Congestive Heart Failure and Digitalis October 11, 2007 Frank F. Vincenzi

New York Heart Association: Classifications of Heart Failure Class I - no limitation of physical activity Class II - slight limitation of activity –dyspnea with moderate physical activity Class III - marked limitation of activity –dyspnea with minimal physical activity Class IV - severe symptoms at rest

Cardiovascular responses to heart failure Inadequate cardiac output Systemic vasoconstriction Adrenergic nervous system (norepinephrine) Renin angiotensin system (aldosterone) Tachycardia

Conditions that may precipitate CHF Infections Arrhythmias Myocardial infarction Pulmonary embolism Undue physical exertion Excessive Na intake Hemorrhage, anemia Pregnancy In- and trans-fusions Anesthesia/surgery High altitude Hypertension D/C digitalis

Pharmacotherapeutic approaches in heart failure Reduction of volume overload (reduce preload) –Diuretics (more about these later when we consider diuretics) Ventricular unloading (reduce afterload) –Acute: nitroglycerin, sodium nitroprusside –Chronic: inhibit renin-angiotensin-aldosterone system, diuretics, ACE inhibitors, angiotensin antagonists (More about these later - when we consider hypertension) –Beta-blockers (also reduce sympathetic activation) Inotropic interventions (improve Starling function) –Acute: dobutamine –Chronic: phosphodiesterase inhibitors, digitalis

Effects of ouabain on cardiac function in a patient with CHF

Effects of ouabain on the CV system of a patient in CHF

Effects of ouabain on the CV system of a normal human volunteer

Digitalization can increase myocardial efficiency in CHF

Determinants of myocardial oxygen demand Intramyocardial tension –blood pressure, ventricular volume Myocardial contractility Heart rate Fiber shortening (Fenn effect) Activation energy Basal (resting) metabolism

Ventricular function (Starling) curves: normal, CHF and with digitalis ventricular end-diastolic volume normal CHF + digitalis CHF congestive symptoms, edema, dyspnea inadequate, fatigue Cardiac Output adequate

Mechanism of positive inotropic effect of digitalis ROC digitalis

Effect of ouabain on cardiac cellular functions

Digitalis: standard swindle of the positive inotropic mechanism Inhibition of Na, K ATPase Altered balance of Na/Ca exchange Enhanced Ca storage/release Increased binding of Ca to troponin Increased actin/myosin ATPase Increased contractility

Pharmacotherapeutic approaches in heart failure Reduction of volume overload (reduce preload) –diuretics Ventricular unloading (reduce afterload) –Acute: nitroglycerin, sodium nitroprusside –Chronic: inhibit renin-angiotensin-aldosterone system, diuretics, ACE inhibitors, angiotensin antagonists –Beta-blockers (also reduce sympathetic activation) Inotropic interventions (improve Starling function) –Acute: dobutamine –Chronic: phosphodiesterase inhibitors, digitalis

dobutamine (Dobutrex®) Positive inotropic effect via beta-1 receptors Reduces afterload via beta-2 receptors Minor activation of alpha-1 receptors May promote sinus tachycardia, PVCs, angina, headache, hypertension Half life about 2 minutes. IV infusion to titrate dobutamine effects.

milrinone (Primacor®) Relatively selective inhibitor of type III cyclic nucleotide phosphodiesterase (cGMP inhibited cAMP hydrolysis) (exerts positive inotropic effect and vasodilation and bronchodilation). Indicated for IV treatment of heart failure. Chronic oral dosage associated with increased mortality. Half life is about 2 hours. Excreted mainly in urine, adjust dosage in renal disease. Adverse reactions included PVCs, SVT, VT and VF

Cardiovascular responses to heart failure Inadequate cardiac output Systemic vasoconstriction Adrenergic nervous system (norepinephrine) Renin angiotensin system (aldosterone) Tachycardia Beta blockers

Beta adrenergic blockers: decrease renin release and afterload (and decrease sympathetic activation of heart) Propranolol (Inderal®) Metoprolol (Lopressor®) Carvedilol (Coreg®) –decreases afterload in part by alpha adrenoceptor antagonism Use of beta-blockers in carefully monitored patients CHF may be beneficial. Until recently, beta blockers were considered to be contraindicated in CHF.

