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 thestroke volume and hencethe 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 FUNCTIONKidney
Glomerulus Mesangial cell contractionProximal tubule Increased reabsorption of sodiumJuxtaglomerular apparatus Decreased renin secretionHeart 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 releaseBrain Vasopressin release, stimulation of thirst;
autonomic activity and cardiovascular reflexesSympathetic 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