Heart Failure PDF

Heart Failure I. WHAT IS HEART FAILURE (HF) HF is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. or HF is an impaired ability of the heart to adequately fill with and/or eject blood. Its cardinal symptoms are dyspnea,...

Heart Failure I. WHAT IS HEART FAILURE (HF) HF is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. or HF is an impaired ability of the heart to adequately fill with and/or eject blood. Its cardinal symptoms are dyspnea, fatigue, and fluid retention. It is often accompanied by abnormal increases in blood volume and interstitial fluid. Types of heart failure 1. Systolic heart failure 2. Diastolic heart failure 1. Systolic heart failure This type of failure is also termed HF with reduced ejection fraction (HFrEF) and is the result of the ventricle being unable to pump effectively. 2. Diastolic heart failure 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 (HFpEF). Types of heart failure Ejection fraction (EF) EF is a measurement of the percentage of blood leaving the heart each time it contracts. It is usually measured in the left ventricle (LV). LVEF ejection fraction of 50% or higher is considered normal. Heart failure with LVEF ≤ 40% is called systolic HF or HF with reduced ejection fraction (HFr EF). The clinical syndrome in which patients have clinical features of heart failure in the presence of normal or near-normal left ventricular ejection fraction, is called diastolic HF or HF with preserved ejection fraction (HFp EF). Underlying causes of HF include: 1. Arteriosclerotic heart disease 2. Myocardial infarction 3. Hypertensive heart disease 4. Valvular heart disease 5. Dilated cardiomyopathy 6. Congenital heart disease Arteriosclerotic heart disease (ASHD) Is a thickening and hardening of the walls of the coronary arteries. Atherosclerosis is a potentially serious condition where arteries become clogged with fatty substances called plaques, or atheroma. Myocardial infarction (MI) commonly known as a heart attack, occurs when blood flow decreases or stops to a part of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck, or jaw. Valvular heart disease Is characterized by damage to or a defect in one of the four heart valves: the mitral, aortic, tricuspid or pulmonary. The mitral and tricuspid valves control the flow of blood between the atria and the ventricles (the upper and lower chambers of the heart). Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. In dilated cardiomyopathy (DCM) the main pumping chamber, the left ventricle, is enlarged and weakened. In some cases, this prevents the heart from filling with blood as it should. Over the time, it can affect the other chambers. Congenital heart disease (CHD) Also known as a congenital heart anomaly or congenital heart defect, is a problem in the structure of the heart that is present at birth. Signs and symptoms depend on the specific type of problem. The defects can involve the walls of the heart, the valves of the heart, and the arteries and veins near the heart.  THE DONKEY ANALOGY A MODALITY TO UNDERSTAND CONGESTIVE HEART FAILURE PHYSIOLOGY AND TREATMENT! THE DONKEY ANALOGY FOR HF § The heart is like a poor donkey pulling a heavy load of sandbags. § The high preload and afterload are represented by the sandbags The result TO HELP THE DONKEY § Either by increasing its heart efficiency to coup or by reducing the extra load it is carrying To make the poor donkey feel better, we may remove some of those sandbags! It is simply like taking a load off the wagon making the work of the donkey much easier This is like the heart after some good diuresis, and afterload/preload reduction with ACEIs or ARBs. How about slowing down! § They are like saying to the donkey "Slow down a bit and rest. Don't work so hard! Regain your strength!" § Beta-blockers reduces the sympathetic nervous system and reduces heart rate HOW ABOUT IF WE GIVE THE DONKEY SOME INCENTIVE TO WORK HARDER? § There are two types of drugs used in congestive heart failure that can do this by directly increasing the cardiac output: § Digoxin and sympathomimetics (dobutamine and milrinone). II. PHYSIOLOGY OF MUSCLE CONTRACTION § 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 Cardiac myocytes are interconnected in groups that respond to stimuli as a unit, contracting together whenever a single cell is stimulated. Large mitochondria (Cell powerhouse) account for 25–35% of the volume of cardiac cells (compared with only 2% in skeletal muscle), a characteristic that makes cardiac cells highly resistant to fatigue 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). Figure 19.2 illustrates the 0 1 major ions contributing to depolarization and repolarization of cardiac myocytes. 2 3 4 Cardiac contractions 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). 4 5 1 2 3 COMPENSATORY PHYSIOLOGICAL RESPONSES IN HF § The failing heart evokes four major compensatory mechanisms to enhance cardiac output (Figure 18.4). § Although initially beneficial, these alterations ultimately result in further deterioration of cardiac function. COMPENSATORY PHYSIOLOGICAL RESPONSES IN HF 1. Increased sympathetic activity via baroreceptors. 