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Using Carvedilol to Treat Heart Failure

To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

Despite current treatments, including use of angiotensin-converting enzyme (ACE) inhibitors, digoxin, and diuretics, morbidity and mortality remain alarmingly high. An estimated 50% of patients with severe signs and symptoms of heart failure will die within 1 year and 70% within 3 years.^3,4 Additional pharmacological therapies to mitigate this disorder, such as ß-blockers, continue to be investigated. ß-Blockers were thought to be contraindicated in patients with heart failure because of the drugs’ negative chronotropic (heart rate) and inotropic (contractility) actions on the heart.⁵ However, the findings of several recent studies^6–10 indicate that ß-blockers decrease morbidity and mortality and improve signs and symptoms and quality of life for patients with heart failure.

In this article, I review the pathophysiology and compensatory mechanisms in patients with heart failure and discuss the beneficial effects of ß-blockers, especially carvedilol, in the treatment of heart failure. Nursing diagnoses and interventions provide nurses with information on how to safely administer carvedilol and monitor its clinical effects. The included guide for teaching patients is a tool nurses can use to instruct patients being treated with carvedilol.

	DEFINITIONS AND CLASSIFICATIONS

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 
Heart failure is classified as systolic and/or diastolic dysfunction. Systolic ventricular dysfunction is a defect in the expulsion of blood (ie, systolic/forward failure) from the ventricles into the aorta and pulmonary artery caused by an impaired inotropic state. The principal manifestations of systolic failure are due to inadequate forward output, causing an increase in end-diastolic volume, and a normal or reduced stroke volume, resulting in a decreased ejection fraction of 0.45 or less. Causes of systolic failure include hypertension, coronary artery disease, valvular disease, pulmonary embolism, and idiopathic cardiomyopathy.^11–13

Diastolic ventricular dysfunction occurs when the filling of one or both ventricles is impaired, causing inadequate emptying of the venous reservoir (ie, diastolic/backward failure). The transient inability of the ventricles to accept blood may occur because of slowed or incomplete ventricular relaxation (lusitropic properties), such as acute ischemia, or may be sustained, as in restrictive cardiomyopathy or concentric myocardial hypertrophy. Diastolic failure due to increased diastolic stiffness causes high ventricular filling pressure and high venous pressure, resulting in pulmonic and/or systemic congestion. Causes of diastolic dysfunction include hypertrophic cardiomyopathy, subendocardial fibrosis, coronary artery disease, and arterial hypertension.¹⁴

In many patients, systolic and diastolic dysfunction coexist. The most common cause is coronary atherosclerosis. In this condition, systolic dysfunction is the result of decreased myocardial contractility associated with myocardial infarction. Diastolic failure is due to replacement of normal, distensible myocardium by nondistensible fibrous scar tissue.¹²

	PATHOPHYSIOLOGY OF HEART FAILURE AND COMPENSATORY MECHANISMS

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 
A primary disturbance in myocardial contractility, an excessive hemodynamic burden placed on the ventricles, or both initiate compensatory mechanisms that attempt to sustain cardiac output and arterial blood pressure. Compensatory mechanisms include the Frank-Starling mechanism, ventricular myocardial hypertrophy, and activation of neurohormonal systems.

Frank-Starling Mechanism
When the ventricles do not eject a normal quantity of blood during each contraction, the residual volume is added to the blood volume entering the ventricle during the next diastole, increasing the end-diastolic volume. As the preload increases, the left ventricle distends, causing elevated left ventricular pressure. According to the Frank-Starling law, the greater the volume of blood in the ventricle during diastole, up to a point, the greater is the force of contraction during systole. The increase in contractile force is related to the lengthening of sarcomeres.¹³ When the ventricles are stretched by a pressure or volume overload, the length of the sarcomeres within the ventricular walls increases, causing optimal overlapping between myofilaments (contractile structures). This increase results in an increased force of muscle contraction as actin and myosin filaments are brought to a more optimal degree of interdigitation.¹⁴ The sacromere length associated with the most forceful contraction is approximately 2.2 µm.^11,13 The deterioration in cardiac function is not due to a loss of optimal overlap of actin or myosin (due to further distortion) but rather to a failure of the latching mechanism itself. Increased sacromere length enhances the concentration of calcium ions released into the myocyte, potentiating the force of contraction.¹⁵

