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Heart failure  Heart failure HF is complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. symptoms are; dyspnea, fatigue, fluid retention.  Heart failure accompanied by abnormal increases in blood volume and interstitial fluid. Underly...

Heart failure  Heart failure HF is complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. symptoms are; dyspnea, fatigue, fluid retention.  Heart failure accompanied by abnormal increases in blood volume and interstitial fluid. Underlying causes of HF : atherosclerotic heart disease, myocardial infarction, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, congenital heart disease.  Heart failure Role of physiologic compensatory mechanisms in the progression of HF Chronic activation of the sympathetic nervous system and renin– angiotensin–aldosterone system is associated with remodeling of cardiac tissue, loss of myocytes, hypertrophy, fibrosis Heart failure Goals of pharmacologic intervention in HF treatment are to alleviate symptoms, slow disease progression, and improve survival. DRUGS classes 1) angiotensin-converting enzyme inhibitors, 2) angiotensin-receptor blockers, 3) aldosterone antagonists, 4) β-blockers, 5) diuretics, 6) direct vaso- and venodilators, 7) positive inotropic agents 8) Angiotensin Receptor–Neprilysin Inhibitor 9) Hyperpolarization-Activated Cyclic Nucleotide– Gated channel blocker 10) Recombinant B-type Natriuretic Peptide Heart failure Pharmacologic intervention provides the following benefits in HF: reduced myocardial work load, decreased extracellular fluid volume, improved cardiac contractility, reduced rate of cardiac remodeling. PHYSIOLOGY OF MUSCLE CONTRACTION Action potential Cardiac myocytes are electrically excitable and have a spontaneous, intrinsic rhythm generated by specialized “pacemaker” cells located in the sinoatrial (SA) and atrioventricular (AV) nodes. Cardiac myocytes also have an unusually long action potential, which can be divided into five phases  Heart failure Cardiac contraction The force of contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium. agents that increase intracellular calcium levels (or that increase the sensitivity of the contractile machinery to calcium) increase the force of contraction (inotropic effect). Heart failure Compensatory physiological responses in HF The failing heart evokes three major compensatory mechanisms to enhance cardiac output Heart failure 1. Increased sympathetic activity: Baroreceptors sense a decrease in blood pressure and activate the sympathetic nervous system. stimulation of β-adrenergic receptors results in an increased heart rate and a greater force of contraction and vasoconstriction to enhances venous return and increases cardiac preload. Heart failure An increase in preload (stretch on the heart) increases stroke volume, which, in turn, increases cardiac output. These compensatory responses increase the work of the heart, which, in the long term, contributes to further decline in cardiac function  Heart failure 2. Activation of the renin–angiotensin–aldosterone A fall in COP decreases blood flow to the kidney, prompting the release of renin, and resulting in increased formation of; angiotensin II and release of aldosterone. results in increased peripheral resistance (afterload) and retention of sodium and water. volume increases, and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral and pulmonary edema occur.  3-Activation of natriuretic peptides An increase in preload also increases the release of natriuretic peptides. Natriuretic peptides, which include atrial, B type, and C-type, have differing roles in HF; atrial and B-type natriuretic peptides are the most important. Activation of the natriuretic peptides ultimately results in vasodilation, natriuresis, inhibition of renin and aldosterone release, and a reduction in myocardial fibrosis. This beneficial response may improve cardiac function and HF symptoms Heart failure 4. Myocardial hypertrophy : The heart increases in size, and the chambers dilate and become more globular. Initially, stretching of the heart muscle leads to a stronger contraction of the heart Heart failure excessive elongation of the fibers results in weaker contractions, and the geometry diminishes the ability to eject blood. This type of failure is termed “ systolic failure ” or HF with reduced ejection fraction (HFrEF) and is the result of the ventricle unable to pump effectively 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). Diastolic dysfunction, in its pure form, is characterized by symptoms of HF in the presence of a normal functioning left ventricle. However, both systolic and diastolic dysfunction commonly coexist in HF.  Heart failure D. Acute (decompensated) HF If the adaptive mechanisms adequately restore cardiac output, HF is said to be compensated. If the adaptive mechanisms fail to maintain COP, 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.  