CLINICAL PHARMACY IN CARDIOLOGY (IV)
Clinical Pharmacy in cardiology. Symptoms and syndromes in major cardiovascular system diseases. Clinical pharmacology of drugs used for the treatment of atherosclerosis, coronary heart disease, hypertension, chronic heart failure
DRUGS USED IN HEART FAILURE
Heart failure occurs when cardiac output is inadequate to provide the oxygeeeded by the body. It is a highly lethal condition, with a 5-year mortality rate conventionally said to be about 50%. The most common cause of heart failure in the USA is coronary artery disease, with hypertension also an important factor. Two major types of failure may be distinguished. Approximately 50% of patients have systolic failure, with reduced mechanical pumping action (contractility) and reduced ejection fraction. The remaining group has diastolic failure, with stiffening and loss of adequate relaxation playing a major role in reducing filling and cardiac output; ejection fraction may be normal even though stroke volume is significantly reduced. Because other cardiovascular conditions are now being treated more effectively (especially myocardial infarction), more patients are surviving long enough for heart failure to develop, making heart failure one of the cardiovascular conditions that is actually increasing in prevalence.
Heart failure is a progressive disease that is characterized by a gradual reduction in cardiac performance, punctuated in many cases by episodes of acute decompensation, often requiring hospitalization. Treatment is therefore directed at two somewhat different goals: (1) reducing symptoms and slowing progression as much as possible during relatively stable periods and (2) managing acute episodes of decompensated failure. Furthermore, management of systolic failure is not identical with management of diastolic failure.
Although it is believed that the primary defect in early systolic heart failure resides in the excitation-contraction coupling machinery of the heart, the clinical condition also involves many other processes and organs, including the baroreceptor reflex, the sympathetic nervous system, the kidneys, angiotensin II and other peptides, aldosterone, and apoptosis of cardiac cells. Recognition of these factors has resulted in evolution of a variety of drug treatment strategies.
Classification of Heart Failure
Heart failure can be classified by how much physical activity you can do before you start feeling symptoms. The table below is the New York Heart Association Classification which separates heart failure into five categories.
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Large clinical trials have shown that therapy directed at noncardiac targets is more valuable in the long-term treatment of heart failure than traditional positive inotropic agents (cardiac glycosides [digitalis]). Extensive trials have shown that ACE inhibitors, angiotensin receptor blockers, beta-blockers, aldosterone receptor antagonists, and combined hydralazine-nitrate therapy are the only agents in current use that actually prolong life in patients with chronic heart failure. These strategies are useful in both systolic and diastolic failure. Positive inotropic drugs, on the other hand, can be helpful in acute failure. Cardiac glycosides also reduce symptoms in chronic systolic heart failure. Other positive inotropic drugs have consistently reduced survival in chronic failure.
PATHOPHYSIOLOGY OF HEART FAILURE
Heart failure is a syndrome with many causes that may involve either ventricle or both. Cardiac output is usually below the normal range. Systolic dysfunction, with reduced cardiac output and significantly reduced ejection fraction (< 45%), is typical of acute failure, especially that resulting from myocardial infarction. Diastolic dysfunction often occurs as a result of hypertrophy and stiffening of the myocardium, and although cardiac output is reduced, ejection fraction may be normal. Heart failure due to diastolic dysfunction does not usually respond optimally to positive inotropic drugs.
“High-output” failure is a rare form of heart failure. In this condition, the demands of the body are so great that even increased cardiac output is insufficient. High-output failure can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts. This form of failure responds poorly to the drugs discussed in this chapter and should be treated by correcting the underlying cause.
The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary edema, and cardiomegaly. Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect.
Neurohumoral (extrinsic) compensation involves two major mechanisms – the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. The result is a vicious cycle that is characteristic of heart failure. Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. Neurohumoral antagonists and vasodilators reduce heart failure mortality by interrupting the cycle and slowing the downward spiral.