Myocardial Hypertrophy
Increased systolic stress (myocardial workload and oxygen requirements) causes the heart to increase muscle mass and contractile strength, similar to the hypertrophy in skeletal muscles caused by exercise.¹⁶ The development of ventricular hypertrophy is the primary mechanism by which the heart compensates for an increased load.¹¹ When hypertrophy is the result of pressure overload, the resultant increase in systolic wall stress leads to parallel replication of myofibrils and thickening of myocytes. When the primary stimulus is volume overload, increased diastolic wall stress leads to replication of sarcomeres, elongation of myocytes, and ventricular dilatation. In both types of hypertrophy, ventricular remodeling occurs to maintain a normal level of systolic stress, improve cardiac output, and minimize pulmonary edema. However, as left ventricular failure progresses, lysis of myofibrils occurs, the number of lysosomes increases (to digest worn-out cells), and fibrous tissue replaces cardiac cells. The resulting ischemia may contribute further to the impairment of cardiac function.¹¹

Activation of Neurohormonal Systems
A series of neurohormonal changes occurs as a result of reduced cardiac output and arterial hypertension. Many of these changes occur in response to inadequate arterial blood volume, a characteristic of systolic heart failure. In the early stages of systolic failure, activation of the sympathetic nervous system and the renin-angiotensin system maintains perfusion to vital organs and expands the arterial blood volume. However, as heart failure becomes chronic, these mechanisms cause undesirable effects such as excessive vasoconstriction, increased afterload, excessive retention of sodium and water, electrolyte abnormalities, and arrhythmias.¹¹

Increased Sympathetic Activity.
Activation of the sympathetic nervous system, with a concomitant decrease in parasympathetic tone, causes the release of norepinephrine from adrenergic nerve fibers, resulting in venous and arterial vasoconstriction. Venoconstriction, mediated through the -adrenergic fibers, causes constriction of the splanchnic and cutaneous veins. Constriction of these highly capacious vascular beds causes translocation of blood back into the central circulation, increasing preload in accordance with the Frank-Starling law. Increased preload predisposes patients to pulmonary congestion and worsening of heart failure.^11,13

Chronic arterial vasoconstriction caused by norepinephrine increases afterload (the force a ventricle must overcome while it contracts during ejection) and peripheral vascular resistance, making ejection of blood by the failing heart more difficult.¹³ Increased filling pressures and ventricular wall stress accelerate cell death due to the increased workload of the ventricles. Norepinephrine causes ß-adrenergic stimulation, increasing the heart rate and myocardial contractility. Tachycardia decreases the time available for diastolic filling, decreases coronary artery perfusion, increases myocardial oxygen demand, and may trigger ventricular tachycardia or sudden cardiac death.¹¹

Renin - Angiotensin System.
Compensatory mechanisms to restore circulatory volume include activation of the renin-angiotensin system. Renin is released because of increased activation by the sympathetic nervous system of the afferent and efferent arterioles in the renal glomeruli, decreased renal perfusion, and decreased sodium concentration in the macula densa. Renin is secreted from the renal juxtaglomerular cells, increases blood flow to the kidneys, and maintains arterial blood pressure. Renin converts angiotensinogen to angiotensin I, which is then converted to angiotensin II by ACE. Angiotensin II is a potent arterial vasoconstrictor that causes increased systemic vascular resistance (SVR) and maintenance of blood pressure. It also stimulates the release of aldosterone from the adrenal gland, causing sodium and water reabsorption by the renal tubules, ultimately increasing intravascular volume. However, the increased sodium and water retention predisposes patients to fluid overload and electrolyte imbalances.¹² Fluid retention and the inability of the heart to pump blood adequately cause elevated filling pressures. Eventually, the heart is so overstressed that the pump fails.