Heart failure Therapeutic strategies in HF HF is typically managed by fluid limitations (less than 1.5 to 2 L daily); low intake of sodium (less than 2000 mg/d); treatment of comorbid conditions; diuretics, inhibitors of the renin–angiotensin–aldosterone system, and inhibitors of the sympathetic nervous system. Inotropic agents are reserved for acute HF signs and symptoms in mostly the inpatient setting. Heart failure Drugs that may precipitate or exacerbate HF, such as; nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, non dihydropyridine calcium channel blockers, and some antiarrhythmic drugs,  inhibitors of of the renin–angiotensin–aldostero ne system HF leads to activation of the renin–angiotensin–aldosterone system via two mechanisms: 1) increased renin release by juxtaglomerular cells in renal afferent arterioles due to diminished renal perfusion pressure 2) renin release by juxtaglomerular cells promoted by sympathetic stimulation and activation of β receptors. The production of angiotensin II, a potent vasoconstrictor, and the subsequent stimulation of aldosterone release that causes salt and water retention lead to increases in both preload and afterload.  Heart failure Angiotensin-converting enzyme inhibitors (ACE) inhibitors are a part of standard pharmacotherapy in HFrEF. drugs block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. They also diminish the inactivation of bradykinin. Vasodilation occurs as a result of decreased levels of the vasoconstrictor angiotensin II and increased levels of bradykinin (a potent vasodilator). By reducing angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone. Heart failure Captopril Enalapril Fosinopril Lisinopril Quinapril Ramipril Heart failure 1. Actions on the heart: ACE inhibitors decrease vascular resistance (afterload) and venous tone (preload), resulting in increased cardiac output. ACE inhibitors also blunt the usual angiotensin II–mediated increase in epinephrine and aldosterone seen in HF. Heart failure 2. Indications: ACE inhibitors may be considered for patients with asymptomatic and symptomatic HFrEF. Importantly, ACE inhibitors are indicated for patients with all stages of left ventricular failure. Heart failure 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. Heart failure Pharmacokinetics: ACE inhibitors are absorbed following oral administration. Food may decrease the absorption of captopril , so it should be taken on an empty stomach. Except for captopril, ACE inhibitors are prodrugs that require activation by hydrolysis via hepatic enzymes. Renal elimination of the active moiety is important for most ACE inhibitors except fosinopril. Heart failure Adverse effects: postural hypotension, renal insufficiency, hyperkalemia, a persistent dry cough, and angioedema (rare). Potassium levels must be monitored Heart failure Angiotensin receptor blockers Angiotensin receptor blockers (ARBs) are orally active compounds that are competitive antagonists of the angiotensin II type 1 receptor. ARBs have the advantage of more complete blockade of angiotensin II action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II. Heart failure Actions on the cardiovascular system: Although ARBs have a different mechanism of action than ACE inhibitors, their actions on preload and afterload are similar. Their use in HF is mainly as a substitute for ACE inhibitors in those patients with severe cough or Angioedema.  Heart failure Pharmacokinetics: All the drugs are orally active and are dosed once-daily, with the exception of valsartan which is twice a day. They are highly plasma protein bound and, except for candesartan ,have large volumes of distribution.  Heart failure undergoes extensive first-pass hepatic metabolism, including conversion to its active metabolite. The other drugs have inactive metabolites. Elimination of metabolites and parent compounds occurs in urine and feces.  Heart failure Adverse effects: ARBs have an adverse effect and drug interaction profile similar to that of ACE inhibitors. the ARBs have a lower incidence of cough and angioedema. Like ACE inhibitors, ARBs are contraindicated in pregnancy  Heart failure Aldosterone antagonists advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. Spironolactone is a direct antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy, and hypokalemia.  Heart failure Eplerenone competitive antagonist of aldosterone at mineralocorticoid receptors. Although similar in action to spironolactone eplerenone has a lower incidence of endocrine-related side effects due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors.  Heart failure -BLOCKERS evidence clearly demonstrates improved systolic functioning and reverse cardiac remodeling in patients receiving β-blockers.  