NCLEX: Heart Failure

Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. Its cardinal symptoms are dyspnea, fatigue, and fluid retention. HF is due to an impaired ability of the heart to adequately fill with and/or eject blood. It is often accompanied by abnormal increases in blood volume and interstitial fluid. Underlying causes of HF include arteriosclerotic heart disease, myocardial infarction, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, and congenital heart disease.

A. Role of physiologic compensatory mechanisms in the progression of HF

Chronic activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system is associated with remodeling of cardiac tissue, loss of myocytes, hypertrophy, and fibrosis. This prompts additional neurohormonal activation, creating a vicious cycle that, if left untreated, leads to death.

B. Goals of pharmacologic intervention in HF

Goals of treatment are to alleviate symptoms, slow disease progression, and improve survival. Accordingly, seven classes of drugs have been shown to be effective: 1) angiotensin-converting enzyme inhibitors, 2) angiotensin-receptor blockers, 3) aldosterone antagonists, 4) β-blockers, 5) diuretics, 6) direct vaso- and venodilators, and 7) inotropic agents. Depending on the severity of HF and individual patient factors, one or more of these classes of drugs are administered. Pharmacologic intervention provides the following benefits in HF: reduced myocardial work load, decreased extracellular fluid volume, improved cardiac contractility, and a reduced rate of cardiac remodeling. Knowledge of the physiology of cardiac muscle contraction is essential for understanding the compensatory responses evoked by the failing heart, as well as the actions of drugs used to treat HF.

 Heart Failure

 Heart Failure:L PHYSIOLOGY OF MUSCLE CONTRACTION

Focus topic:  Heart Failure

The myocardium, like smooth and skeletal muscle, responds to stimulation by depolarization of the membrane, which is followed by shortening of the contractile proteins and ends with relaxation and return to the resting state (repolarization). Cardiac myocytes are interconnected in groups that respond to stimuli as a unit, contracting together whenever a single cell is stimulated.

A. Action potential

Cardiac myocytes are electrically excitable and have a spontaneous, intrinsic rhythm generated by specialized “pacemaker” cells located in the sinoatrial and atrioventricular (AV) nodes. Cardiac myocytes also have an unusually long action potential, which can be divided into five phases (0 to 4).

B. Cardiac contraction

The force of contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium. Therefore, agents that increase intracellular calcium levels (or that increase the sensitivity of the contractile machinery to calcium) increase the force of contraction (inotropic effect). [Note: The inotropic agents increase the contractility of the heart by directly or indirectly altering the mechanisms that control the concentration of intracellular calcium.]

C. Compensatory physiological responses in HF

The failing heart evokes three major compensatory mechanisms to enhance cardiac output. Although initially beneficial, these alterations ultimately result in further deterioration of cardiac function.

  • Increased sympathetic activity: Baroreceptors sense a decrease in blood pressure and activate the sympathetic nervous system. In an attempt to sustain tissue perfusion, this stimulation of β-adrenergic receptors results in an increased heart rate and a greater force of contraction of the heart muscle. In addition, vasoconstriction enhances venous return and increases cardiac preload. An increase in preload (stretch on the heart) increases stroke volume, which, in turn, increases cardiac output. These compensatory responses increase the work of the heart, which, in the long term, contributes to further decline in cardiac function.
  • Activation of the renin–angiotensin–aldosterone system: A fall in cardiac output decreases blood flow to the kidney, prompting the release of renin, and resulting in increased formation of angiotensin II and release of aldosterone. This results in increased peripheral resistance (after load) and retention of sodium and water. Blood volume increases, and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral and pulmonary edema occur. Again, these compensatory responses increase the work of the heart, contributing to further decline in cardiac function.
  • Myocardial hypertrophy: The heart increases in size, and the chambers dilate and become more globular. Initially, stretching of the heart muscle leads to a stronger contraction of the heart. However, excessive elongation of the fibers results in weaker contractions, and the geometry diminishes the ability to eject blood. This type of failure is termed “systolic failure” or HF with reduced ejection fraction (HFrEF) and is the result of the ventricle being unable to pump effectively. Less commonly, patients with HF may have “diastolic dysfunction,” a term applied when the ability of the ventricles to relax and accept blood is impaired by structural changes such as hypertrophy. The thickening of the ventricular wall and subsequent decrease in ventricular volume decrease the ability of heart muscle to relax. In this case, the ventricle does not fill adequately, and the inadequacy of cardiac output is termed “diastolic HF” or HF with preserved ejection fraction. Diastolic dysfunction, in its pure form, is characterized by signs and symptoms of HF in the presence of a normal functioning left ventricle. However, both systolic and diastolic dysfunction commonly coexist in HF.

