Download Congestive heart failure

Congestive heart failure
Congestive heart failure (CHF)
• It is a condition in which the heart is unable to
pump sufficient amount of blood to meet the
metabolic demands of the body
• It is a syndrome with multiple causes that may
involve the
- right ventricle
- left ventricle
- both ventricles
The ventricular dysfunction may be primarily
• Systolic
- inadequate force generation to eject blood
normally
- ↓ CO EF ↓45%
- typical of acute failure especially resulting from
myocardial infarction (MI)
• Diastolic
- inadequate relaxation to permit normal filling
- CO, EF may be normal
- result of hypertrophy & stiffening of myocardium
- does not respond to +ve ionotrophic drugs
High output failure:
• Demands of the body are so great that even ↑↑
CO is insufficient
eg. beriberi
hyperthyroidism
anemia
arteriovenus shunts
• Respond poorly to +ve ionotrophic drugs
• Cause should be treated
↓↓ FC
Heart failure
↓↓ CO
↓↓ renal perfusion
↓↓ carotid sinus firing
↑↑ sympathetic
discharge
↑↑ renin release
ventricular dilatation
↓↓ GFR
AT-1
vasoconstriction ß1 activation
↑ preload
↑ afterload
↑ FC
↑ HR
↑ AT-2 ↑ preload
↑ afterload
↑ aldosterone
CARDIAC
REMODELLING
BACK PRESSURE
pulmonary
congestion
dyspnea & cyanosis
EDEMA
HEPATIC CONGESTION
ENLARGED LIVER
ANOREXIA
peripheral congestion
Na &
H2O
retention
• The therapeutic goal in the management of
heart failure is to ↑↑ the cardiac output
Drugs used in heart failure
1) Drugs with positive ionotrophic effects
a) Cardiac glycosides –
digoxin, digitoxin, oubain
b) Phosphodiesterase inhibitors –
inamrinone, milrinone
c) ß adrenergic agonists –
dopamine, dobutamine
2) Drugs without positive ionotrophic effects
a) Diuretics –
furosemide, hydrochlorthiazide
b) ACE inhibitors – enalapril
c) ß blockers –
carvedilol, bisoprolol, metoprolol
d) Vasodilators –
hydrallazine, Na nitroprusside
Cardiac glycosides
(cardenolides)
Cardiac glycosides
• If a sugar molecule is joined together with a nonsugar molecule by an ether linkage it is called a
glycoside
sugar
ether non-sugar
glycoside
link
Digitoxose
X
steroidal
cardiac
lactone
glycoside
• Pharmacological activity – non-sugar moiety
• Pharmacokinetic properties – sugar part
• Digitalis lanata (leaves) – 2 active principles
digoxin, digitoxin
• Digitalis purpurea (foxglove) - digitoxin
Mechanism of action
• The force of contraction of the cardiac muscle is
directly related to the concentration of free
cytosolic Ca2+
• Any drug that increases free cytosolic Ca2+ levels
↑↑ force of contraction
sensitivity of contractile mechanisms to Ca2+
• Ca2+ initially enter through voltage sensitive L-type of Ca2+
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channels
It triggers the release of larger quantity of Ca2+ from the
sarcoplasmic reticulum (SR) by activating SR- Ca2+ release
– ryanodine receptor
The ↑↑ Ca2+ concentration initiates the contractile
process
During restorative process of periodic contractions Ca2+
ions are removed by re-uptake into SR by SR- Ca2+
ATPase
It is also extruded by a Na+/ Ca2+ pump exchange pump
Intracellular Na+ balance is then restored by
Na+/K+/ATPase pump
• Mechanism of action:
• Digitalis binds to & reversibly inhibits cardiac cell
membrane associated Na+/K+/ATPase
• Progressive accumulation of intracellular Na+ and loss of
intracellular K+
• ↑↑ intracellular Na+ concentration prompts diversion
Na+ ions to the Na+/ Ca2+ exchange mechanisms
• This exchanger normally extrudes Ca2+ in exchange for
Na+
• In the presence of ↑↑ intracellular Na+ concentration it
