Drugs for Congestive Heart Failure

Afnan Atallah, Ph.D.

 BACKGROUND
DEFINITION:
 Heart failure is the progressive inability of the heart to
supply adequate blood flow to vital organs.
 It is classically accompanied by significant fluid
retention.
 It is a leading cause of mortality and morbidity.
.
 PATHOLOGY:
Myocardium contraction & heart load
SYMPTOMS:
• weakness, fatigue and dyspnea, , fluid retention edema .
 Congestive Heart Failure (CHF)

NYHA Classification
Class I: Symptoms with more than ordinary
activity
Class II: Symptoms with ordinary activity
Class III: Symptoms with minimal activity
Class IIIa: No Dyspnea at rest
Class IIIb: Recent Dyspnea at rest
Class IV: Symptoms at rest
Change of myocardial structure in CHF

 Apoptosis, loss of myocyte

 Hypertrophy and fibrosis
 Remodeling: changes in size, shape,
structure, and function of the heart
Drugs for CCF
Goal of treatment:
1. To elevate symptoms
2. To slow disease progression
3. Improve survival

Through
 Reduce myocardial work load
 Decrease ECF volume
 Improve cardiac contractility
 Reduce rate of cardiac remodeling
Classification of Drugs for CHF

1. ACEI
2. ARBs
3. Diuretics and aldosterone antagonists
4. β-blockers
5. Direct vaso- and venodilators
6. Ionotropic agents
7. Neprilysin inhibitor with an angiotensin receptor
blocker
8. Recombinant B-type natriuretic peptide
9. Hyperpolarization-activated cyclic nucleotide-
gated channel blockers
 Combination Therapy is Used

 Old way (still common):

– Digoxin + diuretic
 New (and “better”) way for all but severe
chronic CHF:
– ACE Inhibitor + Diuretic (as
needed) + ß-blocker
Drugs for CHF

Angiotensin Converting Enzyme (ACE)

Inhibitors :

 ACE inhibitors improve mortality, morbidity,

exercise tolerance, left ventricular ejection
fraction.
 Captopril, Lisinopril, Enalapril, Ramipril,
Quinapril.
ACE Inhibitors for CCF
Drugs for CHF

Angiotensin Converting Enzyme (ACE)

Inhibitors :

 Reduction in arterial resistance (afterload)

 Reduction in venous tension (preload)
 Reduction in aldosterone secretion
 Inhibition of cardiac and vascular remodeling
Drugs for CHF

Angiotensin Converting Enzyme (ACE)

Inhibitors :

Adverse effects :
 Postural hypotension
 Dry irritating persistent cough
 Hyperkalemia
 Angioedema
 Fetal toxicity
Drugs for CHF

Angiotensin Receptor AT-1 blockers (ARB) :

Losartan, valsartan

 Competitive antagonists of Angiotensin II (AT-1).

 Similar action of ACEI
Beta blockers in CHF
Drugs for CHF
Beta blockers for congestive heart failure :

 Acts primarily by inhibiting the sympathetic nervous

system.
 Inhibit release of renin
 Increases beta receptor sensitivity (upregulation)
 Anti-arrhythmic properties.
 Anti-oxidant properties.
 Reverse cardiac remodeling,
Drugs for CHF

Beta blockers for congestive heart failure :

 Start at low dose and monitor for bradycardia

 Carvedilol, Metoprolol and bisoprolol are the
most commonly used for CHF among beta
blockers
 Drugs for CHF

Ivabradine: Corlanor®
 Hyperpolarization-
activated cyclic
nucleotide–gated (HCN)
channel blockers
 Reduction in heart rate
is use and dose
dependent
Drugs for CHF

Diuretics :
These are useful in reducing the symptoms of
volume overload by
 Decreasing the extracellular volume
 Decreasing the venous return (preload)
 Loop diuretics are the most commonly used
diuretics in HF (renal insufficiency)
 Thiazides are effective in mild cases only
Drugs for CHF

Diuretics: Adverse effects

 Loop diuretics and thiazides cause

hypokalemia
 Potassium sparing diuretics help in reducing
the hypokalemia due to these diuretics
Drugs for CHF
Potassium Sparing Diuretics (Aldosterone
antagonists):
Spironolactone, elperenone
 Prevent sodium and water retention
 Aldosterone inhibition minimize potassium loss
 Prevent myocardial hypertrophy and
myocardial fibrosis
 Indication: to patients with sever stage of HF
and recent MI
Drugs for CHF

Vasodilators :

 Isosorbide dinitrate and hydralazine are

used specially in patients who cannot
tolerate ACE inhibitors.
 Amlodipine and prazosin are other
vasodilators can be used in CHF.
Nitrates in CHF
Cardiac Glycosides: Digoxin

