This presentation was used for BNS 1st year (2020)

1. Drugs Used in Heart Failure
Dr. Pravin Prasad
MBBS, MD Clinical Pharmacology
Asst. Professor, Department of Clinical Pharmacology
Maharajgunj Medical Campus
4 June, 2020 (22 Jestha 2077), Thursday

2. Heart Failure: An Overview
Reduced
Cardiac Output
Ventricular
Remodelling
Myocardial
inadequacy
Compensatory mechanisms
Sympathetic stimulation
RAAS activation
Increased Systemic
Vascular Resistance
Increased impedance
to ventricular outflow
Increased Stroke
Volume (initially)
Ventricular
dilatation (later)
Volume Expansion
Aldosterone
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3. Drugs Used in Heart Failure
Relief of congestive/low output symptoms Arrest/reversal of disease progression and
prolongation of survival
Inotropic drugs: Angiotensin Converting Enzyme inhibitors (ACE-
inhibitors), Angiotensin Receptor Blockers (ARBs)Digoxin, Dobutamine, Dopamine,
Amrinone/Milrinone
Diuretics:
Furosemide, Thiazides β- blockers
RAS inhibitors:
ACE inhibitors, ARBs Aldosterone Antagonists:
Vasodilators: Spironolactone, Eplerenone
Hydralazine, Nitrate, Nitroprusside
β- blockers:
Metoprolol, Bisoprolol, Carvedilol, Nebivolol
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4. Digoxin
 A cardiac glycoside; source: Digitalis lanata
 Digitoxin (D. purpurea); Ouabain (Strophanthus gratus)
 Pharmacological Actions:
 Direct effect on myocardial contractility:
o Increased force of contraction
o Decreased Heart Rate
o Electrophysiological properties
 Others: Vagomimetic action, altered sympathetic
activity (due to direct CNS effects), reflex effects
(altered haemodynamics)
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5. Digoxin: Electrophysiological
Properties
 Action Potential:
 Less negative RMP: Increased
excitability (low dose)
 Slow Conduction: reduced
slope of phase 0
 Ectopic automaticity enhanced:
extra-systoles
 Decreased automaticity of SA &
AV node: hyperpolarization d/t
vagal action
 Diminished Duration and
amplitude
Direct as well as indirect autonomic influences
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6. Digoxin: Electrophysiological Properties
 Effective Refractory Period
(ERP):
Inhomogeneous response in
atria
A-V node and Bundle of
His: reduced rate of
impulse transmission
Ventricles: decreased ERP
by direct action
 Conduction:
Therapeutic Dose: slowed
A-V conduction
High doses: decreased
conduction at Purkinje
Fibres (PF)
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7. Digoxin: ECG changes
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Electrocardiogram (ECG):
1. Decreased amplitude or inversion of T-wave
2. Increased PR interval
3. Short Q-T interval
4. Depressed ST segment
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2
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8. Digoxin: Mechanism of Action
→ Selectively binds to extracellular
face of the membrane associated
Na+K+ ATPase of myocardial fibres
and inhibits it
→ Progressive accumulation of Na+
intracellularly
→ Accumulation of Ca++ intracellularly
→ Taken up by Sarcoplasmic Reticulum
→ Augumented subsequent Ca++
transients
→ Increased force of contraction
Slow and gradual response
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9. Digoxin: Other Actions
 Blood Vessels:
CHF patients: improved circulation  decreased
sympathetic over-activity  decrease peripheral
resistance
 Kidney:
Diuresis
Excretion of retained salt and water
 CNS:
Little apparent effect in therapeutic doses
Higher dose: CTZ activation  side effects
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10. Digoxin: Pharmacokinetics
Oral Absorption 60-80%
Time course of action
• Onset
• Peak
• Duration
15-30 mins
2-5 hrs
2-6 days
Plasma t1/2 40 hrs
Therapeutic concentration 0.5-1.4 ng/mL
Daily maintenance dose 0.125-0.5 mg
Route of elimination Renal
Route of administration Oral, i.v.
