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TREATMENT OF CONGESTIVE HEART FAILURE (CHF)

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TREATMENT OF CONGESTIVE HEART FAILURE (CHF) DIGITALIS GLYCOSIDES AND OTHER POSITIVE INOTROPIC AGENTS Common Diseases Contributing to CHF - Cardiomyopathy Hypertension ... – PowerPoint PPT presentation

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Title: TREATMENT OF CONGESTIVE HEART FAILURE (CHF)


1
TREATMENT OF CONGESTIVE HEART FAILURE (CHF)
  • DIGITALIS GLYCOSIDES AND OTHER POSITIVE INOTROPIC
    AGENTS

2
Common Diseases Contributing to CHF-
  • Cardiomyopathy
  • Hypertension
  • Myocardial ischemia infarction
  • Cardiac valve disease
  • Coronary artery disease

3
Clinical Features of CHF
  • Reduced force of cardiac contraction
  • Reduced cardiac output
  • Reduced tissue perfusion
  • Oedema (congestion)
  • Increased peripheral vascular resistance

4
Congestive Heart Failure Events
5
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

6
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

7
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
8
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

9
Baroreceptor Dysfunction
  • Baroreceptor dysfunction may account for
    increased sympathetic reduced parasympathetic
    nervous system activity in most patients with
    congestive heart failure

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
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

18
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

19
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

20
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?

21
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

22
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?

23
Angiotensin Converting Enzyme Inhibitors (ACEIs)
Captopril, ACEIs
24
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
25
Effect of ACEIs on Bradykinin
26
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

27
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

28
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

29
AT-1 Receptor Blockers (ARBs)
  • ARBs have the same side-effects like ACEIs except
    they dont cause cough

30
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
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