TREATMENT OF CONGESTIVE HEART FAILURE (CHF) DIGITALIS GLYCOSIDES AND OTHER POSITIVE INOTROPIC AGENTS

Common Diseases Contributing to CHF -  Cardiomyopathy  Hypertension  Myocardial ischemia & infarction  Cardiac valve disease  Coronary artery disease

Clinical Features of CHF  Reduced force of cardiac contraction  Reduced cardiac output  Reduced tissue perfusion  Oedema (congestion)  Increased peripheral vascular resistance

Congestive Heart Failure Events

CARDIOTONIC DRUGS Cardiac Glycosides Mechanism of the beneficial positive inotropic pharmacodynamic effect The principal beneficial effect of digitalis in CHF is the increase in cardiac contractility (+ve inotropism) leading to the following: o increased cardiac output o decreased cardiac size o decreased venous pressure and blood volume o diuresis and relief of edema

Molecular mechanism of the +ve inotropic effect  Inhibition of the Na + -K + - pump (Na + -K + -ATPase) on the cardiac myocyes sarcolemma  A gradual increase in intracellular Na + ([Na + ] i ) and a gradual small fall in [K + ] i  An inhibitory effect on the non-enzymatic Na + - Ca 2+ - exchanger, which exchanges extracellular Na + for intracellular Ca 2+  The net effect is the increase in intracellular Ca 2+ [Ca 2+ ] I  The increased [Ca 2+ ] I stimulates more Ca 2+ ions to influx via voltage gated Ca 2+ channels and increase the storage of Ca 2+ into sarcoplasmic reticulum available for release upon arrival of an action potential

Sodium pump inhibition by cardiac glycosides The mechanism by which the cardiac glycosides induce a positive inotropic effect in cardiac muscle is based on the specificity of these drugs for Na + K + - ATPase (the “sodium pump”) Digoxin

The direction & magnitude of Na + & Ca 2+ transport during depolarized myocyte (systole)  The exchanger may briefly run in reverse during cell depolarization when the electrical gradient across the plasma membrane is transiently reversed  The capacity of the exchanger to extrude Ca 2+ from the cell depends critically on the intracellular Na + concentrations

Baroreceptor Dysfunction Baroreceptor dysfunction may account for increased sympathetic & reduced parasympathetic nervous system activity in most patients with congestive heart failure

Pharmacological Actions of Digitalis Glycosides  Inotropism. Digitalis exerts positive inotropic effect both in the normal and failing heart via inhibition of Na + -K + -ATPase at cardiac sarcolemma. Cardiac output (CO)  Digitalis increases the stroke volume and hence the CO No increase in oxygen Consumption  Decreased EDV

Heart Rate  Cardiac glycosides slow the accelerated heart rate in CHF via two mechanisms:  A direct extravagal effect & an indirect vagal effect leading to: Slowing of SA nodal firing rate Slowing of the AV conduction and prolongation of the refractory period of the AV node  The indirect vagal tends to increase the vagal tone to the heart through: Enhancement of the sensitivity of the SA node to vagal stimulation resulting in diminished firing rate. Stimulation of the vagal central nuclei

Myocardial Automaticity/Conductivity  SA nodal firing rate and AV conduction are slowed down by the direct and indirect mechanisms  Prolongation of the effective refractory period of the A-V node  At high doses, automaticity is enhanced as result of the gradual loss of the intracellular K +

Venous Pressure Venous pressure is increased in CHF Digitalis reduces venous pressure as a result of improved circulation and tissue perfusion produced by the enhanced myocardial contractility (decreased blood volume) This in turn relieves congestion Ventricular end-diastolic volume (VEDV) is reduced

Diuresis Digitalis causes relief of CHF-induced edema This depends on the improved CO that increases renal blood flow & consequently glomerular filtration rate is increased This results in down-regulation of the renin- angiotensin-aldosterone (RAA) system that is stimulated in CHF Hence, the edema (pulmonary and peripheral) is improved in response to digitalis as a result of the inhibition of the RAA-induced water and salt retention

Therapeutic Uses of Digitalis Glycosides  Treatment of congestive heart failure which does not respond optimally to diuretics or ACEI.  Treatment of atrial fibrillation and flutter by slowing SA nodal firing rate as well as AV conduction preventing the occurrence of the life-threatening ventricular arrhythmias

Adverse Effects of Digitalis Glycosides Ventricular Arrhythmias With increasing cardiac glycoside concentrations, free intracellular [Ca 2+ ] I reaches toxic levels This high [Ca 2+ ] I concentration saturates the sarcoplasmic reticulum sequestration mechanisms resulting in oscillations in [Ca 2+ ] I levels due to Ca 2+ -induced [Ca 2+ ] I release leading to membrane potential oscillations (oscillatory after potentials) Arrhythmias resulting from oscillatory after potentials include single and multiple ventricular premature beats and tachy-arrhythmias