extrudes Na+ in exchange for extracellular Ca2+
• There is also an ↑↑ in Ca2+ permeability through
voltage sensitive L channels during plateau phase
• Digitalis also inhibits SR- Ca2+ ATPase & reduces
reuptake of Ca2+ by SR
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Ultimately ↑↑↑ cytosolic Ca2+
triggers contractile mechanisms of failing
heart
↑↑ cardiac output
• Higher serum K+ concentration inhibits digitalis
binding to Na+/K+/ATPase
- hyperkalemia can ↓ digitalis toxicity
- hypokalemia ↑↑ risk of digitalis toxicity
Hypercalcemia
↑↑ risk of digitalis
Hypomagnesemia induced arrhythmias
Pharmacological actions
Cardiovascular system (CVS)
• In normal individuals no significant variation
- ↑↑ force of contraction
- ↑↑ cardiac output
Also ↑↑ peripheral resistance affect
↑↑ venous pressure
nullified
• Heart rate unchanged
• Contractility
In heart failure - ↑↑ force of contraction
↑↑ stroke volume
complete emptying of heart
Diastolic size of heart ↓↓
↓↓ O2 consumption for work output
i.e ↑↑ work done for ↓↓ O2 consumption &
↓↓ energy
Hence, known as cardiotonic drug
Heart rate
• It decreases heart rate by
- direct Na+/K+/ATPase inhibition
- ↓ sympathetic activity
- indirect vagal stimulation
Conduction velocity
• Irrespective of the dose it
- ↓↓ conduction velocity
- ↑↑ ERP of the AV node & purkinje fibres by
- vagal action
- extravagal action (Na+/K+/ATPase)
• This protects the ventricles from
- atrial flutter
- atrial fibrillation
• In relatively smaller doses it
↑↑ conduction velocity
↓↓ ERP
of atrial muscles
• High doses –
↑↑ automaticity contractility
↓↓ ERP
of atria & ventricles causing
- extrasystoles
- pulsus bigeminus
- ventricular fibrillation
• As the cholinergic innervation is only upto the AV node – vagal
effects of digitalis are more pronounced at
- the AV node & atria
- than on purkinje system or ventricles
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Blood vessels
In normal people it has direct vasoconstrictor effect
In heart failure compensatory sympathetic over activity removed
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↓↓ in heart rate
↓↓ in peripheral resistance
↓↓ in preload
Blood pressure
No prominent effect
Coronary circulation
Improvement secondary to ↑↑ in CO & ↓↓ in heart rate
Venous system
↓↓ in venous pressure secondary to improvement in circulation
In CHF ↓↓ venous tone
↑↑ peripheral blood flow
• Extra cardiac effects
Kidney
• Diuresis occurs due to improvement in renal perfusion
which brings edematous fluid into circulation
• It occurs due to –
- ↓↓ sympathetic activity
- ↓↓ renin angiotensin aldosterone system
- ↓↓ aldosterone
- ↓↓ Na & H2O retention
GIT
• Anorexia, nausea, vomiting
CNS
• Disorientation, hallucinations, visual disturbances
Kinetics
• The safety margin of cardiac glycosides is very
narrow
• Minor variations in bioavailability
therapeutic failure
toxicity
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Digoxin
Fairly well absorbed orally (40-60%)
Half life – 38-40 days
Eliminated largely by the kidney
Digitoxin
Absorbed rapidly & completely
Half life 6-7 days
Metabolized in the liver
Excreted via bile into the gut
Entero-hepatic circulation is present
Can be used in renal failure
ADRs
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Cardiac side effects
Bradycardia
Partial or complete heart block
Atrial & ventricular extrasystoles
Pulsus bigeminy (coupled beats)
Ventricular fibrillation
Fatal cardiac arrhythmias
If cardiac arrhythmias develop Ca2+ Mg2+ & K+
states should be corrected
