Drugs used in Congestive Heart

Failure
BBMS 3014
Advanced Pharmacology Course

Susan Leung
Department of Pharmacology and Pharmacy
The University of Hong Kong
Learning Outcomes

• Identify the rationale underlying the different

pharmacological approaches in the management of congestive
heart failure

• Indicate the adverse effects of these drugs and the precautions

with their uses

• Compare and explain the therapeutic advantages and

disadvantages among the different drugs
Heart Failure

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http://7serengeti2.wikispaces.com/it%27s+a+flamer

Supply Demand
Primary Cause of Heart Failure

 Cardiac Output

•  Heart Rate

•  Force of Contraction of Heart   Volume of blood

ejected from the
•  Volume of Blood in Heart heart with each heart
beat
Types of Heart Failure

• Acute Heart Failure

- develops rapidly (hours/days)
- life threatening
- successful management by pharmacological or surgical
interventions

• Chronic Heart Failure

- long-term condition (months/years)
- associated with adaptive changes in the heart
Drugs Used in Heart Failure
•  Force of Contraction
- positive inotropic drugs

•  Renin-Angiotensin-Aldosterone System
- angiotensin-converting enzyme (ACE) inhibitors
- angiotensin receptor antagonists
- aldosterone antagonists
- renin inhibitors

•  Fluid Retention
- diuretics

•  Constriction of Blood Vessels

- vasodilators

•  Sympathetic Activity
- β-adrenergic receptor blockers
Positive Inotropic Drugs
Positive Inotropic Drugs
-  Force of Contraction of the Heart
• Cardiac Glycosides
e.g. digoxin

• b-Adrenergic Receptor Stimulants   intracellular

e.g. dopamine or dobutamine calcium
concentration
• Phosphodiesterase Inhibitors
e.g. milrinone, enoximone

• Calcium Sensitizer
e.g. levosimendan
Mechanism for Contraction of the Heart

Na+ Ca2+

Ca2+

Sarcoplasmic Reticulum
Cardiomyocytes
Mechanism for Relaxation of the Heart

Na+ K+ Na+ Ca2+ Ca2+

ATP ATP

Na+/K+ Na+/Ca2+ Ca2+

ATPase exchanger
ATP

Sarcoplasmic Reticulum
Cardiomyocytes
Cardiac Glycosides
Cardiac Glycosides e.g. digoxin
- mechanism of actions
• inhibit Na+/K+-ATPase (sodium pump)
  intracellular sodium concentration
  Ca2+ expulsion by Na+/Ca2+ exchanger
  intracellular calcium concentration
- facilitate parasympathetic activation
Na+ K+ Na+ Ca2+ Ca2+ Ca2+

ATP ATP

Na+/K+ Na+/Ca2+ Ca2+

ATPase exchanger
ATP

Sarcoplasmic Reticulum
Cardiomyocytes
Characteristics of Digoxin

- facilitate parasympathetic activation

Advantages Anti-arrhythmic drug

Characteristics of Digoxin

Advantages Anti-arrhythmic drug

K+
ATP

Pro-arrhythmic Ca
Ca2+Na+/Ca2+ Na
Na+
Adverse exchanger
Effects

Cardiomyocytes
Characteristics of Digoxin

Advantages Anti-arrhythmic drug

K+
ATP

Pro-arrhythmic Ca
Ca2+Na+/Ca2+ Na
Na+
Adverse GI Disturbances exchanger
Effects CNS Disturbances
Narrow Safety Margin
Cardiomyocytes
Characteristics of Digoxin

Advantages Anti-arrhythmic drug

K+
ATP

Pro-arrhythmic Ca
Ca2+Na+/Ca2+ Na
Na+
Adverse GI Disturbances exchanger
Effects CNS Disturbances
Narrow Safety Margin
Cardiomyocytes
NOT 1st-line therapy
Applications Effect opposed by  K+
Effect opposed by  Mg2+
β-Adrenergic Receptor Stimulants
β-Adrenergic Receptor Stimulants
e.g. dobutamine, dopamine
- mechanism of actions
• activate b1-adrenoceptor in the heart
  intracellular concentration of cyclic adenosine
monophosphate (cAMP)
 activate protein kinase A (PKA)
  calcium entry in cardiac cells
  intracellular calcium concentration
b-AR

