DRUG TREATMENT

OF HEART FAILURE
Professor Nor Azizan Abdullah
Department of Pharmacology
 Heart
• Has 4 chambers
•right atrium and right ventricle for
pulmonary circuit
•left atrium and left ventricle for
systemic circuit
• Left ventricle has a greater
workload
•much more massive than the
right ventricle but the 2
chambers pump equal amount
of blood
• AV valves prevent backflow
from ventricles into atria
• Semilunar valves prevent
 backflow from aortic and
pulmonary trunks into ventricles
 Some Physiology of the Heart
Cardiac Output: amount of blood pumped by the left ventricle each minute
CO= HR x SV (stroke volume: volume of blood ejected per beat)

• SV regulated by:
venous return
1. PRELOAD: load on the heart created by volume of blood in left
 ventricle, amount of stretch to which the ventricle is subject to

outflow resistance
2. AFTERLOAD: resistance against which the heart must pump blood
(aortic impedance and systemic vascular resistance)
increase in preload, contractility increases
3. CONTRACTILITY: capacity of the myocardium to generate the force
necessary to respond to preload & to overcome afterload
 FACTORS AFFECTING CO

Adapted from C.D.Kemp, JV Conte; Cardiovascular pathology 21

 WHAT IS HEART FAILURE?
• Debilitating & potentially life-
threatening disease

• Chronic HF is characterised by
elevated filling pressures, reduced CO
& decreased tissue oxygen delivery

• Symptoms (breathlessness, fatigue, fluid

retention) can appear slowly and
worsen over time, significantly
impacting quality of life
• Different types of heart failure (HF)
– Systolic vs. diastolic
(bipedal pitting edema)
– Acute vs. chronic
 TYPES OF HEART FAILURE: SYSTOLIC VS.
DIASTOLIC
• Also referred to as congestive heart failure (CHF) because
frequently there is congestion
• Systolic HF:
– Impaired myocardial contraction during systole
– Approximately 2/3 of heart failure patients have systolic dysfunction

• Diastolic HF:
– Impaired relaxation and ventricular filling during diastole

 Systolic dysfunction

EF < 40% Diastolic dysfunction

ejection fraction
 TYPES OF HEART FAILURE: ACUTE VS.
 CHRONIC

Acute Chronic causes: HPT, CAD

   
• Develops rapidly (hours/days) • Long-term condition (months/years)
   
• Can be immediately life • More insidious
 
 threatening
  • Associated with the heart
• Dramatic drop in cardiac output  undergoing adaptive responses
   (e.g. dilation, hypertrophy) to a
• May be new (e.g. acute MI, sepsis)  precipitating cause
 or an exacerbation of chronic
 disease damage heart muscle
 Compensatory
   Mechanisms
 
 
 
 
 
 
 
 
 
Nuerohormonal  Frank-Starling Ventricular
 
 activation      Mechanism remodelling
eg: fibrous
 NEUROHORMONAL ACTIVATION
• In HF, cardiac dysfunction causes drop in cardiac output (CO)
• Fall in CO leads to activation of several neurohormonal pathways:
– Sympathetic Nervous System (SNS) and release of catecholamines (eg: Adr)
– Renin –Angiotensin – Aldosterone System (RAAS)
– Antidiuretic hormone (vasopressin) cause fluid retention
– Other neurohormones: natriuretic peptides, endothelium-derived vasoactive
substances (nitric oxide, bradykinin, prostacyclin, endothelin-1)

These pathways initially are compensatory & beneficial in the early stages but
prolonged activation contributes to the pathophysiology  of HF, resulting in
• myocardial hypertrophy, fibrosis and apoptosis
• increased systemic vascular resistance (TPR)
• increased sodium and water retention
 NEUROHORMONAL ACTIVATION
- SYMPATHETIC NERVOUS SYSTEM
• One of the first responses to a decreased cardiac output
 
• Increase in circulating catecholamines (e.g. noradrenaline)
increase
– Augmentation of ventricular contractility and heart rate
– Systemic and pulmonary vasoconstriction
– Stimulates secretion of renin from juxtaglomerular apparatus of the kidney
– Catecholamines aggravate ischemia, potentiate arrhythmias, promote
cardiac remodelling and are directly toxic to myocytes
 RENIN –ANGIOTENSIN - ALDOSTERONE
SYSTEM(RAAS)
• RAAS is activated as a result of
 increased sympathetic stimulation
 and decreased renal perfusion

