Dr. Kramer On: New Cardiac Drugs
(Continued from cover page)
… adrenergic agents that increase contractility but cause the cardiac myocyte to use more ATP. The vasodilator effect of pimobendan reduces both afterload and preload. The vasodilation that occurs involves both the peripheral and coronary vasculature.
Pimobendan is highly protein bound and consideration should be given to the animal's serum albumin concentration when dosing the drug. Additionally, treatment with pimobendan should be monitored carefully if used in conjunction with other drugs that have high protein binding properties. There is first pass hepatic metabolism (O-desmethylation) which produces the active metabolite. The drug is cleared from the body via fecal excretion.
Pimobendan should be used only in dogs that are symptomatic for heart failure (modified NYHA class II-IV). The recommended dose is 0.25-0.35mg/kg BID. The drug is used in both dogs with DCM and chronic valvular heart disease. It may have more value in dogs with DCM due to the positive inotropic effect since all dogs with DCM have decreased myocardial contractility. Most dogs with chronic valvular heart disease do not have decreased contractility and do not need positive inotropic support. Both types of heart disease benefit from the vasodilatory properties of the drug. According to Boehringer-Ingelheim, "treatment should be initiated only in symptomatic cases which will benefit from increased myocardial contractility (positive inotropy)."
The drug is often used in combination with other cardiac drugs used for the treatment of heart failure (e.g. furosemide, ACE-inhibitors, digoxin, spironolactone, nitrates). It probably should not be used in conjunction with other phosphodiesterase inhibitors (e.g. theophylline, aminophylline, etc) and should not be used concurrently with sympathomimetic inotropic agents (e.g. dobutamine). Concurrent use with a beta-blocker or calcium channel blocker may attenuate the positive inotropic action of pimobendan.
Adverse side effects that have been reported after clinical use include: tachycardia, vomiting, diarrhea, inappetence, incoordination, convulsions, polyuria, and polydypsia.
Dosed dependant cardiotoxic effects include damage to the chordae tendineae that can lead to rupture, thickening of the mitral valve, and jet lesions on the endocardial surfaces. The lesions seem to be associated with the positive inotropic properties of the drug. These findings raise concerns that, used inappropriately in dogs with chronic valvular disease, pimobendan could lead to left atrial tears or rupture of the chordae tendineae. There is a report out of Europe that documented negative effects on the heart and worsening of the mitral regurgitation in dogs chronically treated with pimobendan for valvular disease. The changes were reversed when the drug was discontinued. There is also a concern that the drug could predispose the heart to tachyarrhythmias and lead to an increased incidence of sudden death. Although pimobendan has been shown to cause a dose dependent tachycardia, to-date no studies have documented an increased risk of sudden death. One study comparing pimobendan to enalapril showed an increase in ventricular ectopy after 14 days of treatment. Many new studies are underway which will help advance our understanding of this drug.
The question always arises when to use this drug and with what combination of other drugs. There is no single answer. It depends on the clinical presentation, progression over time of the underlying lesion (i.e. valvular insufficiency or cardiomyopathy), the condition of the heart as seen via echocardiogram, presence or absence of arrhythmias, concurrent diseases, and the clinical response to first-line treatment of the congestive heart failure episode. Only when all of those factors are taken into consideration can an appropriate treatment plan be made.
- Carvedilol (Corgeg). Although not exactly a "new" drug, it is one with which most veterinarians have little experience. This drug is a non-selective beta-blocker and an alpha-adrenergic blocker. The pharmacologic effect on the heart helps prevent the cardiotoxic effects of excessive sympathetic activation, helps prevent downgrade of beta adrenergic receptor activity within the myocardium, and helps decrease afterload. It also has anti-oxidant properties which may give additional protection to the diseased heart. As with any beta-blocker used in dogs, care should be taken to insure that the animal is not in congestive heart failure at the time therapy is instituted. The drug dose should be started at the low end of the dosing range and gradually titrated up carefully watching to avoid excessive negative inotropic effects. The usual starting dose is 1/4 to 1/2 3.25-mg tablet BID.
- Bisoprolol. This drug is in the same class and has very similar properties to carvedilol but may have better pharmacokenetic properties in dogs compared to carvedilol. More research with its use in dogs with heart failure is needed.
- Sildenafil (Viagra). Sildenafil is a phoshodiesterase V inhibitor that is commonly used for erectile dysfunction in men. It also has significant vasodilator properties on the pulmonary vascular bed. As a result, it has been used successfully in dogs as well as humans for the treatment of pulmonary hypertension. Pulmonary hypertension can be a common sequelae in chronic mitral valve disease in dogs. Moderate to severe pulmonary hypertension complicates the treatment of congestive heart failure and can lead to concurrent right-sided failure. Prior to the successful use of sildenafil for this condition, pulmonary hypertension has been a very difficult condition to treat. The dose is 0.3mg/kg BID. Pulmonary pressures should be monitored via Doppler echocardiography to measure the response to treatment. Caution should be used when administering this drug along with other vasodilators (especially nitrates).
- Losartan. This drug is in a new class of drug call angiotensin II receptor blockers (ARBs). The drug's action is mediated by preventing binding of angiotensin II to the AT1 receptor. In people, the clinical effects of ARBs are comparable to those obtained with ACE-inhibitors. There may be addition synergistic benefit in using ARBs in combination with ACE inhibitors. Experimental studies in cats showed that losartan administration prevented myocardial damage after an ischemic-reperfusion insult to the heart. Additional work will need to be done to demonstrate whether there is significant clinical value in using this drug in veterinary patients with heart failure or hypertension.
- D-Ribose. This agent would fall into the nutraceutical category. Ribose is a sugar that is involved in restoring energy pools within a stressed heart via the pentose phosphate pathway. Animal studies have shown that supplementing D-ribose lead to reduction in diastolic dysfunction and accelerated recovery of myocardial ATP levels. Recent results in people showed improvements in NYHA class II and class III heart failure after oral supplementation with D-ribose.