ATP cAMP PKA

Ca2+

Ca2+
Sarcoplasmic Reticulum
Cardiomyocytes ATP, adenosine triphosphate
Dopamine
- Pharmacological effect is concentration-dependent
- low doses ( 2 g/kg/min)
 cAMP-dependent vasodilatation [activation of D1 receptors
in vascular smooth muscle]
 inhibits noradrenaline release and so  -adrenergic
receptor-mediated vasoconstriction [particularly in
splanchnic and renal arterial beds; due to activation of D2 receptors
on sympathetic nerves in the peripheral circulation]
- intermediate doses (2 to 5 g/kg/min)
 activates cardiac b1-adrenergic receptors
 positive inotrophy
- high doses (5 to 15 g/kg/min)
 activates vascular -adrenergic receptors
 peripheral arterial and venous constriction
  afterload and further  cardiac output
Dobutamine
- Pharmacological effect is enantiomer-selective
- (-) enantiomer: agonist of -adrenergic receptors
- (+) enantiomer: partial agonist (or antagonist) of -
adrenergic receptors
- both: non-selective agonists of b-adrenergic receptors
 in heart: positive inotropic effect
 in vasculature: effect of (-) enantiomer offset by (+)
enantiomer + activation of b2-adrenergic receptors
[  systemic vascular resistance]
- Pharmacological effect limited by tolerance development
  efficacy beyond 4 days
 addition or substitution with phosphodiesterase III
inhibitor needed
- Clinical effect blunted by use of β-adrenergic receptor
blockers
Characteristics of β-Adrenergic Receptor
Stimulants

Fast Onset
Advantages Short Duration of
b-AR Action

ATP cAMP PKA

Adverse Pro-arrhythmic
Effects Ca2+ Pro-angina
Tachyphylaxis
Ca2+
Sarcoplasmic Reticulum Used For
Applications Cardiomyocytes Acute Heart Failure
Phosphodiesterase Inhibitors
Phosphodiesterase Inhibitors e.g. milrinone, enoximone
- mechanism of actions
• inhibit the enzyme phosphodiesterase III
  breakdown of cAMP
  PKA activation
  intracellular calcium concentration

b-AR

ATP cAMP PKA

PDE Ca2+
AMP
Ca2+
Sarcoplasmic Reticulum
Cardiomyocytes
AMP, adenosine monophosphate; ATP, adenosine triphosphate; PKA, protein kinase A
Characteristics of Phosphodiesterase
Inhibitors

Advantages Vasodilating Action

Vascular Smooth
Muscle

http://cvphysiology.com/Blood%20Pressure/BP026.htm
Characteristics of Phosphodiesterase
Inhibitors

Advantages Vasodilating Action

b-AR
Adverse Pro-arrhythmic
Effects ATP cAMP PKA GI Disturbances

PDE Ca2+
AMP
Ca2+ Used For
Applications Sarcoplasmic Reticulum
Acute Heart Failure
Cardiomyocytes
Choices of Positive Inotropic Drugs

Digitalis b-adrenergic Phosphodiesterase

receptor stimulants inhibitors

Fast Onset
Advantages Anti-arrhythmic drug Short Duration of Vasodilating Action
Action

Pro-arrhythmic
Adverse GI Disturbances Pro-arrhythmic Pro-arrhythmic
Effects CNS Disturbances Pro-angina GI Disturbances
Narrow Safety Margin Tachyphylaxis

NOT 1st-line therapy Used For Used For

Applications Effect opposed by  K+ Acute Heart Failure Acute Heart Failure
Effect opposed by  Mg2+
Calcium Sensitizers
Calcium Sensitizer e.g. levosimendan
- mechanism of actions
• stabilize the binding between troponin C and calcium
-  the affinity of troponin C for calcium
  sensitivity to calcium
  contractility WITHOUT  intracellular calcium
concentration

Antoniades et al., 2007. Pharmacol Ther 114, 184-197.

