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The Clinical Pharmacology of

Heart Failure

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Heart Failure
• Chronic heart failure is a syndrome
characterised
– by progressive cardiac dysfunction
– breathlessness
– tiredness
– neurohormonal disturbances
– sudden death

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• Chronic heart failure
– affects 2-10% of the population
– incidence rises with increasing age
– commonly due to coronary artery disease
– has a poor prognosis with a 5 year mortality of
50% rising to 80% in a year for some patients

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A prevalent condition
evalence of HF (per 1000 population)

Age (years) Men Women

50-59 8 8

80-89 66 79

All ages 7.4 7.7

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A growing burden
eaths from HF 1979-1997 (USA)
50000

40000

30000
HF deaths

20000

10000

0
1979 1985 1991 1997
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stics of the United States, National Center for Health Statistics
Physiology
• Normal circulation and circulatory volume
are maintained by means of two opposing
systems
– Salt and water retaining and vasoconstrictor
system
– Salt and water excretion and vasodilatation

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• Salt and water retaining and vasoconstrictor
system
– The renin-angiotensin-aldosterone system
– The sympathetic system
– The endothelin system
• Salt and water excretion and vasodilatation
– Natriuretic peptide system
– EDRF

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• Heart failure usually occurs
– following myocardial damage i.e. an MI
• Systolic Dysfunction
– Following upon sustained hypertension
• Diastolic Dysfunction
• As a result cardiac output falls as does perfusion
• The body registers this as a loss in circulatory
volume
• The salt and water retaining systems are activated
(RAAS)
• The vasoconstrictor systems are activated
(Sympathetic systems)

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• The RAAS causes the release of
– angiotensin II a potent vasoconstrictor and
hypertrophogenic and fibrogenic peptide
– and aldosterone a potent antinatriuretic peptide

• The result is salt and water retention,


vasoconstriction and hypertrophy and
fibrosis of cardiac myocytes

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• Activation of the Sympathetic System
causes the release of noradrenaline and
adrenaline
– both are potent vasoconstrictors
– both stimulate renin release
– both are also hypertrophogenic

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Systolic Dysfunction
• According to the Frank-Starling Law if the
muscle of a healthy heart is stretched it will
contract with greater force and so pump out
more blood.
• In the failing or damaged heart this
relationship is lost
• As the circulatory volume increases the
heart dilates, as the heart dilates the force of
contraction weakens and the cardiac output
drops further
• This fall in cardiac output then activates the
RAAS further 11
• The result is a vicious cycle in which the
RAAS is activated, circulatory volume
increases and cardiac performance
deteriorates further
• As the heart starts to dilate the cardiac
myocytes undergo hypertrophy and then
fibrosis and thus the heart is further
weakened
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The Final Result
• A failing heart that can not pump out sufficient
blood to supply the needs of the body
• Progressive retention of salt and water which
results in oedema, pulmonary oedema
• Progressive myocyte death and fibrosis

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Usual treatment today has two
aims
ims of heart failure management
To improve symptoms
• Diuretics
• Digoxin
• ACE inhibitors

To improve survival
• ACE inhibitors
∀ β Blockers
• Spironolactone

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vies et al. BMJ 2000;320:428-431
Treatment Regimes
• Symptomatic treatment
• Inhibition of detrimental neurohormonal
adaptations
• Enhancement of beneficial neurohormonal
adaptations
• Enhancement of cardiac function

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Symptomatic Treatment
– Loop Diuretics
– the mainstay of symptomatic treatment
– FRUSEMIDE or BUMETANIDE
Blocking detrimental hormonal changes
• Sympathetic activation
– CARVEDILOL, BISOPROLOL and
METOPROLOL are beta blockers which are of
proven benefit in the treatment of CHF