• Results in:
– formation of angiotensin II
– release of noradrenaline
– further arteriolar vasoconstriction
– sodium and water retention
– release of aldosterone:
Ø sodium and water retention
Ø endothelial dysfunction
Ø organ fibrosis
 VASOPRESSIN
• Antidiuretic Hormone (ADH)
• Synthesized in the hypothalamus and secreted by posterior
pituitary gland
• Triggered by low cardiac output, additionally facilitated by
angiotensin II
• Enhances water reabsorption by the kidneys, promotes water
retention
 NATRIURETIC PEPTIDES SYSTEM
• What are Natriuretic peptides (NP)?
– ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide), C-NP (c-
type natriuretic peptide)
– mediate beneficial cardiorenal effects
– promote sodium and water excretion (counter-regulate RAAS)
– inhibitory actions on RAAS & sympathetic system
– have potent cardiac antihypertrophic and antifibrotic properties
 NEUROHORMONAL IMBALANCE IN
DECOMPENSATED HEART FAILURE

UMMP
 contractility increases, C.O. increase

FRANK STARLING MECHANISMS

 Neurohormonal Responses to
Impaired Cardiac Performance
• Initially Adaptive, Deleterious if Sustained
Response Short-Term Effects Long-Term Effects

Salt and Water Augments Preload Pulmonary Congestion

Retention increase
Vasoconstriction Maintains BP for Exacerbates pump
perfusion of vital organs dysfunction (excessive
afterload), increases
cardiac energy
expenditure
Sympathetic Stimulation Increases HR and Increases energy
 ejection expenditure
 DRUGS USED TO TREAT CHRONIC HF
• To counteract the deleterious effects of the compensatory
mechanisms
– LOOP DIURETICS
– ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS
– ANGIOTENSIN RECEPTOR BLOCKERS
– ALDOSTERONE ANTAGONISTS
– Β-BLOCKERS
– INHIBITOR OF ‘FUNNY’ CURRENTS in SAN new drug
– ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITION (LCZ696)
– DIGOXIN
no longer common due to many adverse effects
 LOOP DIURETIC
• Decreases plasma volume,
 decreases venous return and
 ventricular filling pressure (or
“preload”) leading to reduction
in peripheral oedema and
pulmonary congestion
• For both acute and chronic
heart failure
• e.g. frusemide
• Inhibits Na+/K+/2Cl–transporter in
the TAL of Henle's loop
Thick Ascending Limb
 LOOP DIURETIC peripheral oedema
pulmonary congestion
• Diuretic therapy relieves symptoms,
does not improve left ventricular
function and decrease mortality
rates
• Adverse effects: affect sodium-potassium pump
– K+depletion (muscle cramps,
arrhythmias)
– Hyperuricaemia (gout)
– Allergic reactions
– Ototoxicity, dose-related & reversible
 ANGIOTENSIN-CONVERTING ENZYME
(ACE) INHIBITORS
• Block conversion of Ang I to Ang II thus
inhibit activation of RAAS
• 1st line drugs for patients with impaired
left ventricular systolic function
with/without symptoms of overt heart
failure
• Reduce both afterload (due to
 reduction of circulating Ang II) and
 preload (due to reduction of
aldosterone and blood volume)
• Increase survival, improves outcomes,
decrease symptoms
initially inactive form, after consumed, became active form
• e.g. enalapril (converted to the active
drug, enalaprilat) lisinopril, quinapril,
ramipril
reduce bl. vol.
ACE INHIBITORS
ADVERSE EFFECTS CONTRAINDICATIONS
   
• symptomatic hypotension • renal artery stenosis
   
• persistent dry cough: may be • severe renal impairment
 
 mediated by bradykinin
  • hyperkalemia
• hyperkalaemia esp. in patients with  
 renal insufficiency or in patients • hypotension
 taking K+ sparing diuretics, K+
 supplements
 
• worsening of renal function in
 certain patients
 
• angioedema
ANGIOTENSIN RECEPTOR BLOCKERS (ARB)
block the binding

• 2 subtypes of Ang II receptors: AT1 & AT2 ; most clinical actions of

Ang II are mediated thru AT1 receptor
• ARBs block AT1,thus block ability of angiotensin II to
– stimulate vascular smooth muscle contraction (vasoconstriction)
– aldosterone release
– cardiac remodeling
– cardiac hypertrophy

