Pharmacological Management of

Congestive Heart Failure

 Objectives
• List major drug groups used in treatment of heart failure
• Explain mechanism of action of digitalis and its major effects
• Explain the nature and mechanism of digitalis toxic effects
• Describe the clinical implications of diuretics, vasodilators,
ACE inhibitors and other drugs that lack positive inotropic
effects in heart failure
• Describe the strategies used in the treatment of heart failure
 What is heart failure
• Gagal jantung (heart failure) adalah suatu
kondisi yang terjadi karena jantung tidak
dapat memompa darah dengan baik ke
seluruh tubuh. Tanpa adanya aliran darah yang
cukup, semua fungsi dari organ tubuh akan
terganggu.
 Compensatory responses during heart failure
Heart failure

↑ Sympathetic ↓ FOC ↓ COP ↓ Renal perfusion

discharge

Ventricular
• Vasoconstriction dilation ↑ Renin ↓ GFR
•β1 activation release

Cardiac Na &
remodelling ↑ AT-1
↑ preload ↑ FOC water
↑ afterload ↑ HR ↑ AT-II retention
Back pressure (Oedema)
Initially ↑CO ↑ Aldosterone
Later ↓ CO Oedema
 Vasodilators

Diuretics
Inotropics

Drugs Used in
Heart Failure
Aldosterone
-blockers Antagonists
 Inotropic drugs
• Cardiac glycosides:
• Digoxin, digitoxin
• Sympathomimetic amines:
• Dopamine , dobutamine
• Phosphodiesterase inhibitors:
Like the carrot placed in
• Amrinone , milrinone front of the donkey
 Vasodilators

• Arteriolar: hydralazine , minoxidil, nicorandil

• Venodilators: nitrates
• Arteriolar and venodilators: ACE inhibitors,
angiotensin receptor blockers

Increase the donkey’s

efficiency
 Diuretics

• Loop diuretics: furosemide, torsemide

• Thiazide diuretics: hydrochlorthiazide
• K+ Sparing diuretics:
• Spironolactone (Also is aldosterone antagonist)
• Amiloride

Reduce the number of

sacks on the wagon
 Beta Blockers
• Metoprolol, bisoprolol, carvedilol

Limit the donkey’s speed,

thus saving energy
 Inotropic Agents
• Cardiac glycosides: Digoxin

William Withering 1785

Foxglove plant
Chemistry of cardiac glycosides

Aglycone
Responsible for
pharmacodynamic
activity

Sugar influence
pharmacokinetics
 Digitalis Mechanism of the
+ve inotropic action:
Digitalis In therapeutic dose leads to partial inhibition of Na+/K+
Normally ATPase enzyme
ca

++

K+
 Na+

ATPase Na + /ca + + ca++

exchange

Na+ ca++++ca
++
ca++ ca++ ca++
Na+ Na+
Na + ca ca++ ca++
troponin
Na+ Na+
Na +

 intracellular Na +
resulting in:  ca++ caca
++
++
ca++
sarcoplasmic reticulum Actin Myosin

 Force Of Contractility
 Pharmacological actions

CARDIAC EXTRA CARDIAC

• ↑force of contraction & • Kidney:
Cardiac Output – Due to improvement in
•  Heart rate circulation and renal
•  Refractory period (RP) & ↑ perfusion
Conduction velocity (CV) in – Retained salt and water
atria/ventricles is gradually excreted
• ↑ RP &  CV in AV node • CNS:
• Increased automaticity – Nausea, vomiting
• ECG: ↑PR interval ,  QT
interval
 Pharmacokinetic properties
Property Digoxin Digitoxin
Oral absorption 60 -80 % 90 -100 %
Plasma protein binding 25 % 95%
Onset of action 15 -30 min ½ to 1 hour
Duration of action 2-6 days 2-3 weeks
Plasma t ½ 40 hrs 5-7 days
Route of elimination Renal excretion Hepatic metabolism
Time for digitalization 5-7 days 25-30 days
Daily maintainence dose 0.125 – 0.5 mg 0.05 -0.2 mg
Administration Oral / IV Oral
 Cardiac Glycosides (Digitalis)