Adverse Effects of Digitalis Glycosides CNS side-effects Stimulation of the vagal centre and chemoreceptor trigger zone (CTZ) results in nausea, vomiting, diarrhea & anorexia Other CNS effects include blurred vision, headache, dizziness, fatigue, and hallucinations Gynecomastia Gynecomastia may occur in men either due to peripheral esterogenic actions of cardiac glycosides or hypothalamic stimulation

Treatment of Digitalis Toxicity Digitalis should be immediately withdrawn, toxicity symptoms may persist for some time due to slow elimination K + Supplementation, Digitalis treatment usually results in myocardial K + loss  Hence, intravenous administration of K + salts usually produces immediate relief, since K + loss is the probable cause of dysrhythmias  K + supplementation would raise the extracellular K + decreasing the slope of phase-4 depolarization and diminishing increased automaticity  However K + supplementation may lead to complete A-V block in cases of depresses automaticity or decreased conduction (contraindicated with digitalis-induced second- and third-degree heart block) Lidocaine or phenytoin is effective against K + digitalis- induced dysryhthmias

Digoxin-specific Fab fragments Digoxin-specific Fab fragments are used safely for the treatment of the life-threatening cardiac glycosides- induced arrhythmias and heart block  Digoxin-specific Fab fragments are produced by purification of antibodies raised in sheep by immunization against digoxin  The crude antiserum from sheep is fractionated to separate the IgG fraction, which is cleaved into Fab and Fc fragments by papain digestion  The Fab fragments are not antigenic and with no complement binding  They are excreted fairly rapidly excreted by the kidney as a digoxin-bound complex

Selective ß 1 - Adrenergic Agonists Dobutamine (and dopamine), at doses equal to or less than 5 µg/kg/min, has a selective ß 1 - adrenergic agonistic activity Beneficial effects in emergency treatment of acute CHF include the following: o 1- Increased cardiac output as a result of enhanced contractility without appreciably altering the heart rate. o 2- Reduction of mean arterial blood pressure. o 3- Lowering of the total peripheral vascular resistance and consequently decreasing the afterload o 4- Reduction of ventricular filling pressure o MOLECULAR MECHANISM OF INOTROPIC EFFECT OF DOBUTAMINE?

Phosphodiesterase III (PD-III) Inhibitors Inhibition of myocardial phosphodiesterase III (PD-III), the enzyme responsible for c.AMP degradation, results in +ve inotropism via c.AMP-PKC cascade in a similar way to the selective ß 1 - adrenergic agonists Agents in this class include: Amrinone, and milrinone PD-III inhibitors are suitable only for acute CHF because they can induce life-threatening arrhythmias on chronic use

OTHER DRUGS OF USE IN CHF WITHOUT INOTROPIC EFFECT Diuretics Diuretics cardiac preload by inhibiting sodium and water retention Cardiac pumping improves with the consequent reduction in venous pressure relieving edema Thiazide (e.g., hydrochlothiazide) and loop diuretics (e.g., frusemide) are routinely used in combination with digitalis Potassium-sparing diuretics can be concurrently used to correct hypokalemia o Spironolactone+Digitalis+ACEI clinical trials: improved survival?

Angiotensin Converting Enzyme Inhibitors (ACEIs) Captopril, ACEIs

LOCATIONFUNCTION Kidney Glomerulus Mesangial cell contraction Proximal tubule Increased reabsorption of sodium Juxtaglomerular apparatus Decreased renin secretion Heart Inotropic effect and release of growth factors with ensuing stimulation of cardiac myocyte hypertrophy and increased extracellular matrix production Blood vessels Vasconstriction with an increase in afterload as well as local release of growth factors Adrenal gland Aldosterone and catecholamine release Brain Vasopressin release, stimulation of thirst; autonomic activity and cardiovascular reflexes Sympathetic nervous system Increased sympathetic outflow Angiotensin II Type-1 Receptor Antagonists (ARBs) Physiologic functions of AT1 receptors according to their location

Effect of ACEIs on Bradykinin

Angiotensin Converting Enzyme Inhibitors (ACEIs) the use of ACEIs produces the following actions:  1. Reduced sympathetic nervous system tone  2. Increased vasodilator tone of vascular smooth muscle and hence total vascular resistance falls promptly via: Decreased circulating AngII Increased bradykinin Decreased catecholamines  3. Reduced sodium and water retention as a result of the reduced AngII-induced reduced aldosterone secretion Ultimately both preload and afterload are reduced Clinical trials showed that the use of ACEIs in CHF has significantly reduced morbidity and mortality

Adverse Effects of ACEIs 1. Postural hypotension 2. Hyperkalemia 3. Renal insufficiency 4. Persistent dry cough 5. ACEIs are contraindicated in pregnancy  ACEIs include agents like: captopril, enalapril, lisinopril and many others

AT-1 Receptor Blockers (ARBs) Agents include: losartan and valsartan They are recently approved for treatment of CHF They have the same beneficial effect of ACEIs They don’t cause cough

AT-1 Receptor Blockers (ARBs) ARBs have the same side-effects like ACEIs except they don’t cause cough

Nitrovasodilators Sodium nitroprusside i.v. infusion is used at a dose of µg/kg/min only in acute CHF to lower preload and afterload Nitrates can be used as well to decrease preload