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 sizeo decreased venous pressure and blood

volumeo 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+- 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 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+ & 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 reversed

The capacity of the exchanger to extrude Ca2+ 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 [Ca2+]I reaches toxic levels

This 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 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 ß1- Adrenergic Agonists

Dobutamine (and dopamine), at doses equal to or less than 5 µg/kg/min, has a selective ß1- 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 afterloado 4- Reduction of ventricular filling pressureo 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 ß1- 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

LOCATION FUNCTION

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 0.1-0.2 µg/kg/min only in acute CHF to lower preload and afterload

Nitrates can be used as well to decrease preload