 Positive inotropic effect

1. Cardiac glycosides inhibit Na+/K+-ATPase, resulting
in
• Increased Intracellular Na+
• Decreased intracellular K+
2. Increased Na+ reduces the normal exchange of
intracellular Ca2+ for extracellular Na+ and yields
somewhat elevated intracellular Ca2+
 Effects on neural-hormone
 To inhibit sympathetic nerve activity
 To enhance vagus nerve activity
Digoxin

P.K
 Available in oral and injectable formulations
 Large volume of distribution
 Long half-life 30 to 40 hours
 Eliminated by the kidney (dose adjustment)
 Narrow therapeutic index
 Bioavailability clinically significant differences
between...
– Dosage forms.
– Generic, brand name products of same dosage form
 Digoxin’s Effect

 At high K concentrations, K reduces binding of Dig

to ATPase
– Therefore effects of Dig, at any given blood level, are
reduced in presence of hyperkalemia
 Hypercalcemia : increases in intracellular
calcium, which can lead to calcium overload and
increased susceptibility to digitalis-induced
arrhythmias
Digoxin Toxicity

 Affects > 50% of pts receiving dig chronically

 #1 cause = hypokalemia caused by K+
wasting diuretics
– Can occur w/ “therapeutic” dig levels

 Quinidine, Amiodarone and verapamil can

increase the plasma concentration of digoxin
by inhibiting its excretion.
– Plasma digoxin must be monitored carefully
Digoxin

Adverse effects :
 Nausea, vomiting, gynecomastia, visual
disturbances (xanthopsia) and psychosis
(signs of toxicity)

 Ventricular tachycardia (signs of sever toxicity)

Digoxin

Digoxin toxicity treatment:

 Discontinuing the drug
 Toxicity can be treated with higher than normal
doses of potassium
 Digoxin antibody (digibind) is used specifically
to treat life-threatening digoxin overdose
 Antiarrhythmic agents may be helpful in
treating acute digoxin-induced arrhythmias
Drugs/Conditions that Decrease
Digoxin Levels or Effects

 Diarrhea } these
 Laxatives } all
 Antacids } decrease
 Cholestyramine } absorption
 Hyperkalemia
Drugs for CHF

Cardiac Inotropes:

 Phosphodiesterase III Inhibitors Positive

inotropic and vasodilator – INO-DILATOR ; Eg.,
Milrinone, Amrinine.
 Dopamine, Dobutamine: beta-1 agonist which
increase contractility and cardiac output.
– IV for acute HF
Phosphodiesterase III Inhibitors
 Phosphodiesterase III Inhibitors:
Amrinone, Milrinone

Mechanism of Action
• Inhibition of type III phosphodiesterase
 Intracellular cAMP
 Activation of protein kinase A
o Ca2+ entry through L type Ca channels
o Inhibition of Ca2+ sequestration by SR

• Are IV agents for acute heart failure

• Peripheral vasodilators
 Drugs for Acute HF

 Intravenous positive Inotropes.

– Dobutamine, Dopamine.
– Milrinone and Amrinone

 Intravenous diuretics: furosemide

 Intravenous Nesiritide: Recombinant B-type
Natriuretic Peptide
 Intravenous vasodilators reducers.
– Nitroprusside.
– Isosorbide dinitrate .
– Hydralazine
Heart Pump
Case # 1

 A 55 year old man has recently been diagnosed

with Hypertension and started on monotherapy
designed to reduce peripheral resistance and
prevent Na and water retention. He developed a
persistent cough.
– The drug class that the patient start with?
– Which drug would have the same benefits but do not
produce cough?
 CCBs
 ARBs
 ACEI
 BBs
Case # 2

 A 58 year old man is admitted to the hospital

with acute heart failure and pulmonary edema.
Which one of the following drugs would be
1. Most useful in treating acute heart failure?
2. Most useful in treating pulmonary edema?
a) Digoxin
b) Minoxidil
c) Dobutamine
d) Spironolactone
e) Furosemide
Case # 3

 A 51-year-old woman goes to her physician for a follow-up

examination. She has a history of borderline asthma for 5
years. Repeated blood pressure measurements over
multiple visits average 148/102 mmHg and is diagnosed as
hypertensive. Her physician prescribes a beta-
adrenoreceptor blocking agent. Which of the following
agents is the most appropriate for this patient?

A. Pindolol
B. Propranolol
C. Metoprolol
D. Esmelol
E. More than one choice
 STAGE DISABILITY
CLASS 1 No symptoms Can perform ordinary
MILD activities without any limitations

CLASS 2 Mild symptoms - occasional

MILD swelling Somewhat limited in ability to
exercise or do other strenuous activities

CLASS 3 Noticeable limitations in ability to

exercise or participate in mildly
strenuous activities
MODERATE
Comfortable only at rest

CLASS 4 Unable to do any physical activity

SEVERE without discomfort Some HF symptoms
at rest