Heart failure benefit of β-blockers is attributed, in part, to their ability to prevent the changes that occur because of chronic activation of the sympathetic nervous system. These agents decrease heart rate inhibit release of renin in the kidneys. In addition, β- blockers prevent the deleterious effects of norepinephrine on the cardiac muscle fibers, ◦decreasing remodeling, hypertrophy, and cell death. Heart failure Three β-blockers have shown benefit in HF: bisoprolol carvedilol , metoprolol succinate Heart failure Carvedilol is a nonselective β-adrenoreceptor antagonist that also blocks α-adrenoreceptors, bisoprolol and metoprolol succinate are β1-selective antagonists  Heart failure β-Blockade is recommended for all patients with chronic, stable HF. Bisoprolol, carvedilol, and metoprolol succinate reduce morbidity and mortality associated with HFrEF.  Heart failure DIURETICS Diuretics relieve pulmonary congestion and peripheral edema. These agents are also useful in reducing the symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea. Diuretics decrease plasma volume and, subsequently, decrease venous return to the heart (preload) Heart failure This decreases cardiac workload and oxygen demand. Diuretics may also decrease afterload by reducing plasma volume, thereby decreasing blood pressure. Loop diuretics are the most commonly used diuretics in HF.  Heart failure 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. Heart failure If the patient is intolerant of ACE inhibitors or β-blockers, or if additional vasodilator response is required, a combination of hydralazine and isosorbide dinitrate may be used Heart failure Headache, hypotension, and tachycardia are common adverse effects with this combination. Rarely, hydralazine has been associated with drug- induced lupus  Heart failure INOTROPIC DRUGS + inotropic agents enhance contractility and, thus, increase cardiac output. All positive inotropes in HFrEF that increase intracellular calcium concentration have been associated with reduced survival, especially in patients with HFrEF due to coronary artery disease. For this reason, these agents, with exception of digoxin, are only used for a short period  Heart failure Digitalis glycosides increase the contractility of the heart muscle and, therefore, are used in treating HF. The digitalis glycosides have a low therapeutic index, with only a small difference between a therapeutic dose and doses that are toxic or even fatal.  Heart failure The most widely used agent is digoxin , Digitoxin is seldom used due to its considerable duration of action  Heart failure Mechanism of action Regulation of cytosolic calcium concentration: By inhibiting Na+/K+-adenosine triphosphatase (ATPase) enzyme, digoxin reduces the ability of the myocyte to actively pump Na+ from the cell This decreases the Na+ concentration gradient and, consequently, the ability of the Na+/ Ca++ exchanger to move calcium out of the cell  Heart failure higher cellular Na+ is exchanged for extracellular Ca2+ by the Na+/Ca2+-exchanger, increasing intracellular Ca2+. A small but physiologically important increase occurs in free Ca2+ that is available at the next contraction cycle of the cardiac muscle, thereby increasing cardiac contractility.  Heart failure Increased contractility of the cardiac muscle: Digoxin increases the force of cardiac contraction, causing cardiac output to more closely resemble that of the normal heart  Heart failure Vagal tone is also enhanced, so both heart rate and myocardial oxygen demand decrease. Digoxin slows conduction velocity through the AV node, making it useful for atrial fibrillation.  Heart failure Neuro hormonal inhibition: Although the exact mechanism of this effect has not been elucidated, low-dose digoxin inhibits sympathetic activation with minimal effects on contractility. This effect is the reason a lower serum drug concentration is targeted in HFrEF  Heart failure Therapeutic uses: Digoxin therapy is indicated in patients with severe HFrEF after initiation of ACE inhibitor, β-blocker, and diuretic therapy. A low serum drug concentration of digoxin (0.5 to 0.8 ng/ mL) is beneficial in HFrEF. At this level, patients may see a reduction in HF admissions, along with improved survival  Heart failure Pharmacokinetics: Digoxin. It has a large volume of distribution, because it accumulatesin muscle. The dosage is based on lean body weight. In acute atrial fibrillation, a loading dose Digoxin has a long half-life of 30 to 40 hours. It is mainly eliminated by the kidney, requiring dose adjustment in renal dysfunction.  Heart failure 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  Heart failure Toxicity can often be managed by discontinuing digoxin, determining serum potassium levels, and, if indicated, replenishing potassium. Decreased levels of serum potassium (hypokalemia) predispose a patient to digoxin toxicity, since digoxin normally competes with potassium for the same binding site on the Na+/K+- ATPase pump  Heart failure Patients receiving thiazide or loop diuretics may be prone to hypokalemia. Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs and the use of antibodies to digoxin (digoxin immune Fab), which bind and inactivate the drug  Heart failure β-Adrenergic agonists β-Adrenergic agonists, such as dobutamine and dopamine , causing positive inotropic effects and vasodilation. Dobutamine is the most commonly used inotropic agent other than digoxin. lead to an increase in intracellular (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 Heart failure Phosphodiesterase inhibitors Milrinone is a phosphodiesterase inhibitor that increases the intracellular concentration of cAMP. Like β-adrenergic agonists, this results in an increase of intracellular calcium and, therefore, cardiac contractility  Angiotensin Receptor–Neprilysin Inhibitor Neprilysin is the enzyme responsible for breaking down vasoactive peptides, such as angiotensin I and II, bradykinin, and natriuretic peptides. Inhibition of neprilysin augments the activity of the vasoactive peptides. To maximize the effect of natriuretic peptides, stimulation of the RAAS must be offset without further increase in bradykinin. Therefore an ARB, instead of an ACE inhibitor, is combined with a neprilysin inhibitor to reduce the incidence of angioedema Neprilysin inhibitors are a new class of drugs used to treat high blood pressure and heart failure. They work by blocking the action of neprilysin thus preventing the breakdown of natriuretic peptides. Neprilysin enzyme is also called neutral endopeptidase that plays a role in the degradation of natriuretic peptides and other vasoactive peptides including bradykinin. Natriuretic peptides remove sodium from the blood and excrete it in the urine. In the absence of natriuretic peptides, sodium levels increase in the blood, leading to increased blood pressure. Bradykinin is a vasodilator that relaxes and widens the walls of blood vessels. This facilitates the free flow of blood in the vessels. In the absence of bradykinin, the blood vessels may not relax and may cause an increase in blood pressure. Neprilysin inhibitor increases the availability of natriuretic peptides, helps bradykinin to achieve vasodilation and natriuresis (excretion of sodium), and decreases blood pressure. Sacubitril/valsartan Sacubitril/ valsartan combines the actions of an ARB with neprilysin inhibition. Inhibition of neprilysin results in increased concentration of vasoactive peptides, leading to natriuresis, diuresis, vasodilation, and inhibition of fibrosis. Together, the combination decreases afterload, preload, and myocardial fibrosis. An ARNI improves survival and symptoms of HF, as compared to therapy with an ACE inhibitor. 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. 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 allows for twice-daily dosing. adverse effect 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.. Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Blocker 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. Reduction in heart rate is use and dose dependent cardiac pacemaker current (I f), a mixed sodium- potassium inward current that controls the spontaneous diastolic depolarization in the sinoatrial (SA) node and hence regulates the heart rate. Ivabradine Ivabradine is the only approved drug in the class of HCN channel blockers By selectively slowing the( If) current in the SA node, reduction of heart rate occurs 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.  Ivabradine is used in HFrEF to improve symptoms in patients who are in sinus rhythm with a heart rate above 70 beats per minute and are on optimized HF pharmacotherapy. Specifically, patients should be on an optimal dose of β-blocker or have a contraindication to β- blockers Ivabradine administered with meals to increase absorption. It undergoes extensive first-pass metabolism by cytochrome P450 3A4 to an active metabolite, which is also a 3A4 substrate. Ivabradine has a high volume of distribution and is 70% protein bound. The half-life is 6 hours Bradycardia which may improve with dose reduction. Because ivabradine is mostly selective for the SA node, it is not effective for rate control in atrial fibrillation and has been shown to increase the risk of atrial fibrillation. Ivabradine should not be used in pregnancy or breast-feeding, with more advanced heart block, or with potent 3A4 inhibitors Recombinant B-type Natriuretic Peptide Natriuretic peptides ( ANP, BNP, and CNP ) are a family of hormone/paracrine factors that are structurally related. The main function of ANP( aterial natriuretic peptides) is causing a reduction in expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized and secreted by cardiac muscle cells in the walls of the atria in the heart. Recombinant B-type Natriuretic Peptide recombinant B-type natriuretic peptide (BNP), or nesiritide can be used as an alternative. Through binding to natriuretic peptide receptors, nesiritide stimulates natriuresis and diuresis and reduces preload and afterload. Nesiritide is administered IV as a bolus (most often) and continuous infusion. 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.