoxin, type and state of cardiac disease, and adjuvant medications and method of monitoring (time of sample collection, analytic technique) varied among animals. The rate of oral absorption was markedly variable. The slowest absorbers (n=19) were prospectively studied and as such had been admitted 2 hours before dosing, compared with the remaining 142 cases, in which dosing occurred at home. Based on the reported rate constant, the absorption half-life in the slow absorbers approximated 6.1 hours compared with 1 hour for the fast absorbers. The type of formulation (Lanoxin tablets versus elixir) did not statistically influence the absorption rate constant. These data suggest that the stress of admission may profoundly affect the rate of absorption and perhaps the peak plasma drug concentration of digoxin, indicating that patients ideally be dosed at home before monitoring. Elimination rate constants (and thus half-life) were not reported. Potassium was negatively correlated to volume of distribution corrected for oral bioavailability (Vd/F), potentially reflecting displacement of digoxin from its tissue binding sites (Na⁺/K⁺ ATPase) by potassium, resulting in a smaller volume of distribution. Creatinine was a poor predictor of changes in digoxin clearance even when corrected for bioavailability (Cl/F).

Preparations and Dosing Information

Digoxin is available for intravenous or oral administration. Intravenous administration results in pharmacologic effects in 5 to 30 minutes, with a maximal effect in 2 hours. Intravenous administration might (very cautiously) substitute for oral dosing in animals intolerant to the latter. Digoxin should not be given intramuscularly because it is erratically absorbed and causes pain and tissue necrosis. Oral administration results in pharmacologic effects in 1 to 2 hours, although peak effects will not occur until steady state is reached. Digoxin elixir is more orally bioavailable, and it may be necessary to decrease doses by 15%. If deemed necessary, oral digitalization is best accomplished with digoxin tablets. In the absence of a loading dose, steady-state concentrations can be achieved within 48 hours of oral dosing in most patients. If necessary, a prudent intravenous loading dose is administration of the oral daily maintenance dose over a 12-hour period.¹⁹¹ Doses should be calculated on lean body weight; toxicosis is likely to be minimized if dosing is based on body surface area (0.44 mg/m²). Daily doses should be divided if warranted on the basis of drug elimination half-life (as calculated from therapeutic drug monitoring) to minimize fluctuation in plasma drug concentrations.

Drug Interactions

The concurrent administration of quinidine increases plasma concentrations of digoxin; the mechanism may reflect displacement from tissue binding sites, although this mechanism is controversial.^117,199 Quinidine also appears to decrease renal digoxin clearance by decreasing renal blood flow.²⁰⁰ Verapamil also increases concentrations of digoxin.¹⁹¹ Interactions between digitalis and diuretics have been reported and stem primarily from the effects on potassium (hypokalemia). Diuretics do not seem to alter the disposition of digoxin.²⁰¹ Phenobarbital has been reported to increase (rather than decrease) digoxin concentrations; the clinical relevance of this report is not clear.^201,202 Administration of β-adrenergic agonists increases the likelihood of arrhythmias. Amphotericin B may also cause hypokalemia and thus potentiate digitalis intoxication.

Clinical Efficacy

Inotropic response to digoxin is greatest in the initially depressed state of the failing heart. Stroke volume increases as ventricular emptying improves, with a reduction in end-diastolic volume.¹⁹¹ This positive effect is less likely if intrinsic compensatory mechanisms are maintaining cardiac output. The inotropic response to digoxin occurs before evidence of electrophysiologic changes. As a positive inotrope, withdrawal of digoxin in human patients with mild to moderate CHF and a normal sinus rhythm resulted in a significant (compared to placebo) worsening of clinical signs. In patients with severe CHF, fewer patients receiving digoxin died or were hospitalized as a result of CHF during the study period. Retrospectively, digoxin effects were best when concentrations were below 1 ng/mL. However, it is not clear if this effect is due to decreased heart rate or a positive inotropic effect: clinically, animals may have the greatest improvement immediately before accumulated glycoside toxicosis.¹⁹¹ Digoxin may also decrease myocardial remodeling: ouabain increased mediators associated with ventricular remodeling after myocardial infarction.³⁵ Digoxin modulates neurohumoral and autonomic states.³⁵ Currently, in humans digoxin therapy generally is reserved for patients with heart failure accompanied by atrial fibrillation or for patients with a sinus rhythm but who have not yet sufficiently responded to ACE inhibitors and adrenergic receptor antagonists.

Proof of efficacy of digoxin in the treatment of CHF in dogs has been difficult to establish, in part because of poorly designed clinical trials.¹⁹¹ Studies are complicated by failure to control variables and, most notably, adjunct therapy. Subclinical measures based on hemodynamic response often have not been included, making it more difficult to identify efficacy. Different levels of disease also influence outcome; response to digoxin may be less obvious in the terminal stages of congestive cardiomyopathy (shortening fraction of 20%).¹⁹¹ Clinical trials based on survival analysis similarly have been fraught with poor methodologies. Controversy also exists regarding the relative efficacy of digoxin versus digitoxin in the treatment of CHF in dogs.¹⁹¹ Early studies with dogs receiving either drug revealed greater clinical improvement in dogs with CHF treated with digoxin (85%) than digitoxin (55%) but a greater risk of toxicity (based on electrophysiologic changes in the PR interval.^203,204 It is likely, however, that digitoxin was underdosed in these studies.¹⁹¹ Current consensus among cardiologists is that digoxin is the preferred drug on the basis of both pharmacodynamics and pharmacokinetics.

Knight¹⁹¹ offered a description of the canine patient most likely to respond to digoxin therapy. Such a patient is asymptomatic, with CHF characterized primarily by systolic ventricular dysfunction accompanied by supraventricular tachycardia, including sinus tachycardia, atrial flutter, and fibrillation. Chronic mitral regurgitation is included in the indications, although timing of the use of digoxin as treatment in this syndrome may be less clear unless myocardial failure is evident. Digoxin is not indicated for the compensated patient that is asymptomatic (including normal sinus rhythm; plus or minus diuretics). Aggressive treatment may be necessary to control heart rate. Whereas vagally mediated effects occur at subtoxic concentrations (50% of the toxic dose), the direct effects on atrioventricular nodal conduction occur only at full digitalization—that is, as toxic concentrations are approached.¹⁹¹ Such concentrations may be more necessary in patients with atrial flutter or fibrillation for which response might be dependent on atrioventricular nodal effects. The negative chronotropic effects are decreased in the presence of concurrent sympathetic stimulation, which is more likely as the severity and chronicity of heart failure increases. Thus sinus tachycardia is most likely to normalize if cardiac function improves sufficiently to minimize sympathetic stimulation. β-adrenergic blockers or CCBs may be useful adjunct therapies if heart rate remains unacceptably high in patients receiving digoxin.¹⁹¹

Controversy exists regarding whether digoxin should precede, accompany, or follow vasodilator therapy and, more specifically, ACE inhibitor therapy. Preference generally favors the latter. Digoxin is, however, indicated for symptomatic patients that cannot tolerate ACE inhibitors and for patients that presented with moderate to severe clinical manifestations of decompensation, particularly if the patient is no longer responsive to diuretic or vasodilator therapy.¹⁹¹

Monitoring

Monitoring recommendations for digoxin are extrapolated from human medicine. The traditional recommended therapeutic range of 0.8 to 2.0 ng/mL is intended to prevent toxic concentrations but not necessarily identify efficacy. Maximal contractile activity in humans generally occurs at concentrations between 0.5 and 1.5 ng/mL.²⁰⁵ Neurohormonal benefits may occur at concentrations of 0.5 to 1 ng/mL.⁶ Although inotropic effects will continue to increase as drug concentrations increase, peak effects are likely to be limited by toxicity. Because the risk of death increases at higher concentrations associated with maximal contractility, concentrations below 1 ng/mL are recommended for humans.

Therapeutic concentrations of digitoxin and digoxin differ. For digitoxin recommended concentrations are 1.4 to 2.6 ng/mL.³ The recommended range for digoxin is likely to vary with the laboratory but generally is 1 to 2 ng/mL or 1.5 to 2.5 ng/mL.¹⁹⁵ Because the time needed for C_max to decline to C_min is one half-life, the dosing interval should not exceed patient half-life. The targeted concentration for either cardiac glycoside in the individual animal should be based on clinical signs, including response to therapy. Traditionally, single samples (generally mid trough) have been collected at mid interval for monitoring. However, based on 2 hr peak and 12 hr trough samples, the author has documented a shortening of digoxin half-life in a patient treated with ACE inhibitors (presumably due to increased glomerular filtration rate and thus renal digoxin clearance) or other therapy. In such patients plasma drug concentrations can fluctuate twofold during a dosing interval, causing the patient to become both toxic or subtherapeutic. For such patients design of a dosing regimen might best be based on both peak and trough concentrations (at 2 and 11.5 hours after oral administration at home). If only a single sample is possible, selection of the time of collection depends on the intent of monitoring. If toxicity is of concern, a peak sample should be collected 1 to 2 hours after administration at home; if efficacy is of concern, then a trough sample should be collected just before the next dose. However, neither situation will provide guidance regarding drug concentrations throughout the dosing interval.