 Heart Failure

Heart Failure

 Heart Failure

D. Acute (decompensated) HF

If the adaptive mechanisms adequately restore cardiac output, HF is said to be compensated. If the adaptive mechanisms fail to maintain cardiac output, HF is decompensated and the patient develops worsening HF signs and symptoms. Typical HF signs and symptoms include dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and peripheral edema.

E. Therapeutic strategies in HF

Chronic HF is typically managed by fluid limitations (less than 1.5 to 2 L daily); low dietary intake of sodium (less than 2000 mg/d); treatment of comorbid conditions; and judicious use of diuretics, inhibitors of the renin–angiotensin–aldosterone system, and inhibitors of the sympathetic nervous system. Inotropic agents are reserved for acute HF signs and symptoms in mostly the inpatient setting. Drugs that may precipitate or exacerbate HF, such as nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, nondihydropyridine calcium channel blockers, and some antiarrhythmic drugs, should be avoided if possible.

 Heart Failure: INHIBITORS OF THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

Focus topic:  Heart Failure

HF leads to activation of the renin–angiotensin–aldosterone system via two mechanisms: 1) increased renin release by juxtaglomerular cells in renal afferent arterioles due to diminished renal perfusion pressure produced by the failing heart and 2) renin release by juxtaglomerular cells promoted by sympathetic stimulation and activation of β receptors. The production of angiotensin II, a potent vasoconstrictor, and the subsequent stimulation of aldosterone release that causes salt and water retention lead to increases in both preload and afterload that are characteristic of the failing heart. In addition, high levels of angiotensin II and of aldosterone have direct detrimental effects on the cardiac muscle, favoring remodeling, fibrosis, and inflammatory changes.

A. Angiotensin-converting enzyme inhibitors

Focus topic:  Heart Failure

Angiotensin-converting enzyme (ACE) inhibitors are a part of standard pharmacotherapy in HFrEF. These drugs block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. They also diminish the inactivation of bradykinin. Vasodilation occurs as a result of decreased levels of the vasoconstrictor angiotensin II and increased levels of bradykinin (a potent vasodilator). By reducing angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone.

  • Actions on the heart: ACE inhibitors decrease vascular resistance (afterload) and venous tone (preload), resulting in increased cardiac output. ACE inhibitors also blunt the usual angiotensin II–mediated increase in epinephrine and aldosterone seen in HF. ACE inhibitors improve clinical signs and symptoms of HF and have been shown to significantly improve patient survival in HF.
  • Indications: ACE inhibitors may be considered for patients with asymptomatic and symptomatic HFrEF. Importantly, ACE inhibitors are indicated for patients with all stages of left ventricular failure. Patients with the lowest ejection fraction show the greatest benefit from use of ACE inhibitors. Depending on the severity of HF, ACE inhibitors may be used in combination with diuretics, β-blockers, digoxin, aldosterone antagonists, and hydralazine/isosorbide dinitrate fixed-dose combination. Patients who have had a recent myocardial infarction or are at high risk for a cardiovascular event also benefit from long-term ACE inhibitor therapy. ACE inhibitors are also used for the treatment of hypertension.
  • Pharmacokinetics: ACE inhibitors are adequately absorbed following oral administration. Food may decrease the absorption of captopril [CAP-toe-pril], so it should be taken on an empty stomach. Except for captopril, ACE inhibitors are prodrugs that require activation by hydrolysis via hepatic enzymes. Renal elimination of the active moiety is important for most ACE inhibitors except fosinopril [foe-SIH-no-pril]. Plasma half-lives of active compounds vary from 2 to 12 hours, although the inhibition of ACE may be much longer.
  • Adverse effects: These include postural hypotension, renal insufficiency, hyperkalemia, a persistent dry cough, and angioedema (rare). Potassium levels must be monitored, particularly with concurrent use of potassium supplements, potassium-sparing diuretics, or aldosterone antagonists due to risk of hyperkalemia. Serum creatinine levels should also be monitored, particularly in patients with underlying renal disease. The potential for symptomatic hypotension with ACE inhibitors is much more common if used concomitantly with a diuretic. ACE inhibitors are teratogenic and should not be used in pregnant women.