After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac beta1-adrenoceptor–G protein-effector system take place that result in diminished stimulatory effects. Beta2 receptors are not down-regulated and may develop increased coupling to the IP3-DAG cascade. It has also been suggested that cardiac beta3 receptors (which do not appear to be down-regulated in failure) may mediate negative inotropic effects. Excessive activation can lead to leakage of calcium from the SR via RyR channels and contributes to stiffening of the ventricles and arrhythmias. Prolonged activation also increases caspases, the enzymes responsible for apoptosis. Increased angiotensin II production leads to increased aldosterone secretion (with sodium and water retention), to increased afterload, and to remodeling of both heart and vessels. Other hormones are released, including natriuretic peptide, endothelin, and vasopressin. Within the heart, failure-induced changes have been documented in calcium handling in the SR by SERCA and phospholamban; in transcription factors that lead to hypertrophy and fibrosis; in mitochondrial function, which is critical for energy production in the overworked heart; and in ion channels, especially potassium channels, which facilitate arrhythmogenesis, a primary cause of death in heart failure. Phosphorylation of RyR in the sarcoplasmic reticulum enhances and dephosphorylation reduces Ca2+ release; studies in animal models indicate that the enzyme primarily responsible for RyR dephosphorylation, protein phosphatase 1 (PP1), is upregulated in heart failure. These cellular changes provide many potential targets for future drugs.
The most important intrinsic compensatory mechanism is myocardial hypertrophy. This increase in muscle mass helps maintain cardiac performance. However, after an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes. Ultimately, myocytes in the failing heart die at an accelerated rate through apoptosis, leaving the remaining myocytes subject to even greater stress.
INOTROPIC AGENTS
The therapeutic goal for CHF is to increase cardiac output. Several drugs are used to treat acute HF, and a combination of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a diuretic is first-line therapy for chronic failure. Increasingly, digoxin, a betaadrenergic blocking agent, or spironolactone is being added to the ACE inhibitor or ARB and diuretic regimen.
Drug therapy of HF continues to evolve as the pathophysiologic mechanisms are better understood and research studies indicate more effective regimens. Combinations of drugs are commonly used in efforts to improve circulation, alter the compensatory mechanisms, and reverse heart damage. Most of the drugs used to treat HF are also used in other disorders and are discussed in other chapters; their effects inHF are described in
. The primary focus of this chapter is inotropic agents, which include digoxin, a cardiac glycoside, and the phosphodiesterase inhibitors inamrinone and milrinone. These drugs are discussed in the following sections and in Drugs at a Glance: Drugs for Heart Failure.
Two new classifications of drugs, humaatriuretic peptides and endothelin receptor antagonists, are also presented.
Three classes of drugs have been shown to be clinically effective in reducing symptoms and prolonging life:
1. VASODILATORS that reduce the load on the myocardium – ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril), hydralazine, isosorbide, minoxidil, sodium nitroprusside.
2. DIURETICS that decrease extracellular fluid volume – bumetanide, furosemide, hydrochlorothiazide, metolazone.
3. INOTROPIC AGENTS that increase the strength of contraction of cardiac muscle – cardiac glycosides (digitoxin, digoxin), dobutamine – b-adrenergic agonist, amrinone, milrinone – phosphodiesterase inhibitors.
Therapeutic strategies in CHF. Chronic heart failure is typically managed by reduction in physical activity, low dietary intake of sodium (less than 1500 mg sodium per day), and treatment with vasodilators, diuretics and inotropic agents. Drug that may precipitate or exacerbate CHF – nonsteroidal anti-inflammatory drugs, alcohol, b-blockers, calcium channel-blockers, some antiarrhythmic drugs – should be avoided if possible. Patients with CHF complain of dyspnea on exertion, orthopnea, paroxysmal noctural dyspnea, fatigue, and dependent edema.