Treatment of digitalis toxicity
• Brief cases of bigeminy –
- oral K+ supplementation
- withdrawal of digoxin
• Serious arrhythmias
- parenteral K+
- lignocaine
• Ventricular fibrillation (digitalis induced) cardioversion
• Ventricular & supraventricular tachycardia
- propranolol (if AV block not ++)
• Severe digitalis intoxication
(with depressed automaticity)
- anti-arrhythmatic drugs fatal
- Digiband Fab fragments - digitalis antibodies
• Such patients can be saved by administration of
these antibodies
• They are extremely useful in reversing severe
intoxication
Extra cardiac ADRs
• GIT
- anorexia, nausea, vomiting, diarrhea, abdominal
cramps
• CNS
- headache, fatigue, neuralgias, blurred vision,
loss of color perception
• Endocrinal
- gynaecomastia
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Drug interactions:
Loop diuretics
Thiazides
↓↓ K+ levels
Corticosteroids
Ca salts
synergistic action
Catecholamines
cause
Succinylcholine arrhythmias
Amiodarone
Quinidine
displace
Verapamil
digitalis from
Tetracyclines
protein binding
Erythromycin
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Digitalis effects ↓↓ by
Antacids
Sucralfate ↓↓ absorption
Neomycin
Enzyme inducers
Phenobarbitone ↑↑ metabolism
Phenytoin
↓↓ entero-hepatic
Cholestyramine
circulation
Hyperthyroidism
↑↑ renal clearance
Uses
• Congestive heart failure
• Paroxysmal supra-ventricular tachycardia
• Atrial flutter & atrial fibrillation
Phosphodiesterase inhibitors
• Amrinone
• Milrinone
• Levosimendon
Mechanism of action
• These drugs inhibit the enzyme
phosphodiesterase isoenzyme III which is
specially located in cardiac myocytes & vascular
smooth muscle
• They prevent degradation of cAMP
↑↑ cAMP
↑↑ contractility (heart)
↑↑ vasodilatation (blood vessels)
• They also have direct vasodilating effect
• They also ↑↑ inward Ca2+ influx during action
potential
• In patients of CHF they
- ↑↑ CO
- ↓↓ pulmonary wedge pressure
- ↓↓ PR
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Kinetics
They are administered in loading dose by
intravenous (IV) infusion
Followed by slow maintenance infusions in saline
They are unstable in dextrose
Fluid balance
potential problem & drawback
in CHF patients
Toxicities also limit their use
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Amrinone
Toxicity - nausea, vomiting
Dose dependent thrombocytopenia
Arrhythmias – ventricular rate ↑↑ in patients of
atrial flutter & atrial fibrillation
Milrinone
Safer than amrinone
Arrhythmias ↑↑ incidence
Renal impairment - ↑↑ plasma half life
ß1 adrenergic agonists
• ß1 adrenergic stimulation improves cardiac
performance by +ve ionotropic effects
• They cause an ↑↑ in intracellular cAMP
activation of protein kinases
phosphorylation of slow Ca channels
↑↑ Ca inflow into myocardial cells
↑↑ force of contraction
ß1 agonists
Ca++
ß1 agonist
Ca++
Adenyl cyclase
ATP
Active protein kinases
Inactive protein kinases
myofibrils
cAMP
PDE Θ
↑↑ force of contraction
phosphodiesterase AMP
inhibitors
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Dobutamine
It is a derivative of dopamine with selective ionotrophic
effect, negligible chronotropic effect & peripheral
vascular effects
It is a selective ß1 agonist
Given as an infusion, half life is 2 minutes
Dose 5-15 μ mg/kg/minute
It ↑↑ cardiac output
↑↑ urinary output
↑↑ stroke volume without affecting heart rate, total
peripheral resistance (TPR) or blood pressure (BP)
Uses
Acute heart failure with MI
Cardiac surgery
Dopamine
• Acts on dopamine & ß1 receptors
• Given as intravenous infusion 2-5 μ
