Treatment of Chronic Heart Failure PDF

Treatment of Heart Failure Yam Mun Fei School of Pharmaceutical Sciences, Universiti Sains Malaysia Chronic heart failure Chronic heart failure (CHF)is described as a failure of the heart to adequately pump enough blood to supply the tissues and organs of the bo...

Treatment of Heart Failure Yam Mun Fei School of Pharmaceutical Sciences, Universiti Sains Malaysia Chronic heart failure Chronic heart failure (CHF)is described as a failure of the heart to adequately pump enough blood to supply the tissues and organs of the body with oxygen and other nutrients. In untreated CHF there are compensatory mechanisms that are activated by the body that attempt to overcome the heart failure. Cardiac muscle undergoes hypertrophy, where the walls of the heart chambers increase in size and undergo structural remodeling in an attempt to generate more forceful contractions. In addition, neurohumoral compensatory responses involving the sympathetic nervous system and kidneys are activated. Compensatory responses Sympathetic activation stimulates the release of norepinephrine and epinephrine from adrenergic nerves and the adrenal medulla. This produces vasoconstriction (alpha-1 effect), increased heart rate, and force of myocardial contraction (beta-1 effects). These actions are an attempt by the body to increase blood pressure and increase cardiac output. The kidneys respond by releasing a substance called renin. Renin stimulates the enzymatic conversion of a precursor protein from the liver, angiotensinogen, to angiotensin I. An enzyme produced by the lungs, angiotensin-converting enzyme (ACE), convertsangiotensin I into angiotensin II. Angiotensin II is a potent vasoconstrictor and also stimulates the release of aldosterone from the adrenal cortex and antidiuretic hormone (ADH) from the hypothalamus and pituitary gland. This sequence of actions is referred to as the renin-angiotensin- aldosterone (RAA) mechanism. Aldosterone is a hormone that causes retention of sodium by the kidneys and ADH acts on the hypothalamus to stimulate thirst and on the kidney tubules to retain water. These actions attempt to increase blood volume and blood pressure. Unfortunately the compensatory responses do not usually reverse heart failure. Over time, these compensatory mechanisms cause “remodeling” of the heart, where the heart enlarges (hypertrophy) and becomes weaker and less efficient.  Treatment of CHF The treatment of CHF has evolved over the years away from the use of drugs such as the cardiac glycosides (also referred to as digitalis glycosides) that stimulate myocardial contraction to other drugs such as the vasodilators that relax vascular smooth muscle. Vasodilator drugs increase cardiac output by dilating blood vessels, which reduces the workload on the heart. Vasodilators that primarily dilate veins and decrease venous return are said to decrease preload. Preload is the amount of blood returning to the heart (venous return). Vasodilators that dilate arteries reduce blood pressure and peripheral resistance and are said to decrease afterload. Afterload is the force (force of ventricular contraction) that the heart must generate in order to overcome vascular resistance (open the aortic valve) and eject blood out of the left ventricle. Decreasing preload, afterload, or both decreases the workload of the heart (volume of blood the heart must pump) and allows the heart to contract more efficiently. This increases cardiac output in CHF and is the main therapeutic effect of vasodilator drugs. Diuretics have always been very useful in CHF and primarily prevent the retention and accumulation of fluid that is the cause of edema and congestion. Beta blockers reduce the heart rate and sympathetic activation, which is usually excessive in CHF. Digoxin is the only cardiac glycoside still available in the United States. Digoxin is now considered a second-line drug and may be added to diuretics and vasodilator drugs when additional myocardial stimulation is required. Diuretic therapy for CHF The main therapeutic effect produced by diuretics is the elimination of excess sodium and water by the kidneys. Sodium and water retention are the main cause of edema and congestion in CHF. The excretion of sodium also produces a vasodilating effect, which also can contribute to the therapeutic effect. There are three different types of diuretics used in CHF: the thiazides, organic acids (loop diuretics), and aldosterone antagonists Thiazide diuretics The thiazide and thiazide-like diuretics are similarly acting drugs that block the reabsorption of sodium in the distal tubules of the kidney nephrons. The potency of these diuretics is considered moderate and they are most effective in mild to moderate CHF in patients with normal renal function. Thiazides increase the excretion of sodium, but they also cause the loss of potassium and can cause hypokalemia. The main difference among the thiazides is the potency, which determines dosage, and the duration of action. Loop diuretics The organic acids are commonly referred to as the loop diuretics because the site of diuretic action in kidney nephrons is the thick ascending limb of the loop of Henle. Loop diuretics are the most potent diuretics and primarily indicated for patients with impaired renal function or severe heart failure. Like the thiazides, these diuretics increase the excretion of sodium and water