VASODILATORS. In CHF, the impaired contractile function of the heart is exacerbated by compensatory increases in both preload and afterload. Preload is the volume pf blood that fills the ventricle during diastole. Elevated preload causes overfilling of the heart, which increases the workload. Afterload is the pressure that must be overcome for the heart to pump blood into the arterial system. Elevated afterload causes the heart to work harder to pump blood into the arterial system. Vasodilators are useful in reducing excessive preload and afterload. Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance; arterial dilators reduce systemic arteriolar resistance and decrease afterload.
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Angiotensin converting enzyme (ACE) inhibitors
ACE inhibitors are the drugs of choice in CHF and are superior to other vasodilators. Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention.
ACE inhibitors decrease vascular resistance, venous tone, and blood pressure, resulting in an increased cardiac output. Ace inhibitors improve clinical signs and symptoms in patients also receiving a diuretic and/or digoxin. The use of ACE inhibitors in the treatment of CHF has significantly decreased both morbidity and mortality. Treatment with ACE inhibitors also reduce arrhythmic death, myocardial infarction, and strokes.
Indications. ACE inhibitors may be considered for single-agent therapy in patients who present with mild dyspnea on exertion and who do not show signs or symptoms of volume overload. ACE inhibitors are useful in decreasing CHF in asymptomatic patients with ejection fraction less than 35 % (left ventricular dysfunction). Patients who have had a recent myocardial infarction also benefil from long-term ACE inhibitor therapy. Patients with the lowest ejection fraction show the greatest benefit. Early use of ACE inhibitors is indicated in treating patients with all stages of left ventricular failure, with and without symptoms, and therapy should be initiated immediately after myocardial infarction.
Adverse effects include postural hypotension, renal insufficiency, hyperkalemia, and a persistant dry cough. The potential of symptomatic hypotension with ACE inhibitor therapy requires careful monitoring. ACE inhibitors should not be used in pregnant women.
Direct smooth muscle relaxants
Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance; arterial dilators reduce systemic arteriolar resistance and decrease afterload. Nitrates are commonly employed venous dilators for patients with CHF. If the patients is intolerant of ACE inhibitors, the combination of hydralazine and isosorbide dinitrate is the most commonly used. Amlodipine and felodipine have less negative inotropic effect than ather calsium channel blockers, and seem to decrease sympathetic nervous activity.
DIURETICS. Diuretics relieve pulmonary congestion and peripheral edema. These agents are 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 decrease the cardiac workload and oxygen demand. Diuretics also decrease afterload by reducing plasma volume, thus decreasing blood pressure.
Thiazide and Related Diuretics
Thiazide diuretics are synthetic drugs that are chemically related to the sulfonamides and differ mainly in their duration of action. Hydrochlorothiazide is the most commonly used; chlorothiazide is the only one that can be given IV. Related diuretics are nonthiazides whose pharmacologic actions are essentially the same as those of the thiazides; they include chlorthalidone, metolazone, and quinethazone.
Thiazides and related diuretics are frequently prescribed in the long-term management of heart failure and hypertension. They act to decrease reabsorption of sodium, water, chloride, and bicarbonate in the distal convoluted tubule. Most sodium is reabsorbed before it reaches the distal convoluted tubule and only a small amount is reabsorbed at this site. Thus, these drugs are not strong diuretics. In addition, they are ineffective when immediate diuresis is required (because of their slow onset of action) and relatively ineffective with decreased renal function. They work efficiently only when urine flow is adequate. These drugs are well absorbed, widely distributed in body fluids, and highly bound to plasma proteins. They accumulate only in the kidneys. Diuretic effects usually occur within 2 hours, peak at 4 to 6 hours, and last 6 to 24 hours. Antihypertensive effects usually last long enough to allow use of a single daily dose. Most of the drugs are excreted unchanged by the kidneys within 3 to 6 hours; some (eg, polythiazide, chlorthalidone) have longer durations of action (48 to 72 hours), attributed to slower excretion. Thiazides and related drugs are contraindicated in clients allergic to sulfonamide drugs. They must be used cautiously during pregnancy because they cross the placenta and may have adverse effects on the fetus by compromising placental perfusion.
necessary.