Characteristics of Levosimendan

Advantages Coronary and systemic

vasodilator

Vascular Smooth
Muscle
Characteristics of Levosimendan

Advantages Coronary and systemic

vasodilator

Available Intravenous
Formulations

Vascular Smooth
Muscle
Adverse Headache
Effects Hypotension
Choices of Positive Inotropic Drugs

Levosimendan Milrinone Dobutamine

(calcium sensitizer) (phosphodiesterase (b-adrenergic
inhibitor) receptor stimulant)

Advantages Coronary and systemic Peripheral Mild vasodilator

vasodilator vasodilator

Available Intravenous Intravenous, Intravenous

Formulations Peritoneal

Adverse Headache Pro-arrhythmic Pro-arrhythmic

Effects Hypotension Headache Pro-angina
Hypotension
Types of Heart Failure

• Acute Heart Failure

- develops rapidly (hours/days)
- life threatening
- successful management by pharmacological or surgical
interventions

• Chronic Heart Failure

- long-term condition (months/years)
- associated with adaptive changes in the heart
Compensatory Mechanisms to Restore
Cardiac Output
Compensatory Mechanisms to Restore
Cardiac Output
•  Sympathetic Activity  constriction of blood vessel
-  heart rate 
-  force of contraction  arterial blood pressure

 resistance to blood flow

 cardiac output !

•  Renin-Angiotensin-Aldosterone System
 retention of water and salt (sodium) in kidney
  volume of blood returning to the heart
Consequences of Compensatory
Mechanisms in Chronic Heart Failure
•  Sympathetic Activity
 constriction of blood vessels
  arterial blood pressure
  cardiac workload
 myocardial hypertrophy

•  Renin-Angiotensin-Aldosterone System
  water and salt retention
+ constriction of blood vessels
 oedema of peripheral tissues
e.g.swelling of legs and ankles
fluid in lungs ( shortness of breath)
 myocardial hypertrophy
Drugs Used in Heart Failure
•  Force of Contraction
- positive inotropic drugs

•  Renin-Angiotensin-Aldosterone System
- angiotensin-converting enzyme (ACE) inhibitors
- angiotensin receptor antagonists
- aldosterone antagonists
- renin inhibitors

•  Fluid Retention
- diuretics

•  Constriction of Blood Vessels

- vasodilators

•  Sympathetic Activity
- β-adrenergic receptor blockers
Inhibitors of Renin-Angiotensin-
Aldosterone System (RAAS)
 Compensatory Mechanisms During
Heart Failure
•  Renin-Angiotensin-Aldosterone System
Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction Fluid Retention Vasodilatation

- direct action on smooth muscle -  Na+ reabsorption in proximal tubule
-  sympathetic function -  release of aldosterone and vasopressin
 Inhibition of Renin-Angiotensin-
Aldosterone System (RAAS)
•  Renin-Angiotensin-Aldosterone System
Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction Fluid Retention Vasodilatation

Angiotensin Converting Enzyme Inhibitors
e.g. captopril, enalapril, lisinopril, quinapril

•  Formation of Angiotensin II
  fluid retention →  oedema
  vasoconstriction →  cardiac workload
  ventricular remodeling  improve survival

Angiotensin Receptor Blockers

e.g. losartan, valsartan

• Inhibit the Actions of Angiotensin II

(selective antagonists of type I angiotensin receptor)
  fluid retention →  oedema
  vasoconstriction →  cardiac workload
  ventricular remodeling  improve survival
Adverse Effects of ACE Inhibitors /
Angiotensin Receptor Blockers
• Severe Hypotension (e.g. in patients with fluid loss)

• Acute Renal Failure

• Hyperkalemia ( caution with K+-sparing diuretics)

