Medications Used in the Management of Heart Failure



Medications Used in the Management of Heart Failure


David S. Roffman



The past 30 years have provided remarkable advances in the pharmacotherapeutic management of patients with acute and chronic heart failure. Major improvements in both survival and symptom management now provide practitioners with the ability to provide therapy that is well tolerated, decreases recurrent hospitalizations, and improves quality of life. As the incidence of heart failure continues to increase with the advancing age of the population, and improved postinfarction survival, maximizing the use of currently available agents, development of new class of drugs, and the continued development of implantable devices for treatment of mechanical and electrical complications of heart failure should further our ability to improve patient care.


INOTROPES

Intravenous inotropes are useful in patients with severe systolic dysfunction with relative hypotension and evidence of inadequate end-organ perfusion, who are not responsive to, or are intolerant of, vasodilators and diuretics. Inotropic agents relieve acute heart failure symptoms and may preserve end-organ function but have not been demonstrated to improve survival. On the contrary, several studies have demonstrated increased adverse outcomes, including increased mortality with chronic intravenous inotropic therapy.


DOBUTAMINE

Dobutamine, a synthetic catecholamine, is primarily a β-adrenergic stimulant with minimal α1-cardiac sympathetic activity. Its β1-sympathetic activity accounts for its inotropic activity through β-receptor mediated-activation of intracellular cyclic AMP. The resulting sarcoplasmic reticulum calcium release mediates myocardial contractility. Similar β1 activity at the sinoatrial (SA) node accounts for its modest chronotropic activity. Patients taking β-blockers on admission may have an attenuated initial response to dobutamine, until the β-blocker has been metabolized or renally eliminated.1 However, cardiac output response to increasing doses of dobutamine has been observed in patients on chronic carvedilol.2 The dose-dependent β2 effect produces mild peripheral arteriolar dilation. As with most intravenous sympathetic stimulants, dobutamine has a rapid onset of action (1 to 2 minutes) and has a peak effect within 10 minutes. The drug is rapidly methylated providing for a short duration of action (t 1: 2 minutes), ideal for a drug requiring titration based on hemodynamic effects.

The hemodynamic effects of dobutamine in heart failure patients include increased cardiac output, arteriolar dilation, reduction of pulmonary artery occlusive pressure (PAOP or wedge pressure), and small but variable change in blood pressure (Table 14.1). In responsive patients, the hemodynamic benefits of the drug increase end-organ perfusion, manifest by improved renal function and urine output, decreased pulmonary vascular congestion, and improved skin perfusion and mentation.

Adverse effects that should be monitored in heart failure patients include dose-related tachycardia, most concerning in ischemic cardiomyopathy, and atrial (atrial fibrillation) or ventricular (ventricular tachycardia) arrhythmias.

Dobutamine dosing begins at 2.5 to 5 μg/kg/minute and is progressively increased based on clinical and hemodynamic response. Because it is not a vasoconstrictor (pressor), dobutamine does not need to be administered through a central line. Dosing may be increased to 15 μg/kg/minute, although maximum hemodynamic benefit may be achieved at lower doses, and ventricular ectopy risk increases as the dose is increased. Once hemodynamic stability has been accomplished, dobutamine infusions should be gradually tapered off. Although intermittent ambulatory dobutamine infusions have been used for quality of life enhancement in patients who are not candidates for transplantation or pump implantation, or as a pharmacologic bridge to cardiac transplantation, the practice has generally been replaced by implantation of ventricular assist devices.3 In addition randomized trials have demonstrated increased mortality with the use of ambulatory dobutamine infusions.4


MILRINONE

Milrinone is a selective inhibitor of phospodiesterase III, an enzyme responsible for the intracellular breakdown of c-AMP. Cyclic-AMP accumulation increases intracellular calcium and thereby facilitates myocardial contractility. Although milrinone’s hemodynamic effects are similar to those of dobutamine, milrinone produces more arterial and venous dilation, earning it the label “inodilator” (Table 14.1). Theoretical advantages of milrinone as compared with dobutamine include greater afterload reduction, augmenting the cardiac output produced by its inotropic effect, and its postreceptor mechanism of action, a potential benefit in patients receiving β-blockers for chronic heart failure. Hemodynamic improvement is usually observed within 15 minutes of initiation of therapy. The drug is renally eliminated with an elimination half-life of approximately
3 hours in heart failure patients, and the maintenance infusion should be adjusted based on creatinine clearance (Table 14.2).