Furosemide is the most commonly used loop diuretic and serves as the prototype for the group. Bumetanide may be used to produce diuresis in some clients who are allergic to or no longer respond to furosemide. It is more potent than furosemide on a weight basis, and large doses can be given in small volumes. These drugs differ mainly in potency and produce similar effects at equivalent doses (eg, furosemide 40 mg = bumetanide 1 mg).
Potassium-Sparing Diuretics
Sodium is normally reabsorbed in the distal tubule in exchange for potassium and hydrogen ions. Potassium-sparing diuretics act at the distal tubule to decrease sodium reabsorption and potassium excretion. This group includes three drugs. One is spironolactone, an aldosterone antagonist. Aldosterone is a hormone secreted by the adrenal cortex. It promotes retention of sodium and water and excretion of potassium by stimulating the sodium–potassium exchange mechanism in the distal tubule. Spironolactone blocks the sodium-retaining effects of aldosterone, and aldosterone must be present for spironolactone to be effective. The other two drugs, amiloride and triamterene, act directly on the distal tubule to decrease the exchange of sodium for potassium, and have similar diuretic activity.
Potassium-sparing diuretics are weak diuretics when used alone. Thus, they are usually given in combination with potassium-losing diuretics to increase diuretic activity and decrease potassium loss. They are contraindicated in the presence of renal insufficiency because their use may cause hyperkalemia through the inhibition of aldosterone and subsequent retention of potassium. Hyperkalemia is the major adverse effect of these drugs; clients receiving potassium-sparing diuretics should not be given potassium supplements and should not be encouraged to eat foods high in potassium or allowed to use salt substitutes. Salt substitutes contain potassium chloride rather than sodium chloride.
Thiazide diuretics are relatively mild diuretics and lose efficacy if patient creatinine is less than 50 ml/min.
Chlorothiazide is administered in doses of up to 500 mg every 6 h. Ethacrynic acid and furosemide are usually effective by mouth, in doses of 25 to 199 mg two or four times daily, and intravenously in doses ranging from 10 to 100 mg. both can be given intravenously , and furosemide intramuscularly as well. Aldosterone antagonists – spironolactone – may be administered in doses of 25 to 100 mg three to four times daily by mouth. The maximal effect of this regimen is not observed for approximately 4 days. Triamterene and amiloride exert renal effects similar to thoses of the spironolactones. The effective dose of triamterene is 100 mg once or twice daily. These drugs are effective in preventing the hypokalemia characteristic of the administration of thiazides, furosemide, and ethacrynic acid.
When digoxin and diuretics are given concomitantly, as is common for clients with heart failure, the risk of digoxin toxicity is increased. Digoxin toxicity is related to diureticinduced hypokalemia. Potassium is a myocardial depressant and antidysrhythmic; it has essentially opposite cardiac effects to those of digoxin. In other words, extracellular potassium decreases the excitability of myocardial tissue, but digoxin increases excitability. The higher the serum potassium, the less effective a given dose of digoxin will be. Conversely, decreased serum potassium increases the likelihood of digoxininduced cardiac dysrhythmias, even with small doses and therapeutic serum levels of digoxin. Supplemental potassium chloride, a potassium-sparing diuretic, and other measures to prevent hypokalemia are often used to maintaiormal serum potassium levels (3.5 to 5.0 mEq/L).
INOTROPIC DRUGS. Positive inotropic agents enhance cardiac muscle contractility, and thus increase cardiac output.
Digitalis
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 are therefore widely used in treating heart failure. The cardiac glycosides influence the sodium and calcium ion flows in the cardiac muscle, thereby increasing contraction of the atrial and ventricular myocardium (positive inotropic action). The cardiac glycosides bind to and block the action of the sodium-potassium ATPase. They inhibit the extrusion of sodium from the cell, leading to an increase in sodium levels within the cell.
The digitalis glycosides show only a small difference between a therapeutically effective dose and doses that are toxic or even fatal. Therefore, the drugs have a low therapeutic index. The cardiac glycosides include digitoxin, and the most widely used agent, digoxin.
