PH402 Congestive Heart Failure

Chris Hague, PhD chague@u.washington.edu Technical Advisor: Seth Goldenberg, PhD

References
Brodys Human Pharmacology, 4th Edition Guyton Human Physiology http://www.nlm.nih.gov/medlineplus/tutorials /congestiveheartfailure/htm/lesson.htm http://www.nhlbi.nih.gov/health/dci/Diseases/ Hf/HF_WhatIs.html http://www.americanheart.org/presenter.jhtml ?identifier=337

Outline
1. What is congestive heart failure? 2. Cardiac Glycosides 3. Phosphodiesterase inhibitors 4. Beta-adrenergic receptor antagonists 5. Sympathomimetics 6. ACE inhibitors/angiotensin receptor antagonists 7. Vasodilators 8. Diuretics 9. Aldosterone antagonists

Congestive Heart Failure

the heart is unable to provide adequate perfusion of peripheral organs to meet their metabolic requirements ~4.7 million with CHF in USA survival post diagnosis: Men 1.7 years Women 3.2 years 287,000 deaths in 2004

Patient Classification
Class I (asymptomatic) Class II (mild) Class III (moderate) Class IV (severe)

Factors contributing to CHF

Ischemic Heart Disease: most prevalent CAD: less blood flow to heart, increased damage Myocardial Infarct: damaged tissue Hypertension: overworked heart Diabetes Lung Disease

Factors contributing to CHF

Cardiomyopathies: heart muscle disease dilated - enlarged chambers (ventricle/atria) hypertrophic - thickened ventricle walls Abnormal heart valves: inefficient pumping causes are genetic, infection or disease Congenital heart defects: present at birth Severe Anemia Hyperthyroidism Cardiac Arrhythmia

Effect on Cardiac Output

Overall decrease in Frank-Starling curve with CHF

Examples of CHF factors

Hypertrophic Cardiomyopathy

Congenital Heart Defects

Types of Heart Failure

include left, right or both sides left ventricular heart failure most common systolic failure: unable to contract diastolic failure: unable to relax right ventricular heart failure usually occurs after left failure less blood received causes right damage less pumping by right side venous pooling of blood in legs

Onset of disease
chronic disease: can take years to develop endogenous compensatory mechanisms enlargement of size increased cardiac muscle mass increased heart rate narrowing of blood vessels: increase BP diversion of blood flow (brain, heart) increased SNS output

Compensatory Mechanisms

Symptoms of CHF
shortness of breath blood pooling in pulmonary veins fluid in lungs occurs during activity, rest, or sleeping persistent coughing/wheezing produces white/blood mucus edema (or excess fluid buildup in body tissues) venous pooling swelling in extremities necrosis

Symptoms of CHF
tiredness/fatigue decreased O2 supply diversion of blood supply from limbs lack of appetite/nausea decreased blood supply to digestive tract confusion/impaired thinking increased heart rate baroreceptor reflex SNS output

Therapeutic Overview
Problems
Reduced force of contraction Decreased cardiac output Increased TPR Inadequate organ perfusion Development of edema Decreased exercise tolerance Ischemic heart disease Sudden death

Goals
alleviate symptoms improve quality of life arrest cardiac remodeling prevent sudden death

Therapies
Drug
Chronic heart failure ACE inhibitors Beta-blockers ATII antagonists aldosterone antagonists digoxin diuretics Acute heart failure diuretics PDE inhibitors vasodilators

Non-drug
Reduce cardiac work Rest Weight loss low Na+ diet

Cardiac Glycosides
discovered by William Withering published An Account of Foxglove and some of Its Medical Uses in 1785 Foxglove plant active ingredient digitalis

Cardiac Glycosides
derived from plants Strophanus - Ouabain Digitalis lanata - Digoxin, Digitoxin increase force of myocardial contraction alters electrophysiological properties toxic side-effects Digoxin most common used in USA