TABLE 14.1 Hemodynamic Effects of Intravenous Agents Used in the Treatment of Acute Decompensated Heart Failure





















































































































Drug


Dose


HR


MAP


PAOP


CO


SVR


Dobutamine


2.5-15








μg/kg/min


0/+


0



+



Milrinone


0.375-0.75








μg/kg/min


0/+


0/-



+



Dopamine


0.5-3








μg/kg/min


0


0


0


0/+



Dopamine


3-10 μg/kg/min


+


+


0


+


0


Dopamine


>10 μg/kg/min


+


+


+


+


+


Nesiritide


Bolus: 2 μg/kg








Infusion: 0.01 μg/kg/min


0


0/-



+



Nitroglycerin


5-200 μg/min


0/+


0/-



0/+


0/-


Nitroprusside


0.25-3.0








μg/kg/min


0/+


0/-



+



CO, cardiac output; HR, heart rate; MAP, mean arterial pressure; PAOP, pulmonary artery occlusive pressure; SVR, systemic vascular resistance. Adopted from DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw Hill; 1999.


Although the package insert recommends a 50 μg per kg loading dose, many heart failure practitioners refrain from administering the loading dose to reduce the risk of hypotension. Typical maintenance doses of milrinone range from 0.375 to 0.75 μg/kg/minute (Table 14.1). At maintenance doses above 0.5 μg/kg/minute, once hemodynamic and clinical stability has been achieved, the infusion should be gradually tapered. However, because the drug has a longer elimination half-life than dobutamine, lower milrinone maintenance doses may be reduced more rapidly than dobutamine, provided hemodynamic stability has been achieved. In addition to hypotension, the most common side effects are tachyarrhythmias. Milrinone may produce less tachycardia than dobutamine, but it also has the potential to produce both atrial and ventricular arrhythmias.

Despite the potential adverse long-term impact on morbidity and mortality related to intravenous inotropic therapy, patients with acute decompensated heart failure benefit from the short-term hemodynamic improvement associated with the administration of these agents, pending the resolution of the underlying events that precipitate their hemodynamic deterioration.








TABLE 14.2 Renal Dosing of Milrinone
























Creatinine Clearance (ml/min/1.73m2)


Milrinone Infusion Rate (µg/kg/min)


5


0.20


10


0.23


20


0.28


30


0.33


40


0.38


50


0.43



DOPAMINE

Dopamine possesses dose-dependent hemodynamic effects, stimulating D1 dopamine receptors, α1-, β1-, and β2-receptors. Other than the diuretic effect of low-dose (renal dose) dopamine to enhance volume loss in patients with diuretic-resistant heart failure, dopamine use is typically reserved for use in markedly hypotensive patients including those with cardiogenic shock. Inotropic doses in the 2 to 5 μg/kg/minute range promote increase cardiac output; however, intermediate- and high-dose dopamine increase systemic vascular resistance, increase afterload and PAOP, and impede cardiac output (Table 14.1). In the setting of cardiogenic shock, dopamine may be required to maintain mean arterial pressure and coronary perfusion pressure until the underlying etiology can be treated or resolved.


DIGOXIN

Digoxin is a moderately potent inotrope with additional neurohormonal modulating effects producing increased parasympathetic nervous system activity and decreased central sympathetic nervous system drive. Its inotropic effect is related to inhibition of sarcolemmal sodium-potassium-ATPase, resulting in increased myocardial cell calcium, the final common pathway for all currently available inotropic agents. The benefit of digoxin in heart failure was debated for most of its first 200-year history. The drug has little use in the treatment of acute heart failure in patients with sinus rhythm. Perhaps the least controversial use of the drug in heart failure patients is to assist (in combination with β-blockers or amiodarone) in
the management of rate control in patients with atrial fibrillation. The Digoxin Investigation Group (DIG) clarified the role for digoxin in the management of heart failure patients with normal sinus rhythm.5 This study demonstrated that digoxin, in addition to background angiotensin converting enzyme inhibitor (ACEI) and diuretic therapy, improved exercise tolerance, and reduced heart failure related hospitalizations, but did not improve survival. Therefore, digoxin therapy for heart failure may be considered either in patients with atrial fibrillation, or in patients in sinus rhythm on target doses (if tolerated) of ACEI/ARB and β-blockers who exhibit continued exercise intolerance or recurrent heart failure related hospitalizations.

Digoxin is primarily renally eliminated with a serum elimination half-life of 1.6 days in patients with normal renal function. Recent trials have demonstrated that the efficacy of digoxin in heart failure can be achieved with doses that produce serum concentrations of 0.5 to 1.0 ng per ml, lower than those previously defined as “therapeutic.”6 Higher serum concentrations provide no added benefit and increase the risk of digoxin toxicity.


