Drugs Acting on the Heart Munir Gharaibeh Faculty of Medicine Second Semester, 2010/2011 mgharaib@ju.edu.jo

Munir Gharaibeh MD, PhD, MHPE Heart Failure Definition. Factors Affecting Cardiac Output: Preload. Afterload. Heart rate. Contractility of heart muscle. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Heart Failure Causes of Heart Failure: Ischemic heart disease. Hypertension. Cardiomyopathy. Valvular heart disease. Etc…. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Heart Failure Clinical Picture: Sympathetic compensation: a- Tachycardia. b- Increased myocardial contractility. c- Vasoconstriction leading to redistribution of blood to important viscera d- Renin release leading to increased plasma volume Decreased cardiac output Congestion. April 19 Munir Gharaibeh MD, PhD, MHPE

Compensatory Mechanisms in Heart Failure April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Drugs used in Heart Failure Most of the drugs are used only to relieve the symptoms, they do not really cure the disease. Diuretics. Angiotensin converting enzyme inhibitors(ACEI). Positive inotropic drugs. Vasodilators. ß blockers. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Diuretics Work directly on the kidneys to increase salt and water excretion. They only relieve edema; pulmonary, leg edema, and heart distension. May cause dehydration and hypokalemia. In high doses, might decrease cardiac output. They stimulate renin-angiotensin- aldosterone system. Will be discussed later. April 19 Munir Gharaibeh MD, PhD, MHPE

Angiotensin Converting Enzyme Inhibitors(ACEI). Also used in hypertension. Reduce salt and water retention. Cause dilation of arterioles, and consequently, reduce the afterload, leading to enhancement of cardiac output. Only drugs which prolong the survival of patients. Can cause hypotension and hyperkalemia. April 19 Munir Gharaibeh MD, PhD, MHPE

Angiotensin Converting Enzyme Inhibitors "ACEI" Captopril Enalapril Lisinolapril Quinalapril Fosinolapril All are similarly effective Might differ in toxicity April 19 Munir Gharaibeh MD, PhD, MHPE

Angiotensin Converting Enzyme Inhibitors "ACEI" Toxicity: Hypotension Renal Impairment ............ proteinurea K+ retention Cough April 19 Munir Gharaibeh MD, PhD, MHPE

Angiotensin (AT1) Receptor Blockers (ARBs) Losartan. Candesartan. Valsartan. Irbesartan. Telmisartan. Not superior to ACEIs, but may be useful for patients who can not tolerate ACEIs because of cough. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Positive Inotropic Agents Cyclic AMP Independent Agents: Digoxin Cyclic AMP Dependant Agents: -adrenergic Agonists April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Digitalis Glycosides History: Prototype for inotropic agents. Egyptians ------- Squill Chinese -------- Toad skin William Withering ----- Foxglove 1785 April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Digitalis Glycosides Mechanism: Inhibition of Na+/K+ ATPase April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Digitalis Glycosides Actions: Positive Inotropic Stimulate the vagus nerve Block AV conduction. Enhance ventricular electrical activity. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Digitalis Glycosides Pharmacokinetics: Long half life. Loading dose required. Can accumulate. Acceptable plasma levels: 1-2 meq/liter. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Digitalis Glycosides Toxicity: G.I.T. Visual. Neurologic. Cardiac: bradycardia, heart block, ventricular extrasystoles. Interactions. Treatment of Toxicity: Stop the dug or reduce the dose. Ensure adequate K+ level. Cardiac pacemeker. Digitalis antibodies( Digoxin Immune Fab) April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Digitalis Glycosides Therapeutic Benefits: Nowadays, only indicated in CCHF associated with supraventricular arrhythmia. Decreases morbidity. Does not reduce mortality. April 19 Munir Gharaibeh MD, PhD, MHPE

Positive Inotropic Agents Cyclic AMP Dependent Agents: -adrenergic Agonists: All increase myocardial oxygen consumption, so not helpful for chronic use. May be used (IV) for short term or in acute heart failure. NE: Was used in cardiogenic shock, but caused severe vasospasm and gangrene . EP: Still used in cardiac arrest, by intracardiac injection. April 19 Munir Gharaibeh MD, PhD, MHPE

Positive Inotropic Agents Dopamine: Widely used in cardiogenic shock. Low doses: stimulates DA1 receptors leading to renal vasodilation and improved renal function. Intermediate doses: works on β1 receptors leading to positive inotropic actions. High doses: stimulates α receptors leading to vasoconstriction and elevation of blood pressure. Can cause arrhythmias and ischemic changes. Dobutamine: Selective β1 agonist, used intermittently (IV) in CCHF. Has more inotropic than chronotropic actions. April 19 Munir Gharaibeh MD, PhD, MHPE

Munir Gharaibeh MD, PhD, MHPE Vasodilators Affect preload and/or afterload without directly affecting contractility. Consequently, can decrease myocardial ischemia, enhance coronary blood flow and decrease O2 consumption. Can be used, only by expert hands, in acute heart failure and for short periods in CCHF. Can be combined with ACEI, Diuretics and digitalis. April 19 Munir Gharaibeh MD, PhD, MHPE