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Heart failure Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, and cardiomegaly. Peripheral and pulmonary edema (the congestion of congestive heart failure) are often but not always present. Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect. Underlying causes of HF include arteriosclerotic heart disease, myocardial infarction, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, and congenital heart disease. Pathophysiology: Cardiac performance is a function of four primary factors: 1- Preload: mainly a measure of left ventricular filling pressure; It is affected by venous blood pressure and volume of circulating blood (venous return). 2-Afterload: is the resistance against which the heart must pump blood and is represented by aortic and systemic vascular resistance. 3- Contractility. 4-Heart rate: beats/ mint. In heart failure, the C.O↓ so B.p & renal blood↓ so sympathetic activity & Renin secretion ↑ leading to Tachycardia, sodium and water retention, edema, increase blood volume, vasoconstriction thus Preload & Afterload ↑ these consequences Further harm the heart and so further exacerbate H.F. SO treatment of heart failure needs: 1- ↑ C.O: INOTROPIC DRUGS (Digitalis glycosides, β-Adrenergic agonists, Phosphodiesterase inhibitors). 2-↓ Sympathetic over activation: β-blocker (discussed previously) 3- ↓Renin angiotensin system overactivation: ACEI , ARB, Spironolacton (discussed previously) 4- Edema: Diuretics (discussed previously) INOTROPIC DRUGS: Positive inotropic agents enhance cardiac muscle contractility and, thus, increase cardiac output. Although these drugs act by different mechanisms, in each case the inotropic action is the result of an increased cytoplasmic calcium concentration that enhances the contractility of cardiac muscle. A. Digitalis glycosides Most of the drugs come from the digitalis (foxglove) plant. The cardiac glycosides influence the sodium and calcium ion flows in the cardiac muscle, thereby increasing contraction of the atrial and ventricular myocardium (positive inotropic action). The most widely used agent is digoxin . Mechanism of action: Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration. This increase in calcium concentration is the result of a two-step process: first, an increase of intracellular sodium concentration because of Na + /K + -ATPase inhibition; and second, a relative reduction of calcium expulsion from the cell by the sodium calcium exchanger {NCX} caused by the increase in intracellular sodium (Figure); Pharmacokinetics Digoxin, the only cardiac glycoside used in the USA, is 65–80% absorbed after oral administration. Once present in the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system. Digoxin is not extensively metabolized in humans; almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance, and the half-life is 36–40 hours in patients with normal renal function. Interactions with Potassium, Calcium, and Magnesium Potassium and digitalis inhibit each other’s binding to Na + /K + -ATPase; therefore, hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores that appears to be responsible for digitalis-induced abnormal automaticity.Hypercalcemia therefore increases the risk of a digitalis-induced arrhythmia. The effects of magnesium ion are opposite to those of calcium. These interactions mandate careful evaluation of serum electrolytes in patients with digitalis-induced arrhythmias. Adverse effects: a. Cardiac effects: The common cardiac side effect is arrhythmia, characterized by slowing of AV conduction associated with atrial arrhythmias. A decrease in intracellular potassium is the primary predisposing factor in these effects. b. Gastrointestinal effects: Anorexia, nausea, and vomiting are commonly encountered adverse effects. c. Central nervous system effects: These include headache, fatigue, confusion, blurred vision, alteration of color perception, and halos on dark objects. d- The digitalis glycosides show only a small difference between a therapeutically effective dose and doses that are toxic or even fatal. Therefore, the drugs have a low therapeutic index. e- Digoxin toxicity is one of the most commonly encountered adverse drug reactions. Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs and the use of antibodies to digoxin (digoxin immune Fab). Digoxin levels must be closely monitored in the presence of renal insufficiency, and dosage adjustment may be necessary. Drug-drug interactions: Fig; B. β-Adrenergic agonists: β-Adrenergic stimulation improves cardiac performance by causing positive inotropic effects and vasodilation. Dobutamine is the most commonly used inotropic agent other than digoxin. Dobutamine leads to an increase in intracellular cyclic adenosine monophosphate (cAMP), which results in the activation of protein kinase. Slow calcium channels are one kind of important site of phosphorylation by protein kinase. When phosphorylated, the entry of calcium ion into the myocardial cells increases, thereby enhancing contraction (Figure↓). Dobutamine must be given by intravenous infusion and is primarily used in the treatment of acute HF in a hospital setting. C. Phosphodiesterase inhibitors: Inamrinone and milrinone are phosphodiesterase inhibitors that increase the intracellular concentration of cAMP (Figure↓). This results in an increase of intracellular calcium and, therefore, cardiac contractility.Both long-term inamrinone and milrinone therapy may be associated with a substantial increase in the risk of mortality. However, short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in patients with refractory HF.