Carvedilol may be new therapeutic strategy for canine heart disease

The past 15 years have seen a resurgence of interest and developmentsin new medical therapies for congestive heart failure (CHF).

Neurohormonal antagonism has become a primary strategy for combatingthe mechanisms that contribute to progressive cardiac dysfunction. Beta-andrenergicreceptor blockers are some of the newer agents used for this purpose.

Neurohormonal changes

Increased sympathetic nervous system (SNS) tone and decreased parasympatheticactivity characterize some of the neurohormonal changes that accompany CHF.

While these changes result in short term increases in cardiac outputand blood pressure, they have deleterious chronic effects, including cardiachypertrophy and remodeling, increased afterload, myocardial fibrosis/necrosis,and induction of cardiac arrhythmias. Beta blockade limits these harmfuleffects, decreases morbidity and improves long-term survival in humans withCHF secondary to a variety of causes.

Beneficial properties

Carvedilol was the first beta-blocker approved for the treatment of CHFin human patients.

This non-selective beta blocker (blocks ß1 and ß2 receptors)has several unique properties that may help explain its beneficial effectsin heart failure patients.

Carvedilol also blocks 1 receptors, decreasing peripheral vascular resistance(the drug was originally evaluated as an antihypertensive agent). Carvedilolhas antioxidant properties, actively scavenging oxygen-free radicals inhumans and dogs. The drug also acts as an antiarrhythmic agent with ClassII and reportedly Class I actions on ventricular myocytes.

Use of carvedilol (and other beta-blockers) for the treatment of CHFin humans is commonplace, but experience with the drug is limited in veterinarymedicine. Dr. Robert Hamlin and his research team have recently evaluatedthe pharmacology of carvedilol in the dog (pages 57-60 AJVR, Jan 2000, Vol61:1) and presented this and other information at the ACVIM Forum last May(page 107, Proceedings of the 19th Annual Veterinary Medical Forum, 2001.)

Carvedilol has a bioavailability of approximately 10 percent after oraladministration in dogs, and most (95 percent) of the drug is protein bound.It is lipophilic and accumulates in cell membranes. The major routes ofmetabolism are in the liver and >75 percent is excreted in the feces.Only 8 percent of the compound is excreted in urine. Doses up to 1.25 mg/kgare well tolerated, achieving peak plasma concentrations two to four hoursafter oral administration.

Veterinary uses

Given carvedilol's multiple pharmacologic effects, it has several potentialuses in veterinary cardiology patients. Early and continued interest hasfocused on its use in dogs with myocardial systolic dysfunction, primarilyidiopathic dilated cardiomyopathy.

The first reported improvements in clinical condition and survival inhumans were in such patients. As all beta-blockers have negative inotropiceffects, careful patient selection is required before prescribing carvedilolin dogs with dilated cardiomyopathy.

The author has adopted a human protocol of upward titration startingat 3.125 mg PO BID <25 kg) or 25 mg BID (patients >25 kg.) The ownersare instructed to monitor for symptoms of cardiac decompensation (lethargy,tachypnea, coughing) during the titration period. Carvedilol is contraindicatedin unstable cardiac patients. The drug must be used with extreme cautionin patients with severe myocardial systolic dysfunction (i.e. shorteningfraction <15 percent), as it may precipitate congestive heart failurein an otherwise compensated patient.

Carvedilol is theoretically an ideal agent for treatment of doxorubicincardiotoxicity. This chemotherapeutic agent causes myocyte damage throughthe generation of oxygen free radicals, resulting in cardiac electricaldisturbances and myocardial failure. The disease is progressive and oftenresults in death from cardiac causes.

Carvedilol's antioxidant properties, antiarrhythmic effects and antagonismof the SNS make it ideally suited to treat patients with doxorubicin-inducedcardiac disease.

Carvedilol may prove useful in the treatment of cardiac arrhythmias aswell. The author has documented antiarrhythmic efficacy (>80 percentreduction in ventricular ectopy as measured by 24-Holter recordings) ina Doberman Pinscher and Boxer with dilated cardiomyopathy treated with carvedilol.

Despite overwhelming support for the use of this drug in human patientsand anecdotal reports of efficacy in dogs, objective data supporting theuse of carvedilol in veterinary patients are lacking and await the resultsof veterinary clinical trials. New research is also evaluating the use ofthis drug in dogs with myxomatous valvular degeneration. Results of thesestudies may soon add carvedilol to the armamentarium of drugs availableto the veterinary practitioner to treat patients with congestive heart failure.