• e.g. losartan, candesartan, valsartan

• for patients who cannot tolerate or have an unsatisfactory
response to ACE inhibitors
X cough
 more expensive than ACE blocker
ARB: Losartan
• COZAARR EP 3174
 
 
i. t1/2: 6-9 h
 Losartan, t1/2: ii. more potent AT -receptor
1

   2.5 h CYP2C9 antagonist than losartan

 
&  
 
CYP3A4    inactive
 metabolites
enzyme of metabolites
 ANGIOTENSIN RECEPTOR BLOCKERS (ARB)
• Adverse Effects
– Angioedema (much less than with ACE inhibitors)
– Hyperkalemia in patients with renal disease or taking K+supplements or K+-
sparing diuretics

• Caution: patients with renal artery stenosis, hypotension, oliguria,

progressive azotemia, or acute renal failure
 ACE INHIBITORS
Inhibit the breakdown of
bradykinin:
induce vasodilation
• Advantage: vasodilation,
thrombolytic activity and
inhibition of cell growth
• Disadvantage: side effects of
cough and angiodema
VS ARBs
Advantages
• Angiotensin II is produced by
enzymes other than ACE. ARBs
therefore might be more
effective by providing a more
complete blockade
• ARBs still allow angiotensin II to
stimulate AII type 2 receptors.
This may have beneficial
cardiovascular effects
 BETA-BLOCKERS
• Protect the heart and vasculature from the deleterious effects of
overstimulation of the sympathetic system

• Improve left ventricular structure (ventricular remodelling

regresses) & function with a ↓ in chamber size & an ↑ in ejection
fraction
• Shown to reduce morbidity (symptoms & hospitalisation) &
mortality

• Drug examples: bisoprolol (β1-selective antagonist),

carvedilol(nonselective β receptor antagonist, α1-selective antagonist),
metoprolol (β1-selective antagonist)
 BETA-BLOCKERS (causes drastic drop in CO)
• Not recommended for patients in acute HF
• Started after normal blood volume is restored and oedema
relieved
• Adverse effects:
– Bradycardia, reduced exercise capacity, hypotension, AV block
– Bronchoconstriction can occur, esp. when non-selective beta- blockers
are administered to asthmatic patients
 ALDOSTERONE ANTAGONIST
• Weak diuretic, K+ sparing e.g. spironolactone, eplerenone
 
• Aldosterone can
– induce fibrotic change in myocardium → worsening systolic function
& pathological remodeling
∴ aldosterone antagonist can ↓ decompensation, retard disease
progression & death due to HF
– Induce sodium & water retention and impair vascular function
∴ aldosterone antagonist reduces these effects
• As add-on therapy to ACE inhibitors (+ other drugs) in
moderate-to- severe CHF
Antimineralocorticoid
• Eplerenone added to recommended therapy for systolic heart failure
in patients with mild symptoms was associated with a reduction in the
rate of death from a cardiovascular cause or hospitalization for heart
failure.
 ALDOSTERONE ANTAGONIST
• Adverse effects
– hyperkalaemia (requires K+ monitoring)
– gastric disturbances (gastritis and peptic ulcer)
– CNS effects (lethargy and confusion)
enlargement of a man's breasts
– gynaecomastia, decreased libido, and menstrual irregularities
性欲

• C/I in renal insufficiency

 SELECTIVE INHIBITOR OF If CURRENT:
IVABRADINE
The current resulting from activation of hyperpolarised-
activated, cyclic-nucleotide-gated (HCN) channels is
called funny (If) because it is activated by
hyperpolarization, unlike other voltage-dependent
currents

Ivabradine
less steep, takes
• specifically binds and inhibits the funny channels
longer time to reach
that is involved in the regulation of pacemaker threshold
activity in the SA node

• Reduces the slope for diastolic depolarization of the

AP in the SA node cells & decreases HR
Action potential
• Does not alter
– Ventricular repolarization
– Myocardial contractility
– Blood pressure
 SELECTIVE INHIBITOR OF If CURRENT:
IVABRADINE
• Nice Guidelines on ivabradine:
– have symptoms of heart failure and heart isn’t contracting properly, but
condition is stable
– regular heartbeat of 75 beats per minute or more
– taken together with other standard drugs for heart failure, or instead of
beta-blockers if cannot take them.
– LVEF (the amount of blood pumped out by the left side of your heart) is
below 35 %