Administration of digitalis glycosides increases the force of cardiac contractility causing the cardiac output to more closely resemble that of the normal heart. An increased myocardial contraction leads to a decrease in end diastolic volume, thus increasing the efficiency of contraction. the resulting improve circulation leads to reduced sympathetic activity, which then reduces peripheral resistance. Together, these effects cause a reduction in heart rate. Vagal tone is also enhanced so the heart rate decreases and myocardial oxygen demand is diminished.
Therapeutic uses. Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of diuretic and vasodilation therapy. Digoxin is not indicated in patients with diastolic or right-sided heart failure. Dobutamine, another inotropic agent, can be given intravenously in the hospital, but at present no good oral inotropic agents exist other than digoxin. Patients with mild to moderate heart failure often respond to treatment with ACE inhibitors and diuretics and do not require digoxin.
1. Rapid digitalization. In previously undigitalized patients , a single initial digoxin dose of 0.4-0.6 mg usually produces a detectable effect in 0.5-2 hours that become maximal in 2 to 6 hours. Additional doses of 0.1 to 0.3 mg may be given cautiously at 6 to 8 hour intervals until clinical evidence of an adequate effect is noted.
2. Gradual digitalization. A patient in heart failure with an estimated lean body weight of 70 kg and creatinine clearance of 60 ml/min, should be given 0.2 mg of digoxin per day, usually taken as a 0.1 mg tablet after the morning and evening meals. Steady-state serum concentrarions should not be anticipated before 11 days.
Contraindications to Use
Digoxin is contraindicated in severe myocarditis, ventricular tachycardia, or ventricular fibrillation and must be used cautiously in clients with acute myocardial infarction, heart block, Adams-Stokes syndrome, Wolff-Parkinson-White syndrome (risk of fatal dysrhythmias), electrolyte imbalances (hypokalemia, hypomagnesemia, hypercalcemia), and renal impairment.
Adverse effects. Digitalis toxicity is one of the most commonly encountered adverse drug reactions. Side effects can often be managed by discontinuing cardiac glycoside therapy, determing serum potassium levels, and if indicated, by giving potassium supplements. In general, decreased serum levels of potassium predispose a patient to digoxin toxicity. Digoxin levels must be closely monitored in the presence of renal insufficiency and dosage adjustment may be necessary.
Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs, and the use of antibodies to digoxin, which bind and inactivate the drug. Types of adverse effects include:
1. Cardiac effects. The major effect is progressively more severe dysrhythmia, paroxysmal supraventricular tachycardia, atrial fibrillation, ventricular fibrillation, and complete heart block. The electrocardiogram is fundamental in determining the presence and nature of these cardiac dicturbances. Digoxin may also induce other changes in the ECG (e.g. PR prolongation, ST depression), which represent digoxin effect and may or may not be associated with digitalis toxicity.
2. Castrointestinal effects. Anorexia, nausea, and vomiting are commonly encountered adverse effects.
3. CNS effects. These include headache, fatigue, confusion, blurred vision, alteration of color perception , and haloes on dark objects.
Factors predisposing to digitalis toxicity. Electrolytic disturbances. Hypokalemia can precipitate serious arrhythmia. Reduction of serum potassium levels is the most frequently observed in patients receiving thiazide or loop diuretics, and can usually be prevented with potassium chloride. Hyperkalemia and hypomagnesemia also predispose to digitalis toxicity.
Drugs. Quinidine can cause digitalis intoxication both by displacing digitalis from plasma protein binding sites, and by competing with digitalis for renal excretion. Verapamil also displaces digitalis from plasma protein binding sites and can increase digoxin levels by 50 to 75 %; this may require a reduction in the dose of digoxin. Potassium-depleting diuretics, corticosteroids, and a variety of other drugs can also increase digitalis toxicity. Hypothyroidism, hypoxia, renal failure, and myocarditis are also predisposing factors to digitalis toxicity.