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RAAS
• Angiotensin II
– Two groups of drugs available to block the
effects of angiotensin II
– ACE Inhibitors (ENALAPRIL, CAPTOPRIL)
– Angiotensin antagonists (LOSARTAN) but these
are not as effective (ELITE II)
• Aldosterone
– Effects blocked by SPIRONOLACTONE
– Produces a significant reduction in morbidity
(RALES)
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Enhancement of cardiac function
• Positive Inotropes
– These drugs improve the ability of the heart to
pump and so improve cardiac status
– DIGOXIN is the only drug in common use
• Vasodilators
– The nitrovasodilators by reducing preload and
after load improve cardiac function
(ISOSORBIDE MONO or DINITRATE
– Hydralazine an arterial dilator has also been
shown to improve cardiac function
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Mortality remains high

• ACEI
Risk reduction 35% (mortality and hospitalizations)

∀ β Blockers
Risk reduction 38% (mortality and hospitalizations)

• Oral nitrates and hydralazine


Benefit vs. placebo; inferior to enalapril (mortality)

However: 4-year mortality


remains ~40%
vies et al. BMJ 2000;320:428-431 21
bbs et al. BMJ 2000;320:495-498
The Drugs
• Loop Diuretics (FRUSEMIDE)
– The main stay of treatment
– It is essential to remove excess salt and water
before introducing other agents
– The loop diuretics induce profound diuresis
– Act by inhibiting the NA-K-Cl transporter in the
Loop of Henle
– Work at very low glomerular filtration rates
– Prevent the reabsorption of 20% of filtered
sodium and water
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• In the most severely affected patients or in
resistant patients they can be used in
combination with thiazide diuretics
• This combination is very powerful and may
induce a diuresis of 5-10 litres a day
Adverse Drug Reactions
– Dehydration
– Hypotension
– Hypokalaemia, Hyponatraemia
– Gout
– Impaired glucose tolerance, diabetes
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Drug Drug Interactions
Frusemide and
– aminoglycosides aural and renal toxicity
– lithium renal toxicity
– NSAIDs renal toxicity
– antihypertensives profound hypotension
– vancomycin renal toxicity

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Reducing Mortality
• Angiotensin Blockade
• Beta receptor blockade
• Aldosterone blockade

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Several pathways of Ang II
generation
cal Ang II synthesis is independent of ACE
Angiotensinogen
(Liver)

Renin Chymase
inhibit
or Angiotensin I
Bradykinin
ACE
Peptides inhibito
r Angiotensin II
Valsartan
AT1 receptor
blocker
AT1 AT2
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asparo et al. Pharmacol Rev 2000; 52:415
Angiotensin-II plays a central role in
organ damage
Atherosclerosis* Stroke
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction Hypertension

A-II AT1 LV hypertrophy


receptor Fibrosis
Remodelling Heart failure DEATH
Apoptosis MI

GFR
Proteinuria
Renal failure
Aldosterone release
Glomerular sclerosis

*Preclinical data
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LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Angiotensin Converting Enzyme Inhibitors
• ENALAPRIL, LISINOPRIL, CAPTOPRIL
– A major breakthrough in the treatment of CHF
– Improve symptoms, reduce mortality, slow
down progressive deterioration in cardiac
function
– Competitively block angiotensin converting
enzyme
– Prevent the conversion of angiotensin I to
angiotensin II
– Reduce preload and after load on the heart
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ACE Inhibitors
• Conclusively demonstrated in CHF patients to
reduce
– morbidity
– mortality
• Post MI patients to reduce
– morbidity
– mortality
– onset of heart failure
• Main studies CONCENSUS, SOLVD, SAVE,
AIRE, ISSIS-4
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• Adverse Drug Reactions
– First dose hypotension
– Cough
– Angioedema
– Renal impairment
– Renal failure
– Hyperkalaemia
• Drug-Drug Interactions
– NSAIDs acute renal failure
– Potassium supplements hyperkalaemia
– Potassium sparing diuretics hyperkalaemia

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Angiotensin Receptor Blockers
• ARBs selectively block the angiotensin II, AT1
receptor.
• They are effective in the treatment of heart failure.
– NOT AS EFFECTIVE AS ACEIs
• At present recommended for use in ACEI intolerant
patients.
• Some suggestion that they may have benefit when
added to ACEIs.
• Major outcome studies Elite II, Charm, ValHeft
Valiant
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Different roles of AT1 and AT2
receptors
Angiotensin II