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11. Digoxin: Adverse Effects
 Cardiac:
 Arrhythmias: all types
 Partial to complete A-V block
 Extra-cardiac:
 GIT: nausea, vomiting, abdominal pain (gastric irritation,
mesenteric vasoconstriction, CTZ stimulation)
 CNS: fatigue, malaise, headache, mental confusion,
restlessness, hyperapnoea, disorientation, psychosis,
visual disturbances
 Skin: rashes
 Endocrine: gynaecomastia
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12. Digoxin: Additional Points
Precautions and Contraindications
Hypokalemia
Elderly, renal insufficiency, hepatic disease
Myocardial ischaemia
Thyrotoxicosis, Myxoedema
Ventricular tachycardia
Partial A-V block
Acute Myocarditis
Wolff-Parkinson-White syndrome
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13. Digoxin: Uses
 Congestive Heart Failure
 Cardiac arrhythmias
Atrial Fibrillation
Atrial Flutter
Paroxysmal Supraventricular Tachycardia (PSVT)
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14. Diuretics
 High ceiling diuretics (Furosemide, Bumetanide):
Mobilizing edema fluid;
Later they may be continued in lower doses
 Thiazide alone has limited role in CHF
 Acts by:
Decreasing preload and improve ventricular
efficiency by reducing circulating volume
Remove edema and pulmonary congestion
 S/E: hypovolemia, hypokalemia, alkalosis,
carbohydrate intolerance
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15. Renin Angiotensin System (RAS)
inhibitors
 Includes: ACE inhibitors and ARBs
 Afford symptomatic as well as disease modifying benefits
by:
 Vasodilation
 Retarding/preventing pathological changes
 Raises levels of kinins: increased production of NO and
PGs
 Recommended for all stages of CHF, unless contraindicated
 Started at low dose, gradually increased to obtain maximal
benefit
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16. Vasodilators
Venodilators (primarily ↓ preload):
Glyceryl trinitrate, Isosorbide dinitrate
Arteriolar dilators (Primarily ↓ afterload):
Potassium Channel Openers: Hydralazine, Minoxidil, Nicorandil
Calcium Channel Blockers: Verapamil, Nifedipine, Diltiazem
Mixed dilators (↓ pre- and afterload):
ACE inhibitors: Captopril, Enalapril
ARBs (AT1 receptor antagonists): Losartan, Candesartan,
Irbesartan
α1 blockers: Prazosin
Phosphodiesterase (PDE) 3 inhibitors: Amrinone, Milrinone
Nitroprusside Sodium
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17. Venodilators
 Pooling of blood in systemic capacitance vessels
(systemic veins)  reduction in ventricular end-
diastolic pressure and volume  reduced ventricles
size, improved effectiveness
 S/E:
Excessive use, or when used in combination may
reduce output of a failing heart  decreased
performance;
Tolerance on chronic use
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18. Arteriodilators
 Dilates resistance vessels (arterial tree)  reduced aortic
impedance  improved output, improved performance
 Hydralazine
Can be used with isosorbide dinitrate for patients with renal
insufficiency, low renal blood flow, renal artery stenosis
 S/E:
Marked Tachycardia; Worsening of myocardial ischaemia
Fluid retention
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19. Mixed dilators
 Nitroprusside Sod.
 Decreases both ventricular filling pressure as well as
systemic vascular resistance
 Cardiac output and renal blood flow improved
 Fast and brief action  titrated i.v. infusion to tide-
over crisis (along with furosemide)
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20. β- blockers (Metoprolol, Bisoprolol,
Carvedilol, Nebivolol)
 Used in Mild to Moderate CHF
 Initial decrease in cardiac contractility and ejection
fraction  gradual improvements seen over weeks, higher
than baseline after few months
 Acts by (probably):
 Decreasing sympathetic over-activity that is responsible
for:
o Ventricular wall stress enhancement
o Apoptosis promotion and pathological remodelling
 Prevention of arrhythmia
 Demands caution, proper patient selection and other
considerations.
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21. Aldosterone Antagonist
(Spironolactone, Eplerenone)
 Acts by antagonising the effects of aldosterone which
is:
Expansion of e.c.f. volume  increased cardiac
preload
Fibroblast proliferation and fibrotic change in
myocardium  worsening systolic dysfunction and
pathological remodelling
Hypokalemia and hypomagnesemia  increased risk
of ventricular arrhythmias, sudden cardiac death
 Indicated as add on therapy
 S/E: hyperkalemia, gynaecomastia (spironolactone)
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22. Sympathomimetic inotropes
 Drugs with β adrenergic and dopaminergic D1 agonistic action:
 Positive inotropes
 Vasodilator properties
 Dobutamine:
 Selective β1 agonist: prominent inotropic action
 Used in acute heart failure d/t MI, Cardiac surgery, to tide over
crisis in advanced decompensated CHF
 Dopamine:
 Cardiogenic shock d/t MI
 Restores response to diuretics
 Disadvantage: increases afterload
S/E:
Tolerance
Cardiotoxic Potential
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23. Phosphodiesterase 3 (PDE 3) Inhibitors
 Inamrinone (amrinone):
 Selective PDE 3 inhibitor: specific for cAMP in heart,
blood vessels, bronchial smooth muscles
 Increases myocardial cAMP and transmembrane influx of
Ca++: positive inotropy
 Direct vasodilation
 S/E: thrombocytopenia (transient and asymptomatic);
nausea, diarrhoea, abdominal pain, liver damage, fever,
arrhythmias
 Only used for short term, i.v. in severe and refractory
CCF, add on drug
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24. Reduced
Cardiac
Output
Ventricular
Remodelling
Myocardia
l
inadequac
y
Compensatory mechanisms
Sympathetic stimulation
RAAS activation
Increased Systemic
Vascular Resistance
Increased impedance
to ventricular outflow
Increased
Stroke Volume
(initially)
Ventricular
dilatation
(later)
Volume Expansion
Aldosterone
Venodilators
Diuretics
Spironolactone
β blockers
ACE-I/ ARBs
Spironolactone
Arteriolar dilator
Digitalis
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