gm/kg/minute
Diuretics
• They are most commonly used in CHF
• Mechanism of action
They ↓↓ salt & H2O retention
↓↓ ventricular preload
↓↓ in venous pressure
↓↓ edema
↓↓ of cardiac size
Improved efficiency of pump function
Loop diuretics:
Bumetanide, Furosemide
• They promptly ↓↓ pulmonary edema by rapid diuresis
• Though widely used they do not influence the primary
disease process in CHF
• Enhanced urinary loss of Na+ & H2O
resultant ↑↑ in urinary excretion of H+ & K+
arrhythmias
digitalis toxicity
• Mg2+ & Ca2+ loss by loop diuretics further exacerbates
arrhythmias
• These drawbacks overcome by using loop diuretics with
aldosterone antagonists
Thiazide diuretics
Hydrochlorthiazide
Metolazone
• Used ↓↓ frequently
• In advanced CHF – chronic use of loop
diuretics
resistance
Hydrochlorthiazide or sphironolactone
Metolazone
added to loop diuretics
• Mild heart failure- hydrochlorthiazide +
sphironolactone
Sphironolactone
• The kidneys perceive ↓↓ CO from the failing
heart & activate the
renin angiotensin aldosterone system to
retain Na+ & H2O
Sphironolactone being aldosterone antagonist
enhances diuresis by promoting Na+ & H2O
excretion & retaining K+
• It prevents myocardial & vascular fibrosis which is
responsible for pathological re-modelling of the heart
• Evidence has shown aldosterone receptors on cardiac
myocytes
• Studies have shown that low-moderate doses of
sphironolactone in patients with severe CHF
↓↓ morbidity & mortality in patients who were also
receiving standard therapy (diuretics, ACE inhibitors)
• This shows that aldosterone plays a pathological role in
the progression of CHF – other than that of Na+ retention
i.e prevents re-modelling
• Low dose sphironolactone – beneficial in CHF
ACE inhibitors:
• Presently they are the 1st choice of drugs in CHF
Angiotensin I
Θ
ACE (angiotensin converting enzyme)
Angiotensin II
Θ
ACE
Aldosterone secretion
↓↓ salt & H2O retention
• They also prevent breakdown of bradykinin
promotes dilatation
↓↓ in venous return
vasodilatation
↓↓ preload
↓↓ afterload
improve cardiac output
• They prolong survival by ↓↓ re-modelling of heart &
blood vessels
• They also ↓↓ death rate due to
- arrhythmias
- myocardial infarction (MI)
- stroke
• They also ↓↓ damaging effects of left ventricular
dysfunction in patients of CHF with EF ↓↓ 35%
• ACE inhibitors
+
more beneficial effects +
Sphironolactone
↓↓ mortality
ß blockers
• Generally ß blockers are contraindicated in CHF as these
patients have a ↓↓ CO
CO = stroke volume (SV) x heart rate (HR)
• An ↑↑ HR would be necessary to maintain an adequate
CO in the presence of ↓↓ SV as in CHF
ß blockers
↓↓ heart rate
↓↓ contractility
Acute de-compensation in CHF
• Nevertheless certain ß blockers
- carvedelol
- bisoprolol
- metoprolol
- improve ventricular function
- prolong survival in these patients
• In CHF due to stress circulating levels of nor-adrenaline ↑↑
- peripheral vasoconstriction
- down regulation ß1 receptors
- up regulation of ß2 receptors
cardiac hypertrophy
apoptosis
• This rationale favors the use of a combined nonselective ß & α blocker – carvedilol
• It has ß1, ß2 &
α blocking properties
(↑↑↑)
(↑)
• It also
- inhibits free radical induced lipid peroxidation
- prevents cardiac & vascular smooth muscle
mitogenesis
• These actions are independent of α & ß blocking
effects
• Therefore ß blockers (not all) are beneficial in CHF
(carvedilol, bisoprolol, metoprolol)
• Mechanisms –
- ↓↓ in cardiac remodelling
(by ↓↓ mitogenesis)
- blunting the adverse effects of higher