Toxicity and Side Effects

Digitalis intoxication is not uncommon, although improper use plays a large role in the incidence of adversity. In addition, signs of toxicity are more easily recognized than are signs of efficacy, contributing to the perceived narrow therapeutic margin. It is likely that with proper use the risk–benefit ratio is not as narrow as perceived. Serious toxic effects of digitalis are due to altered electrical activity, which reflects changes in intracellular calcium, sodium, and potassium changes and thus the electric potential formed across the cell membrane. Digitalis causes an increase in automaticity and ectopic beats. As concentrations surpass 2 ng/mL, the risk of sinus bradycardia or arrest, prolongation of atrioventricular conduction, heart block, or increased sympathetic nervous activity with increased automaticity increases. The negative chronotropic effects of digitalis can be ameliorated with atropine.

Digoxin binds preferentially to the phosphorylated form of Na⁺,K⁺-ATPase, whose concentration is decreased by extracellular potassium. Thus hypokalemia increases digoxin toxicity by facilitating binding to the target protein.⁶ Increased intracellular calcium also contributes to the arrhythmogenicity of digoxin.⁶ The increased calcium causes the cytoplasmic membrane to become unstable immediately after repolarization and cell membrane permeability to Na⁺, Ca²⁺, and K⁺ increases. Ion flow of Na⁺ and Ca²⁺ follows the concentration gradient, tending to hypopolarize the membrane (i.e., it moves toward 0 mV); flow of potassium is less important because concentration and electrochemical gradients for potassium tend to balance one another. Dysrhythmias tend to worsen as calcium increases as the risk of after-depolarization–mediated automaticity increases.⁵

Because the mechanism of arrhythmogenicity for digoxin is the same as the mechanism of efficacy (positive inotropic and negative chronotropic effects), it is not surprising that cardiac glycosides are characterized by a narrow safety margin. Any cardiac antiarrhythmia may be induced by digitalis. An electrocardiogram should be useful in diagnosing digitalis toxicity if compared with an electrocardiogram obtained before drug administration. Changes in sodium, calcium, or potassium increase the risk of arrhythmias associated with automaticity. In the atrium digoxin shortens the action potential, predisposing it to atrial fibrillation.⁵ The negative chronotropic effects of digoxin also can directly slow sinus nodal activity, leading to heart blockade. Arrhythmias include sinus bradycardia; disturbances of atrial rhythm; atrioventricular conduction, including complete atrioventricular block (third-degree heart block); and disturbances of ventricular rhythm, especially premature beats. Ventricular tachycardia and flutter may also occur. The likelihood and severity of toxicity are related to the severity of cardiac disease. Toxic effects with digitalis are frequent and can be lethal if allowed to persist. Dogs with severe cardiomegaly and CHF are probably at greater risk of developing ectopic ventricular arrhythmias. Other factors predisposing to digoxin toxicity include but are not limited to hypokalemia, hypercalcemia, hypomagnesemia, hypothyroidism, acid–base imbalances, and abnormal renal function.⁶ Combination therapy with selected drugs also predisposes the patient to toxicity. The cat is more sensitive to digoxin than the dog.

Digoxin also causes noncardiac toxicities as a result of impaired Na⁺-K⁺ pump activity on neuronal and secretory organs. Frequently, the earliest indications of digoxin toxicity are gastrointestinal adversities including anorexia; nausea; vomiting; and, less frequently, diarrhea. Vomiting also results from direct stimulation of the chemoreceptor trigger zone. Neurologic effects include malaise and drowsiness.

The most frequent cause of digoxin toxicity is probably overdosing, which includes failure to individualize dosing regimens. The potential for toxicity is increased with hypokalemia because binding to the Na⁺-ATPase pump is facilitated. This may occur, for example, if the patient is also receiving diuretic therapy that causes potassium loss (furosemide, thiazides, and other “nonsparing” diuretics). Digitalis toxicity can be diagnosed and the risk minimized by plasma drug concentration monitoring. Therapeutic concentrations of digitoxin and digoxin differ. For digitoxin concentrations greater than 3.4 ng/mL are considered toxic.³ For digoxin the risk of toxicosis is greater if concentrations exceed 2 to 2.5 ng/mL.¹⁹⁵ Because of overlap between toxicity and efficacy, concentrations should be considered in the context of clinical signs.

The treatment of cardiac glycoside intoxication includes (1) discontinuation of digitalis therapy for at least one drug elimination half-life; (2) discontinuation of potassium-depleting diuretics; and (3) administration (as needed) of phenytoin, which blocks atrioventricular nodal effects of digitalis (bradyarrhythmias), lidocaine (for ventricular arrhythmias)²⁰⁶ (1-3 mg/kg intravenously), and oral potassium supplementation (e.g., potassium chloride), but only if hypokalemia exists.³ Atropine may be useful to treat sinus bradycardia and second- or third-degree heart block induced by cholinergic augmentation. Procainamide also has been shown experimentally to be useful for treatment of digoxin-induced ventricular arrhythmias in the canine heart when plasma drug concentrations approximate 8 to 12 ng/mL.^207,208 Cholestyramine can be used as a binding agent to decrease absorption from the gastrointestinal tract (including drug undergoing enterohepatic circulation).

The large volume of distribution of digoxin prevents the use of techniques for increasing clearance as an approach to decreasing the risk of toxicity in the case of overdose. Purified ovine antibody fractions (Fab) to digoxin (DIGIBIND® or DIGIFAB®) have proved to be an effective antidote to life threatening digoxin toxicity (e.g, ventricular arrhythmias) following massive overdose in humans. Although they have been successfully used by the author to treat an accidental overdose of digoxin, their cost is likely to be prohibitive. The drug costs $700-800 per vial; an adequate dose may result in a cost of thousands of dollars. Dosing is complicated, being based on the total amount of digoxin in the body. This can be estimated on the basis of the amount ingested and the average bioavailability or on serum digoxin concentrations and the average volume of distribution.⁶ Toxicity can recur once the Fab has been eliminated 1 to 2 days after therapy, particularly in patients with impaired renal function.

Clinical Use

The recent approval of pimobendan for use in dogs should result in a decline in the use of cardiac glycosides as positive inotropes. Clinical uses of digitalis have included restoration of adequate circulation in patients with CHF and reduction of the ventricular rate as a treatment of atrial fibrillation or flutter. Both syndromes require long-term treatment. If there is no urgency in treatment, the drug can be administered orally. Maximal effect is achieved in four half-lives. Digoxin is the cardiac glycoside drug of choice except for the patient with renal disease; digitoxin should then be administered. Calculation of digoxin doses should be based on lean body weight, and dosages should be reduced in the obese patient or in the presence of ascites. Electrolyte disorders should be corrected before dosage.

Methylxanthine Derivatives

Methylxanthine derivatives have been classified as PDE inhibitors, but the mechanism of action is controversial. Their positive inotropic effects may actually reflect altered calcium fluxes or other mechanisms. Of the methylxanthines, theophylline is the most cardiopotent. The positive inotropic effects of these drugs are complex because they have a variety of pharmacologic actions. In addition to their cardiac effects, these drugs have significant central nervous system, renal, and smooth muscle effects. Thus their use for cardiac disease is limited.

Fatal toxicities can and often do occur during chronic oral or rapid intravenous administration of methylxanthines, probably as a result of cardiac effects. Tachycardia and central nervous system signs (restlessness, hyperexcitability, sensory disturbances) can be correlated with increased plasma concentrations. Plasma monitoring may be used to control toxicity. Local gastrointestinal irritation and nausea, vomiting, and diarrhea may occur with oral administration. These can be prevented by administration of the drugs with food. Therapeutic uses for the methylxanthines in cardiac disease are limited. In veterinary medicine theophylline has been used to treat CHF. Currently, these drugs should be used only in cardiac patients with respiratory disease.