Treatment of digitalis intoxication. When `tachyarrhythmias result from digitalis intoxication, withdrawal of the drug and treatment with potassium, phenytoin, propranolol, or lidocaine are indicated. Potassium should be administered cautiously and by the oral route whenever possible if hypokalemia is present. It should be administered intravenously in 5 % dextrose. Potassium must not be employed in the presence of atrioventricular block or hyperkalemia, when phenytoin is most appropriate. Lidocaine is effective in the treatment of digitalis-induced ventricular tachyarrhythmias in the absence of preceding atrioventricular block.
b-Adrenergic agonists (dopamine, dobutamine, epinephrine, isoproterenol)
b-Adrenergic stimulation improve cardiac performance by positive inotropic effects and vasodilation. Dobutamine is the most commonly used inotropic agent other than digitalis. Dobutamine leads to an increase in intracellular cAMP, which results in the activation of protein kinase. Slow calcium channels are one important site of phosphorylation by protein kinase. When phosphorylated, the entry of calcium ion into the myocardial cells increases, thus enhancing contraction. Dobutamine must be given by intravenous infusion of 2.5 to 15 (mg/kg)/min, and is primarily used in the treatment of acute heart failure in a hospital setting. Adverse effecte include sinus tachycardia, tachyarrhythmias, and hypertension.
Phosphodiesterase inhibitors
Amrinone and milrinone are phosphodiesterase inhibitors that increase the intracellular concentration of cAMP. This results in an increase in intracellular calcium, and therefore cardiac contractility, as discussed above for the b-adrenergic agonists. Recent clinical trials have shown that amiodarone did not reduce the incidence of sudden death or prolong survival in patients with CHF. Milrinone showed increase mortality and no beneficial effects.
Inamrinone (Inocor), formerly amrinone, and milrinone IV also relax vascular smooth muscle to produce vasodilation and decrease preload and afterload. In HF, inotropic and vasodilator effects increase cardiac output. The effects of these drugs are additive to those of digoxin and may be synergistic with those of adrenergic drugs (eg, dobutamine). There is a time delay before the drugs reach therapeutic serum levels as well as inter-individual variability in therapeutic doses. Compared with inamrinone, milrinone is more potent as an inotropic agent and causes fewer adverse effects. Both drugs are given IV by bolus injection followed by continuous infusion. Flow rate is titrated to maintain adequate circulation. Milrinone can be used alone or with other drugs such as dobutamine and nitroprusside. Its dosage should be reduced in the presence of renal impairment. Dose-limiting adverse effects of the drugs include tachycardia, atrial or ventricular dysrhythmias, and hypotension. Hypotension is more likely to occur in clients who are hypovolemic. Milrinone has a long half-life of approximately 80 hours and may accumulate with prolonged infusions.
Human Natriuretic Peptide B-type
Nesiritide (Natrecor) is the first in this new class of drugs to be used in the management of acute HF. Produced by recombinant DNA technology, nesiritide is identical to endogenous human B-type natriuretic peptide, which is secreted primarily by the ventricles in response to fluid and pressure overload. This drug acts to compensate for deteriorating cardiac function by reducing preload and afterload, increasing diuresis and secretion of sodium, suppressing the renin–angiotensin–aldosterone system, and decreasing secretion of the neurohormones endothelin and norepinephrine. Onset of action is immediate with peak effects attained in 15 minutes with a bolus dose followed by continuous IV infusion. Administration should be by a separate IV line because nesiritide is incompatible with many other drugs. Hemodynamic monitoring of pulmonary artery pressure is indicated to determine drug effectiveness. Clearance of the drug is proportional to body weight and partially by the kidneys; however, no adjustment in dosing is required for age, gender, race/ethnicity, or renal function impairment. Clinical studies have not been conducted on the use of nesiritide for more than 48 hours.