 Heart Failure

 Heart Failure

B. Angiotensin receptor blockers

Focus topic:  Heart Failure

Angiotensin receptor blockers (ARBs) are orally active compounds that are competitive antagonists of the angiotensin II type 1 receptor. ARBs have the advantage of more complete blockade of angiotensin II action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II. Further, ARBs do not affect bradykinin levels. Although ARBs have actions similar to those of ACE inhibitors, they are not therapeutically identical. Even so, ARBs are a substitute for ACE inhibitors in those patients who cannot tolerate the latter.

  • Actions on the cardiovascular system: Although ARBs have a different mechanism of action than ACE inhibitors, their actions on preload and afterload are similar. Their use in HF is mainly as a substitute for ACE inhibitors in those patients with severe cough or angioedema, which are thought to be mediated by elevated bradykinin levels. ARBs are also used in the treatment of hypertension.
  • Pharmacokinetics: All the drugs are orally active and are dosed once-daily, with the exception of valsartan [val-SAR-tan] which is twice a day. They are highly plasma protein bound and, except for candesartan [kan-de-SAR-tan], have large volumes of distribution. Losartan [loe-SAR-tan], the prototype of the class, differs in that it undergoes extensive first-pass hepatic metabolism, including conversion to its active metabolite. The other drugs have inactive metabolites. Elimination of metabolites and parent compounds occurs in urine and feces.
  • Adverse effects: ARBs have an adverse effect and drug interaction profile similar to that of ACE inhibitors. However, the ARBs have a lower incidence of cough and angioedema. Like ACE inhibitors, ARBs are contraindicated in pregnancy.

C. Aldosterone antagonists

Focus topic:  Heart Failure

Patients with advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. Spironolactone [spy-ro-no-LAC-tone] is a direct antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy, and hypokalemia. Eplerenone [eh-PLEH-reh-none] is a competitive antagonist of aldosterone at mineralocorticoid receptors. Although similar in action to spironolactone at the mineralocorticoid receptor, eplerenone has a lower incidence of endocrine-related side effects due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors. Aldosterone antagonists are indicated in patients with more severe stages of HFrEF or HFrEF and recent myocardial infarction. Please see Chapter 18 for a full discussion of aldosterone receptor antagonists.

 Heart Failure: 𝝱-BLOCKERS

Focus topic:  Heart Failure

Although it may seem counterintuitive to administer drugs with negative inotropic activity in HF, evidence clearly demonstrates improved systolic functioning and reverse cardiac remodeling in patients receiving β-blockers. These benefits arise in spite of an occasional, initial exacerbation of symptoms. The benefit of β-blockers is attributed, in part, to their ability to prevent the changes that occur because of chronic activation of the sympathetic nervous system. These agents decrease heart rate and inhibit release of renin in the kidneys. In addition, β-blockers prevent the deleterious effects of norepinephrine on the cardiac muscle fibers, decreasing remodeling, hypertrophy, and cell death. Three β-blockers have shown benefit in HF: bisoprolol [bis-oh-PROE-lol], carvedilol [KARve-dil-ol], and long-acting metoprolol succinate [me-TOE-proe-lol SUKsi-nate]. Carvedilol is a nonselective β-adrenoreceptor antagonist that also blocks α-adrenoreceptors, whereas bisoprolol and metoprolol succinate are β1-selective antagonists. β-Blockade is recommended for all patients with chronic, stable HF. Bisoprolol, carvedilol, and metoprolol succinate reduce morbidity and mortality associated with HFrEF. Treatment should be started at low doses and gradually titrated to target doses based on patient tolerance and vital signs. Both carvedilol and metoprolol are metabolized by the cytochrome P450 2D6 isoenzyme, and inhibitors of this metabolic pathway may increase levels of these drugs and increase the risk of adverse effects. In addition, carvedilol is a substrate of P-glycoprotein (P-gp). Increased effects of carvedilol may occur if it is coadministered with P-gp inhibitors. β-Blockers should also be used with caution with other drugs that slow AV conduction, such as amiodarone, verapamil, and diltiazem.