and also cause loss of potassium. Loop diuretics can be administered intravenously in acute heart failure to rapidly relieve edema and pulmonary congestion. Furosemide ( Lasix ), bumetanide ( Bumex ), and torsemide ( Demadex ) are the most widely used loop diuretics and indicated when a more potent diuretic effect is required. The duration of action of these drugs averages 4 to 8 hours. Aldosterone antagonists The aldosterone antagonists are weak diuretics that act on the collecting ducts of the nephron. Aldosterone is a steroid from the adrenal cortex that normally causes the retention of sodium ions and excretion of potassium ions. The main effects of the aldosterone antagonists are to increase excretion of sodium and cause retention of potassium. In CHF there can be excessive activity of aldosterone and studies have shown that treatment with these drugs reduces mortality. Spironolactone ( Aldactone ) is a competitive antagonist of the aldosterone receptor and is only effective when aldosterone levels are increased. Eplerenone ( Inspra ) is an analog of aldosterone that produces fewer adverse effects. Two other drugs, amiloride ( Midamor ) and triamterene ( Dyrenium ), reduce aldosterone activity by blocking the sodium channel in the collecting ducts of the nephron. These drugs are also more effective when aldosterone levels are increased. Because these diuretics increase potassium levels in the blood, they are often referred to as “potassium sparing diuretics.” The potassium sparing diuretics are frequently combined with thiazide and loop diuretics to counterbalance the loss of potassium by these diuretics. Adverse effect of diuretics The adverse effects of the thiazides and loop diuretics are similar and include nausea, hypotension, hypokalemia, hyperuricemia, and hyperglycemia. The main adverse effect associated with the potassium- sparing diuretics is hyperkalemia. More detailed information on the mechanisms of action and adverse effects of the diuretics is discussed in coming lecture.  Vasodilator treatment of CHF The main effect of vasodilator drugs is to relax or dilate blood vessels. Vasodilation lowers peripheral resistance and blood pressure. These changes decrease cardiac work and oxygen consumption. The heart is able to pump more efficiently (increased cardiac output) with less effort. Drugs that primarily dilate arteries have a greater effect to lower arterial blood pressure. This effect is referred to as decreasing the afterload of the heart, which simply stated means that the heart doesn’t have to work as hard to pump blood after the blood pressure has been lowered. Drugs that primarily dilate veins (venodilators) mainly decrease the venous return of blood back to the heart. This is referred to as decreasing preload, which also reduces cardiac work. Some drugs dilate both arteries and veins and produce a “balanced” vasodilation that decreases both pre- and afterload. Vasodilator therapy of CHF has been shown to be very beneficial, especially with the drug classes known as the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). These drugs have become the preferred agents for the treatment of CHF. There is less risk of toxicity with these vasodilators than with drugs such as digoxin. Vasodilator drugs are used alone and in combination with other drugs. The vasodilators can be divided into different subtypes—arterial dilators, venous dilators, and balanced dilators—based on their sites and mechanisms of action. Arterial dilators Hydralazine is a drug that produces arterial vasodilation, decreased blood pressure, and a reduction in afterload. The mechanism of action is believed to involve the formation of nitric oxide (NO), a substance normally produced in the vasculature that produces vasodilation. By reducing systemic blood pressure, the force (afterload) that the left ventricle must generate in order to eject blood is reduced. The result in CHF is an increase in CO. Adverse effects are mostly due to excessive decreases in blood pressure and include nausea, postural hypotension, headache, and reflex tachycardia. Venodilators Nitrate drugs such as nitroglycerine and isosorbide dinitrate primarily cause venodilation, especially of the larger veins and vena cava. When the heart is congested and overloaded with blood, the contractile force is greatly reduced. Venodilators reduce venous return and preload. The amount of blood returning to the heart is decreased, which allows the heart to pump more forcefully to increase CO. Adverse effects of the nitrates include headache, dizziness, vasomotor flushing, postural hypotension, and reflex tachycardia. Balanced vasodilators These drugs dilate both arteries and veins. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are two rather large classes of drugs that produce this effect. These drugs inhibit the actions of angiotensin II, which causes vasoconstriction, release of aldosterone, and release of ADH. Aldosterone and ADH cause retention of sodium and water. ACE Inhibitors ACEIs have two mechanisms of action. First, they inhibit the angiotensin-converting enzyme (ACE), which reduces the formation of angiotensin II. This action promotes vasodilation and excretion of sodium and water from the kidneys. Second, inhibition of ACE also decreases inactivation of bradykinin. Bradykinin is an endogenous vasodilator and this action increases bradykinin levels in the plasma and contributes to the vasodilation produced by the ACEIs. Angiotensin Receptor Blockers ARBs bind to and block the angiotensin II receptor, referred to as the angiotensin-1 (AT 1 ) receptor. This blocks the actions of angiotensin II and results in vasodilation and increased excretion of sodium and water. ARBs do not affect bradykinin. Both drug classes produce a balanced vasodilatation that reduces both pre- and afterload. These drugs have become the preferred therapy for CHF and can be combined with diuretics and other drugs indicated for CHF. The major difference between the ACEIs and the ARBs is that the ARBs do not increase bradykinin concentrations. While bradykinin contributes to the vasodilation, it also increases adverse respiratory and allergic reactions. Adverse Effects of ACEIs and ARBs Adverse effects of both ACEIs and ARBs include headache, dizziness, hypotension, hyperkalemia, and GI disturbances. The ACEIs also can cause a dry cough and allergic reactions that may include angioedema. The cough and allergic reactions are thought to be related to the increased levels of bradykinin, which can increase the formation of allergic and inflammatory chemical mediators.  Use of adrenergic receptor blocker in CHF Beta-blockers bind to beta adrenergic receptors and block the actions of norepinephrine and epinephrine. The therapeutic action of beta-blockers in CHF is to block beta-1 receptors on the heart; this decreases heart rate and force of contraction. These actions would seem to be opposite to the effects required in CHF. However, in CHF, there is excessive activation of the sympathetic nervous system that causes tachycardia and increased stress on the heart. By slowing the heart rate, beta-blockers allow the heart to fill and function more efficiently. There are also beta-1 receptors on specialized cells in the kidneys, the juxtaglomerular cells that release renin. Renin-angiotensin-aldosterone mechanism causes vasoconstriction and retention of sodium and water. Therefore, blocking these beta-1 receptors reduces the release of renin and activation of the RAA mechanism. Any of the beta-blockers will produce the desired therapeutic effects, but metoprolol ( Lopressor ) bisoprolol (Zebeta), nebivolol (Bystolic) and carvedilol ( Coreg ) are usually the preferred drugs for treatment of CHF. In addition to blocking beta receptors, carvedilol also produces vasodilation by blocking adrenergic alpha-1 receptors. The dosages of beta-blockers in CHF are usually in the lower therapeutic range and it is important not to cause excessive beta blockade of cardiac function, which would then decrease contractility and cardiac output. Cardiac glycosides The cardiac glycosides are a group of compounds originally obtained from the plant leaves of Digitalis purpurea and Digitalis lanata. The term digitalis also refers to these drugs. The major action of these drugs is to increase cardiac contractility. Digoxin ( Lanoxin ) is the only drug of this class that is still available in the United States, so this discussion will focus on the pharmacology of digoxin. Pharmacological Effects The unique and main pharmacological effect of digoxin is to increase the force of myocardial contractions (also referred to as a positive inotropic effect) in CHF without causing an increase in oxygen consumption. The efficiency of the heart is improved, restoring normal blood circulation. Kidney function increases due to the increased cardiac output and renal blood flow. This increase in kidney function contributes to the elimination of the excess fluid and electrolytes associated with edema. A second action of digoxin is to stimulate the vagus nerve (parasympathetic effect), which slows the activity of the SA and AV nodes. This slows the heart rate (also referred to as a negative chronotropic effect) and decreases AV conduction. On the electrocardiogram (ECG) this is observed as a lengthening of the PR interval. At higher doses, the decreased conduction through the AV node can lead to various degrees of heart block.  Heart block occurs when conduction of electrical impulses from the atria through the AV node to the ventricles is delayed or blocked. A slight delay in AV conduction is useful in the treatment of atrial flutter and atrial fibrillation. In these conditions, digoxin reduces the ventricular rate by slowing conduction through the AV node. This causes prolongation of the PR interval and is referred to as first-degree heart block. Second-degree heart block is characterized by failure of some impulses to get through the AV node. The result is that every P wave is not followed by a QRS wave. When every other P wave is blocked the arrhythmia is referred to as 2:1 AV block. Other ratios also can be seen, for example, 3:1, 4:1, and so on. In third-degree or complete heart block, no impulses go through the AV node and the atria and ventricles beat independently. Second- and third-degree heart block are arrhythmias that require treatment. Special Considerations Before administering glycosides, a patient’s pulse should be taken to ensure that the heart rate is between 60 and 100 beats per minute. If the rate is below 60 or above 100, the attending physician should be consulted before the drug is given. Mechanism of Action Digoxin increases the force of myocardial contractions by increasing the concentration of calcium ions inside cardiac muscle cells. First, digoxin inhibits the enzyme