• Two glycosides:
Used
– Short acting Digoxin (t½: 1.5 days)

– Long acting Digitoxin (t½: 5 days)

Severely
limited Use
 Uses of digoxin

• Congestive heart failure

• Cardiac arrhythmias
– Atrial fibrillation
– Atrial flutter
– Paroxysmal supraventricular tachycardia
 Adverse effects of digoxin
Extra-Cardiac Cardiac
• GIT: Nausea & vomiting • Bradycardia
(first to appear) (first cardiac toxic sign)
• CNS: Vomiting • Pulsus bigemini
Restlessness, • Atrial extra-systole 
Disorientation, Visual
flutter  fibrillation
disturbance
• Ventricular extra-systole
• Endocrine:
 tachycardia 
Gynaecomastia
fibrillation
• Partial heart block 
complete block
 Treatment of toxicity
• Stop digitalis
• Oral or parenteral potassium supplements
• For ventricular arrhythmias:
– Lidocaine IV drug of choice
• For supraventricular arrhythmia:
– Propranolol may be given IV or orally
• For AV block and bradycardia
– Atropine 0.6 -1.2 mg IM
• Digoxin antibody
Phosphodiesterase inhibitors in heart failure

• Amrinone & milrinone are selective phosphodiesterase

III inhibitors
• ↑ cAMP levels
• The PDE III isoenzyme is specific for intracellular
degradation of cAMP in heart, blood vessels and
bronchial smooth muscles.
• Inodilators
• IV administration for short term treatment of severe
heart failure
• Milrinone is more potent than amrinone and does not
produce thrombocytopenia
Preservation
of cAMP cAMP Adenylyl cyclase ATP

Activation of Phosphdiesterase III Milrinone

Protein kinase
Myocardial & Vascular
smooth muscles
Phosphorylation 5’AMP
of Ca++ Channels
Mechanism of Action
Increased of Inodilators
Ca++ Flow
Positive  CO
inotropism
Elevated
Cytosolic Ca++
Relaxation of Pre-load Inodilatation
Resistance &
Capacitance
vessels After-load
 Other inotropic drugs
• Dopamine
• Dobutamine
 Role of diuretics in heart failure

• Almost all symptomatic Patients treated with a

diuretic
• High ceiling diuretics (loop diuretics) preferred
– Low dose therapy for maintainence
• They increase salt and water excretion &
reduce blood volume
– Reduce preload & venous pressure
– Improve cardiac performance & relieve edema
 ACE Inhibitors in heart failure

• Angiotensin converting enzyme inhibitors

– Captopril, enalapril, ramipril, lisinopril
• Act by
– Reduction of after load
– Reduction of preload
– Reversing the compensatory changes
• ACE inhibitors are the most preferred drugs
for treatment of Congestive cardiac failure
 Angiotensinogen
Renin
Synthesis
Angiotensin I Blocker

Angiotensin Converting Enzyme ACE

(ACE) inhibitor

Angiotensin II

Angiotensin
Receptor
Blocker
AT2 AT1 Receptor
Blocker
Angiotensin III
Angiotensin receptor blockers in heart failure

• Losartan , candesartan, valsartan, telmisartan

• Block AT1 receptor on the heart, peripheral
vasculature and kidney
• As effective as ACE inhibitors
• Used mainly in patients who cannot tolerate
ACE inhibitors because of cough, angioedema,
neutropenia
 Approach to the Patient with Heart Failure

Assessment of LV function (echocardiogram)

EF < 40%

Assessment of
volume status

Signs and symptoms of No signs and symptoms of

fluid retention fluid retention

Diuretic ACE Inhibitor

(titrate to euvolemic state)
Digoxin
b-blocker
 Drugs used in heart failure
Chronic heart failure Acute heart failure
• Diuretics • Diuretics
• Aldosterone receptor • Vasodilators
antagonist • Dopamine, dobutamine
• ACE inhibitors • Amrinone
• Angiotensin receptor
blockers
• Cardiac glycosides
• Vasodilators
 Summary  blockers
Diuretics, ACE inhibitors

Reduce the number of Limit the speed, thus saving

sacks on the wagon energy

Increase the efficiency

Like the carrot placed in
front Vasodilators

Inotrops