Failure to pump blood into the systemic circulation increases the volume of blood in the lungs, increasing the pulmonary capillary pressure. If the pressure increases to levels greater than that of plasma colloid osmotic pressure (approximately 18 mm Hg), fluid begins to filter out of the capillaries into the interstitial spaces and alveoli, resulting in pulmonary edema and/or systemic congestion.¹² Signs and symptoms of pulmonary congestion include dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. The same pathophysiological factors are responsible for systemic edema. Signs and symptoms of systemic congestion include edema, ascites, and hepatic congestion.¹²

Summary
Compensatory mechanisms such as the Frank-Starling mechanism, myocardial hypertrophy, and activation of neurohormonal systems are finite, and they become maladaptive when chronically maintained. A vicious cycle of neurohormonal secretions, excessive vasoconstriction, and tachycardia compromises the balance between myocardial oxygen demand and supply. The resultant increased SVR, fluid and electrolyte imbalance, and arrhythmias ultimately lead to deteriorating ventricular function, cardiac failure, and death.¹⁷

	CARDIOVASCULAR DISABILITY

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 
The best measure of a patient’s cardiovascular disability is an assessment of his or her status over time and an evaluation of the effects of therapeutic intervention. The New York Heart Association (NYHA) classification of functional ability in patients with heart failure has 4 classes: I, asymptomatic; II, symptomatic with moderate exertion; III, symptomatic with minimal exertion; and IV, symptomatic at rest.^18,19

	CURRENT STANDARDS OF CARE FOR TREATMENT OF HEART FAILURE

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 
Traditional treatment of heart failure includes the use of diuretics, which reduce fluid overload and relieve signs and symptoms. The addition of cardiac glycosides was initiated to increase cardiac contractility. However, treatment with diuretics and cardiac glycosides improved signs and symptoms but did not improve mortality rates.²⁰ This situation prompted an investigation of new drugs during the past decade, as cardiologists continue to gain new understanding of the role of neurohormonal systems and vascular endothelium in heart failure. Current treatment of heart failure, in addition to diuretics and inotropic drugs, includes ACE inhibitors and ß-blockers.²⁰

Diuretics
Diuretics reduce extracellular fluid volume and ventricular filling pressures by inhibiting reabsorption of solutes by the renal tubules and inducing sodium and water excretion. In addition to reducing signs and symptoms of heart failure, diuretics are also associated with a decreased rate of hospitalization.²⁰ The most commonly used diuretics are the loop diuretics (ie, furosemide and ethacrynic acid) because of their rapid onset of action, high potency, and ability to induce diuresis when renal blood flow is reduced.^21,22 Loop diuretics are preferred in patients with compromised renal function and decompensated heart failure.^20,21 Thiazide diuretics and potassium-sparing diuretics are useful for volume retention in patients with mild heart failure, because these agents have a weak diuretic action.²³ A combination of diuretics, such as thiazides (metalozone) plus loop diuretics, can have a synergistic effect.²² Combination therapy is highly beneficial for patients refractory to loop diuretics alone. Similarly, potassium-sparing diuretics (spironolactone, triamterene, amiloride) greatly augment diuresis when combined with thiazide or loop diuretics.^20–22

The use of diuretics predisposes patients to electrolyte abnormalities, including hyponatremia, hypochloremic metabolic alkalosis, hypomagnesemia, and hypokalemia. Potassium depletion can be prevented by administration of oral potassium chloride supplements or by use of a potassium-sparing diuretic. Patients on long-term diuretic therapy need routine monitoring of serum levels of potassium, particularly when they are taking agents that limit renal potassium losses (ie, nonsteroidal anti-inflammatory drugs and ACE inhibitors).²³

Cardiac Glycosides
Digoxin has a negative chronotropic effect and a positive inotropic effect.²¹ The inotropic effects are mediated by inhibition of sodium and potassium ATPase activity. This inhibition increases sodium influx in the cells and, in turn, increases calcium accumulation in exchange for sodium through the sodium-calcium exchange system. The increased amount of cytosolic calcium interacts with contractile proteins, increasing the velocity of sacromere shortening, changes that augment contractility.²²