Bipyridines

Bipyridines are nonglycosidic, noncatecholamine positive inotropes that have cardiac effects similar to catecholamines. The mechanism of action of these drugs is probably inhibition of PDE and increased intracellular cAMP concentrations. However, unlike catecholamines, myocardial oxygen consumption does not increase and may actually decrease in patients with CHF. Differences in potency and toxicity when compared with theophylline may reflect selective PDE isoenzyme inhibition for each group of drugs. The bipyridines inhibit PDE III only, whereas theophylline may be a nonselective inhibitor of PDE. Amrinone was the first of this class of drugs to be used therapeutically, but side effects limited its use. Milrinone is more potent than amrinone (20 to 30 times) yet characterized by a toxic to therapeutic ratio of 100 in normal dogs. Milrinone is a selective PDE III inhibitor. It lowers pulmonary vascular resistance in patients with CHF and pulmonary hypertension. Peripheral vasodilation is another major therapeutic benefit of PDE III inhibitors. Milrinone increases renin secretion, presumably by increasing cAMP in juxtaglomerular cells.²¹¹ Side effects at higher doses limit long term use. Intravenous milrinone lowers pulmonary vascular resistance in human patients with CHF and pulmonary hypertension.²¹⁰

Intravenous or oral administration of milrinone results in marked positive inotropic effects in patients with CHF. Effects are dose dependent. Contractility increases up to 100% at plasma concentrations of 200 mm/L after infusion of 10 μg/kg per minute in anesthetized dogs versus only 60% in patients receiving digitalis. An oral dose of 1 mg/kg increases contractility by 90% and decreases blood pressure by 10%. As with the cardiac glycosides, animals with very poor myocardial function may not be able to respond to the bipyridines. In contrast to cardiac glycosides, heart rate increases 40%. As with drug disposition, individual animal response to milrinone appears to be quite variable.²¹² Pilot studies indicate an elimination half-life of about 1.4 hours for milrinone in dogs, although this is likely to be quite variable.²¹² Oral bioavailability approximates 92%. Milrinone does not appear to be as effective a positive inotrope for people as it is for dogs. In clinical trials in dogs with CHF, approximately 80% of animals reportedly respond to milrinone.²¹³ Survival data were not reported for dogs. Milrinone appears to be substantially safer than digoxin when given at an oral dose of 0.5 to 1 mg/kg twice daily. However, exacerbations of arrhythmias may occur in some animals. Ruptured chordae tendineae (4%) and sudden death (13%) were other complications reported in clinical trials with dogs with CHF.

Pimobendan and levosimendan

Pimobendan is a benzimidazole–pyridazinone derivative that acts as a specific type III PDE inhibitor, causing positive inotropy. However, its efficacy may reflect actions as a calcium sensitizer. Pimobendan enhances calcium–troponin C interaction. Pimobendan increases sensitivity at low concentrations, increasing the risk of diastolic dysfunction resulting from decreased lusitropy (relaxation). However, neither pimobendan nor its congener, levosimendan, affect or improve myocardial lusitropy. In addition to its positive inotropic effects, pimobendan prolongs the action potential duration by enhancing calcium current through L-type calcium channels in the sarcolemma. However, prolonged action potential duration may increase the risk of QT syndrome. In contrast to the other Ca²⁺-sensitizers, both pimobendan and levosimendan cause vasodilation of both the arterial and venous vessels, reflecting activation of the Ca²⁺-dependent K⁺-channels (and ATP-sensitive K⁺-channels for levosimendan); As such, pimobendan is referred to as an inodilator. Additionally, pimobendan is associated with a reduction of proinflammatory cytokines that initiate or perpetuate myocardial remodeling associated with progressive CHF.³⁵ As such, pimobendan appears to provide some level of cardioprotection. Finally, pimobendan also exerts antithrombotic effects. ^192,209 In contrast to pimobendan, an advantage of levosimendan is that it appears to sensitize to calcium without influencing PDIII activity unless higher concentrations are achieved. As such, levosimendan may be the perfect “designer” drug for treatment of systolic dysfunction in patient with CHF. Treatment with levosimendan improved hemodynamics and patient survival in one study, although the study groups were too small to allow mortality assessment. Improvement occurred even in patients treated with beta-adrenoceptor blockers, which currently are associated with the best evidence of improved hemodynamics and survival in patients with chronic heart failure.²⁰⁹

Pimobendan is prepared as a mixture of stereoisomers. In humans, although the pharmacokinetics of the enantiomers is the same, the l-isomer is 1.5 times more potent in increasing strength of contraction than the d-isomer. In humans both enantiomers accumulate in red blood cells, with the respective (+)- and (−)-pimobendan ratio (red blood cell: plasma) being 5.8 and 8.4. Similar data could not be found in dogs. Food may slow or impair oral absorption. Oral bioavailability is 60 to 65%, In normal dogs, peak plasma drug concentration (C_max) for the parent and metabolite following administration of 0.2 mg/kg orally was 3.09 ± 0.76 ng/mL and 3.66 ± 1.21 ng/mL, respectively. Pimobendan is highly (>90%) protein bound in dogs. The apparent volume of distribution at steady state (presumably of unbound drug) is 2.6 L/kg. In dogs pimobendan is demethylated to an active metabolite (UDCG-212) that contributes substantially to its pharmacodynamic effects. The metabolite is a more potent inhibitor of PDIII; however, its mechanism of calcium sensitization may be different from that of the parent compound. Metabolism appears to occur primarily by CYP1A2 (in humans), although its contribution to metabolism is variable, ranging from 18 to 76%; CYP3A4 accounts for less than 10% of elimination. The active metabolite is then excreted by sulfation or glucuronidation and eliminated through feces. Elimination half-life of pimobendan and its metabolite in dogs are 0.5 and 2 hours, respectively (which is similar to both isomers in humans).

A delay occurs between peak pimobendan concentration and peak left ventricular contractility response; further, response persists beyond elimination of drug. In both dogs and humans, effects are still evident at 8 hours, despite a short half-life in either species. In humans pharmacodynamic effects include increased ejection fraction, mean shortening velocity, cardiac index, and stroke volume index (each increased 50% to 60%). Left ventricular end-systolic dimension, SBP, and diastolic blood pressure are decreased 8% to 11% in humans. However, although pimobendan improves morbidity and the physical exercise capacity of human heart failure patients, decreased mortality has not yet been demonstrated.

Pimobendan has been used extensively in dogs with acquired cardiac disease including mitral valve insufficieny and dilated cardiomyopathy; its use should be considered in dogs with systolic dysfunction associated with primary myocardial disease or chronic volume loading. The labeled dose of pimobendan in dogs is 0.5 mg/kg administered every 12 hours and given at least 1 hour before food. Dosing is usually started at the low end of the dose range. Pimobendan can be combined with a variety of cardiac drugs, including diuretics, ACE inhibitors, or digoxin. However, the positive inotropic effects may be reduced when given in conjunction with calcium channel antagonists or β-adrenergic antagonists.

Pimobendan has been compared to levosimendan and milrinone in anesthetized dogs.^213a All three drugs increased myocardial contractility, venous and arteriolar vasodilation, left ventricular -arterial coupling and mechanical efficiency; levosimendan increased myocardial efficiency. The clinical use of pimobendan in dogs has been reviewed.^214-216a

In normal dogs pimobendan moderately reduced systemic and pulmonary vascular resistance, markedly reduced left ventricular end-diastolic pressure, and moderately increased heart rate and cardiac output. Myocardial blood flow also is increased. A lusitropic effect also has been demonstrated in the left ventricle of normal dogs.⁵⁴ Efficacy in diseased dogs may be superior to that in humans. Summaries of the field (clinical) trial (n=355 dogs) supporting approval of pimobendan found efficacy to be equivalent to that of enalapril in dogs with grades II to IV CHF associated with either valvular disease or DCM. Dogs also received diuretics and, as needed, digoxin for supraventricular arrhythmias. Side effects were similar in both groups.

Kanno and coworkers²¹⁹ described the effects of pimobendan (0.25 mg/kg twice daily) on cardiac, hemodynamic, and neurohumoral factors in dogs with mild mitral regurgitation. Dogs were treated for 4 weeks. Pimobendan was associated with a decrease in SBP and the degree of regurgitation, an increase in renal blood flow and glomerular filtration rate, decreased norepinephrine concentrations, and improved heart size. Using a randomized, placebo controlled, double-blinded study in dogs (10 English Cocker Spaniels, 10 Doberman Pinschers) with DCM, when added to standard therapies (i.e., furosemide, enalapril, digoxin), pimobendan (0.3 to 0.6 mg/kg/day) was demonstrated to improve heart failure class, and to prolong survival in Doberman Pinschers (mean of 329 days compared with 50 in placebo group).²¹⁶ O’Grady and coworkers²²⁰ also found that the addition of pimobendan (0.25 mg/kg PO every 12 hr) to standard diuretic (furosemide) and afterload reduction (benazepril) therapy was associated with a longer time (130.5 days) to treatment failure in Doberman Pinschers with DCM and CHF compared with the placebo group (63 ± 14 days).

