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Drugs for Congestive Heart Failure
Required reading: Katzung, 9th ed. pp , Drugs for Congestive Heart Failure Digitalis Lanata Cardiovascular System Course William B. Jeffries, Ph.D. Room 570A Criss III, flap.creighton.edu
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Compensatory Mechanisms in Heart Failure
Mechanisms designed for acute loss in cardiac output Chronic activation of these mechanisms worsens heart failure
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Potential Therapeutic Targets in Heart Failure
Preload Afterload Contractility Remodeling
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Positive Inotropic Agents
Cardiac Glycosides Phosphodiesterase inhibitors b-adrenoceptor agonists
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Cardiac Glycosides digoxin digitoxin deslanoside ouabain
William Withering (March 17, October 6, 1799) was a British botanist, physician and the discoverer of digitalis. Trained as a doctor at Edinburgh University, he worked at Birmingham General Hospital from In 1775, he learned from a "grand old dame" of Shropshire that she had a successful formula mixture of some 20 drugs for the treatment of dropsy. She was unable to differentiate between renal, cardiac, hepatic or cerebral dropsy. Botanist Withering perceived that the recipe had foxglove in it. Withering then undertook a careful study of the effects, administering infusions and powders from the foxglove leaf, stems, and the roots of the plant. After cautioning of the toxicity, he provided quantities of the drug for his fellow physicians to try, but heedless that in their administration quite a number of people were evidently being "poisoned" by it with symptoms of nausea, vomiting, yellow vision, diarrhea, and slow pulse. The active ingredient is now known as digitalis, after the plant's scientific name. In 1785, Withering published An Account of the Foxglove and some of its Medical Uses, which contained reports on clinical trials and notes on digitalis toxicity.
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Mechanism of Digitalis Action: Molecular
Inhibition of Na/K ATPase blunting of Ca2+ extrusion Ca2+i sarcomere shortening
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Effects on Cardiac Function
Three Types of Effects: Mechanical Effects: Positive inotropy Caused by increased Ca2+ Availability Direct Electrophysiological Effects Altered cellular action potential Afterdepolarizations Indirect Electrophysiological Effects: Mediated through increased vagal tone and withdrawal of sympathetic tone
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Direct Electrophysiological Effects: Cellular Action Potential
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Afterdepolarizations
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Parasympathomimetic Effects
Vagus-mediated hyperpolarization of AV node. Leads to: Decreased conduction velocity in the AV node Increased effective refractory period in the AV node AV block (toxic concentrations)
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Therapeutic Uses of Digitalis
Congestive Heart Failure Atrial fibrillation
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Overall Benefit of Digitalis to Myocardial Function
cardiac output cardiac efficiency ¯ heart rate ¯ cardiac size NO survival benefit
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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
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Adverse Effects Therapeutic index is ~ 2! Cardiac CNS GI AV block
Bradycardia Ventricular extrasystole Arrhythmias CNS GI Therapeutic index is ~ 2!
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Serum Electrolytes Affect Toxicity
K+ Digitalis competes for K binding at Na/K ATPase Hypokalemia: increase toxicity Hyperkalemia: decrease toxicity Ca2+ Hypercalcemia: increases toxicity
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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 increased Ca2+ sequestration by SR Phosphorylation of MLCK cardiac output ¯ peripheral vascular resistance “Inamrinone”
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Phosphodiesterase Inhibitors: Therapeutic Use
short term support in advanced decompensated cardiac failure long term use not possible
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Adverse Effects of Phosphodiesterase Inhibitors
Cardiac arrhythmias GI: Nausea and vomiting Sudden death
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b-Adrenoceptor and Dopamine Receptor Agonists
Dobutamine Dopamine
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Mechanism of Action: Dobutamine
Stimulation of cardiac b1-adrenoceptors: inotropy > chronotropy peripheral vasodilatation myocardial oxygen demand
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Mechanism of Action: Dopamine
Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors Splanchnic and renal vasodilatation
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Therapeutic Use Dobutamine: management of acute decompensated failure only Dopamine: restore renal blood in acute failure
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Adverse Effects Dobutamine Dopamine Tolerance Tachycardia Arrhythmias
Peripheral vasoconstriction
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ACE Inhibitors in Heart Failure
Therapeutic targets in heart failure
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Mechanism of Action Afterload reduction Preload reduction
Reduction of cardiac remodeling (hypertrophy) Withdrawal of sympathetic tone
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ACE Inhibitors: Therapeutic Uses
Drugs of choice in heart failure (with diuretics) Acute myocardial infarction ATII antagonists
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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
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Vasodilators Mechanism of action: reduce preload and afterload
Drugs used Isosorbide dinitrate + Hydralazine Demonstrated survival benefit Inferior to ACE inhibition Ca2+ channel blockers No benefit in systolic failure Use in diastolic failure? Alpha-1 adrenergic antagonists: no proven benefit Neseritide
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Nesiritide Recombinant B-type natriuretic peptide Mechanism of Action
Activates smooth muscle guanylyl cyclase Dilatation of venous and arterial beds Natriuresis/diuresis (but not in decompensated heart failure) Preload and afterload reduction Reduced pulmonary capillary wedge pressure Reduced dyspnia BNP produced in ventricular myocardium Regulation via gene expression (as opposed to granular release as in ANP) Stimulus for release is myocyte stretch Three receptor subtypes NPR-A, B and C (A and B are guanylyl cyclases, NRPC is a clearance receptor) BNP Actions Increase intracellular cGMP Relax arteriolar and venous smooth muscle Decreased preload and afterload Reduce cardiac sympathetic tone Inhibition of renin release Inhibits Ang II stimulation of aldosterone release Direct lusitropic (relaxing) effects on myocardium Antiproliferative effects
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Nesiritide Approved in acute decompensated failure
See: Topol, NEJM 353: , 2005 Nesiritide Approved in acute decompensated failure Off Label Use: Ambulatory heart failure Effects similar to nitrates Adverse effects: hypotension (NO arrhythmias) Increased renal failure? Increased death rate? BNP produced in ventricular myocardium Regulation via gene expression (as opposed to granular release as in ANP) Stimulus for release is myocyte stretch Three receptor subtypes NPR-A, B and C (A and B are guanylyl cyclases, NRPC is a clearance receptor) BNP Actions Increase intracellular cGMP Relax arteriolar and venous smooth muscle Decreased preload and afterload Reduce cardiac sympathetic tone Inhibition of renin release Inhibits Ang II stimulation of aldosterone release Direct lusitropic (relaxing) effects on myocardium Antiproliferative effects
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-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
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Aldosterone Antagonists
Rationale: Aldosterone promotes increased plasma volume, Increased serum K, and (possibly) hypertrophic effects on the heart Aldosterone inappropriately elevated in CHF (even after ACE inhibition) Thus, positive outcome if aldosterone effects on heart and kidney are prevented Evidence: Aldosterone antagonists have been shown to reduce mortality in CHF Available aldosterone antagonists Spironolactone Eplerenone
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Spironolactone and Eplerenone
Aldosterone antagonists, K-sparing diuretics Effects in Heart Failure Potassium Sparing Diuretics Mobilize edema fluid in heart failure Prevent K loss caused by other diuretics (protection against digitalis toxicity?) Reduction of cardiovascular remodeling Potential side effects Hyperkalemia Androgenic effects (spironolactone) Gynecomastia (spironolactone)
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