DIGOXIN TOXICITY

Digitalis intoxication is a clinical diagnosis based on the presence of signs and/or symptoms including anorexia, nausea, and vomiting, and atrial or ventricular arrhythmias. Given the establishment of lower effective serum concentration, the incidence of digoxin toxicity has likely diminished. It is important to understand that the diagnosis of digoxin toxicity is never based solely on the digoxin concentration. Elevated serum digoxin concentrations are only one etiology of drug toxicity, usually related to maintenance doses inappropriate for the level of renal function. Most patients with normal renal function require 0.125 mg digoxin daily. Patients with renal insufficiency typically require 0.125 mg every other day or less. Many other factors that do not produce elevated serum digoxin concentrations are capable of causing digoxin toxicity including diuretic-induced hypokalemia or hypomagnesemia, hypoxemia, acidosis, hyperthyroidism, and others. Concurrent amiodarone therapy may double the serum digoxin concentration, and typical digoxin dosing in these patients should be reduced by 50% of the usual dose, considering renal function.








TABLE 14.3 Diuretics Used in the Treatment of Heart Failure































































Drug


Initial Daily Dose(s)


Maximum Total Daily Dose


Duration of Action


LOOP DIURETICS





Bumetanide


0.5-1.0 mg once or twice


10 mg


4-6 h


Furosemide


20-40 mg once or twice


600 mg


6-8 h


Torsemide


10-20 mg once


200 mg


12-16 h


POTASSIUM SPARING DIURETICS





Eplerenone


25 mg once


50 mg once


24 h


Spironolactone


12.5-25 mg once


50 mg


2-3 d


Triamterene


50-75 mg


200 mg


7-9 h


SEQUENTIAL NEPHRON BLOCKADE





Metolazone


2.5-10 mg once plus loop diuretic




Chlorothiazide (IV)


500-1000 mg once plus loop diuretic





DIURETICS

Classical descriptions of acute decompensated heart failure characterize patients as volume overloaded but well perfused (“wet and warm”), or hypoperfused and not volume overloaded (“cool and dry”). The majority of hospitalized patients, however, will require acute diuretic therapy to relieve signs and symptoms associated with their acute presentation. Much of the efficacy data associated with diuretic therapy for acute heart failure are derived from experience prior to the era of randomized controlled trials. Despite their effectiveness for symptom relief, diuretics have not been demonstrated to improve survival in heart failure. Because of their potency, and rapid onset of action, loop diuretics (furosemide, torsemide, bumetanide) are considered the mainstay of treatment (Table 14.3). These agents inhibit sodium and chloride reabsorption in the ascending limb of the Loop of Henle. Their effect to reduce venous tone and therefore pulmonary capillary wedge pressure often begins to improve pulmonary symptoms prior to a significant increase in urinary output. It is important to recognize that patients with chronic heart failure may have increased pulmonary capillary pressures and progressive dyspnea in the absence of significant pulmonary crackles on physical examination. On the contrary, patients with new-onset heart failure are more likely to demonstrate pulmonary vascular congestion (crackles) on examination.


Dosing of loop diuretics is empiric. In general, a 40-mg oral furosemide dose is equivalent to a 20-mg intravenous dose. In volume overloaded patients with normal renal function, an initial intravenous dose of furosemide should be one to two times the chronic oral dose. Response to an individual intravenous dose can be assessed in several hours. Patient response is based on relief of pulmonary vascular congestion, daily weight, hepatic congestion, and peripheral edema. Because Loop diuretics require a threshold serum concentration to affect their natriuretic response, patients with chronic heart failure, and those with moderate-tosevere renal insufficiency will usually require higher initial doses than patients with normal renal function or new-onset heart failure (diuretic naive patients). Alternative furosemide dosing strategies comparing bolus dosing to continuous infusions have been evaluated in a number of small uncontrolled trials. Earlier studies, in addition to a review of eight randomized trials, suggest that continuous intravenous infusions of furosemide ranging from 10 to 40 mg per hour, depending on renal function, produce a greater diuretic effect than similar total doses administered by intermittent bolus dosing, with fewer adverse effects.7 The recent diuretic optimization strategies evaluation (DOSE) trial, a randomized, open-label comparison between twice daily furosemide and continuous infusion demonstrated no differences in outcomes in 41 hospitalized, volume-overloaded heart failure patients from admission to hospital day 3.8 There was a trend towards less hypokalemia and hypotension in the continuous infusion group. Although no definitive data currently resolve the dosing route of administration controversy, it does not appear that continuous infusion offers a significant advantage over traditional bolus dosing of furosemide.

Monitoring for adverse effects of diuresis includes electrolytes, orthostatic hypotension, prerenal azotemia or increasing serum creatinine. Less commonly, patients with a history of chronic gout may experience an acute gout exacerbation. Excessive diuresis can enhance undesired neurohormonal activation, increasing the risk of excessive hypotensive effects from ACE inhibitors and β-blockers.

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May 27, 2016 | Posted by in CARDIAC SURGERY | Comments Off on Medications Used in the Management of Heart Failure
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