Endothelin Receptor Antagonists
This new class of drugs relaxes blood vessels and improves blood flow by targeting endothelin-1 (a neurohormone) that is produced in excess in heart failure. Endothelin-1 causes blood vessels to constrict, forcing the ailing heart to work harder to pump blood through the narrowed vessels. Studies indicate that endothelin antagonist drugs improve heart function, as measured by cardiac index; animal studies indicate that structural changes of heart failure (eg, hypertrophy) may be reversed by the drugs. Currently, one endothelin receptor antagonist, bosentan (Tracleer), is Food and Drug Administration (FDA) approved but only for treatment of pulmonary hypertension.
PRINCIPLES OF THERAPY
Goals of Management
The goals for clients with asymptomatic (compensated) HF are to maintain function as nearly normal as possible and to prevent symptomatic (acute, congestive, or decompensated) HF, hospitalizations, and death. When symptoms or decompensation occurs, the goals are to relieve symptoms, restore function, and prevent progressive cardiac deterioration.
Management of Chronic Heart Failure
The major steps in the management of patients with chronic heart failure are outlined in Table. The ACC/AHA 2005 guidelines suggest that treatment of patients at high risk (stages A and B) should be focused on control of hypertension, hyperlipidemia, and diabetes, if present. Once symptoms and signs of failure are present, stage C has been entered, and active treatment of failure must be initiated.
Nonpharmacologic Management Measures
1. Prevent or treat conditions that precipitate cardiac decompensation and failure (eg, fluid and sodium retention, factors that impair myocardial contractility or increase cardiac workload).
2. Restrict dietary sodium intake to reduce edema and other symptoms and allow a decrease in diuretic dosage. For most clients, sodium restrictioeed not be severe. A common order, “no added salt,” may be accomplished by avoiding obviously salty foods (eg, ham, potato chips, snack foods) and by not adding salt during cooking or eating. For clients with more severe HF, dietary intake may be more restricted (eg, no more than 2 g daily). A major source of sodium intake is table salt: A level teaspoonful contains 2300 mg of sodium.
3. If hyponatremia (serum sodium <130 mEq/L) develops from sodium restrictions and diuretic therapy, fluids may need to be restricted (eg, 1.5 L/day or less) until the serum sodium level increases. Severe hyponatremia (<125 mEq/L) may lead to dysrhythmias.
4. For clients who are obese, weight loss is desirable to decrease systemic vascular resistance and myocardial oxygen demand.
5. Reduce physical activity in clients with symptomatic HF. This decreases the workload and oxygen consumption of the myocardium. If bed rest is instituted, antithrombotic measures such as compression stockings/ devices or heparin therapy should be prescribed to prevent deep vein thrombosis.
6. Administer oxygen, if needed, to relieve dyspnea, improve oxygen delivery, reduce the work of breathing, and decrease constriction of pulmonary blood vessels (which is a compensatory measure in clients with hypoxemia).
Pharmacologic Management
А combination of drugs is the standard of care for both acute and chronic HF. Specific drug components depend on the client’s symptoms and hemodynamic status.
1. For acute HF, the first drugs of choice may include an IV loop diuretic, a cardiotonic-inotropic agent (eg, digoxin, dobutamine, or milrinone), and vasodilators (eg, nitroglycerin and hydralazine or nitroprusside). This combination reduces preload and afterload and increases myocardial contractility.
2. For chronic HF, an ACE inhibi tor or ARB and a diuretiс are the basic standard of care. Digoxin, a betaadrenergic blocking agent, and spironolactone may also be added. Although the use of digoxin in clients with normal sinus rhythm has been questioned, studies indicate improved ejection fraction and exercise tolerance in clients who receive digoxin. In addition, in clients stabilized on digoxin, a diuretic, and an ACE inhibitor or ARB, symptoms worsen if digoxin is discontinued. Overall, these drugs improve clients’ quality of life by decreasing their symptoms and increasing their ability to function in activities of daily living. They also decrease hospitalizations and deaths from HF.