Pimobendan also has proven useful for treatment of degenerative mitral valvular disease. The QUEST study²²¹ compared the impact of pimobendan (n=124) versus benazepril (n=128) on mortality in dogs from Europe, Canada, and Australia afflicted with myxomatous mitral valve disease. Of the dogs reaching an endpoint associated with decline the median time was 267 days for pimobendan compared to 140 for benazepril. Pimobendan (0.2 to 0.3 mg/kg twice daily) did not have a sustained positive effect on echocardiographic values of asymptomatic dogs (some were receiving ACE inhibitors) (n=24) with mitral valve disease using a randomized, blinded design. An initial increase in systolic function at 30 days did not persist to study end (6 months). However, a major limitation of the study was the sample size.²²²

Other studies have compared pimobendan to ACE inhibitor therapy in an attempt to identify the most effective approach. Using a prospective, randomized, single-blinded parallel design, the clinical efficacy and safety of pimobendan was compared in a 6-month study to ramipril in client-owned dogs (n=43) with mild to moderate heart failure associated with mitral valve disease. Treatment was well tolerated in both groups; pimobendan-treated dogs were only 25% as likely to have an adverse outcome related to heart failure (odds ratio 4.09, 95% confidence interval 1.03 to 16.3, P=0.046). However, despite randomization, dogs receiving ramipril began with a higher overall score, suggesting this group had more severe disease.²¹⁷ The efficacy of pimobendan (n=41) was also compared to benazepril as a positive control (n=35) in dogs with atrioventricular disease using a parallel, randomized, blinded multicenter clinical trial (VetSCOPE). Animals were assessed at 56 days, and long-term survival was determined.²¹⁸ Scores in dogs receiving pimobendan improved compared with those of animals not receiving pimobendan; further, long-term survival was greater at 415 days compared with 128 for dogs not receiving pimobendan.

Timing of pimobendan administration in the progression of myocardial disease may be important. Discontinuation of pimobendan improved mitral regurgitation in two dogs⁵⁷ led to a double blinded parallel clinical trial comparing the effect of either pimobendan or benazepril in dogs (Beagles; n=12; 6 per group) with asymptomatic, naturally occurring mitral valvular disease.²²³ Increased systolic function associated with a longer regurgitant jet characterized by a greater velocity was detected in the pimobendan group within 15 days of initiation of therapy. Histologic mitral valvular lesions were worse (moderate to severe) in three dogs at the end of the 512-day treatment period in the pimobendan group compared with the benazepril group (mild to slight in six dogs).

Evidence exists that pimobendan can be combined with standard cardiovascular drugs with no apparent adverse effects, as has been suggested by clinical trials assessing efficacy. In addition, Fusellier and coworkers²²⁴ failed to detect significant differences in adversities when pimobendan was combined with meloxicam in 10 Beagles using a randomized, crossover design. However, dogs were studied 4 times (placebo, meloxicam, pimobendan, and the combination), and the power to detect a significant difference was not addressed, indicating that an adverse reaction cannot be ruled out.

Pimobendan has been associated with histologic damage to the endocardium, myocardium and valves, particularly at high intravenous disease. ^224a A randomized, blinded, controlled clinical trail in Beagles (n=12) with mitral valvular disease comparing the impact of 512 days of therapy with either benazepril and pimobendan found that pimobendan was associated with an increase in the maximum area and peak velocity of the regurgitant jet turbulence. Further, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans occurred in the pimobendan-treated dogs. These studies support avoiding pimobendan use unless indicated.

Dopamine

Dopamine is an endogenous catecholamine (norepinephrine) precursor with selective β₁ activity. It is widely used as a cardiac stimulant. Because it stimulates the release of norepinephrine, however, it has α-receptor-, β₂-receptor-, and dopaminergic-receptor–mediated actions as well. Its inotropic effects are due to β₁-receptor stimulation in the heart. At low doses (4 μg/kg per minute) in dogs, dopamine increases stroke volume and cardiac output and stimulates renal dopaminergic receptors, causing increased renal blood flow and diuresis. This is useful during situations of systemic vasoconstriction (e.g., shock), during which it is important to maintain renal blood flow. At high doses, however, it causes α-adrenergic stimulation and vasoconstriction. This may potentially reduce renal blood flow. Vasoconstriction can be reversed with alpha-adrenergic blocking drugs (e.g, phenothiazines). Dopamine appears to increase systolic pressure without significantly affecting diastolic pressure.

Dopamine is not effectively absorbed orally. It is rapidly metabolized by the body by monoamine oxidize and catechol O-methyl transferase (COMT) and has a half-life of less than 2 minutes. Dopamine is most commonly marketed as a solution that is further diluted with saline or dextrose. The drug is administered intravenously. Because the pharmacologic effects of dopamine are short lived, it is usually administered by constant infusion, and rate of administration can be used to control the intensity of effects.

Cardiac arrhythmias may occur following dopamine therapy due to α-adrenergic activity. Dopamine should not be used in the hypovolemic patient (in part because of the potential for enhanced vasoconstriction in response to α-adrenergic activity). Tissue sloughing may occur in the event of perivascular leakage. Indications include cardiogenic, or endotoxic, shock and oliguria. Dopamine has been compared to norepinephrine as a pressor agent in humans; although statistical difference in 28 day mortality could not be demonstrated between the two groups, dopamine was associated with more life-threatening arrhythmias.^223a Dopamine can be diluted in a variety of fluids; an exception is fluids containing sodium bicarbonate or other alkaline infusions that will inactivate the drug. It will remain stable for at least 24 h after dilution.

Dopamine receptors are present in the cat, with D1 receptors identified in the feline renal cortex. The concentration appears to be lower than that in rats, dogs, and humans. The status of dopamine receptors in the feline renal vasculature is not clear. However, fenoldopam, a dopamine agonist, exhibits 300-fold greater affinity than dopamine for feline dopamine receptors, suggesting that failure of feline renal response to dopamine reflects a lack of dopamine receptors.²²⁵ This suggestion is supported by the observation that low-dose dopamine can provide effective diuresis in the dog but not the cat, yet higher doses of dopamine do increase diuresis and natriuresis in the cat.^225,226 Fenaldopam is used for treatment of emergency hypertension and to stimulate systemic vasodilation, natriuresis, and diuresis in human patients with renal disease.²²⁷ Dopamine is likewise indicated in veterinary patients to induce diuresis in dogs with oliguric renal failure, in dogs and cats as a pressor agent in the presence of hypotension, and to provide inotropic support in the failing congestive heart.

Dobutamine

Dobutamine is a synthetic drug that is similar to dopamine but with the addition of a large bulky molecule that reduces non-β₁ effects. Dobutamine is a more effective inotrope than dopamine and is not associated with increased cardiac rates at lower doses. Therapeutic and pharmacologic ranges, respectively, are 0.1-10 μM; 10-100 μM.²²⁸ Dobutamine appears to increase cardiac contractility with less cardiac oxygen consumption than other catecholamines. Dobutamine does not dilate the renal vascular bed as does dopamine, although in a canine model of endotoxic shock it increased urine output and mesenteric blood flow at 5 and 10 μg/kg per minute, probably resulting from cardiac effects.²²⁹ Because of its greater selective effect on contractility as opposed to increasing heart rate, it is preferred to dopamine as a positive inotrope for treatment of CHF that is severe and eminently life threatening. Its arrhythmogenicity is less than that of epinephrine and is not likely to occur (in normal dogs or dogs with ventricular ectopic beats) until therapeutic doses have been exceeded.

