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Edit Comment Close Premium member Presentation Transcript Drugs for Congestive Heart Failure : Drugs for Congestive Heart Failure Pharmacy Pharmacology PHR 241 William B. Jeffries, Ph.D. Room 570A Criss III, 280-4092 Email: email@example.com flap.creighton.edu Required reading: Katzung, 7th ed. pp. 197-215, 287-293 Compensatory Mechanisms in Heart Failure : Compensatory Mechanisms in Heart Failure Mechanisms designed for acute loss in cardiac output Chronic activation of these mechanisms worsens heart failure Potential Therapeutic Targets in Heart Failure : Potential Therapeutic Targets in Heart Failure Preload Afterload Contractility Positive Inotropic Agents : Positive Inotropic Agents Cardiac Glycosides Phosphodiesterase inhibitors b-adrenoceptor agonists and dopamine receptor agonists Cardiac Glycosides : Cardiac Glycosides digoxin digitoxin deslanoside ouabain Mechanism of Digitalis Action: Molecular : Mechanism of Digitalis Action: Molecular Inhibition of Na/K ATPase blunting of Ca2+ extrusion Ca2+i sarcomere shortening Effects on Cardiac Function : Effects on Cardiac Function Positive inotropy Direct electrophysiological effects Effects mediated through increased vagal tone Direct Electrophysiological Effects:Cellular Action Potential : Direct Electrophysiological Effects:Cellular Action Potential Afterdepolarizations : Afterdepolarizations Summary Direct Electrophysiological Effects : Summary Direct Electrophysiological Effects Less negative membrane potential: decreased conduction velocity Decreased action potential duration: decreased refractory period in ventricles Enhanced automaticity due to Steeper phase 4 Afterdepolarizations Parasympathomimetic Effects : Parasympathomimetic Effects Decreased conduction velocity in the AV node increased effective refractory period in the AV Heart block (toxic concentrations) EKG Effects of Digitalis : EKG Effects of Digitalis decrease in R-T interval inversion of T wave Uncoupled P waves (Toxic concentrations) Bigeminy (toxic concentrations) Therapeutic Uses of Digitalis : Therapeutic Uses of Digitalis Congestive Heart Failure Atrial fibrillation Overall Benefit of Digitalis to Myocardial Function : Overall Benefit of Digitalis to Myocardial Function cardiac output cardiac efficiency ¯ heart rate ¯ cardiac size NO survival benefit Other Beneficial Effects : Other Beneficial Effects Restoration of baroreceptor sensitivity Reduction in sympathetic activity increased renal perfusion, with ¯ edema formation Administration : Administration Digoxin has a long enough half life (24-36 hr.) and high enough bioavailability to allow once daily dosing Digoxin has a large volume of distribution and dose must be based on lean body mass Increased cardiac performance can increase renal function and clearance of digoxin Eubacterium lentum Adverse Effects : Adverse Effects Cardiac AV block Bradycardia Ventricular extrasystole Arrhythmias CNS GI Therapeutic index is ~ 2! Serum Electrolytes Affect Toxicity : Serum Electrolytes Affect Toxicity K+ Digitalis competes for K binding at Na/K ATPase Hypokalemia: increase toxicity Hyperkalemia: decrease toxicity Mg2+ Hypomagnesemia: increases toxicity Ca2+ Hypercalcemia: increases toxicity Treatment of Digitalis Toxicity : Treatment of Digitalis Toxicity reduce dose: 1st degree heart block, ectopic beats Atropine: advanced heart block KCl: increased automaticity Antiarrythmics: ventricular arrhythmias Fab antibodies: toxic serum concentration; acute toxicity Phosphodiesterase Inhibitors : Phosphodiesterase Inhibitors amrinone milrinone Mechanism of Action inhibition of type III phosphodiesterase intracellular cAMP activation of protein kinase A Ca2+ entry through L type Ca channels inhibition of Ca2+ sequestration by SR cardiac output ¯ peripheral vascular resistance Phosphodiesterase Inhibitors: Therapeutic Use : Phosphodiesterase Inhibitors: Therapeutic Use short term support in advanced cardiac failure long term use not possible Adverse Effects of Phosphodiesterase Inhibitors : Adverse Effects of Phosphodiesterase Inhibitors Cardiac arrhythmias GI: Nausea and vomiting Sudden death b-Adrenoceptor and Dopamine Receptor Agonists : b-Adrenoceptor and Dopamine Receptor Agonists Dobutamine Dopamine Mechanism of Action: Dobutamine : Mechanism of Action: Dobutamine Stimulation of cardiac b1-adrenoceptors: inotropy > chronotropy peripheral vasodilatation myocardial oxygen demand Mechanism of Action: Dopamine : Mechanism of Action: Dopamine Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors Splanchnic and renal vasodilatation Therapeutic Use : Therapeutic Use Dobutamine: management of acute failure only Dopamine: restore renal blood in acute failure Adverse Effects : Adverse Effects Dobutamine Tolerance Tachycardia Dopamine tachycardia arrhythmias peripheral vasoconstriction ACE Inhibitors in Heart Failure : ACE Inhibitors in Heart Failure Mechanism of Action : Mechanism of Action Afterload reduction Preload reduction Reduction of facilitation of sympathetic nervous system Reduction of cardiac hypertrophy ACE Inhibitors: Therapeutic Uses : ACE Inhibitors: Therapeutic Uses Drugs of choice in heart failure (with diuretics) Current investigational use: Acute myocardial infarction ATII antagonists Diuretics: Mechanism of Action in Heart Failure : Diuretics: Mechanism of Action in Heart Failure Preload reduction: reduction of excess plasma volume and edema fluid Afterload reduction: lowered blood pressure Reduction of facilitation of sympathetic nervous system Vasodilators : Vasodilators Mechanism of action: reduce preload and afterload Drugs used Sodium nitroprusside Hydralazine Ca2+ channel blockers Prazosin -Blockers in Heart Failure: Mechanism of Action : -Blockers in Heart Failure: Mechanism of Action Standard b-blockers: Reduction in damaging sympathetic influences in the heart (tachycardia, arrhythmias, remodeling) inhibition of renin release Carvedilol: Beta blockade effects peripheral vasodilatation via a1-adrenoceptor blockade (carvedilol) Spironolactone : Spironolactone Aldosterone antagonist, K-sparing diuretic Prevention of aldosterone effects on: Kidney Heart? Aldosterone inappropriately elevated in CHF Mobilizes edema fluid in heart failure Prevention of hypokalemia induced by loop diuretics (protection against digitalis toxicity?) Prolongs life in CHF patients Slide 35: back You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.