TREATMENT OF CONGESTIVE HEART FAILURE (CHF)

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TREATMENT OF CONGESTIVE HEART FAILURE (CHF)

• DIGITALIS GLYCOSIDES AND OTHER POSITIVE INOTROPIC
  AGENTS

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Common Diseases Contributing to CHF-

• Cardiomyopathy
• Hypertension
• Myocardial ischemia infarction
  
• Cardiac valve disease
• Coronary artery disease

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Clinical Features of CHF

• Reduced force of cardiac contraction
• Reduced cardiac output
• Reduced tissue perfusion
  
• Oedema (congestion)
• Increased peripheral vascular resistance

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Congestive Heart Failure Events
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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
• increased cardiac output
• decreased cardiac size
• decreased venous pressure and blood volume
• diuresis and relief of edema

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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 (Nai)
  and a gradual small fall in Ki
• 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 Ca2I
• The increased Ca2I 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

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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 NaK-ATPase (the sodium pump)

Digoxin
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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

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Baroreceptor Dysfunction

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

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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

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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

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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

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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

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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

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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

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Adverse Effects of Digitalis Glycosides

• Ventricular Arrhythmias
• With increasing cardiac glycoside concentrations,
  free intracellular Ca2I reaches toxic levels
• This high Ca2I concentration saturates the
  sarcoplasmic reticulum sequestration mechanisms
  resulting in oscillations in Ca2I levels due
  to Ca2-induced Ca2I 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

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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

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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

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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

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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
• 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
  afterload
• 4- Reduction of ventricular filling pressure
• MOLECULAR MECHANISM OF INOTROPIC EFFECT OF
  DOBUTAMINE?

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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

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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
• SpironolactoneDigitalisACEI clinical trials
  improved survival?

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Angiotensin Converting Enzyme Inhibitors (ACEIs)
Captopril, ACEIs
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Angiotensin II Type-1 Receptor Antagonists (ARBs)
Physiologic functions of AT1 receptors according
to their location
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
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Effect of ACEIs on Bradykinin
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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

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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

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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 dont cause cough

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AT-1 Receptor Blockers (ARBs)

• ARBs have the same side-effects like ACEIs except
  they dont cause cough

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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