TREATMENT OF CONGESTIVE HEART FAILURE (CHF)

DIGITALIS GLYCOSIDES AND OTHER POSITIVE INOTROPIC AGENTS

Common Diseases Contributing to CHF-CardiomyopathyHypertensionMyocardial ischemia & infarction Cardiac valve diseaseCoronary artery disease

Clinical Features of CHFReduced force of cardiac contraction Reduced cardiac outputReduced tissue perfusion Oedema (congestion) Increased peripheral vascular resistance

Congestive Heart Failure Events

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

Molecular mechanism of the +ve inotropic effect

Inhibition of the Na+-K+- pump (Na+-K+-ATPase) on the cardiac myocyes sarcolemmaA gradual increase in intracellular Na+ ([Na+]i) and a gradual small fall in [K+]i An inhibitory effect on the non-enzymatic Na+- Ca2+- exchanger, which exchanges extracellular Na+ for intracellular Ca2+The net effect is the increase in intracellular Ca2+ [Ca2+]I The increased [Ca2+]I stimulates more Ca2+ ions to influx via voltage gated Ca2+ channels and increase the storage of Ca2+ into sarcoplasmic reticulum available for release upon arrival of an action potential

Sodium pump inhibition by cardiac glycosidesThe 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+ & Ca2+ 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 reversedThe capacity of the exchanger to extrude Ca2+ from the cell depends critically on the intracellular Na+ concentrations

Baroreceptor DysfunctionBaroreceptor 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 thestroke volume and hencethe CO No increase in oxygen ConsumptionDecreased EDV

Heart RateCardiac 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 rateSlowing of the AV conduction and prolongation of the refractory period of the AV nodeThe 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/ConductivitySA nodal firing rate and AV conduction are slowed down by the direct and indirect mechanismsProlongation of the effective refractory period of the A-V nodeAt high doses, automaticity is enhanced as result of the gradual loss of the intracellular K+

Venous PressureVenous pressure is increased in CHFDigitalis 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 congestionVentricular end-diastolic volume (VEDV) is reduced

DiuresisDigitalis causes relief of CHF-induced edemaThis depends on the improved CO that increases renal blood flow & consequently glomerular filtration rate is increasedThis results in down-regulation of the renin-angiotensin-aldosterone (RAA) system that is stimulated in CHFHence, 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 GlycosidesTreatment 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 GlycosidesVentricular ArrhythmiasWith increasing cardiac glycoside concentrations, free intracellular [Ca2+]I reaches toxic levelsThis high [Ca2+]I concentration saturates the sarcoplasmic reticulum sequestration mechanisms resulting in oscillations in [Ca2+]I levels due to Ca2+-induced [Ca2+]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 GlycosidesCNS side-effectsStimulation of the vagal centre and chemoreceptor trigger zone (CTZ) results in nausea, vomiting, diarrhea & anorexiaOther 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 ToxicityDigitalis should be immediately withdrawn, toxicity symptoms may persist for some time due to slow eliminationK+ 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 dysrhythmiasK+ supplementation would raise the extracellular K+ decreasing the slope of phase-4 depolarization and diminishing increased automaticityHowever 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 fragmentsDigoxin-specific Fab fragments are used safely for the treatment of the life-threatening cardiac glycosides-induced arrhythmias and heart blockDigoxin-specific Fab fragments are produced by purification of antibodies raised in sheep by immunization against digoxinThe crude antiserum from sheep is fractionated to separate the IgG fraction, which is cleaved into Fab and Fc fragments by papain digestionThe Fab fragments are not antigenic and with no complement bindingThey are excreted fairly rapidly excreted by the kidney as a digoxin-bound complex

Selective 1- Adrenergic AgonistsDobutamine (and dopamine), at doses equal to or less than 5 g/kg/min, has a selective 1- adrenergic agonistic activityBeneficial effects in emergency treatment of acute CHF include the following:1- Increased cardiac output as a result of enhanced contractility without appreciably altering the heart rate.2- Reduction of mean arterial blood pressure.3- Lowering of the total peripheral vascular resistance and consequently decreasing the afterload4- Reduction of ventricular filling pressureMOLECULAR 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 1- adrenergic agonistsAgents in this class include: Amrinone, and milrinonePD-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 retentionCardiac pumping improves with the consequent reduction in venous pressure relieving edemaThiazide (e.g., hydrochlothiazide) and loop diuretics (e.g., frusemide) are routinely used in combination with digitalisPotassium-sparing diuretics can be concurrently used to correct hypokalemiaSpironolactone+Digitalis+ACEI clinical trials: improved survival?

Angiotensin Converting Enzyme Inhibitors (ACEIs)Captopril, ACEIs

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 tone2. Increased vasodilator tone of vascular smooth muscle and hence total vascular resistance falls promptly via:Decreased circulating AngIIIncreased bradykininDecreased catecholamines3. Reduced sodium and water retention as a result of the reduced AngII-induced reduced aldosterone secretionUltimately both preload and afterload are reducedClinical trials showed that the use of ACEIs in CHF has significantly reduced morbidity and mortality

Adverse Effects of ACEIs1. Postural hypotension 2. Hyperkalemia3. Renal insufficiency 4. Persistent dry cough5. ACEIs are contraindicated in pregnancyACEIs include agents like: captopril, enalapril,lisinopril and many others

AT-1 Receptor Blockers (ARBs)Agents include: losartan and valsartanThey are recently approved for treatment of CHFThey have the same beneficial effect of ACEIsThey dont cause cough

AT-1 Receptor Blockers (ARBs)ARBs have the same side-effects like ACEIs except they dont cause cough

NitrovasodilatorsSodium nitroprusside i.v. infusion is used at a dose of 0.1-0.2 g/kg/min only in acute CHF to lower preload and afterloadNitrates can be used as well to decrease preload