• Risk of Fetal Hypotension, Renal Failure or

Malformation ( contraindicated during pregnancy)

• Dry Cough
more selective to ACE inhibitors
• Angioedema [due to  level of bradykinin]
 ?
Renin Inhibitors e.g. aliskiren
•  the Activity of Renin
  fluid retention →  oedema
  vasoconstriction →  cardiac workload
  ventricular remodeling  improve survival

Adverse Effects of Renin Inhibitors

• Acute Renal Failure

• Hyperkalemia

• Risk of Fetal Hypotension, Renal Failure or

Malformation
 contraindicated during pregnancy
 Inhibition of Renin-Angiotensin-
Aldosterone System
•  Renin-Angiotensin-Aldosterone System
Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction  Fluid Retention Vasodilatation

- direct action on smooth muscle -  Na+ reabsorption in proximal tubule
-  sympathetic function -  release of aldosterone and vasopressin
Aldosterone Antagonists
e.g. spironolactone, eplerenone

• Compete with aldosterone for its receptors

  sodium reabsorption from collecting tubules in the
kidney
  oedema
  sympathetic activation and  parasympathetic
inhibition
  baroreceptor dysfunction
  ventricular remodeling
 improve survival

• Considered as Potassium Sparing Diuretics

[please refer to the Lecture on Antihypertensive Drugs]
Diuretics
Diuretics [details in previous lecture on antihypertensive drugs]
•  Fluid Excretion
  oedema especially in lungs
  pulmonary vascular congestion
  oxygenation of blood
 improve myocardial function

• Loop Diuretics
e.g. furosemide, ethacrynic acid

• Thiazide Diuretics
e.g. hydrochlorothiazide, chlorthalidone

• Potassium-Sparing Diuretics
e.g. amiloride, spironolactone, eplerenone
Sites of Action of Diuretics

Cortex
Cortex
Medulla
Medulla

Rang, Dale, Ritter, Moore; Pharmacology, 5th Edition

(1) Na+/H+ exchange PCT - proximal convoluted tubule
(2) Na+/K+/2Cl- co-transport TAL - thick ascending loop
(3) Na+/Cl- co-transport DT - distal tubule
(4) Na+ channel CT - collecting tubule
Precautions with Diuretics in Heart Failure

•  Fluid Excretion
  venous return
 further impair cardiac output
 reduced perfusion pressures in the kidneys
 renal dysfunction

 Dosage needed to be titrated carefully to

maximize the benefit-to-risk ratio

Or
Co-administration of positive inotropic drugs (e.g. dobutamine)
Characteristics of Diuretics
• Efficacy in reducing blood volume:
- loop diuretics > thiazide diuretics > K+-sparing diuretics

• Combination Therapy
- synergistic effect with loop diuretics + thiazide diuretics
- K+-sparing diuretics + (loop diuretics / thiazide diuretics) to
manage hypokalemia

• No correction of the underlying causes contributing

to congestive heart failure
 use of vasodilators are more direct approaches
→  peripheral vascular resistance
Compensatory Mechanisms to Restore
Cardiac Output
•  Sympathetic Activity  constriction of blood vessel
-  heart rate 
-  force of contraction  arterial blood pressure

 resistance to blood flow

 cardiac output !

•  Renin-Angiotensin-Aldosterone System
 retention of water and salt (sodium) in kidney
  volume of blood returning to the heart
Vasodilators
Vasodilators (I) – Nitrovasodilators
e.g. nitroglycerin, isosorbide dinitrate
[details in previous lecture on antihypertensive drugs]

• Vascular Actions of Nitrovasodilators

- effective dilator of veins
  amount of blood into the heart
  cardiac workload
  pulmonary congestion
- effective dilator of large arteries
  peripheral vascular resistance
  cardiac workload
- effective dilator of epicardial coronary artery
 improve coronary blood flow
 improve ventricular function
Vasodilators (II) - Hydralazine
• Vascular Actions
- effective dilator of arterioles
  peripheral vascular resistance
  cardiac workload
- effective dilator of renal artery
 improve renal blood flow
 used in patients with renal dysfunction
- effective antioxidant
  bioavailable level of endogenous nitric oxide
 used in patients with endothelial dysfunction

Münzel et al., 2015. Eur Heart J 36, 2555-64.