Digitalis lanata

Mechanism of Action
inhibitor of Na+/K+ ATPase pump increased [Na+]i increased Ca2+ influx through Na+/Ca2+ exchanger new Ca2+ steady-state: increased Ca2+ release during cardiac action potential

Electrophysiological Effects
Direct effects spontaneous depolarization of atrial cardiomyocytes at high doses

Electrophysiological Effects
Indirect effects increased parasympathetic tone decreased SA/AV node automaticity decreased AV node conduction velocity and increased refractory period net effect: decrease HR and impair impulse transmission in AV node

Overall Effect on Cardiac Function

increased cardiac output increased cardiac efficiency decrease in heart rate decrease in cardiac size

Foxglove

Therapeutic Uses
only orally effective inotropic agent approved in US also for CHF secondary to ischemic heart disease contraindicated in patients with WolffParkinson-White syndrome does not stop disease progression or prolong life in CHF patients

Pharmacokinetics
long half-life (24-36 h): once daily dosing high bioavailability from oral dosing large volume of distribution digoxin excreted in kidneys digitoxin metabolized in liver, active metabolites intestinal flora cause variations in toxicity

Side Effects
extremely low therapeutic index (~2) most effects caused by inhibition of Na+/K+ ATPase in extracardiac tissues CNS: malaise, confusion, depression, vertigo, vision GI: anorexia, nausea, intestinal cramping, diarrhea Cardiac: bradycardia, arrhythmias anti-digoxin antibody in toxic emergencies

Serum Electrolytes affect Toxicity

Ca2+ hypercalcemia: increases toxicity K+ digitalis competes for K+ binding site on Na+/K+ ATPase contraindicated with K+ depleting diuretics or patients with hypo/hyperkalemia hypokalemia: increased toxicity hyperkalemia: decrease toxicity

Example of cardiac side effects

action potential recordings from purkinje fiber cells toxic doses produce oscillatory after depolorizations leads to ventricular tachycardia (C)

Vision Effects
yellow-tinted vision or yellow corona-like spots

Phosphodiesterase Inhibitors
primarily used for management of acute heart failure positive inotropic effects increase rate of myocardial relaxation decrease total peripheral resistance and afterload

Mechanism of Action
inhibitor of type III cAMP phosphodiesterase increased [cAMP] increased PKA phosphorylation of Ca2+ channels in cardiac muscle increased cardiac contraction relaxes vascular smooth muscle

Therapeutic Use
Amrinone (Inocor) and Milrinone (Primacor) administered IV milrinone is ~1o fold more potent T 1/2 = 2.5 h for amrinone and 30-60 min for milrinone effective in patients taking Beta-blockers does not stop disease progression or prolong life in CHF patients prescribed to patients non-responsive to other therapies

sudden death secondary to ventricular arrhythmia hypotension thrombocytopenia long term clinical trials associated with increased adverse effects and increased mortality now only prescribed for acute cardiac decompensation in patients non-responsive to diuretics or digoxin

Side Effects

-adrenergic receptor antagonists

-blockers standard therapy for treatment of CHF cheap!

Propranolol
reduce sudden death caused by other drugs Propranolol: prototype Carvedilol: combination effects

Carvedilol

Mechanism of Action
mechanism still unclear antagonizes -adrenergic receptors on cardiac myocytes counterbalances increased SNS activity in CHF prevents development of arrhythmias reduces cardiac remodeling prevents renin release

Therapeutic Use
administered orally usually given in conjunction with other therapy ACE inhibitors Digoxin effective in patients with chronic systolic heart failure in Class II (mild) to Class III (moderate) prevents remodeling and cardiac damage

Side Effects
cardiac decompensation bradycardia hypoglycemia cold extremeties fluid retention fatigue

Direct acting sympathomimetics

cause immediate increases in cardiac inotropy goal: to increase cardiac output but not effect total peripheral resistance used in treatment of acute life-threatening CHF