2. Activation of the renin–angiotensin– aldosterone system. 3. Activation of natriuretic peptides 4. Myocardial dysfunction (hypertrophy) 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. MANAGEMENT OF HF 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. Reserve of inotropic agents for acute HF signs and symptoms in mostly the inpatient setting. Avoidance, if possible, of drugs that may precipitate or exacerbate HF, such as nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, non-dihydropyridine calcium channel blockers, and some antiarrhythmic drugs. Pharmacologic intervention provides the following benefits in HF: 1. reduce myocardial workload 2. decrease extracellular fluid volume 3. improve cardiac contractility 4. reduce rate of cardiac remodeling GOALS OF PHARMACOLOGIC INTERVENTION IN HF Goals of treatment are: 1. To alleviate symptoms, 2. Slow disease progression, and 3. Improve survival. For in-hospital patients, in addition to the above goals, other goals of therapy are to: 1. Reduce the hospital stay and subsequent readmission, 2. Prevent end-organ damage, 3. Appropriately manage the comorbidities that may contribute to poor prognosis. DRUG CLASSES USED IN HF 1. angiotensin-converting enzyme inhibitors, 2. angiotensin-receptor blockers, 3. aldosterone antagonists, 4. β-blockers, 5. diuretics, 6. Angiotensin Receptor-Neprilysin Inhibitor 7. Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Blocker (HCN channel blocker) 8. direct vaso- and venodilators, 9. inotropic agents. 10. Recombinant B-type Natriuretic Peptide ¢ One or more of these classes of drugs are administered depending on the severity of HF and individual patient factors ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS ACTIONS OF ACE INHIBITORS IN HF ¢ ACE inhibitors have proven to be very effective in the treatment of heart failure. ¢ Beneficial effects of ACE inhibition in heart failure include: ¢ Reducing vascular resistance (afterload) and venous tone (preload) which decreases pulmonary and systemic congestion and edema. ¢ Reducing sympathetic activation, which has been shown to be deleterious in heart failure. ¢ Improving the oxygen supply/demand ratio primarily by decreasing demand through the reductions in afterload and preload. ¢ Preventing angiotensin II from triggering deleterious cardiac remodeling. INDICATIONS OF ACE INHIBITORS: § ACE inhibitors are indicated for: § Patients with all stages of left ventricular failure. (LVHF) § Patients who have had a recent myocardial infarction § Patients who are at high risk for a cardiovascular event § The treatment of hypertension. § 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. ANGIOTENSIN RECEPTOR BLOCKERS Angiotensin receptor blockers (ARBs) are competitive antagonists of the angiotensin II type 1 receptor. The actions of ARBs and ACE inhibitors 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. They are also used in hypertension ALDOSTERONE ANTAGONISTS § Patients with advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. § Spironolactone and eplerenone are aldosterone antagonists indicated in patients with more severe stages of HFrEF or HFrEF and recent myocardial infarction. 𝝱-BLOCKERS § Although β-blockers have negative inotropic activity in HF, evidence clearly demonstrates improved systolic functioning and reverse cardiac remodeling in patients receiving β-blockers. § Therefore, β –Blockers are recommended for all patients with chronic, stable HF. § These agents decrease heart rate and inhibit release of renin in the kidneys. § 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. 𝝱-BLOCKERS IN HF § Three β-blockers have shown benefit in HF: Bisoprolol, carvedilol, and long-acting metoprolol succinate reduce morbidity and mortality associated with HFrEF. § Carvedilol is a nonselective αβ-adrenergic receptor antagonist. § Bisoprolol and metoprolol succinate are β1 -selective antagonists. § Treatment should start at low doses and gradually titrated to target doses based on patient tolerance and vital signs. § β -Blockers should be used with caution with other drugs that slow AV conduction, such as amiodarone , verapamil , and diltiazem. DIURETICS § Diuretics relieve pulmonary and peripheral edema. § Pulmonary edema is often caused by congestive heart failure. § When the heart is not able to pump efficiently, blood can back up into the veins that take blood through the lungs. § As the pressure in these blood vessels increases, fluid is pushed into the air spaces (alveoli) in the lungs DIURETICS § These agents are also useful in reducing the symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea. § Diuretics decrease the 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 cardiac output, thereby decreasing blood pressure. § Loop diuretics are the most used diuretics in HF. ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI) § In order to understand this new modality of therapy, we must understand: The natriuretic peptides, neprilysin, and neprilysin inhibition § Natriuretic peptides (atrial and brain natriuretic peptides) cause natriuresis (sodium and water to pass into the urine). § This natriuretic effect reduces the work on the heart and reduces blood pressure. § Neprilysin is the enzyme responsible for breaking down these natriuretic peptides. § Neprilysin inhibition augments the activity of the natriuretic peptides. § The first neprilysin inhibitor marketed is sacubitril but it has no stand-alone application. § Angiotensin Receptor-Neprilysin Inhibitor (ARNI) is a medicine resulting from the combination of two anti-hypertensive drugs (sacubitril and valsartan) that reduce blood pressure. § Sacubitril /valsartan is the first available (ARNI) marketed under the brand name ‘Entresto”. SACUBITRIL/VALSARTAN 1. Actions: § Sacubitril/valsartan combines the actions of an ARB with neprilysin inhibition. § Inhibition of neprilysin results in increased concentration of natriuretic peptides, leading to natriuresis, diuresis, vasodilation, and inhibition of fibrosis. § Together, the combination decreases afterload, preload, and myocardial fibrosis. § An ARNI improves survival and clinical signs and symptoms of HF, as compared to therapy with an ACE inhibitor or an ARB. 2. Therapeutic use: § An ARNI should replace an ACE inhibitor or ARB in patients with HFrEF who remain symptomatic on optimal doses of a β- blocker and an ACE inhibitor or ARB. 3. Pharmacokinetics: § Sacubitril/valsartan is orally active, administered with or without food, and quickly breaks down into the separate components. Sacubitril is transformed to active drug by plasma esterases. § Both drugs have a high volume of distribution and are highly bound to plasma proteins. § Sacubitril is mainly excreted in the urine. § The half-life of approximately 10 hours for both components allowing for twice-daily dosing. 4.Adverse effects: § The adverse effect profile is similar to that of an ACE inhibitor or ARB. § Because of the added reduction of afterload, hypotension is more common with an ARNI. § Due to inhibition of neprilysin with sacubitril, bradykinin levels may increase, and angioedema may occur. Therefore, the combination is contraindicated in patients with a history of hereditary angioedema or angioedema associated with an ACE inhibitor or ARB. § To minimize risk of angioedema, an ACE inhibitor must be stopped at least 36 hours prior to starting sacubitril/valsartan. HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE–GATED CHANNEL (HCN) BLOCKERS § The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is responsible for the If current and setting the pace within the SA node. § Inhibition of the HCN channel results in slowing of depolarization and a lower heart rate. § This reduction in heart rate is dose-dependent § Ivabradine is the only approved drug in the class of HCN-gated channel blockers. IVABRADINE 1. Actions: § By selectively slowing the If current in the SA node, Ivabradine reduces the heart rate without a reduction in contractility, AV conduction, ventricular repolarization, or blood pressure. § In patients with HFrEF, a slower heart rate increases stroke volume and improves symptoms of HF. 2. Therapeutic use: § Ivabradine is indicated to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with a left ventricular ejection fraction (LVEF) of 35% or less, who are in sinus rhythm with a resting heart rate of 70 beats per minute (bpm) or greater and are either receiving maximally tolerated doses of beta blockers or have a contraindication to beta-blocker use. 3. Pharmacokinetics: § Ivabradine should be administered with meals to increase absorption. § It undergoes extensive first-pass metabolism by CYP450 3A4. § Ivabradine has a high volume of distribution and is 70% protein bound. § The half-life is 6 hours which allows for twice-daily dosing 4. Adverse effects: § Ivabradine may cause bradycardia which may improve with dose reduction. § Bing mostly selective for the SA node, ivabradine is not effective for rate control in atrial fibrillation and has been shown to increase the risk of atrial fibrillation. § Ivabradine inhibits similar channels in the eye, and luminous phenomena may occur early in therapy. § This enhanced brightness may be ameliorated by dose reduction. § Ivabradine should not be used in pregnancy or breast- feeding, with more advanced heart block, or with potent 3A4 inhibitors. VASO- AND VENODILATORS § 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 reduce systemic arteriolar resistance and decrease afterload. § If the patient is intolerant of ACE inhibitors or ARBs, or if additional vasodilator response is required, a combination of hydralazine and isosorbide dinitrate may be used. § A fixed-dose combination of these agents has been shown to improve symptoms and survival in patients with HFrEF on standard HF treatment (β-blocker plus ACE inhibitor or ARB). § Headache, dizziness, and hypotension are common adverse effects with this combination. Rarely, hydralazine has been associated with drug- induced lupus. INOTROPIC DRUGS § 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 that increase intracellular calcium concentration (except digoxin) have been associated with reduced survival, especially in patients with HFrEF. § For this reason, these agents, are only used for a short period mainly in the