Dobutamine is not effective orally and has a plasma half-life of approximately 2 minutes because of metabolism by COMT. It is therefore usually administered by constant-rate intravenous infusion. The drug is metabolized in the liver to inactive glucuronide conjugates. Like dopamine, dobutamine is prepared as a solution to be diluted with dextrose or variety of fluids, but is inactivated by alkaline solutions such as those containing sodium bicarbonate. It is stable for only 6 hours after dilution. The major indication for dobutamine is short-term therapy for refractory CHF. It is the preferred drug (e.g., compared with digoxin) because its short half-life reduces the potential for toxicity and the inotropic effects of dobutamine are greater. Treatment beyond 48 hours is discouraged, in part because of the development of tolerance. In people, however, a residual effect occurs for up to several months. Dobutamine and volume replacement are indicated for treatment of hemorrhagic shock.²³⁰ Likewise, in dogs with septic shock, dobutamine (5 to 10 μg/kg per minute) increases mesenteric blood flow and urine output when administered in conjunction with fluid therapy.²²⁹

The dose generally recommended is 2.5 to 20 μg/kg/min in dogs and 0.5-5 μg/kg/min in cats, starting with an initial dose of 2.5 to 5 μg/kg/min and increasing 1-2 μg/kg/min every 5 to 30 minutes. Improvement should occur within 30 minutes. The most common side effect is ventricular arrhythmias, which are less likely to occur if doses of 15 μg/kg per minute are not exceeded. Arrhythmias should not be treated with β-adrenergic blockers; rather, the dose should be decreased until arrhythmias resolve. Animals with very severe CHF and very poor myocardial function may not be able to respond to dobutamine because of little contractile reserve. Tachyphylaxis may occur within 72 hours of continuous treatment owing to downregulation of β1 - receptors.

Epinephrine

Epinephrine is one of the most potent vasopressor drugs known. It causes an immediate rise in blood pressure as a result of (1) direct myocardial stimulation and a positive inotropic effect, (2) an increased heart rate or positive chronotropic effect, and (3) vasoconstriction in many vascular beds. As with the other catecholamines, its cardiac effects are due to direct interaction with β₁-receptors and cells of the pacemaker and conducting tissues. Cardiac systole is shorter and more powerful. Because the formation of cAMP requires ATP, however, 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. Increased work and myocardial oxygen consumption result in reduced cardiac efficiency.

Epinephrine is rapidly metabolized in the gastrointestinal tract and does not reach therapeutic plasma concentrations after oral administration. Absorption is more rapid after intramuscular versus subcutaneous administration because of local vasoconstriction. Epinephrine is rapidly metabolized by the body. The liver plays an important but not essential role in the metabolism of epinephrine. Two enzymes catalyze its degradation: COMT and monoamine oxidase.

Epinephrine is available in several forms of solution that can be used for intravenous, inhalation, and nasal administration. Because of the decreased efficiency of cardiac work, epinephrine is not used simply as a positive inotropic agent. Ventricular arrhythmias can be expected. In addition, central nervous system signs may occur. The primary indication for epinephrine in treatment of cardiac disease is acute cardiac life support (see the discussion of “crash cart” drugs) or for pressor support in patients insufficiently responsive to norepinephrine.

Isoproterenol

Isoproterenol is a nonspecific β-agonist that, like epinephrine, increases myocardial oxygen demand. Tachycardia and the potential for other arrhythmias tend to exclude its use for the cardiac patient.

Miscellaneous Agents

Miscellaneous inotropic agents include calcium when given as a slow intravenous injection or infusion. Care must be taken with the administration of calcium because it can cause cardiac rigor and standstill at high doses; attention must be given to the amount of calcium per dosing unit (e.g., ml or oral dosing form) among the different oral or injectable salts (see Table 14-3). The gluconate form is preferred to calcium chloride. Glucagon is also a positive inotropic agent.

Phenylpropanolamine is used primarily to treat urinary incontinence, but toxicity is manifested predominantly in the cardiac system. Toxicity was reported in a 5-year-old, female Labrador Retriever receiving 48 mg/kg. Clinical signs included tachypnea, tachycardia, and ataxia. Cardiac arrhythmias were characterized by multiform ventricular tachycardia, left ventricular dilation with a focal dyskinetic region in the dorsal intraventricular septum, and elevations in creatinine kinase and cardiac troponin I. Diagnostic tests were attributed to myocardial necrosis following transient infarction or directed myocardial toxicity. All abnormalities resolved within 6 months.¹⁷⁴

Coenzyme Q, also called ubiquinone, is a natural fat-soluble compound similar to vitamin K in structure and ubiquitous in plants and animals. It acts as an antioxidant to protect cell membranes from free radical activity. Coenzyme Q plays a role in the conversion of 95% of energy needs; organs with the highest energy needs have the highest coenzyme Q concentrations. The use of the compound has been in patients with severe CHF (150 to 225 mg/day), particularly for those whose endogenous concentrations fall below 2 μg/mL. The effects of coenzyme Q on myocardial cells is controversial. In cultured myocardial cells, coenzyme Q stimulates beating activity, probably by stimulating the formation of mitochondrial ATP.²³¹ In humans undergoing valve replacement, coenzyme Q appeared to scavenge hydroxyl but not superoxide anions.²³² Singh and coworkers²³³ demonstrated a protective effect of coenzyme Q in patients receiving the compound within 3 days after acute myocardial infarction. However, a lack of effect on ventricular function was reported in patients with CHF.²³⁴ Coenzyme Q may block apoptosis.²³⁵ Foods highest in coenzyme Q include beef, spinach, sardines, albacore tuna, and peanuts. Beta blockers, statin (cholesterol-lowering drugs) and other cardiovascular drugs can decrease coenzyme Q. Coenzyme Q is available as a dietary supplement, generally in capsules ranging in size from 10 to 60 mg.

Nutritional intervention with essential nutrients, including L-arginine and L-carnitine, also has been recommended as effective adjunctive therapy for prevention and control of cardiovascular disease.²³⁶

Chronic Mitral Valve Insufficiency

Tricuspid Valvular Insufficiency

Because a normally functioning left ventricle ensures forward movement of blood in the right ventricle, incompetence of the tricuspid valve generally does not lead to cardiac insufficiency unless accompanied by an underlying disease (e.g., pulmonary hypertension, heartworm disease, CMVI). Identification of any underlying disorder leading to tricuspid valvular insufficiency is critical to successful management of cardiac insufficiency. Loop diuretics (furosemide) or aldosterone antagonists (spironolactone) (or a combination thereof) may be indicated for management of ascites. Spironoloactone may be more effective for right-sided, compared to left-sided therapy. Digoxin may be helpful in the presence of myocardial failure, and antiarrhythmic drugs may be necessary to control tachycardia.⁹⁰ Treatment of pulmonary hypertension associated with heart failure is discussed below.

Dilated Cardiomyopathy (DCM)

Feline Dilated Cardiomyopathy

The recognition that DCM in cats was largely reversible with the administration of taurine has all but eliminated DCM in cats.^244,254 Most commercial feline diets now contain sufficient taurine to prevent the syndrome. A history of unconventional foods or homemade diets will help identify the occasional cat with cardiac disease associated with taurine deficiency. The clinical presentation of DCM in cats is similar to that in dogs, although pleural effusions are more common. Systemic thromboembolism is another potential complication. Plasma taurine concentrations are often but not always low (<30 nM/mL). Systemic thromboembolism apparently can increase, and fasting can decrease, plasma taurine concentrations. Taurine supplementation largely reverses the clinical signs and electrocardiographic abnormalities associated with taurine deficiency. Most animals respond to taurine supplementation (250 to 300 mg/day orally) within 3 to 6 weeks of therapy. Mortality rates are highest, however, during the initial 2 to 3 weeks of therapy. Echocardiography is the preferred method for monitoring response to therapy because response times can markedly vary. Adjuvant therapy may be necessary until clinical response.

Diuretics (furosemide) can be used to manage pulmonary edema and pleural effusions; differences in dosing regimens for cats compared with dogs should be observed. Cats may appear to be dehydrated (based on skin turgor), but this is more likely to represent redistribution of fluids to the pleural cavity or lungs. Fluid may be necessary in the presence of azotemia associated with low-output failure and hypotension but should only be administered cautiously and slowly. Digoxin (0.0035 to 0.0055 mg orally every 12 to 24 hours) may be indicated until the response to taurine is evident. The use of pimobendan for treatment of poor myocardial contractility has not been reported in cats. Differences in response compared with that of dogs might be anticipated if cats do not metabolize pimobendan to an active metabolite. However, anecdotally, cats appear to respond to the positive inotropic effects. Emergency management of myocardial failure may require administration of dobutamine (2 to 5 μg/kg per minute); common side effects of dobutamine administration in cats include seizures and vomiting. Vasodilator therapy should be implemented. Afterload reduction might be accomplished with ACE inhibitors in the presence of compensatory neurohumoral mechanisms or amlodipine (or both). Renal function should be closely monitored, however, particularly in the patient with azotemia.