3. Electrolyte balance must be monitored and maintained during digoxin therapy, particularly normal serum levels of potassium (3.5 to 5 mEq/L), magnesium (1.5 to
2.5 mg/100 mL), and calcium (8.5 to 10 mg/100 mL). Hypokalemia and hypomagnesemia increase cardiac excitability and ectopic pacemaker activity, leading to dysrhythmias; hypercalcemia enhances the effects of digoxin. These electrolyte abnormalities increase the risk of digoxin toxicity. Hypocalcemia increases excitability of nerve and muscle cell membranes and causes myocardial contraction to be weak (leading to a decrease in digoxin effect). In acute HF, there is a high risk of hypokalemia because large doses of potassium-losing diuretics are often given. Serum potassium levels should be monitored regularly and supplemental potassium may be needed. In chronic HF, hypokalemia may be less likely to occur than formerly because lower doses of potassium-losing diuretics are usually being given. In addition, there may be more extensive use of potassium-sparing diuretics (eg, amiloride or triamterene) and spironolactone. Note, however, that hyperkalemia must also be prevented because it is cardiotoxic.
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MANAGEMENT OF DIASTOLIC HEART FAILURE Most clinical trials have been carried out in patients with systolic dysfunction, so the evidence regarding the superiority or inferiority of drugs in heart failure with preserved ejection fraction is meager. Most authorities support the use of the drug groups described above. Control of hypertension is particularly important, and revascularization should be considered if coronary artery disease is present. Tachycardia limits filling time; therefore bradycardic drugs may be particularly useful, at least in theory. MANAGEMENT OF ACUTE HEART FAILURE
Acute heart failure occurs frequently in patients with chronic failure. Such episodes are usually associated with increased exertion, emotion, salt in the diet, noncompliance with medical therapy, or increased metabolic demand occasioned by fever, anemia, etc. A particularly common and important cause of acute failure—with or without chronic failure—is acute myocardial infarction. Patients with acute myocardial infarction are best treated with emergency revascularization using either coronary angioplasty and a stent, or a thrombolytic agent. Even with revascularization, acute failure may develop in such patients. Many of the signs and symptoms of acute and chronic failure are identical, but their therapies diverge because of the need for more rapid response and the relatively greater frequency and severity of pulmonary vascular congestion in the acute form. Measurements of arterial pressure, cardiac output, stroke work index, and pulmonary capillary wedge pressure are particularly useful in patients with acute myocardial infarction and acute heart failure. Such patients can be usefully characterized on the basis of three hemodynamic measurements: arterial pressure, left ventricular filling pressure, and cardiac index. One such classification and therapies that have proved most effective are set forth in Table below. When filling pressure is greater than 15 mm Hg and stroke work index is less than 20 g-m/m2, the mortality rate is high. Intermediate levels of these two variables imply a much better prognosis.
Intravenous treatment is the rule in acute heart failure. Among diuretics, furosemide is the most commonly used. Dopamine or dobutamine are positive inotropic drugs with prompt onset and short durations of action; they are most useful in patients with severe hypotension. Levosimendan has been approved for use in acute failure in Europe, and noninferiority has been demonstrated against dobutamine. Vasodilators in use in patients with acute decompensation include nitroprusside, nitroglycerine, and nesiritide. Reduction in afterload often improves ejection fraction, but improved survival has not been documented. A small subset of patients in acute heart failure will have hyponatremia, presumably due to increased vasopressin activity. A V1a and V2 receptor antagonist, conivaptan, is approved for parenteral treatment of euvolemic hyponatremia. Several clinical trials have indicated that this drug and related V2 antagonists may have a beneficial effect in some patients with acute heart failure and hyponatremia. Thus far, vasopressin antagonists do not seem to reduce mortality. |
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SUMMARY: DRUGS USED IN HEART FAILURE
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PREPARATIONS AVAILABLE
Sympathomimetics Most Commonly Used in Congestive Heart Failure
Angiotensin-Converting Enzyme Inhibitors
Beta Blockers that Have Reduced Mortality in Heart Failure
*Digoxin capsules (Lanoxicaps) have greater bioavailability than digoxin tablets. |
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