In several randomized controlled trials, withdrawal of digox-in in patients with stable mild to moderate heart failure caused significant worsening of signs and symptoms, even in patients receiving an ACE inhibitor.²¹ Therefore, even though cardiac glycosides have not been proven to decrease mortality, they improve contractility, improve diastolic filling, and augment left ventricular function.²¹ A disadvantage of digoxin treatment is a small therapeutic-toxic ratio. Signs and symptoms of toxic reactions include anorexia, nausea, vomiting, confusion, seizures, visual manifestations (blue-green-yellow vision, halos), dysrrhythmias, and increased severity of heart failure.²²

ACE Inhibitors
Patients with chronic heart failure have increased renin-angiotensin-aldosterone activity, resulting in excessive vasoconstriction and water and sodium retention. ACE inhibitors reverse the effects of the renin-angiotensin system by reducing the production of angiotension II and decreasing the release of aldosterone.^20,24 The cumulative effect is improved hemodynamic function, including reduced mean arterial pressure and SVR, thus decreasing afterload and myocardial oxygen consumption. In addition, ACE inhibitors decrease plasma levels of norepinephrine. Circulatory levels of norepinephrine are inversely correlated with signs and symptoms and prognosis of heart failure.²⁵

Despite the benefits observed with ACE inhibitors, many patients with heart failure remain markedly symptomatic, and mortality rates remain relatively high.^26–28 This situation has led to further investigation of additional pharmacotherapeutic treatment for heart failure, such as the use of ß-blockers.

ß-Blockers
Clinical Trials.
During the past 30 years, ß-blockers have been used to treat hypertension, prevent myocardial infarction, and treat arrhythmias.^29,30 Treatment with ß-blockers for heart failure has been controversial because of the negative chronotropic and inotropic actions of these drugs. Recent studies^3,6–9 indicated that ß-blockers improve signs and symptoms, exercise tolerance, and hemodynamics and reduce mortality in patients with heart failure. The Cardiac Insufficiency Bisoprolol Study II³¹ and the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure³² were done to determine the survival benefits of ß-blockers in patients with heart failure. In the Cardiac Insufficiency Bisoprolol Study II, 2647 patients with heart failure (83% with NYHA class III and 17% with class IV) were randomized to receive bisoprolol (a ß₁-selective nonvasodilatory ß-blocker) or a placebo. The bisoprolol group had 34% fewer deaths than the control group did (P<.001). Further subgroup analysis indicated that most of the benefit from bisoprolol was attributable to a reduction in sudden death. The Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure was a placebo-controlled mortality study of metoprolol in 3991 patients with systolic heart failure (ejection fraction, <0.40). The number of deaths due to all causes was 145 in the 1990 patients in the metoprolol group and 217 in the 2001 patients in the placebo group, a 34% decrease in mortality (P<.001). In addition, both sudden death and death due to progressive heart failure were significantly reduced, by 41% and 49%, respectively, in the metoprolol group (P<.001).

Classification of ß-Blockers.
ß-Blockers are classified according to their affinity for adrenergic receptors³³ (Table 1) and according to their generation⁷ (first, second, third; Table 2). The 2 types of identified adrenergic receptors are and ß. ß-Adrenergic receptors are subclassified as ß₁ and ß ₂ and -adrenergic receptors as ₁ and ₂. Stimulation of ß ₁-receptors causes an increase in heart rate, cardiac contraction, and conduction velocity (dromotropic). ß-Blockers interrupt these effects by occupying ß-receptor sites, preventing the binding of norepinephrine and epinephrine. The resultant decrease in inotropic, chronotropic, and dromotropic states reduces myocardial oxygen consumption, enhances coronary blood flow, and improves myocardial perfusion.^17,29 Stimulation of ß₁-receptors in the kidneys causes the release of renin during heart failure. Blockade of ß₁-receptors inhibits the activation of the renin-angiotensin system, thereby decreasing water and sodium retention. Activation of ß₂-receptors causes arterial dilatation. Blockade of these receptors produces vasoconstriction.

