21.1 Heart Failure
Heart failure is a pathophysiological state in which cardiac output is inadequate to meet the demands of the body tissues. The basic cardiac dysfunction is decreased cardiac output. Heart failure is a complex condition in which a variety of primary pathologic events are blended with varying compensatory mechanisms to produce the commonly recognized spectrum of clinical symptoms and signs, including tachycardia, dyspnea (shortness of breath), decreased exercise tolerance, edema, and cardiomegaly. Drug treatment is not curative, but involves attempts to restore cardiac function.
Etiology of heart failure
Heart failure can occur due to several etiologic factors, including intrinsic disease of the heart muscle (e.g., cardiomyopathy, ischemia, and infarction); chronic elevated preload (e.g., fluid overload and mitral regurgitation); chronic elevated afterload (e.g., aortic stenosis and hypertension); disorder of cardiac filling (e.g., cardiac tamponade); and when there is an inadequate heart rate, for example, following myocardial infarction (MI), β-blocker therapy, or negatively inotropic drug therapy (e.g., any antiarrhythmic drug).
Jugular venous pressure
The internal jugular vein passes medial to the clavicular head of the sternocleidomastoid muscle up behind the angle of the mandible. It is a reliable indicator of right atrial pressure. It is not normally visible or palpable but may become distended in right ventricular failure.
Drug Management of Heart Failure
The following drug classes are utilized in the management of heart failure. Most drugs lead to improved cardiac function by decreasing both preload and afterload (Fig. 21.1). The positive inotropic agents act directly on the heart to increase contraction. The mechanism of the beneficial effect of the β-blockers in heart failure is not understood.
2. Angiotensin-converting enzyme (ACE) inhibitors
3. Angiotensin receptor antagonists
5. Positive inotropic agents
6. Direct vasodilators
Up to a point, the heart pumps more when it is filled more during diastole. This is often labeled Starling's law of the heart or the Frank-Starling mechanism. The amount of filling is called preload. It is a reflection of forces in the vasculature acting to fill the ventricle. The amount of preload can be expressed in several ways, e.g., end diastolic volume, end diastolic pressure, or stretch (sarcomere length). It will be low in cases of hypovolemia or low systemic venous tone, and high in cases of fluid retention, many cases of heart failure, or excessive venous sympathetic stimulation. If the right ventricle is impaired, but not the left, right ventricular preload will tend to be high, while left ventricular preload will tend to be low.
Contractility expresses the ability of the heart to contract at a given preload. Greater contractility manifests as greater systolic pressure or greater systolic ejection. At the cellular level, contractility reflects the amount of Ca2+ released from the sarcoplasmic reticulum with each heartbeat. The supply of Ca2+ in the sarcoplasmic reticulum is increased (positive inotropy) by anything that stimulates more Ca2+ to enter the cell through Ca2+ channels, or that stimulates the Ca2+-ATPase (SERCA pump) to take up Ca2+ from the cytosolic space. Both effects increase the amount of Ca2+stored in the sarcoplasmic reticulum between beats. Positive inotropic effectors include agents that cause a faster heart rate (more beats per minute allow more Ca2+ to enter per minute), sympathetic stimulation, drugs that are β-adrenergic agonists, and cardiac glycosides (e.g., digitalis) that reduce efflux of Ca2+ via Na+/Ca2+ antiport. Negative inotropic effectors include β-adrenergic antagonists.
Afterload is the pressure against which the ventricle works to eject blood during systole. At rest it is primarily a function of total peripheral resistance, i.e., it requires greater systolic pressure to eject blood in the face of high peripheral resistance. Afterload also depends on output of the heart, because pressure in the peripheral circulation is a function of the amount of blood ejected. For example, during exercise peripheral resistance is low, which by itself would decrease afterload, but afterload is actually somewhat elevated because the heart is ejecting so much blood that mean arterial pressure is increased.
Fig. 21.1 Congestive heart failure (CHF).
In CHF, the heart is failing as a pump; cardiac output is therefore insufficient to meet the metabolic demand for oxygen in the body. CHF also causes fluid congestion in the lungs and venous circulation. Compensatory mechanisms, such as the activation of the sympathetic system and the renin–angiotensin system, are designed to increase cardiac output on a short-term basis but eventually place further strain on the heart if the heart failure is chronic. Drug therapy in chronic CHF aims to inhibit these unhelpful compensatory mechanisms. (ACE, angiotensin-converting enzyme.)
