Positive inotropic therapy for heart failure patients (Proceedings)

Early descriptions of heart failure focused on the syndrome of congestion, an excess of the wet or melancholic humors, "dropsy," or "backward" failure. Focus on forward failure was sharpened by dramatic initial responses to agents that stimulate contractility. More precise measurement of impaired contraction at the level of the heart and the myocyte itself later redefined heart failure as a malady of impaired forward function. The inability to sustain early improvements in most with inotropic agents in was accompanied by increased mortality in human studies.

While no veterinary studies have demonstrated similar adverse responses to positive inotropic therapy the focus of therapy paralleling human medicine has shifted to mediating chronic response via inhibition of the renin-angiotensin system (RAAS) and peripheral blockade of β-adrenergic receptors. While only RAAS modification has proven to decrease mortality in our patients, β-adrenergic blockade is has been gaining interest as use of these drugs in chronic heart failure have been found over time to help preserve and in some cases improve contractility, decrease filling pressures, and prolong survival. These neurohormonal antagonists decrease the development and worsening of heart failure. The decision to add inotropic therapy has been controversial in human medicine as most of these available drugs result in increase myocardial oxygen consumption hearts that may already be deprived of oxygen secondary to myocardial infarction.

The decision to use inotropic therapy and the selection of inotropic agent should reflect the realistic goals of therapy for the individual with heart failure. The diversity of goals and setting and the limited drugs available have limited the performance of randomized controlled trials to establish evidence on which to base these therapies. Because of new drug classes available for our patients; sharper focus on current practices and outcomes with inotropic therapy could direct efforts to design trials for some situations and guide prospective data collection to advance our understanding of the best time to start utilizting these drugs. Since majority of heart failure in veterinary patients is secondary to mitral valve disease, most of our patients have preserved cardiac output at rest and are limited primarily by impaired volume regulation and diminished cardiac output responses to excitement. Inotropic therapy is frequently considered in hopes that either brief or prolonged stimulation of contractility to increase perfusion may help to restore compensation for a period of time. With myocardial failure (dilated cardiomyopathy, end-stage mitral regurgitation), positive inotropes play an integral role. Positive inotropes may also have a beneficial effect in early mitral regurgitation by reducing the severity of regurgitation through reduction in isovolumetric contraction time and geometrical changes on the mitral annulus.

Digoxin:

Digoxin is the most commonly used oral positive inotrope. The use of digoxin in heart failure has been debated for hundreds of years. It is certainly recognized as a drug with beneficial effects but with a significant risk for toxicity. There is no argument against its use with atrial fibrillation but some controversy still exists about its use with normal sinus rhythm. With the development of a neuroendocrine approach to heart failure therapy, digoxin has experienced a renewed interest and its use is on the rise (to be discussed under neuroendocrine-based therapy). In the author's opinion, digoxin is indicated when moderate to severe congestive heart failure is present (component of "triple-therapy") and possibly earlier. Digoxin has been shown to improve baroreceptor function and reduce sympathetic tone. Given that digoxin is a weak positive inotrope at best, the baroreceptor effect is now the primary indication for its use in heart failure aside from atrial fibrillation therapy. Careful dosing and frequent monitoring of serum levels is necessary especially with concurrent drug therapy or when reduced renal function is present.

Digoxin works by competitive inhibition of the K+ side of Na+ /K+ ATPase pump thus allowing a build up of intracellular Na+ concentration. The cell now counters by exchanging intracellular Na+ for extracellular Ca++ which increases intracellular Ca++ ions available for the next systolic phase. Digoxin is renally excreted and blood levels rise with a decrease in GFR. Digoxin can often still be used with renal insufficiency but the dose administered should be reduced and careful monitoring of levels is necessary. Digitoxin undergoes hepatic metabolism and therefore can be used without modification of dose in the face of renal insufficiency. However, it must be given every 8 hours and is rarely used.