Third-generation ß-blockers that also block ₁-receptors cause arterial vasodilation in addition to the actions associated with blocking of ß-receptors. Because of their greater vasodilating properties, third-generation ß-blockers are better tolerated by patients during the initiation and titration of treatment than are the first- and second-generation drugs. The vasodilatation caused by the third-generation blockers reduces the afterload, which offsets the transient decrease in cardiac output related to the withdrawal of adrenergic support from the failing heart. In addition, third-generation agents produce less bradycardia than do second-generation agents, a characteristic that may be beneficial in patients with low heart rates.^14,16

Although a variety of ß-blockers exist and are associated with decreased mortality and morbidity, it is not clear which agent provides the greatest benefit. The differences between the ß-blockers, including carvedilol (Coreg), a promising new third-generation ß-blocker, are being investigated in clinical trials.

	CARVEDILOL

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 
Carvedilol was approved by the Food and Drug Administration in 1997 for treatment of mild or moderate heart failure of ischemic or cardiomyopathic origin.¹⁷ Its approval was based on the results of large clinical trials in which use of carvedilol reduced the number of hospitalizations for cardiovascular reasons and decreased disease progression and mortality.^7,34

Carvedilol is a nonselective ß-blocker without intrinsic sympathomimetic activity. Drugs with intrinsic sympathomimetic activity not only prevent the binding of endogenous catecholamines but also act as weak agonists. As a result, ß-blockers with intrinsic sympathomimetic activity cause a smaller decline in heart rate, cardiac output, and renin levels than do agents without this activity.¹²

Carvedilol blocks ß₁-, ß₂-, and ₁-adrenergic receptors. The vasodilating effects of carvedilol, exerted primarily through blockade of ₁-receptors, lower cardiac filling pressure and SVR. Compared with second-generation ß-blockers, third-generation drugs (labetalol, carvedilol) are better tolerated during initiation and titration of therapy because the vasodilating properties of the third-generation agents decrease afterload and offset the negative inotropic effects associated with the initiation of ß-blocker treatment.^7,27,35

Labetalol and carvedilol both block -receptors and thus have vasodilating properties. However, long-term treatment with labetalol may result in the loss of blockade of ₁-receptors, leaving blockade of ß-receptors as the major action. This effect does not occur with carvedilol. Labetalol has also been associated with excessive vasodilation in patients with heart failure. Carvedilol produces a less potent vasodilator response than does labetalol because of the former’s modest ₁-adrenergic blocking ability. ³⁵ In addition, unlike the effects of carvedilol, the effects of labetalol on long-term morbidity and mortality are unknown.^7,34

The superior cardiac protection provided by carvedilol is not a consequence of hemodynamic variances but rather is due to the additional antioxidant effects of carvedilol. Studies in animals suggest that antioxidant effects may be protective in myocardial ischemia and may help retard the progression of atherosclerosis. Carvedilol decreases nitric oxide, the chemical that causes endothelial dysfunction and apoptosis (programmed cell death). In addition, carvedilol decreases the expression of structural extracellular proteins, an effect that reverses cardiac remodeling.^36–40

Carvedilol has been evaluated in the treatment of patients with heart failure in a series of randomized, double-blind, placebo-controlled trials that included more than 1600 patients. The studies included a series of 3 pilot trials^9,41,42 and 2 large-scale phase 3 programs.^34,43 Beneficial effects reported from the trials include improved signs and symptoms, improved exercise tolerance, decreased number of hospitalizations for cardiovascular reasons, and reduced mortality rates when carvedilol was added to conventional drug therapy (diuretics, cardiac glycosides, and ACE inhibitors).