Diuretics are first-line agents in heart failure therapy. They are used to resolve the signs and symptoms of volume overload, which are pulmonary and/or peripheral edema (Fig. 21.2). Once this goal has been achieved, diuretics are used to maintain a euvolemic state. The pharmacology of diuretics is discussed in detail in Chapter 19.
Fig. 21.2 Mechanism of edema fluid mobilization by diuretics.
Edema causes the accumulation of fluid, mostly in the interstitial space. Diuretics counteract this by increasing the renal excretion of Na+ and water. This causes a reduction in plasma volume and the concentration of plasma proteins, which increases plasma colloid osmotic pressure and attracts water from the interstitium into the plasma.
21.3 ACE Inhibitors and Angiotensin Receptor Antagonists
ACE inhibitors are discussed in Chapter 20. Specific points in relation to heart failure are:
– ACE inhibitors, along with digitalis and diuretics, are now considered as first-line drugs for heart failure therapy.
– These agents acutely decrease systemic vascular resistance, venous tone, and mean blood pressure while producing a sustained increase in cardiac output.
– There is symptomatic improvement and reduced mortality in patients with heart failure.
– Exercise tolerance in patients with refractory heart failure is improved, and both salt and water retention are reduced.
Angiotensin Receptor Antagonists
Angiotensin receptor antagonists may be used in patients intolerant of ACE inhibitors or in combination with ACE inhibitors when a greater effect is required. These drugs are discussed in Chapter 20.
Although administration of a β-blocker is seemingly paradoxical to improve cardiac function, several clinical trials have demonstrated that bisoprolol, carvedilol, and metoprolol have beneficial effects to improve cardiac function, decrease symptoms, and improve survival rates in chronic heart failure. Trials with other β-blockers have been negative. Bisoprolol and metoprolol are selective for the β1 receptor (cardiac). Carvedilol blocks β1, β2, and α1 receptors. The mechanism of this beneficial effect is unclear but may involve inhibition of pathologic changes of the myocardium that occur in heart failure or prevention of myocardial apoptosis. Beta-blockers are discussed in Chapter 20.
21.5 Positive Inotropic Agents
Digoxin, also known as digitalis, is a cardiac glycoside that was previously one of the mainstays in the treatment of heart failure. Its use is now reserved for when symptoms are not fully treated by standard therapies or in cases of severe heart failure while standard therapies are initiated. It can decrease symptoms and lower the rate of hospitalization for heart failure, but it does not decrease mortality.
Mechanism of action. The therapeutic and toxic effects of digoxin are attributable to inhibition of Na+-K+-ATPase (the digitalis receptor) located on the outside of the myocardial cell membrane. Normally, this Na+-K+-ATPase pump is responsible for the exchange of these ions across the membrane. When the pump is inhibited, Na+ accumulates intracellularly. Secondarily, the decreased Na+ gradient affects Na+-Ca2+ exchange, and Ca2+ accumulates inside the cell. Consequently, more intracytoplasmic Ca2+ (stored in the sarcoplasmic reticulum) is available for release and interaction with the contractile proteins during the excitation-contraction coupling process. At therapeutic doses of digoxin, there is an increase in contractile force. Toxicity to digitalis also relates to inhibition of the Na+-K+-ATPase pump. Inhibition of the Na+-K+-ATPase pump affects the K+ gradient; this may lead to a significant reduction of intracellular K+, predisposing the heart toward arrhythmias. Likewise, Ca2+ overload may contribute to serious arrhythmias.
– Digoxin can be given orally or IV
– The fundamental action of digoxin is to increase the force and velocity of cardiac contraction, resulting in a marked increase in cardiac output of the failing heart. The decrease in end-diastolic volume and pressure leads to a decrease in heart size, decreased venous pressure, and decreased edema.
— The second most important action of digitalis is to slow the heart rate (negative chronotropic action). The magnitude of slowing is dependent upon preexisting vagal or sympathetic tone. Both direct and indirect actions, mediated by the vagus nerve, contribute to the decrease in heart rate, decreasing the O2 demand of the myocardium. The decreased sympathetic tone also increases renal blood flow and leads to diuresis and decreased edema.