Digitalis glycosides have a narrow therapeutic to toxic range. Side effects range from GI signs such as anorexia, vomiting and diarrhea, arrhythmias of any type, (bradycardias or tachycardias) to central nervous system signs such as severe depression, disorientation and delirium.

Digoxin- (Dogs) 0.003 – 0.005 mg/kg PO q 12 hours

0.22 mg/m2 PO q 12 hours (>25 kg)

Rapid oral loading: dose orally q 8 hours for 1-2 days

Measure serum levels in 1 week. Titrate to 1-2 ng/ml at 6-8 hr post-pill.

(Cats) 0.03125 mg (1/4 of 0.125 mg tab) PO q 48 hours (<5 kg)

0.03125 mg (1/4 of 0.125 mg tab) PO q 24 hours (>5 kg)

Measure serum levels in 1 week. Titrate to 1-2 ng/ml at 12 hr post-pill.

Digitoxin- (Dogs) 0.02 –0.03 mg/kg PO q 8 hours

Phosphodiesterase III (PDE-III) Inhibitors:

Amrinone and milrinone are bipyridine compounds that uncommonly used due to their increased risk of ventricular arrhythmias in humans. The incidence of ventricular arrhythmias was not as great in the dog but the drugs are not widely available because of the concerns in humans. These drugs were generally reserved for refractory heart failure patients.

Phosphodiesterase III is an intracellular enzyme that specifically breaks down cAMP in cardiac myocytes. By inhibiting PDE-III, intracellular cAMP concentration increases, resulting in greater availability of calcium to the contractile proteins. Milrinone is about 30 to 40 times more potent than that of amrinone at producing this effect. These drugs also produce arteriolar dilation which is most likely mediated via the mechanism mentioned above.

Amrinonelactate- (Dogs) 1-3 mg/kg IV (loading), then 30-100 μg/kg/min infusion

Milrinone- (Dogs) 0.5-1.0 mg/kg PO q 12 hours

While historically these drugs worked well for veterinary patients there production has been limited due to human trials where there were trends of increased mortality in patients although morbidity tended to be reduced. Thus they have become unavailable or very limited in the veterinary market.

Calcium Sensitizers:

Most of the above mentioned drugs work by increasing intracellular calcium concentration. This group of drugs sensitizes the contractile apparatus to the prevailing level of calcium. Pimobendan is a new oral positive inotrope that increases the sensitivity of troponin C to calcium. It also has significant phosphodiesterase inhibitory effects which results in increased intracellular cyclic adenosine monophosphate (cAMP). The increased cAMP also results in increased inotropy as well as vasodilation which have resulted in this drug being classified as an "inodilator". This drug has gained approval in the United states for dogs in the past year.

Pimobendan - (Dogs) 0.5 mg/kg split PO q 12 hours

Most trials involving Pimobendan have shown very positive results with little side effects. There are sporadic reports of increased arrhythmias and some reports of chordae tendinae rupture and sudden death however these are rare. Numerous studies are still underway assessing beneficial affects of this drug.

Newer more potent calcium sensitizers are currently being studied. Levosemendan is a more potent form of calcium sensitizer that has less PDE-I properties at normal doses that could result in arrhythmogenic potential.

Sympathomimetics Amines:

Sympathomimetic amines increase myocardial contractility by binding to cardiac β-adrenergic receptors. The catecholamines (dobutamine and dopamine) have to be administered parenterally which confines them to in-hospital use with either emergent heart failure cases or periodic use on refractory heart failure patients. Most patients become refractory to the benefits of dobutamine infustion after 72 hrs. However while there are no additional benefits of infusing these patients after the period, the beneficial effects of these drugs appear to be present long after the infusion has ended.

Dobutamine- (Dogs) 5 – 15 μg/kg/min infusion

Since it does not act on dopamine receptors to induce the release of norepinephrine (another α1 agonist), dobutamine is less prone to induce hypertension than is dopamine- chronotropic, arrhythmogenic, and vasodilative effects are negligible. Dopamine is no generally used in heart failure patients.

Uses of these drugs will be discussed.

Reference:

Available upon request