 Heart Failure

 Heart Failure: DIURETICS

Focus topic:  Heart Failure

Diuretics relieve pulmonary congestion and peripheral edema. These agents are also useful in reducing the symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea. Diuretics decrease plasma volume and, subsequently, decrease venous return to the heart (preload). This decreases cardiac workload and oxygen demand. Diuretics may also decrease afterload by reducing plasma volume, thereby decreasing blood pressure. Loop diuretics are the most commonly used diuretics in HF. These agents are used for patients who require extensive diuresis and those with renal insufficiency. [Note: Overdoses of loop diuretics can lead to profound hypovolemia.] As diuretics have not been shown to improve survival in HF, they should only be used to treat signs and symptoms of volume excess.

 Heart Failure: VASO- AND VENODILATORS

Focus topic:  Heart Failure

Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance. Nitrates are commonly used venous dilators to reduce preload for patients with chronic HF. Arterial dilators, such as hydralazine [hye-DRAL-a-zeen] reduce systemic arteriolar resistance and decrease afterload. If the patient is intolerant of ACE inhibitors or β-blockers, or if additional vasodilator response is required, a combination of hydralazine and isosorbide dinitrate [eye-soe-SOR-bide dye-NYE-trate] may be used. A fixed-dose combination of these agents has been shown to improve symptoms and survival in black patients with HFrEF on standard HF treatment (β-blocker plus ACE inhibitor or ARB). Headache, hypotension, and tachycardia are common adverse effects with this combination. Rarely, hydralazine has been associated with drug-induced lupus.

 Heart Failure: INOTROPIC DRUGS

Focus topic:  Heart Failure

Positive inotropic agents enhance cardiac contractility and, thus, increase cardiac output. Although these drugs act by different mechanisms, the inotropic action is the result of an increased cytoplasmic calcium concentration that enhances the contractility of cardiac muscle. All positive inotropes in HFrEF that increase intracellular calcium concentration have been associated with reduced survival, especially in patients with HFrEF due to coronary artery disease. For this reason, these agents, with the exception of digoxin, are only used for a short period mainly in the inpatient setting.

A. Digitalis glycosides

Focus topic:  Heart Failure

The cardiac glycosides are often called digitalis or digitalis glycosides, because most of the drugs come from the digitalis (foxglove) plant. They are a group of chemically similar compounds that can increase the contractility of the heart muscle and, therefore, are used in treating HF. The digitalis glycosides have a low therapeutic index, with only a small difference between a therapeutic dose and doses that are toxic or even fatal. The most widely used agent is digoxin [di-JOX-in]. Digitoxin [dij-i-TOK-sin] is seldom used due to its considerable duration of action.

1. Mechanism of action:

  • Regulation of cytosolic calcium concentration: By inhibiting the Na+/K+-adenosine triphosphatase (ATPase) enzyme, digoxin reduces the ability of the myocyte to actively pump Na+ from the cell (Figure 19.8). This decreases the Na+ concentration gradient and, consequently, the ability of the Na+/ Ca2+-exchanger to move calcium out of the cell. Further, the higher cellular Na+ is exchanged for extracellular Ca2+ by the Na+/Ca2+-exchanger, increasing intracellular Ca2+. A small but physiologically important increase occurs in free Ca2+ that is available at the next contraction cycle of the cardiac muscle, thereby increasing cardiac contractility. When Na+/K+-ATPase is markedly inhibited by digoxin, the resting membrane potential may increase (−70 mV instead of −90 mV), which makes the membrane more excitable, increasing the risk of arrhythmias (toxicity).
  • Increased contractility of the cardiac muscle: Digoxin increases the force of cardiac contraction, causing cardiac output to more closely resemble that of the normal heart. Vagal tone is also enhanced, so both heart rate and myocardial oxygen demand decrease. Digoxin slows conduction velocity through the AV node, making it useful for atrial fibrillation. [Note: In the normal heart, the positive inotropic effect of digitalis glycosides is counteracted by compensatory autonomic reflexes.] c. Neurohormonal inhibition: Although the exact mechanism of this effect has not been elucidated, low-dose digoxin inhibits sympathetic activation with minimal effects on contractility. This effect is the reason a lower serum drug concentration is targeted in HFrEF.