Na/K adenosine triphosphatase (Na/K ATPase) , which energizes the sodium/potassium pump. Normally, the sodium/potassium pump removes sodium from inside the cell (depolarization) and brings potassium back into the cell (after repolarization). Inhibition of Na/K ATPase leads to accumulation of sodium ions inside heart muscle cells. Second, the increase of sodium ions inside heart muscle reduces the activity of another ion exchange mechanism, the sodium-calcium (Na/Ca) exchanger. Normally the Na/Ca exchanger brings Na + into the cell and pumps Ca ++ out of the cell. Inhibition of the Na/K ATPase increases the concentration of Na + inside the cell. The increased intracellular Na + slows the Na/Ca exchanger and slows the loss of intracellular Ca ++. The resulting increased intracellular calcium concentrations increase the formation of the contractile protein actinomyosin, resulting in greater myocardial contraction. After treatment with digoxin, the heart contracts more forcefully to increase cardiac output and relieve the symptoms of heart failure. Pharmacokinetics In acute CHF, the administration of digoxin normally follows a sequence known as digitalization and maintenance. During digitalization, digoxin is administered (PO or IV) at doses and intervals that rapidly produce an effective blood level. Subsequent daily maintenance doses are lower and adjusted to maintain a therapeutic level of glycoside in the blood. Digoxin can be administered orally or intravenously, depending on the urgency of the situation. Food may delay absorption but usually does not interfere with the extent of absorption. Digoxin is not bound significantly to plasma proteins and is excreted mostly unmetabolized by the urinary tract. The half-life of digoxin is normally 1.5 to 2.0 days, but it may be prolonged in older patients. The actions of digoxin are affected by changes in the serum electrolytes, particularly potassium and calcium. Hypokalemia (low serum potassium) sensitizes the heart to the toxic effects of digoxin. Decrease in serum potassium may cause an increased incidence of arrhythmias, which can lead to ventricular fibrillation and sudden death. Administration of potassium salts is required to restore normal electrolyte levels during these crises. In contrast, hyperkalemia (high serum potassium) antagonizes the therapeutic effects of digoxin. Hypercalcemia (high serum calcium) enhances the action of digoxin and can lead to arrhythmias. Many patients with CHF also are treated with diuretics to reduce the edema associated with this condition. It is important that these patients receive adequate amounts of potassium in their diets to counterbalance the excretion of potassium caused by diuretics. Fruit juices, bananas, and vegetables are good sources of dietary potassium. In addition, there are commercial preparations of potassium supplements such as K-Lyte or Slow-K. Adverse and toxic effects The major adverse effects of digoxin are caused by excessive dosage. Mild symptoms include nausea, vomiting, headache, visual disturbances, and rashes. Dose reduction is usually sufficient to relieve these symptoms. The serious toxic effects involve the development of cardiac arrhythmias. Usually, there is an appearance of extra heartbeats (ectopic beats). Most common are premature ventricular contractions (PVCs). An increase in these contractions can lead to ventricular tachycardia, ventricular fibrillation, and cardiac arrest. Treatment involves stopping digoxin and administering potassium and antiarrhythmic drugs to restore the normal cardiac rhythm. In overdose toxicity, an antidote is available to reduce the severity of toxicity. Digoxin Immune Fab (Digibind) is a preparation of antidigoxin antibodies that is administered parenterally. The antibodies bind up digoxin and make it unavailable for producing its pharmacological effects. The symptoms and severity of toxicity are usually reduced within 30 to 60 minutes. The antibody– digoxin complex is eliminated in the urine. The main indication for Digoxin Immune Fab is treatment of life-threatening digoxin intoxication. Drug interactions Antacids, laxatives, kaolinpectin (Kaopectate), and cholestyramine (Questran) can decrease the absorption of digoxin from the GI tract. The antiarrhythmic drug quinidine increases digoxin plasma levels. Reduction in digoxin dosage is usually required when these two drugs are used together. The calcium channel blockers verapamil and diltiazem and any of the beta-blockers decrease heart rate and force of contraction. These drugs may depress cardiac function and precipitate CHF; this can counteract the therapeutic effectiveness of digoxin. Diuretics (thiazides and loop diuretics) cause loss of potassium; hypokalemia can increase digoxin toxicity. Other drugs that increase myocardial contraction There are several drugs that are administered by IV infusion in the treatment of acute heart failure. Dopamine and dobutamine ( Dobutrex ) are adrenergic drugs that stimulate beta-1 receptors and increase the force of contraction. Amrinone and milrinone ( Primacor ) are drugs that increase contractility by increasing calcium concentrations in heart muscle; these drugs also produce vasodilation. The use of these drugs is limited and administered primarily in the hospital setting during the initial treatment of acute heart failure until the patient is stabilized and other therapeutic decisions can be made.