Effects on Left Ventricular Ejection Fraction, Signs and Symptoms, and Exercise Tolerance
Long-term treatment with carvedilol improves cardiac function by decreasing pulmonary artery wedge pressure, right atrial pressure, left ventricular end-systolic and end-diastolic volumes, heart rate, and SVR. The resultant reductions in preload and afterload increase the stroke index and cardiac output.^9,41,44 The cumulative effect is improved signs and symptoms and improved exercise tolerance, findings in several placebo-controlled trials (Table 3).^9,34,41–43

Effect on Hospitalization
In one study,³⁴ compared with placebo, carvedilol was associated with a 27% reduction in the risk for hospitalization for cardiovascular reasons (P = .04). The cost of hospitalizations for cardiovascular problems was also assessed. The cumulative costs for all protocols in the US program were 62% lower for patients receiving carvedilol than for those receiving placebo ($1664 ± $6867 compared with $4327 ± $20 507; P <.001). Reduced numbers of admissions accounted for 44% of hospital savings.³⁴

Current Studies
The Mt. Sinai School of Medicine recently conducted a clinical study comparing the effects of long-term treatment with metoprolol and carvedilol.⁴⁵ The variables investigated in this study included signs and symptoms, exercise tolerance, ejection fraction, and oxidative stress in heart failure. A total of 67 patients with symptomatic stable heart failure were randomly assigned to receive carvedilol or metoprolol in addition to standard therapy. Metoprolol is a ß₁-selective agent, whereas carvedilol combines nonselective blockade of ß-receptors with blockade of -receptors and antioxidant effects.

The 53 patients who completed the protocol in the Mt. Sinai study (23 in the metoprolol group and 30 in the carvedilol group) had significant improvements in all clinical and exercise parameters, with a mild improvement in NYHA class (P<.001). Initial numbers of patients in the various NYHA classes (I/II/II/IV) in the metoprolol group were 0/5/17/1 at baseline and 1/11/11/0 at 6 months. With carvedilol, the numbers were 0/5/22/3 at baseline and 0/9/21/0 at 6 months. With both metoprolol and carvedilol, heart failure symptom scores improved (for metoprolol, from 10 ± 4.7 at baseline to 7.0 ± 4.4, P<.001; for carvedilol, from 9.9 ± 4.5 to 7.3 ± 3.8, P<.001). For exercise parameters, both groups had an improvement in the 6-minute walk, but the differences were not significant. The ejection fraction improved significantly in both groups, with no difference between the groups. Ejection fraction improved from 0.18 ± 0.06 to 0.23 ± 0.07 (P<.005) for patients treated with metoprolol and from 0.19 ± 0.08 to 0.25 ± 0.10 (P<.001) for patients treated with carvedilol.

In addition, no significant change was reported within or between the groups in norepinephrine levels. With metoprolol, plasma levels of norepinephrine were 500 ± 304 pg/mL at baseline and 486 ± 324 pg/mL at 6 months; with carvedilol, the levels were 651 ± 338 pg/mL at baseline and 532 ± 312 pg/mL at 6 months.

In conclusion, the study⁴⁵ indicated parallel beneficial effects in the measured parameters. The only difference reported between the 2 drug groups was a lower heart rate with carvedilol. This difference may reflect the greater degree of blockade achieved with a higher equivalency dose of carvedilol.

	NURSING IMPLICATIONS FOR ADMINISTRATION OF CARVEDILOL

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 
The use of ß-blockers in heart failure is becoming common practice. However, because carvedilol was only recently approved by the Food and Drug Administration for use in treatment of heart failure, nurses may need to update their current knowledge of this medication in order to safely administer the drug and monitor clinical effects.^7,36,44,47

Indications for Use
Carvedilol has previously been used for the treatment of hypertension and angina pectoris. It is now also indicated for the treatment of mild to moderate (NYHA class II or class III) heart failure of cardiomyopathic origin and can be used in conjunction with digoxin, diuretics, and ACE inhibitors to reduce the progression of disease and to decrease the number of hospitalizations and deaths due to cardiovascular conditions.^7,46,47