Vasodilators (I & II)
- Combination Therapy
i.e. isosorbide dinitrate-hydralazine

• Synergistic Vascular Actions

•  Ventricular Remodeling
 improve survival

Münzel et al., 2014. Vasc Pharmacol 63, 105-113.

Vasodilators (III)
• Synthetic brain natriuretic peptide e.g. nesiritide
 activates natriuretic peptide receptor B (NPR-B) in
vascular smooth muscle
 activation of particulate guanylyl cyclase
  cyclic GMP in smooth muscle cells
 arteriolar and venous dilatation
Vasodilators (III)
• Synthetic brain natriuretic peptide e.g. nesiritide
 activates natriuretic peptide receptor B (NPR-B) in
vascular smooth muscle
 activation of particulate guanylyl cyclase
  cyclic GMP in smooth muscle cells
 arteriolar and venous dilatation
 activates natriuretic peptide receptor A (NPR-A) in the
kidney collecting duct
 inhibit cyclic nucleotide gated non-selective cation
channel
 diuresis
- administered intravenously [very short half-life]
 only used for acute heart failure
- adverse effects: renal damage and hypotension
Compensatory Mechanisms During
Heart Failure
•  Sympathetic Activity  constriction of blood vessel
-  heart rate 
-  force of contraction  arterial blood pressure

 resistance to blood flow

 cardiac output !

•  Renin-Angiotensin-Aldosterone System
 retention of water and salt (sodium) in kidney
  volume of blood returning to the heart
β-Adrenergic Receptor Blockers
b-Adrenergic Receptor Blockers
e.g. metoprolol, carvedilol and bisoprolol

• Reversal of Potentially Harmful  Sympathetic

Activity in Heart Failure

•  Rate and Force of Contraction of the Heart

 further  cardiac output Adverse
  risk of arrhythmia Effects?
 initiated with low doses
 improvement observed
after several months of therapy

•  Improve survival in chronic heart failure

Adverse Effects of b-Adrenergic Receptor Blockers
e.g. metoprolol, carvedilol and bisoprolol

• Inhibit b-adrenergic receptors in

respiratory tract Less with
 bronchospasm β1-selective
 contraindicated in patients with asthma or receptor
other forms of obstructive airways disease blockers
because of
• Inhibit b-adrenergic receptors in the liver their cardiac
selectivity
  risk of hypoglycemia
 contraindicated in patients with diabetes
Less with
• Inhibit b-adrenergic receptors in heart pindolol
  rate and force of contraction of heart because it has
small effect
  risk of arrhythmias and heart failure on heart
function
b-Adrenergic Receptor Blockers

• Metoprolol and Bisoprolol

- selective b1-adrenergic receptor blockers
- preferred for patients with diabetes or asthma

• Carvedilol
- non-selective b-adrenergic receptor blocker
- some 1-adrenergic receptor blocking activity
 relaxation of blood vessels
- additional mechanisms:
 oxygen free radical-initiated lipid peroxidation, and
 vascular smooth muscle mitogenesis
 Management of Chronic Heart Failure
Stage of Heart Failure Intervention

A,B Reduce risk factor

[Asymptomatic] e.g. hypertension, hyperlipidemia, diabetes, obesity
Drugs in appropriate patients
- angiotensin inhibitors
- b-blocker

C Restrict salt intake

[Previous/Current Drugs for routine use
Symptoms] - diuretics (if fluid retention is present)
D - angiotensin converting enzyme inhibitors
[Refractory Symptoms]
- b-blocker
Drugs in selected patients
- aldosterone antagonist (with preserved renal function)
- angiotensin receptor blockers (if intolerant to ACE inhibitors)
- cardiac glycosides (if atrial fibrillation is present)
- nitrates/hydralazine (additive to “drugs for routine use”)
ACC/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adult. Circulation 2009; 119: 1977-2016.
“New” Medications for the Management
of Chronic Heart Failure