Dopamine

Dobutamine

Mechanism of Action
Norepinephrine/epinephrine: increase CO, increase TPR Dopamine: activates prejunctional D2 dopamine receptors, inhibit NE release of sympathetic nerves, vasodilation activates cardiac 1-adrenergic receptors, increase cardiac output Dobutamine: racemic mixture, stimulates 1-adrenergic receptors peripheral vasodilation

Therapeutic Use
administered IV, very short T 1/2 Dopamine used in cardiogenic, traumatic or hypovolemic shock used with furosemide in diuretic resistant patients (volume overload) Dobutamine used in patients with low cardiac output and increased left ventricular end-diastolic pressure not for use in hypotensive patients

Side Effects
restlessness tremor headache cerebral hemorrhage cardiac arrhythmias used with caution in patients taking blockers can develop dobutamine tolerance

ACE inhibitors/AT1 receptor antagonists

Goal: to reduce afterload/preload, reduce workload on heart

generates positive cardiac inotropy

used in treatment of chronic CHF

ACE inhibitors/AT1 receptor antagonists

orally active ACE inhibitors Captopril Enalopril AT1 antagonists Losartan Valsartan

Mechanism of Action
ACE inhibitors inhibits angiotensin converting enzyme (ACE) prevents conversion of ATI to ATII AT1 receptor antagonists selectively inhibits ATI receptor activation decreased preload decreased afterload decreased cardiac remodeling decreased SNS effects

Therapeutic Uses
drugs of choice in heart failure increase survival in long term CHF ACE inhibitors slows progression of left ventricular dysfunction in CHF AT1 receptor antagonists more effective then ACE inhibitors AT2 receptors still active: vasodilation, antiproliferative effects used in conjunction with ACE inhibitors for increased effectiveness

Side Effects
ACE inhibitors cough angioneurotic edema hypotension hyperkalemia ACE inhibitors and ATI receptor antagonists are both teratogenic

Vasodilators
Goal: reduce TPR without causing large decrease in BP reduce preload reduce afterload relieves symptoms increase exercise tolerance

Drugs Used
NO Donors Nitroglycerin acute ischemia or acute heart failure orally active also administered I.V. for peripheral vasodilation quick onset for acute relief Isosorbide dinitrate/hydralazine chronic administration for long-term symptom relief administered I.V.

Drugs Used
Nesiritide recombinant brain-natriuretic peptide (BNP) BNP is secreted from ventricular myocytes in response to stretch vasodilator: increases cGMP in SMCs decrease afterload/preload inhibits cardiac remodelling suppresses aldosterone secretion administered IV for acute decompensated CHF adverse effects: hypotension, renal failure (?)

Diuretics
used in CHF to reduce extracellular fluid volume primarily used in patients with acute CHF with volume overload IV infusion causes immediate and predictable diuresis for immediate relief Goal: reduce preload/afterload overdosing can result in excessive reduction in preload, overreduction in stroke volume thiazide and loop diuretics (i.e. Furosemide) commonly used as adjunct therapies in CHF

Aldosterone Antagonists
elevated AngII levels increase production of aldosterone in the adrenal cortex (~20X increase) aldosterone activates mineralocorticoid receptors in renal epithelial cells in kidney aldosterone promotes Na+ retention, Mg2+ and K+ loss increased SNS activity decreased PSNS activity myocardial/vascular fibrosis

Therapeutic Use
Goal: inhibit aldosterone negative effects in CHF aldosterone receptor antagonists spironolactone eplerenone both antagonists reduce mortality in patients with moderate to severe CHF only use in patients with normal renal function and K+ levels use with K+ sparing diuretic

Side Effects
hyperkalemia agranulocytosis anaphylaxis hepatoxicity renal failure Spironolactone: gynecomastia, sexual dysfunction Eplerenone: arrhythmia, myocardial infarct/ischemia