Pharmacodynamics
Carvedilol is a racemic lipophilic aryoxypropanolamine that blocks ₁- and ß-adrenergic receptors. Carvedilol significantly decreases systemic blood pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure because of the vasodilatation that occurs with blocking of ₁-receptors. Blocking of ß-receptors reduces the heart rate and increases diastolic filling time. The combined effects of blocking both - and ß-adrenergic receptors are decreases in preload, afterload, and myocardial oxygen consumption.^36,48,49

Pharmacokinetics
Carvedilol is a white, oval tablet available in doses of 3.125, 6.25, 12.5, and 25 mg. It is rapidly absorbed after oral administration (onset of action, 1 hour), has a plasma half-life of 7 to 10 hours, and reaches peak levels in 7 to 14 days. Carvedilol is metabolized by the liver and excreted via bile into the feces. In serum, 98% of carvedilol is bound to protein, primarily albumin.^7,46,47

The primary cytochrome P-450 enzymes responsible for the metabolism of carvedilol are microsomal CYP2D6 and CYP2C9. Inhibition of carvedilol metabolism via the CYP2D6 isozyme causes greater ₁-adrenergic blockade than does metabolism via CYP2C9 and increases the risk of episodic hypotension. In contrast, inhibitors of CYP2C9 produce greater ß-adrenergic blockade, increasing the risk of more profound bradycardia or overt heart failure.^48,50

Drug Interactions
Patients’ drug profiles should be reviewed for possible interactions between carvedilol and other medications^{7,36,46,47,50} (Table 4) before carvedilol is administered, and when necessary, drugs that interact with it should be discontinued or their dosages decreased. When an interacting drug cannot be discontinued or the dosage deceased, the maximum target serum level of carvedilol may not be attainable. Although carvedilol may interact with other medications, causing an increase or decrease in serum levels of both carvedilol and the other drugs, routine measurement of serum levels of carvedilol is not done. In fact, such measurement requires specific equipment in a research laboratory, and few clinical laboratories have the capacity to perform this test.

Clonidine.
Concurrent treatment with clonidine and carvedilol may potentiate hypotension and bradycardia. When treatment is discontinued, carvedilol should be discontinued first. Clonidine can then be tapered off during the course of several days.^7,36,46,47

Digoxin.
The concomitant use of digoxin and carvedilol increases digoxin levels by 15%. This interaction may lead to greater atrioventricular nodal conduction blockade, causing lower heart rates. Increased monitoring of digoxin levels is recommended when initiating, adjusting, or discontinuing treatment with carvedilol.^7,36,46,47

Diltiazem.
Conduction disturbances may occur if carvedilol is coadministered with drugs that have sinoatrial or atrioventricular nodal properties, such as diltiazem, mibefradil, and verapamil. Drugs with negative inotropic properties such as diltiazem and verapamil should generally be avoided in patients with heart failure, especially patients receiving carvedilol. When carvedilol is used with diltiazem, electrocardiographic findings and blood pressure should be monitored.^7,36,46,47

Glyburide.
Combined administration of carvedilol and glyburide does not cause relevant pharmacokinetic interactions.^7,36,46,47

Hydrochlorothiazide.
Concurrent administration of hydrochlorothiazide and carvedilol has no effect on the pharmacokinetics of either agent.^7,36,46,47

Rifampin.
Concurrent use of rifampin reduces plasma levels of carvedilol by 70%.^7,36,46,47

Vasodilators.
Hypotension is more likely if carvedilol is administered with other vasodilator drugs (hydralazine, ACE inhibitors), especially if the drugs are taken at the same time each day. In order to decrease the likelihood of hypotension, carvedilol and other vasodilators should be taken approximately 2 hours apart.^7,36,46,47

Warfarin.
Coadministration of warfarin and carvedilol does not affect the prothrombin time ratios and does not change the pharmacokinetics of warfarin.^7,36,46,47