circulating levels of catecholamines
Vasodilators
• They can be
- arteriolar (hydrallazine)
- venous (nitroglycerine, nitrates)
- mixed (ACE inhibitors)
• These drugs ↑↑ cardiac output
↓↓ pulmonary congestion
by ↓↓ preload and/or ↓↓ afterload
• They are useful in CHF
as they ↓↓ preload, afterload
& also prevent re-modelling of the heart
Choice of vasodilator depends on the S/S of the patient
• In CHF patients
i) with dyspnoea
- venodilators - nitroglycerine (NTG)
- long acting NO3
↓↓ pulmonary congestion
ii) with ↓↓ ventricular output
- arteriolar dilator – hydrallazine
↑↑ cardiac output
iii) in severe CHF where both are present
- ACE inhibitors
- hydrallazine + long acting NO3 (if ACE contraindicated
or not tolerated)
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Nesiritide
It is a recombinant form of HUMAN B TYPE NATRIURETIC PEPTIDE
naturally occurring hormone secreted by the ventricles
Recently introduced for use in acute heart failure
It ↑↑ c GMP in vascular smooth muscle & ↓↓ venous
& arteriolar tone
It also causes natriuresis
It has a short ½ life (18 minutes)
Administered in a bolus dose of 2 mgm/kg followed by a
continuous IV infusion – 0.01-0.03 μg/kg/mt
It is used in patients with acutely de-compensated heart
failure associated with dyspnea at rest as it
- ↓↓ pulmonary wedge pressure
- systemic vascular resistance
Management of chronic heart
failure
• Major steps in the treatment of chronic heart
failure
1) Reduce workload of the heart
- limit activity level
- reduce weight
- control HTN
2) Restrict Na
3) Diuretics
4) ACE inhibitors or Angiotensin receptor(AR) blockers
5) Digitalis
6) ß blockers
7) Vasodilators
Sodium removal
• It is an important step in the management
salt restriction
diuretic
if edema +
mild - thiazide
severe - stronger agents
• Na loss causes secondary K+ loss
Hazardous if patient is to be given digitalis
• Hypokalemia treatment – K+ supplementation
or
K+ sparing diuretic
ACE inhibitors & angiotensin receptor (AR) blockers
• ACEI should be used in patients with LV dysfunction
without edema
• Studies have shown that ACEI + diuretics considered as
1st line therapy
• In patients who are asymptomatic with LV dysfunction
– ACEI are valuable
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They ↓↓ preload and ↓↓ afterload
slow the rate of ventricular dilatation
delay onset of clinical heart failure
• ACEIs are beneficial in all subsets of patients
- asymptomatic
- severe chronic failure
• AR blockers should be used only in patients who
are intolerant to ACEIs
Vasodilators
• Choice of agent is based in
- patients signs & symptoms
- hemodynamic measurements
• In patients with high filling pressures – dyspnea
principal symptom
- venodilators
- long acting NO3s helpful
↓↓ filling pressures & symptoms of
pulmonary congestion
• In patients with ↓↓ ventricular output –
fatigue - primary symptom
Arteiolar dilator – hydrallazine given
• In patients where both ++
- high filling pressures
- low ventricular output
- hydrallazine
- nitrates
combined therapy given
Digoxin
• It is indicated in patients with heart failure
+
atrial fibrillation
• Also helpful in patients with a dilated heart
+
3rd heart sound
• In patients with normal sinus rhythm – 50% of
patients relieved of symptoms
ß blockers
• Rationale is based on the hypothesis that
- high catecholamine levels
excessive tachycardia
downward course of heart failure patients
• Therapy should be initiated cautiously at low
doses – as acutely blocking the supportive effects
of catecholamines can worsen heart failure