• Ivabradine
- approved in April 2015

• Sacubitril
- in combination with angiotensin receptor blocker
- approved in July 2015
Ivabradine
Ivabradine
• Medication for Treatment of Angina

• Inhibitor of hyperpolarization-activated cyclic

nucleotide-gated (HCN) channels

• Mechanism of Action http://www.cvphysiology.com/

Arrhythmias/A004.htm
- selectively inhibit If current in the sinoatrial node
  rate of spontaneous depolarization
  heart rate
  cardiac work
Adverse Effects of Ivabradine
• Bradycardia
 dizziness, weakness or shortness of breath

• Hypertension
• Phosphenes (flashes of light), blurred vision
- due to inhibition of Ih current in the retinal cells

Patient Selection
• Resting heart rate of at least 70 beats per minute
• Reserved for patients not responding to / intolerate
of b-adrenergic receptor blockers
• Stable symptoms of heart failure
 Sacubitril
(in combination with ARB)
Sacubitril
• Mechanism of Action
- selectively inhibit the enzyme
neprilysin (a neutral endopeptidase)
  the breakdown of vasoactive
peptides
[which are upregulated in heart
failure and serve as counter-regulatory
mechanisms (as opposed to the Angiotensin II
Buggey et al., 2015. J Card Fail 21, 741-750.
compensatory mechanisms)]

ACE, angiotensin converting enzyme; ANP, atrial natriuretic peptide;

ATN, angiotensinogen; AT, angiotensin; ATS, autonomic nervous
system; BNP, brain natriuretic peptide; Epi, adrenaline; NE,
Gordin et al., 2016. Trends Cardiovasc Med 26, 485-492. noradrenaline
Valsartan/Sacubitril (LCZ696)
• A combination of valsartan and sacubitril in a 1:1
ratio by molecule count
 a dual angiotensin receptor-neprilysin
inhibitor (ARNI)
 inhibit the actions of angiotensin II
and neprilysin

Adverse effects of LCZ696

• Hypotension
• Angioedema
[due to accumulation of bradykinin and substance P]
Owens et al., 2017. Annu Rev Med 68, 15.1-15.9.

• Hyperkalemia, renal dysfunction, harm to fetus

[adverse effects of angiotensin receptor blockers]
Precautions for the Use of LCZ696

• Not to use in combination of an angiotensin

converting enzyme inhibitor; discontinue
angiotensin converting enzyme inhibitor for at least
36 hours before valsartan/sacubitril treatment
[to reduce risk of angioedema]

• Check and correct sodium and volume depletion

states before valsartan/sacubitril treatment
[to minimize hypotensive effects]
References
Bader M. Tissue renin-angiotensin-aldosterone systems; targets for pharmacological
therapy. Ann Rev Pharmacol Toxicol 50: 439-465, 2010.
Gordin JS, Fonarow GC. New medications for heart failure. Trends Cardiovasc Med
26(6): 485-492, 2016.
Katzung BG. Chapter 13. Drugs Used in Heart Failure. In: Katzung BG, Masters SB,
Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill;
2012.
Maron BA, Rocco TP. Chapter 28. Pharmacotherapy of Congestive Heart Failure. In:
Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The
Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011.
Rafouli-Stergiou P., Parissis J.T., Anastasiou-Nana M. Inotropes for the management of
acute heart failure patients with renal dysfunction. Still an option? Expert Opin
Pharmacother 13(18):2637-2647, 2012.
Sever PS, Gradmam AH, Azizi M. Managing cardiovascular and renal risk: the
potential of direct renin inhibition. J Renin Angiotensin Aldosterone Syst 10: 65-
76, 2009.
Struthers AD. The clinical implications of aldosterone escape in congestive heart
failure. Eur J Heart Failure 6: 539-545, 2004.
For Queries: swsleung@hku.hk