Alternative therapies include hydralazine (0.5 to 0.8 mg/kg every 12 hours) to control systemic resistance and 2% nitroglycerin topically (¼ inch topically every 8 to 12 hours) for (short-term management) preload reduction. Adjuvant therapy may be required to treat or prevent thromboembolism. Provided that a properly prepared diet is fed, most drugs and taurine supplementation generally can be discontinued within 2 to 3 months of therapy. Failure to respond, particularly in the presence of normal plasma taurine concentrations, may indicate an idiopathic DCM.

Thromboembolism

Treatment of thromboembolism is addressed in depth in Chapter 15.

Feline Aortic Thromboembolism

Feline aortic thromboembolism (FATE) is not an uncommon sequela of feline cardiomyopathy. Thrombus formation reflects the combined result of altered endocardial surface (exposed collagen, von Willebrand factor or tissue factor, hemostatic/inflammatory blood components [e.g., hypercoagulability] and blood flow). In the cat the underlying defect in blood components has not been identified, although vitamin B₁₂ and arginine have been identified as deficient in one study (as reviewed by Smith and Tobias).²⁵⁵ Blood flow derangements usually accompany and may be correlated with the magnitude of left atrial enlargement. Cats with any type of cardiomyopathy are at risk to develop FATE. The pathophysiology and treatment were reviewed by Smith and Tobias,²⁵⁵ and use of selected antithrombotic agents for its treatment also is discussed in Chapter 15.

The goals of therapy include, in addition to rest, control of pain, improved systemic perfusion, (including prevention of further embolism), and supportive therapy as necessary. The latter should address treatment of primary cardiac disease. Newer NSAIDs preferentially target COX-2. As such, the inhibitory effects of prostacyclin will be subdued while the pro-platelet activity will not be. Accordingly, other than the use of aspirin, which is recognized for its unique antiplatelet effect, NSAIDs — particularly those known to be preferential for COX-2, — should be avoided in cats with FATE or cardiac disease in general, unless scientific studies support their use. The use of alternative antiplatelet drugs is discussed in Chapter 16. Opioids and tramadol are reasonable drugs for controlling pain. Resolution of embolism and reinstitution of perfusion are difficult. No controlled clinical trials have established appropriate therapy. Fluid therapy appropriate for the cardiac status is indicated. Scientific evidence regarding the efficacy of acepromazine (as an arterial dilator) is lacking, and the risk of contributing to hypotensive shock warrants avoidance. Smith and Tobias²⁵⁵ reviewed the use of tissue type plasminogen activator (see Chapter 15). The treatment is expensive, and although reperfusion may occur, the risk of mortality associated with FATE, hyperkalemia, and other complications is 50% to 70%.

Hypertrophic Cardiomyopathy

Systemic Hypertension

Systemic hypertension occurs in both cats and dogs, although more commonly in cats, and is associated with a number of underlying causes. The most likely are hyperthyroidism (23% to 87% of afflicted cats) and chronic renal disease. The pathophysiologic cause of hypertension in renal disease is not well known but may include abnormal salt excretion, activation of the sympathetic nervous system or RAAS, altered renopressor mediators, and anemia-induced increased cardiac output.⁴³ Hyperthyroidism apparently causes hypertension by increasing β-receptor number and activity in the myocardium. A thyroid-hormone–specific adenylyl cyclase system mediates the cardiovascular response. Other causes of systemic hypertension include diabetes mellitus, acromegaly, and primary aldosteronism.¹⁹⁰ Occasionally, the recent history may include therapy with steroids (glucocorticoids, progestogens, anabolic steroids).⁴³ An underlying cause cannot, however, be identified for all cases of systemic hypertension.

Clinical signs of hypertension in the cat include signs related to the underlying disease or signs specific to hypertension. The most common sign specific to hypertension is blindness (83% in one study) associated with retinal detachment or hyphema. Less commonly, signs related to cerebral vascular accident (e.g., seizures, ataxia, sudden collapse) may occur. Diagnostic tests may reveal the underlying causes or associated abnormalities that may require medical management.⁴³ Azotemia may not be evident despite chronic renal disease as the precipitating cause. Kidneys may be small. Systolic murmurs and gallop rhythms may be auscultated, but tachycardia is not common. Mild to moderate cardiomegaly may be evident radiographically, but pleural effusion and pulmonary edema are unusual; renal disease will increase the likelihood of abnormal fluid retention. Left ventricular hypertrophy is likely but should not be confused with HCM. Ocular changes are easy to monitor and should be used to establish a baseline before implementation of therapy. Hemorrhage may be present in any chamber of the eye. Retinal hemorrhage should be interpreted as an indication of hypertension. Cats with retinal detachment have a higher pressure than cats without detachment.⁴³ Retinal arteries may be tortuous.

Proper measurement of blood pressure is paramount to successful management of systemic hypertension. Measurements should be taken after an animal has had proper time to acclimate to its surroundings and under conditions of minimal stress.⁴³ Among the indirect methods used to measure systemic blood pressure in cats, the Doppler and photoplethysmographic methods are probably preferred.¹⁹⁰ Care must be taken to follow proper techniques with the appropriate equipment when blood pressure is indirectly measured.⁴³ Several readings should be taken over several days unless contraindicated by clinical signs of hypertension. With indirect methods, normal blood pressure (mm Hg) in the unsedated cat is 118 (Doppler leg method) to 123/81.2 (mean arterial pressure 96.8)⁴³ and in dogs is 133/76 (Dinamap on the tail). Antihypertensive therapy is indicated if the indirect systolic pressure or diastolic pressure is greater than 170 or 100 mm Hg, respectively.⁴³

Returning systolic pressure to normal (i.e., 120 mm Hg) may be an unrealistic goal of therapy; targeting less than 170 mm Hg in cats is more reasonable.⁴³ Response to therapy should be based on appetite and body weight, ophthalmic examinations, and monitoring of blood pressure. Management of hypertension associated with renal disease should include medical management of that disorder. Additional management includes dietary manipulation (low sodium); diuretics; propranolol; and arterial vasodilators, including α-receptor antagonists, CCBs (amlodipine), hydralazine, and ACE inhibitors.¹⁹⁰ Dietary changes probably should be postponed until drug therapy is stabilized.

Amlodipine is generally the preferred medication for treatment of systemic feline hypertension, followed by a combination of amlodipine with either an ACE inhibitor or a β-blocker in refractory cases. Hydralazine should be reserved for cases that continue to fail to respond, in part because of the potential for activation of the RAAS.⁴³ For cats with severe ocular manifestations or neurologic signs, therapy must be more aggressive. Sodium nitroprusside can be given as a constant-rate infusion, but the risk of adverse reactions to this arterial and venous dilator requires administration by an infusion pump with constant monitoring. Alternatively, hydralazine coupled with furosemide can be administered, with the addition of a β-blocker (propranolol or atenolol) if response is not sufficient within 12 hours.⁴³

Long-term management should be based on repetitive monitoring of blood pressure (weekly until the animal is stable at a sufficiently low pressure) and body weight, as well as the underlying disease causing hypertension. If renal disease is the underlying cause, monitoring also should include an ocular examination and serum potassium concentrations. Once control is acceptable, monitoring should take place at 3-month intervals. Multiple drug combinations are more likely to be associated with adverse effects (including sleeping, ataxia, and anorexia).

Emergency treatment of hypertension might be accomplished orally, although a loading dose may be necessary for amlodipine. Nitroprusside tends to be the preferred treatment for intravenous administration because of ease of titration. Acepromazine can be used as well, although its longer half-life precludes titration and hypotension associated with higher doses may negatively affect renal function. Sedation may be an unwanted side effect.

Use of enalapril and amlodipine has been studied in dogs with experimentally induced myocardial infarction. Although both drugs preserved left ventricular volume and function during the healing process, enalapril more effectively limited hypertrophy.²⁶⁰ The role of carvedilol in the management of feline hypertension has not yet been well described.

Pulmonary Hypertension

The pulmonary vasculature is a low-resistance, low-pressure, high-capacitance system. It is influenced by right ventricular cardiac output, pulmonary venous pressure, and pulmonary vascular resistance. Pulmonary hypertension (sustained mean pulmonary arterial pressure [PAP] >30 mm Hg; normal 10 to 14 mm Hg) has been categorized by the World Health Organization, largely on the basis of underlying disease, into five categories: (pulmonary) arterial hypertension (I), (pulmonary) venous hypertension (II), chronic alveolar hypoxia (III), chronic thromboembolic disease (IV), and miscellaneous causes (V). Classes II, III, and IV are most relevant to dogs or cats. As reviewed by Johnson and coworkers^261a in a retrospective study of pulmonary hypertension in dogs (n=53), increased venous pressure caused by myocardial disease, including PDA, represented 46% of cases, followed by alveolar hypoxia (pulmonary fibrosis, pneumonia, others; 23%), and thromboembolism (including that associated with heartworm disease; 20%), with 9% of cases associated with miscellaneous causes. Pulmonary vascular changes (in addition to thromboembolism) that influence hypertension include vasoconstriction, and proliferation of smooth muscle and endothelium.