inpatient setting. DIGITALIS GLYCOSIDES § 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. § Digitalis glycosides have a low (narrow) therapeutic index, § The most widely used agent is digoxin. § Digitoxin is seldom used due to its considerable duration of action. MECHANISM OF ACTION: § Digoxin inhibits Na+/K+-adenosine tri-phosphatase (ATPase) enzyme (Na-K-pump) § By inhibiting this pump, digoxin reduces the ability of the myocyte to actively pump Na+ from the cell. § This decreases the Na+ concentration gradient and consequently, decreases the ability of the Na+/ Ca2+- exchanger to move calcium out of the cell resulting in increasing intracellular Ca2+. § The increase that occurs in free Ca2+ thereby increases cardiac contractility. § Digoxin related increase in the force of cardiac contraction, causes the cardiac output to more closely resemble that of the normal heart THERAPEUTIC USES: § Digoxin therapy is indicated in patients with severe HFrEF after initiation of ACE inhibitor, β-blocker, and diuretic therapy. § 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. § A low serum drug concentration of digoxin (0.5 to 0.8 ng/mL) is beneficial in HFrEF. PHARMACOKINETICS: § Digoxin is available in oral and injectable formulations. § It has a large volume of distribution. § The dosage is based on lean body weight. § 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. ADVERSE EFFECTS: § At low serum drug concentrations, digoxin is fairly well tolerated in HFrEF. 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. § Hypokalemia predispose a patients 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.] § Digoxin should also be used with caution with other drugs that slow AV conduction, such as β-blockers, verapamil, and diltiazem. § 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. § Toxicity can often be managed by discontinuing digoxin, determining serum potassium levels, and, if indicated, replenishing potassium. § 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 Β -ADRENERGIC AGONISTS § β-Adrenergic agonists, such as dobutamine and dopamine, improve cardiac performance by causing positive inotropic effects and vasodilation. § β-Adrenergic agonists ultimately lead to increased entry of calcium ions into myocardial cells and enhanced contraction § Dobutamine is the most commonly used inotropic agent other than digoxin. § Both drugs must be given by intravenous infusion and are primarily used in the short-term treatment of acute HF in the hospital setting. MECHANISM OF ACTION § 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 (Figure 19.10). PHOSPHODIESTERASE INHIBITORS § Milrinone is a phosphodiesterase inhibitor that increases the intracellular concentration of cAMP (Figure 19.10). § Like β-adrenergic agonists, this results in an increase of intracellular calcium and, therefore, cardiac contractility. § Milrinone is usually given by intravenous infusion for short-term treatment of acute HF. § However, dobutamine and milrinone may also be considered in the outpatient setting for palliative care RECOMBINANT B-TYPE NATRIURETIC PEPTIDE § In acute decompensated congestive HF, drugs that reduce preload result in improvement in HF symptoms such as dyspnea. § Most often, IV diuretics are utilized in the acute setting to reduce preload. § When IV diuretics are minimally effective, a recombinant B-type natriuretic peptide (BNP) or nesiritide can be used as an alternative. § Nesiritide (Natrecor) is a recombinant form of human B-type (brain) natriuretic peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal effects. § The drug is administered intravenously for the management of patients with decompensated congestive heart failure (CHF). § Through binding to natriuretic peptide receptors, nesiritide stimulates natriuresis and diuresis and reduces preload and afterload. § Nesiritide is administered intravenously as a bolus (most often) and continuous infusion. § Like endogenous BNP, nesiritide has a short half-life of 20 minutes and is cleared by renal filtration, cleavage by endopeptidases and through internalization after binding to natriuretic peptide receptors. § The most common adverse effects are hypotension and dizziness, and like diuretics, nesiritide can worsen renal function. ORDER OF THERAPY § Experts have classified HF into four stages, from least severe to most severe. § Figure below 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. § 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. § Once at an optimal ACE inhibitor or ARB dose and if patient remains symptomatic, either can be replaced by sacubitril/ valsartan. § Lastly, digoxin and ivabradine are added for symptomatic benefit only in patients on optimal HF pharmacotherapy. § Patients with acute HF require in-patient management in ICU with supportive management (oxygen and respiratory support, in case of respiratory distress). § Pharmacotherapy consists of a judicious mix of vasodilators, diuretics, and ionotropic agents depending on the precipitating factors and symptoms/signs for congestion. § Anticoagulants are added to decrease the risk of thromboembolism, if required, in bedridden patients.