 Heart Failure

 Heart Failure

2. Therapeutic uses: Digoxin therapy is indicated in patients with severe HFrEF after initiation of ACE inhibitor, β-blocker, and diuretic therapy. A low serum drug concentration of digoxin (0.5 to 0.8 ng/mL) is beneficial in HFrEF. At this level, patients may see a reduction in HF admissions, along with improved survival. At higher serum drug concentrations, admissions are prevented, but mortality likely increases. Digoxin is not indicated in patients with diastolic or right sided HF unless the patient has concomitant atrial fibrillation or flutter. Patients with mild to moderate HF often respond to treatment with ACE inhibitors, β-blockers, aldosterone antagonists, direct vaso- and venodilators, and diuretics and may not require digoxin.

3. Pharmacokinetics: Digoxin is available in oral and injectable formulations. It has a large volume of distribution, because it accumulates in muscle. The dosage is based on lean body weight. In acute situations such as symptomatic atrial fibrillation, a loading dose regimen is used. Digoxin has a long half-life of 30 to 40 hours. It is mainly eliminated intact by the kidney, requiring dose adjustment in renal dysfunction.

4. Adverse effects: At low serum drug concentrations, digoxin is fairly well tolerated. However, it has a very narrow therapeutic index, and digoxin toxicity is one of the most common adverse drug reactions leading to hospitalization. Anorexia, nausea, and vomiting may be initial indicators of toxicity. Patients may also experience blurred vision, yellowish vision (xanthopsia), and various cardiac arrhythmias. Toxicity can often be managed by discontinuing digoxin, determining serum potassium levels, and, if indicated, replenishing potassium. Decreased levels of serum potassium (hypokalemia) predispose a patient to digoxin toxicity, since digoxin normally competes with potassium for the same binding site on the Na+/K+-ATPase pump. [Note: Patients receiving thiazide or loop diuretics may be prone to hypokalemia.] Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs and the use of antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug. With the use of a lower serum drug concentration in HFrEF, toxic levels are infrequent. Digoxin is a substrate of P-gp, and inhibitors of P-gp, such as clarithromycin, verapamil, and amiodarone, can significantly increase digoxin levels, necessitating a reduced dose of digoxin. Digoxin should also be used with caution with other drugs that slow AV conduction, such as β-blockers, verapamil, and diltiazem.

B. β-Adrenergic agonists

Focus topic:  Heart Failure

β-Adrenergic agonists, such as dobutamine [doe-BYOO-ta-meen] and dopamine [DOH-puh-meen], improve cardiac performance by causing positive inotropic effects and vasodilation. Dobutamine is the most commonly used inotropic agent other than digoxin. β-Adrenergic agonists lead to an increase in intracellular cyclic adenosine monophosphate (cAMP), which results in the activation of protein kinase. Protein kinase then phosphorylates slow calcium channels, thereby increasing entry of calcium ions into the myocardial cells and enhancing contraction. Both drugs must be given by intravenous infusion and are primarily used in the short-term treatment of acute HF in the hospital setting.

C. Phosphodiesterase inhibitors

Focus topic:  Heart Failure

Milrinone [MIL-rih-nohn] is a phosphodiesterase inhibitor that increases the intracellular concentration of cAMP. Like β-adrenergic agonists, this results in an increase of intracellular calcium and, therefore, cardiac contractility. Long-term, milrinone therapy may be associated with a substantial increased risk of mortality. However, short-term use of intravenous milrinone is not associated with increased mortality in patients without a history of coronary artery disease, and some symptomatic benefit may be obtained in patients with refractory HF.

 Heart Failure

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 Heart Failure: ORDER OF THERAPY

Focus topic:  Heart Failure

Experts have classified HF into four stages, from least severe to most severe. Figure 19.11 shows a treatment strategy using this classification and the drugs described in this chapter. Note that as the disease progresses, polytherapy is initiated. In patients with overt HF, loop diuretics are often introduced first for relief of signs or symptoms of volume overload, such as dyspnea and peripheral edema. ACE inhibitors or ARBs (if ACE inhibitors are not tolerated) are added after the optimization of diuretic therapy. The dosage is gradually titrated to that which is maximally tolerated and/or produces optimal cardiac output. Historically, β-blockers were added after optimization of ACE inhibitor or ARB therapy; however, most patients newly diagnosed with HFrEF are initiated on both low doses of an ACE inhibitor and β-blocker after initial stabilization. These agents are slowly titrated to optimal levels to increase tolerability. Digoxin, aldosterone antagonists, and fixed-dose hydralazine and isosorbide dinitrate are initiated in patients who continue to have HF symptoms despite optimal doses of an ACE inhibitor and β-blocker.

 Heart Failure

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