A number of mediators influence pulmonary vascular response. Arachidonic acid metabolites balance one another by either inhibiting (e.g., prostacyclin, released from endothelial cells in response to prostacyclin synthase) or stimulating (e.g., thromboxane, mediated by thromboxane synthase) vasoconstriction, platelet aggregation, and vascular proliferation. Endothelin and serotonin cause potent vasoconstriction and pulmonary arteriolar smooth muscle proliferation and, for endothelin, potentially fibrosis. In contrast, NO and vasoactive intestinal peptides cause vasodilation and inhibit platelet activation and vascular smooth muscle proliferation. In human patients hypertension is associated with a decrease of vasodilatory mediators (e.g., prostacyclin, NO) and an increase in vasoconstrictive mediators (e.g., thromboxane, serotonin, endothelin). The role of mediators in pulmonary hypertension of dogs is not well defined, although endothelin has been demonstrated to be higher in dogs with heartworm disease compared with other diseases that might cause pulmonary hypertension. However, chronic pulmonary overcirculation is associated with pulmonary vascular remodeling in the dog characterized by pulmonary arterial hypertrophy and increased resistance that may exceed systemic pressure, resulting in right to left shunts. In contrast, pulmonary venous hypertension such as that associated with myocardial disease generally is reduced by pulmonary edema with alveolar hypoxia as a compensatory response that minimizes pulmonary perfusion to poorly ventilated airways. Chronic hypoxia also can lead to pulmonary vascular remodeling.

Treatment of pulmonary hypertension in dogs was recently reviewed.^261b Treatment of pulmonary hypertension focuses on treatment of underlying disease. Oxygen therapy induces vasodilation and is the only therapy associated with decreased mortality in humans. Vasodilatory drug therapy is implemented if the underlying cause cannot be identified or effectively treated. Vasodilators associated with variable efficacy include hydralazine, CCBs, prostacyclin analogs (e.g., epoprostenol), endothelin receptor antagonists (e.g., bosentan) and PDE inhibitors (e.g., sildenfil). Response and justification for long-term therapy is based on the magnitude by which pulmonary arterial pressure is reduced.

PDE-V is located (in humans) in the pulmonary vasculature and the corpus cavernosum. Other locations may occur in dogs. Inhibition of PDE-V specifically results in accumulation of cGMP. Drugs that specifically targeted PDE-V include, but are not limited to, sildenafil and the longer-acting tadalafil. Sildenafil (2 mg/kg once or twice daily; range 0.5 to 3mg/kg orally every 8 to 24 hours) has been studied retrospectively in dogs (n = 13) with pulmonary hypertension PAP≥ 25 mm Hg at rest for a duration of 3 days to 5 months.²⁶² Underlying causes included chronic pulmonary diseases, valvular heart disease, patent ductus arteriosus, and pulmonary thromboembolism; a cause was not identified in five dogs. Ten of the dogs were receiving concurrent mediations oriented toward treating underlying disease. In six of eight dogs for which PAPW as determined before and after treatment, PAP decreased from 4 to 37 mm Hg at approximately 2 days into therapy. However, systolic pressure also decreased a median of 33 mm Hg (beginning pressure was 135/90 mm Hg). A number of clinical signs resolved among treated dogs, including cardiogenic ascites, which resolved in one of two dogs. Median survival time was increased 91 days. Complications associated with therapy were difficult to discern in part because of the number of other drugs dogs were receiving; one dog died after discharge when treated with nitroglycerin. The reported use of tadalafil in dogs is limited to a case report in a Yorkshire Terrier with idiopathic hypertension.²⁶³ Treatment (1 mg/kg every 48 hours) resulted in a 20% reduction (105 to 80 mm Hg) in pulmonary arterial hypertension. However, systemic hypotension occurred, and the dog was euthanized 10 days after therapy began.

Pimobendan has been effective in reducing (but not significantly) the ratio of pulmonary to systemic vascular resistance in human patients with chronic emphysema^263a However, pimobendan was associated with an actue reduction of tricuspid regurgitation flow velocity and NTproBNP in dogs with pulmonary hypertension associated with mitral insufficiency.^237b

Hydralazine may induce preferential dilation of the pulmonary arterial tree compared with the systemic vasculature. Hydralazine decreases pulmonary vascular resistance in both normal lungs and in lungs with experimentally induced embolization.²⁶¹ Because hypoxia can worsen pulmonary arterial vasoconstriction, oxygen therapy is critical to the treatment of pulmonary hypertension associated with CMVI. Aggressive diuretic therapy is indicated to reduce pulmonary edema as well as pulmonary hypertension. Bronchodilator therapy may facilitate bronchiolar smooth muscle spasm, facilitating air movement. In humans CCBs (e.g., diltiazem, nifedipine) are effective in only 10% of patients and only at high doses. A 20% reduction in pulmonary arterial hypertension supports long-term therapy.

Prostacyclin is both a systemic and pulmonary vasodilator. When administered by continuous intravenous infusion it improves mortality and exercise tolerance in human patients with primary pulmonary hypertension. Intravenous prostacyclin also improves right-sided heart structure and function.²¹⁰ Prostacyclin analogs are characterized by half-lives longer than the endogenous compound but sufficiently short that constant infusion is necessary. Most problematic is the cost, which is likely to be prohibitively expensive. Examples include epoprostenol (intravenous) and treprostinil (subcutaneous). Two alternative route preparations are available in the U.S. Iloprost is an inhalant form that is administered 6 to 12 times daily; beraprost is an oral preparation administered every 6 hours. A low dose of a systemic PDE III inhibitor may enhance the cAMP-dependent pulmonary vasodilatory response to inhaled prostacyclin.²¹⁰ Studies do not appear to have addressed their use in dogs or cats.

Endothelin-receptor antagonists include bosentan, which targets both ET-A and -B and is approved in the United States. Cost may be prohibitive. Drugs available outside the United States include sitaxentan and ambrisentan, both ET-A antagonists. As such, vasoconstriction is minimized (ET-A blockade), but ET-B remains responsive to endothelin, thus promoting its clearance and contributing to vasodilation.

Theophylline is a nonselective PDE inhibitor. Additional benefits include fair bronchodilation, as well as some antiinflammatory control. However, is can be associated with ventilation perfusion mismatching, particularly with intravenous administration. Therefore oxygenation is important. The impact of theophylline in mismatching in patients suffering from hypertension is not known.

L-arginine, a substrate of NO synthase, anecdotally has been associated with reduction in pulmonary arterial hypertension.

Unless hyperthyroidism is accompanied by renal insufficiency, the degree of hypertension associated with hyperthyroidism generally is mild. Because hyperthyroidism-induced hypertension is due to high adrenergic output (causing increased cardiac inotropy and rate), β blockers are preferred to calcium channel blockers. However, the addition of amlodipine may be indicated in hyperthyroid hypertensive cats with renal insufficiency.

Supraventricular Arrhythmias

Supraventricular Tachycardias

Supraventricular tachycardia includes sinus, atrial, or junctional tachycardia; atrial flutter; and atrial fibrillation. Therapy should be considered for heart rates above 220 or 260 bpm in the dog and cat, respectively. The most likely underlying cause is atrial enlargement resulting from dilation. Sinus tachycardia is the most common type of supraventricular tachycardia in dogs and is generated by increased sympathetic tone. Treatment includes digitalis glycosides (if CHF is present), the β blockers (e.g., nonselective propranolol or the preferred selective blockers atenolol, metoprolol, or carvedilol), the class III antiarrhythmic amiodarone (less ideal), or the CCBs (e.g., diltiazem). The most appropriate drug should be based on the underlying cause of the tachycardia. Atrial tachycardia may reflect an autonomic dysfunction (generally not amenable to treatment) or, less commonly, a reentrant circuit. For reentrant causes, class IA antiarrhythmics (especially quinidine), digitalis, or a β blocker is indicated. Atrioventricular nodal or junctional tachycardias can be similarly treated.