AT1 AT2

Vasoconstriction Vasodilation
Vascular proliferation Antiprolifera
Aldosterone secretion tion
Cardiac myocyte Apoptosis
proliferation
Increased sympathetic
tone
asparo et al. Pharmacol Rev 2000; 52:415
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Kaplan-Meier analysis of
probability of survival
1.0
Valsartan
p = 0.80
Survival probability (%)

0.9
Placebo

0.8

0.7
0 3 6 9 12 15 18 21 24 27
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Time
ohn et al. NEJM 2001;345:1667 since randomization (months)
Significant benefits on combined
mortality
1.0
/ morbidity endpoint
13.2% risk reduction
Event-free probability

Valsartan p= 0.009
0.9

0.8
Placebo

0.7

0.6
0 3 6 9 12 15 18 21 24 27
37
Time
ohn et al. NEJM 2001 345:1667 since randomization (months)
Primary endpoint: greatest benefits in patients
not on ACE inhibitor therapy
Combined all-cause mortality / morbidity
1.0
44.5%
Event-free probability

risk reduction
p = 0.0002
0.8

0.6

Placebo (n = 181)
Valsartan (n = 185)
Time since randomization (months)
0.4
al. AHA 3
Cohn et 0 6 Sessions
Scientific 9 12 15 18 21 24 27
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2000
Aldosterone Antagonists
• Spironolactone (RALES Study)
– Potassium sparing diuretic
– Inhibits the actions of aldosterone
– Acts in the distal tubule
– Used in combination with loop diuretics
– Particularly useful in resistant oedema
• Proven to reduce mortality when used in
combination with ACEIs
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SARA
Spironolactone (RALES trial)

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Beta Blockers
• CARVEDILOL, BISOPROLOL, METOPROLOL
– The use of beta blockers in the treatment of CHF is
potentially hazardous and patients must be selected
carefully
– Block the actions of the sympathetic system
– May precipitate severe deterioration in CHF
– Have been demonstrated to reduce morbidity and
mortality in mild/moderate and severe heart failure by
30%
– Should be used only when a patient has been stabilized
and not during an acute presentation
– Specialist use only

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US Carvedilol Programme
Survival
Carvedilol
1.0

β blockers in
(n=696)

0.9

0.8
Placebo
(n=398)
heart failure –
0.7 Risk reduction=65%
all-cause mortality
p<0.001
0.6

0.5
0 50 100 150 200 250 300 350 400
Days Packer et al (1996)
Survival Mortality (%)
1.0
CIBIS-II 20
MERIT-HF
Placebo
Bisoprolol 15
0.8

10 Metoprolol CR/XL

Placebo
Risk reduction=34% Risk reduction=34%
0.6 5
p=0.0062
p<0.0001
0 0
0 200 400 600 800 0 3 6 9 12 15 18 21
Time after inclusion (days) Months of follow-up 42
CIBIS-
CIBIS-II Investigators (1999) The MERIT-
MERIT-HF Study Group (1999)
Positive Inotropes
• DIGOXIN (The DIG Study)
– Increases availability of calcium in the myocyte
– Shown to reduce number of hospitalisations
– No effect on mortality
– Narrow therapeutic index
– Arrhythmias
– Nausea
– Confusion
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Anticoagulants
• WARFARIN
– Dilated ventricle gives rise to thrombus
formation and thrombo-embolic events
– Warfarin has proven value in preventing these
events

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Therapeutic Regime
• Frusemide ± thiazide Appropriate dose
• Frusemide + pulsed metolazone
• ACE Inhibitor Appropriate dose
– Angiotensin receptor blocker
• Carvedilol, Bisoprolol, Metoprolol
• Digoxin TDM
• Warfarin TDM
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Monitoring Benefit
• Symptomatic relief
– SOB, tiredness, lethargy
• Clinical relief
– Peripheral oedema, ascites, weight
• Monitor weight regularly
– Patient performs daily weight assessment
– Increase medication according to symptoms or weight
• Patient education

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