Drugs for Congestive Heart

Failure

Cardiovascular System Course

William B. Jeffries, Ph.D.Room 570A Criss III, 280-4092Email: wbjeff@creighton.edu

flap.creighton.edu

Required reading: Katzung, 9th ed. pp. 201-215, 281-290

Digitalis Lanata

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

• Preload

• Afterload

• Contractility

• Remodeling

Positive Inotropic Agents

• Cardiac Glycosides

• Phosphodiesterase inhibitors

• -adrenoceptor agonists

Cardiac Glycosides

• digoxin • digitoxin • deslanoside • ouabain

Mechanism of Digitalis Action: Molecular

• Inhibition of Na/K ATPase

• blunting of Ca2+ extrusion

• Ca2+i

• sarcomere shortening

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

Direct Electrophysiological Effects:Cellular Action Potential

Afterdepolarizations

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)

Therapeutic Uses of Digitalis

• Congestive Heart Failure

• Atrial fibrillation

Overall Benefit of Digitalis to Myocardial Function

• cardiac output

• cardiac efficiency

• heart rate

• cardiac size

NO survival benefit

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

• Cardiac – AV block – Bradycardia – Ventricular extrasystole – Arrhythmias

• CNS

• GI

Therapeutic index is ~ 2!

Serum Electrolytes Affect Toxicity

• K+

– Digitalis competes for K binding at Na/K ATPase

– Hypokalemia: increase toxicity– Hyperkalemia: decrease toxicity

• Ca2+

– Hypercalcemia: increases toxicity

Phosphodiesterase Inhibitors

• amrinone

• milrinone

Mechanism of Action• inhibition of type III phosphodiesterase

intracellular cAMP activation of protein kinase A

o Ca2+ entry through L type Ca channels o increased Ca2+ sequestration by SR o Phosphorylation of MLCK

• cardiac output• peripheral vascular resistance• “Inamrinone”

Phosphodiesterase Inhibitors: Therapeutic Use

• short term support in advanced decompensated cardiac failure

• long term use not possible

Adverse Effects of Phosphodiesterase Inhibitors

• Cardiac arrhythmias

• GI: Nausea and vomiting

• Sudden death

-Adrenoceptor and Dopamine Receptor Agonists

• Dobutamine • Dopamine

Mechanism of Action: Dobutamine

• Stimulation of cardiac adrenoceptors: inotropy > chronotropy

• peripheral vasodilatation

• myocardial oxygen demand

Mechanism of Action: Dopamine

• Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors

• Splanchnic and renal vasodilatation

Therapeutic Use

• Dobutamine: management of acute decompensated failure only

• Dopamine: restore renal blood in acute failure

Adverse Effects

• Dobutamine – Tolerance – Tachycardia

• Dopamine – Tachycardia – Arrhythmias – Peripheral vasoconstriction

ACE Inhibitors in Heart Failure

Therapeutic targets in heart failure

Mechanism of Action

• Afterload reduction

• Preload reduction

• Reduction of cardiac remodeling (hypertrophy)

• Withdrawal of sympathetic tone

ACE Inhibitors: Therapeutic Uses

• Drugs of choice in heart failure (with diuretics)

• Acute myocardial infarction

• ATII antagonists

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

• 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

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

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?

See: Topol, NEJM 353:2 113-116, 2005

-Blockers in Heart Failure: Mechanism of Action

• Standard -blockers: – Reduction in damaging sympathetic

influences in the heart (tachycardia, arrhythmias, remodeling)

– inhibition of renin release

• Carvedilol: – Beta blockade effects– peripheral vasodilatation via 1-adrenoceptor

blockade

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

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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