• Adverse effects: visual symptoms, bradycardia

 ANGIOTENSIN
RECEPTOR NEPRILYSIN
INHIBITOR (LCZ696)
 
 
 
LCZ696
 
 
1. enhances the
 protective
 neurohormonal
 systems of the heart
 (NP system)
 
 
2. suppresses the
 harmful system (the
 RAAS)

Drug Discovery Today: Therapeutic Strategies: Vol 9, No 4 2012

     ANGIOTENSIN RECEPTOR NEPRILYSIN
     INHIBITOR (LCZ696)
 
 
• Adverse effects:
 – Hypotension
 – Angioedema
 – Renal impairment
– Hyperkalaemia less than ACE inhibitors
 DIGOXIN
 
 
 
• Increases SR Ca2+ load by
blocking the Na+-K+ ATPase
 
• Administration: oral or IV
• Long half-life (∼ 40 hr.), narrow
margin of safety (TI:1.5-3) hard to manage the
 
(therapeutic index) therapeutic dosage
• Adverse effects: GI symptoms,
neurological symptoms, arrhythmias,
heart block
• Becoming out of favour as it has
been shown to increase mortality
amongst females; generally no
mortality benefit at all
Katzung: basic & Clinical pharmacology, 11th Edition
  
      DRUGS FOR ACUTE HEART FAILURE
 
 
 
 
• IV Inotropes
 – DOBUTAMINE
 – DOPAMINE
 – PHOSPHODIESTERASE
   INHIBITORS
   (AMRINONE,
   ENOXIMONE,
   MILRINONE)
 
• Nesiritide

Nature Reviews –Drug Discovery Vol 10, July 2011

 IV POSITIVE INOTROPIC DRUGS
• Should usually be reserved for
patients with such severe reduction
in CO that vital organ perfusion is
compromised
• To stabilize the risk of progressive
haemodynamic collapse
• Inotropes can cause sinus
tachycardia and may induce
myocardial ischaemia and
arrhythmias
• Long-standing concern that UMMP
inotropes may increase mortality
 IV POSITIVE INOTROPIC DRUGS
IV Dopamine
• Short term support of the circulation
in acute, severe heart failure

• At low doses, DA causes vasodilation

(splanchnic & renal arterial beds) by:
i. stimulating dopaminergic receptors
(causing cyclic AMP–dependent
relaxation)
ii. stimulating presynaptic D2 receptors
on sympathetic nerves in the peripheral
circulation
iii. renal blood flow ↑, GFR is maintained
in patients who are refractory to
diuretics in CHF
 POSITIVE INOTROPIC DRUGS
• Dobutamine, IV
β agonist for:
i. management of patients with end-stage systolic dysfunction and CHF
ii. acute heart failure accompanying MI
iii. increase in stroke volume (positive inotropic action) with relatively little ↑ in HR
 POSITIVE INOTROPIC DRUGS
• phosphodiesterase inhibitors
 
• decrease the hydrolysis of
 cAMP, cAMP in myocardial
 cells increase, rise in
intracellular Ca2+ → ↑ cardiac
contractility

UMMP
 POSITIVE INOTROPIC DRUGS
• MILRINONE , IV
– Short-term management of acute, severe heart failure
– Also relaxes vascular smooth muscle to produce vasodilatation →
decrease preload & afterload
– Potent inotropic agent
– Long half-life of ∼ 80 hr., may accumulate with prolonged infusions
– Dose-limiting adverse effects: tachycardia, arrhythmias, hypotension
 NESIRITIDE
• Human B-type
natriuretic peptide
(hBNP)
• Produced by
recombinant DNA
technology
• Stimulates soluble
guanylate cyclase &
increases vascular
levels cGMP
• Vascular cGMP
relaxes arteries and
veins
reduce water and sodium
• Natriuresis & diuresis
 
• Suppresses RAAS
 NESIRITIDE
• Administration: IV, peak effects attained in 15 min with bolus
dose, followed by IV infusion
• For use in decompensated CHF to produce a rapid decrease in
peripheral vascular resistance & BP

• Associated with haemodynamic & symptomatic improvements

in patient with acute decompensated HF
• Major side effect: prolonged hypotension