Gelzer and Kraus²⁶⁴ reviewed the management of atrial fibrillation. Atrial fibrillation occurs in the presence of multiple reentering wavelets; its development is facilitated by a large atrium. The authors²⁶⁴ suggest that treatment is indicated when the average heart rate from a Holter recording exceeds 150 bpm in dogs and at any heart rate in cats with atrial fibrillation. The most efficacious antiarrhythmic drugs are those that increase the wavelength (distance traveled by the depolarization impulse during the refractory period). Although this might be accomplished by either increasing the speed of conduction or increasing the refractory period, the former is not a recognized mechanism of action of antiarrhythmic drugs. Treatment may be unnecessary if the ventricular rate is less than 150 bpm in asymptomatic dogs with no evidence of cardiac disease. Treatment of atrial fibrillation should focus on slowing the ventricular response such that cardiac filling improves and myocardial oxygen demand decreases. In symptomatic dogs the atria can be targeted with class IA drugs (quinidine or, less preferred, procainamide), or conduction through the atrioventricular node can be targeted with digitalis, glycosides, CCBs, or β blockers. Although quinidine prolongs wavelength, its paradoxical acceleration (induced by anticholinergic effects) may increase the ventricular response rate, leading to worsening clinical signs. Quinidine can be used to convert atrial fibrillation to a sinus rhythm in dogs. Successful conversion is, however, generally limited to large-breed dogs with no evidence of underlying cardiac disease and is not recommended in dogs with cardiac failure.

Among the drugs, digitalis probably is the preferred treatment for atrial fibrillation despite the fact that it facilitates the arrhythmia by decreasing the impulse wavelength.²⁶⁴ Although Gelzer and Kraus²⁶⁴ recommend monitoring a trough sample 3 to 7 days after starting therapy, for reasons previously discussed, both a peak and trough sample might be prudent to determine half-life at baseline and in response to therapy. Decreased conduction within the atrioventricular node will decrease the ventricular rate. Additionally, positive inotropic effects may benefit the patient with myocardial failure. Previously mentioned precautions should be followed when negative chronotropes that also are negative inotropes are used; CCBs and β blockers may need to be reserved for patients that have not sufficiently responded to digoxin. According to Gelzer and Kraus,²⁶⁴ a CCB is preferred in animals with a rapid ventricular rate resulting from enhanced sympathetic tone. An exception can be made for acute management, in which case digitalis is begun simultaneously with a CCB; β blockers are generally reserved for cases that do not respond to other drugs. Because of a potential protective effect on the diseased myocardium, however, β blockers might be indicated earlier and perhaps preferentially to diltiazem or other CCBs if chronic activation of the sympathetic system is contributing to cardiac failure.

Emergency management of supraventricular arrhythmias is indicated in the presence of sustained arrhythmias in patients that are hemodynamically unstable. Beta blocker therapy includes propranolol (0.02-0.06 mg/kg, slow intravenous administration every 8 hours) or esmolol. Esmolol (0.05-0.1 mg/kg intravenously every 5 minutes up to 0.5 mg/kg) has a shorter half-life compared to propranolol. Failure to convert can be followed with CCB therapy with little risk of negative inotropic effects. Diltiazem (0.25 mg/kg intravenously over 2 minutes followed by 0.25 mg/kg every 15 minutes) can be implemented until conversion occurs, up to a maximum dose of 0.75 mg/kg. Verapamil also has been used (0.05 mg/kg, slow intravenous administration up to 0.15 mg/kg).

Despite the traditional consensus that lidocaine is indicated only for ventricular arrhythmias, Johnson and coworkers¹²⁵ described the impact of lidocaine at a standard dose in five dogs with complex supraventricular arrhythmias. In each case normal sinus rhythm was achieved and then maintained with mexiletine.

Ventricular Arrhythmias

The importance of any ventricular arrhythmia depends on the ventricular rate, duration of the arrhythmia (tachycardia), and the severity of underlying cardiac disease. The clinical sequelae of a detrimentally rapid ventricular rate and insufficient ventricular filling include weakness, syncope, seizures, collapse, and clinical signs indicative of CHF.

Ventricular tachycardias are caused by a variety of underlying disorders, including but not limited to primary cardiac disease, metabolic disorders causing acid–base or electrolyte imbalances, infectious disorders, neoplasia, and trauma. Resolution of the underlying cause is paramount to successful therapy of ventricular tachycardias. Not all ventricular premature contractions require treatment. Generally, ventricular premature contractions that are multifocal, occur more frequently than 25 per minute, or occur in repetitive runs that result in a heart rate of 130 bpm or more should be medically managed. Those that are associated with clinical signs or those that occur in breeds at risk for sudden death (e.g., German Shepherd Dogs, Boxers) might also be treated, although this is controversial.

Ventricular arrhythmias that are considered life threatening should be managed with intravenously administered lidocaine. Generally, a slow intravenous bolus (4 to 8 mg/kg [dogs]; 0.5 to 1 mg/kg [cats]) is followed by a constant infusion (22 to 66 μg/kg per minute [dogs]; 10 to 20 μg/kg per minute [cats]). Once sufficient response has occurred, oral therapy can be phased in. Procainamide can be administered intravenously (2 to 20 mg/kg over 30 minutes followed by a constant infusion of 2 to 40 μg/kg per minute [dogs]; 1 to 2 mg/kg intravenous bolus followed by 10 to 20 μg/kg per minute infusion [cats]) or, in less critical patients, intramuscularly or orally (6.6 to 22 mg/kg every 2 to 6 hours [dogs]) in patients that do not respond to lidocaine. Quinidine also can be used (6.6 to 22 mg/kg orally, intramuscularly every 6 hours). Eradication of the ventricular arrhythmia may not be a reasonable expectation. Insufficient response should lead to confirmation of the diagnosis; evaluation of acid–base or electrolyte disturbance; and, if necessary, addition of a second class IA antiarrhythmic or β blocker (see discussion of precautions in myocardial failure). Ventricular pacing devices may be necessary for animals that continue to fail to respond to antiarrhythmic therapy.

Response (hemodynamic, antiarrhythmic, and adverse) to a single intravenous bolus dose of procainamide was demonstrated to not differ from a single intravenous dose of lidocaine in dogs with postoperative ventricular arrhythmias.²⁶⁵ Neither drug was associated with undesirable hemodynamic changes. Specific information regarding the study (e.g., doses) could not be found.

Bradyarrhythmias

Bradycardia is defined as a heart rate of less than 70 bpm and usually results from sinus nodal or atrioventricular conduction disturbances. Both conduction and automaticity (decreased) disturbances cause bradycardias. In general, medical management of bradyarrhythmias is unreliable, and placement of a pacemaker device is the preferred method of management.

Sinus brachycardia usually is clinically asymptomatic, with the most common clinical sign being syncope or episodic weakness. For animals that are symptomatic, long-acting anticholinergic drugs (e.g., propantheline) might be helpful. Failure to respond will require pacemaker placement.

Atrioventricular nodal block can be first, second, or third degree, depending on the severity. With third-degree block, there is no conduction between the atria and the ventricles. The ventricular escape rhythm approximates 40 bpm. Pacemaker placement is the preferred method of treatment, but emergency cases can be treated with isoproterenol (constant-rate infusion). If the ventricular rate increases in response to atropine, an orally active long-acting (relative to atropine) anticholinergic such as propantheline might be effective. Diphenoxylate reportedly also has been useful.

Pathophysiology

Accumulation of fluid in the pericardial sac most commonly reflects a disorder of the pericardium but can also occur as a manifestation of myocardial failure.^190,266 Causes include but are not limited to pericarditis (septic or foreign body), neoplasia, and idiopathic hemorrhage. If accumulation is severe, cardiac tamponade may develop. Increased intrapericardial pressure and diastolic collapse of the right atrium and potentially the right ventricle can result in reduced preload to the left ventricle, decreased cardiac output, and hypotension. Systemic compensatory mechanisms may be activated in an attempt to maintain cardiac output. Chronic disease ultimately can lead to pleural effusion and (in extreme cases) pulmonary edema.

Pharmacologic Management

Because pericardial effusion often does not respond sufficiently to pharmacologic management, pericardiocentesis and surgical alternatives such as pericardiectomy or balloon dilation should be anticipated if the underlying cause cannot be rapidly resolved. In cats with feline infectious peritonitis, high doses of glucocorticoids may decrease the accumulation of pericardial fluid. Glucocorticoids also have been recommended for dogs with idiopathic hemorrhagic pericardial effusion that has not responded to pericardiocentesis.