Side effects. Digoxin has a low therapeutic index, so toxicities are common and can be dangerous. They may include the following:
– Cardiac arrhythmias: as therapeutic concentrations are exceeded, the automaticity of secondary latent, ectopic pacemaker cells is increased. Premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation are serious arrhythmias that occur in digitalis-toxic patients.
– Gastrointestinal effects are common and are among the earliest signs of toxicity. Anorexia, nausea, vomiting, and abdominal pain occur.
– Fatigue, headache, and drowsiness also are early signs of toxicity. More serious signs are disorientation, delirium, visual disturbances (photophobia, halos, and yellow vision), and, rarely, hallucinations or convulsions.
Treatment of toxicity. Discontinue the drug, correct K+ deficiency, and use digoxin antibodies (Fab fragments).
– Digitalis toxicity is exacerbated most commonly by K+ depletion with diuretics.
– Arrhythmias are enhanced by interaction with sympathomimetic agents.
21.6 Phosphodiesterase Inhibitors
Milrinone and Inamrinone
Mechanism of action. Milrinone and inamrinone inhibit phosphodiesterase, leading to increased cyclic adenosine monophosphate (cAMP) in cardiac cells. This causes an increase in intracellular Ca2+ levels. These agents have positive inotropic effects and vasodilator activity.
Uses. These agents are used infrequently. They are only given parenterally for short-term management of patients with heart failure that is refractory to digoxin, diuretics, and vasodilators. They are unacceptable for long-term use.
Side effects. These include fever, nausea, vomiting, hypersensitivity reactions, hepatotoxicity, and thrombocytopenia. Milrinone is better tolerated.
21.7 Beta-Adrenergic Receptor Agonists
Mechanism of action. Dobutamine is a synthetic catecholamine that stimulates α1 and β1 receptors in both heart and blood vessels but selectively stimulates the cardiac β1 receptors to produce its inotropic action.
Pharmacokinetics. Dobutamine must be given by IV infusion.
Uses. Dobutamine is used for short-term support in severe heart failure but is not used long-term, as it may cause arrhythmias and increase O2 consumption.
Direct Smooth Muscle Relaxants
Hydralazine, Isosorbide Dinitrate, Nitroprusside, and Nitroglycerin
See Fig. 21.3 for an overview of the venous and arterial vasodilation of these agents.
The vasodilators hydralazine and isosorbide dinitrate added to an ACE inhibitor and a β-blocker have been effective in African American patients with more severe, class III and IV, heart failure.
Specific points in relation to heart failure
– Hydralazine is primarily an arteriolar vasodilator and may be beneficial in reducing after-load in congestive heart failure. Tolerance may develop to this drug. It may worsen fluid retention.
– Isosorbide dinitrate is an orally active agent similar in action to nitroglycerin and nitroprusside. It is combined with hydralazine in the treatment of heart failure.
– Nitroprusside is a potent relaxant for both veins and arteries. Its use is limited to short-term IV therapy. Its short half-life allows for titration and makes it beneficial in acute or severe refractory heart failure.
– Nitroglycerin is used for short-term IV treatment of severe heart failure. It dilates large-capacitance veins and reduces preload. Development of tolerance limits its therapeutic usefulness. See Chapter 22 for a more detailed discussion of nitroglycerin.
Stages of Heart Failure
In order to determine the best course of therapy for heart failure, physicians often assess the stage of heart failure according to the New York Heart Association (NYHA) functional classification system. This system relates symptoms to everyday activities and the patient's quality of life. In class 1 (mild) heart failure there is no limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitations, or dyspnea (shortness of breath). In class II (mild) heart failure there is slight limitation of physical activity. The patient is comfortable at rest, but ordinary physical activity results in fatigue, palpitations, or dyspnea. In class III (moderate) heart failure there is marked limitation of physical activity. The patient is comfortable at rest, but less than ordinary activity causes fatigue, palpitations, or dyspnea. In class IV (severe) heart failure the patient is unable to carry out any physical activity without discomfort. There are symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
Fig. 21.3 Vasodilators.
Venous tone regulates the volume of blood returned to the heart and thus affects stroke volume and cardiac output. Arterial tone determines peripheral resistance. Vasodilator drugs may act preferentially on venous tone (nitrates) or on arterial tone (Ca2+ antagonists and hydralazine). They may also affect the tone of both (ACE inhibitors, α1-antagonists, and sodium nitroprusside).