Impact of atrial tachycardia on circulation

Effect of digitalis on a supra- ventricular tachycardia

Effects of lanatoside C on paroxysmal atrial flutter

Circus movement atrial flutter model: effect of digitalis

Vagal (ACh) actions on supraventricular parts of the heart Decreases SA node automaticity (and slows heart rate) Decreases duration of atrial muscle action potential (and decreases refractory period) Slows AV nodal conduction velocity and increases AV nodal refractory period All of the above effects are caused by a single mechanism of action: increased potassium permeability

Effects of transient release of acetylcholine on atrial action potential and contractile force

Vagal (ACh) actions on supraventricular parts of the heart Decreases SA node automaticity (and slows heart rate) Decreases duration of atrial muscle action potential (and decreases refractory period) Slows AV nodal conduction velocity and increases AV nodal refractory period

Effect of digoxin on AV nodal conduction in normally innervated human heart

Lack of effect of digoxin on AV nodal conduction in transplanted (denervated) human heart

Pharmacokinetics of digoxin Well, but variously absorbed from GI tract, bioavailability = 70 ± 13% Vd = (3.12 CLcr ) ± 30% and proportional to thyroid status Most excreted in urine unchanged, elimination depends on kidney function Half life = 39 ± 13 hours (1.6 days)

Accumulation of digoxin during chronic dosing

Pharmacokinetics of digitoxin Well absorbed from GI tract, bioavailability > 90% Vd = 0.54 ± 0.14 liters/kg Non-polar compound, elimination depends on liver function Half life = 6.7 ± 1.7 days

Non-uniform bioavailability of several generic and trade name digoxin preparations

Some adverse reactions to digitalis CNS headache, malaise, confusion, dizziness, changes in color vision GI anorexia, nausea, vomiting, diarrhea CV bradycardia, heart block (various degrees), arrhythmias, ventricular tachycardia, fibrillation, hyperkalemia

digoxin in hospitalized patients 22.4% of patients (est. failure 8%) –CHF (78%), arrhythmias (21%), other (1%) Route –PO (79%), IV (15%), IM (6%) Adverse reactions –Arrhythmias 8.5% –GI disturbances 3.1% –CNS toxicity 0.1% –Gynecomastia 0.1%

Digitalis toxicity In various studies –The minimal inotropic dose of = about 1/5 of the lethal dose –The minimal toxic dose = about 2/3 of the lethal dose Thus, the therapeutic window is narrow

Diagnosis of digoxin toxicity Are there predisposing factors? –large dose, decreased elimination Are there extracardiac symptoms? –anorexia, nausea/vomiting, visual signs Arrhythmias present? Arrhythmias change when digoxin withheld? What is serum digoxin concentration?

Serum digoxin levels in 179 patients Serum concentrations at which the probability of digoxin induced arrhythmias is 10% = 1.7, 50% = 2.5, 90% = 3.3

Treatment of acute digoxin intoxication by digoxin immune Fab (Digibind®)

Simplified diagram of apparent digitalis-induced changes in ANS activity CNS output of autonomic tone Dose of digitalis sympathetic parasympathetic slowing VT VF - death partial AV block PVCs

Digoxin overview About 50% of patients with CHF have elevated endogenous ouabain (EO) EO level is inversely correlated with the cardiac index. Digoxin reduces hospitalization for worsening heart failure Digoxin increases the risk of death from any cause in women, but not in men. Digoxin only benefits some patients - perhaps patients with low levels of EO (untested at this time) Improves the quality but not the length of life