Dosage and Administration
The recommended starting dose of carvedilol is 3.125 mg twice a day. Thereafter, the dose is titrated upward every 2 weeks, according to the patient’s tolerance, to a maximum dosage of 25 to 50 mg twice a day. In a large placebo-controlled trial, patients who were given lower than maximum dosages of carvedilol still derived benefits compared with patients who received a placebo. However, benefits were greater in those patients who were able to achieve the maximum target dose of carvedilol. Therefore, the goal of therapy should be to reach maximum target dosages. Initial difficulties with increasing the dosage of carvedilol do not preclude later attempts to uptitrate the dosage once a patient’s clinical condition is stable.^34,43,51 At the initiation of each higher dose, the patient should be observed for 1 hour for hypotension, dizziness, and lightheadedness. If the systolic blood pressure is less than 85 mm Hg, the medication should be withheld, and a physician should be notified. In addition, as with any agent that affects heart rate and blood pressure, combining carvedilol with other cardiovascular agents may lead to bradycardia and/or hypotension. In order to minimize the occurrence of orthostatic effects, carvedilol should be taken with food.^7,46,47

Excessive hypotension or syncope and signs or symptoms of vasodilatation can be treated by reducing the dose of diuretics or ACE inhibitors. Transient worsening of heart failure (peripheral edema, weight gain, shortness of breath) often responds to increased dosages of diuretics or ACE inhibitor. If the problem persists, the dose of carvedilol may need to be decreased or discontinued. Patients receiving carvedilol who are hospitalized for exacerbation of heart failure and/or cardiogenic shock should not receive carvedilol until the condition is stabilized.^50,52

Contraindications
Carvedilol may cause an initial decrease in chronotropic and inotropic states and is therefore contraindicated in patients with NYHA class IV heart failure. It is also contraindicated in patients with cardiogenic shock, volume overload, or severe bradycardia and in those with second- or third-degree atrioventricular block who do not have a pacemaker.^7,36,46,47 Patients who have clinical evidence of bronchitis or asthma maintained with bronchodilators or corticosteroids and/or whose forced vital capacity/forced expiratory volume in 1 second is less than 0.60 also should not receive this agent. Other contraindications include symptomatic peripheral vascular disease, because ß-blockers may precipitate or aggravate signs and symptoms of arterial insufficiency. Use of carvedilol in patients with hepatic impairment (defined as an increase in the serum level of transaminase 3 times the upper limit of the reference range) is not recommended because the drug is metabolized by the liver.⁵⁰

ß-Blockers may mask signs and symptoms of hypoglycemia and/or hyperglycemia. However, in several trials,^39,53 patients with type 2 diabetes mellitus treated with carvedilol had no significant differences in fasting or post-prandial glucose concentrations or in levels of glycosylated hemoglobin. In addition, in 2 double-blinded comparative trials,^38,54 hypertensive patients treated with carvedilol had improved insulin sensitivity. In these trials,^38,54 neither prolonged hypoglycemia nor delayed recovery of glucose concentrations occurred. Despite the results reported in the studies,^38,39,53,54 blood glucose monitoring should be increased when treatment with carvedilol is initiated, adjusted, or discontinued.

Adverse Reactions
Common adverse reactions associated with use of carvedilol include hypotension, bradycardia, dizziness, fatigue, hyperglycemia, and diarrhea. Less common are syncope, fluid overload, respiratory distress, thrombocytopenia, and urinary tract infection (Table 5). Nursing diagnoses and interventions are reviewed in Table 6.

	CONCLUSION

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

As with any ß-blocker, initial administration may cause a transient decrease in myocardial contractility. Therefore, patients should be monitored for further cardiac decompensation, in addition to other reported adverse reactions. Information given to the patients and their families about the patients’ medications should be reinforced by written material, and discussions with patients’ physicians and pharmacist should be encouraged. +

	Acknowledgment

 
This article was written in memory of my father, Sebastiano Taccetta. I thank Irina Meyman, Dr Edward Chapnick, and Geraldine Rich for their assistance.

	References

Top DEFINITIONS AND CLASSIFICATIONS PATHOPHYSIOLOGY OF HEART FAILURE... CARDIOVASCULAR DISABILITY CURRENT STANDARDS OF CARE... CARVEDILOL NURSING IMPLICATIONS FOR... CONCLUSION References

 

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