Drugs Used in Heart Failure

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 Congestive Heart Failure
 It is the pathophysiologic state in which the
heart is unable to pump blood at a rate
commensurate with the requirements of
metabolizing tissues, or can do so only
from an elevated filling pressure.
Heart Failure
 It is a complex of symptoms—fatigue,
shortness of breath, and congestion—that
are related to the inadequate perfusion of
tissue during exertion and often to the
retention of fluid.
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 Role of physiologic compensatory
mechanisms in the progression of HF
Chronic activation of the sympathetic nervous
system and the RAAS is associated with
remodeling of cardiac tissue __
characterized by loss of myocytes,
hypertrophy, and fibrosis __ interfering with
its ability to efficiently function as a pump.
Finally, neurohumoral effectors such as
NE and Ang II are associated with myocyte
apoptosis, abnormal myocyte gene
expression, and pathologic changes in the
extracellular matrix that increase LV
3 stiffness.
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 Pathophysiology of Cardiac
Performance
Cardiac performance is a function of
four primary factors
Preload
Afterload
Contractility
Heart rate

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 Goals of pharmacologic
intervention in HF
• Alleviate the symptoms,
• Slow disease progression
• Improve survival

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 Drug Treatment of Chronic Systolic
Heart Failure (Stages B and C)
1. Treatment Principle I: Neurohumoral
Modulation
Therapy consists of ACEIs/ARBs, β
blockers, and MRAs
2. Treatment Principle II: Preload
Reduction
Diuretics
3. Treatment Principle III: Afterload
Reduction
 Vasodilators

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 5. Treatment Principle IV: Increasing
Cardiac Contractility
 Cardiac glycosides

6. Treatment Principle V: Heart Rate

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 Therapeutic strategies in HF
Chronic HF is typically managed by:
a reduction in physical activity;
low dietary intake of sodium (<1500
mg/day);
treatment of comorbid conditions; and
judicious use of diuretics,
inhibitors of the renin angiotensin
system, and
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inotropic agents.
 Drugs that may precipitate or exacerbate
HF should be avoided if possible. These
are, such as:
Non-steroidal anti-inflammatory drugs
Alcohol
Calcium-channel blockers
High dose β-blockers and
Some antiarrhythmic drugs

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 Six classes of drugs have been shown to
be effective:
1. Diuretics
2. Inhibitors of the renin-angiotensin
system
3. β-adrenoreceptor blockers
4. Direct vasodilators
5. Inotropic agents
6. Aldosterone antagonists

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 Diuretics
Diuretics remain central in management of
symptoms in patients with CHF.
Diuretics reduce extracellular fluid volume
and ventricular filling pressure (or "preload"
They reduce right-heart pressure,
pulmonary venous congestion, and
peripheral edema.
Diuretics use (both loop and thiazides):
control congestive symptoms and improving
exercise capacity
not associated with a reduction in CHF
15 mortality.
Loop Diuretics
• Furosemide, Bumetanide, and
Torsemide __widely used.
• Furosemide and bumetanide at least
dosed twice daily due to:
They are short-acting drugs, and
rebound Na+ retention that occurs with
sub-steady state drug levels

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 Thiazide Diuretics
– Has a limited role in CHF as monotherapy
– Combination therapy with loop diuretics is
often effective in those refractory to
loop diuretics alone.
– patients with only mild fluid retention and
elevated BP because of their more
persistent antihypertensive effects
compared with loop diuretics

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 K+-Sparing Diuretics
 Spironolactone and eplerenone __ the
aldosterone antagonist
 In CHF circulating plasma aldosterone
levels increase to 20-fold above normal.
 Have the additional benefit of
decreasing morbidity and mortality in
patients with severe heart failure who are
also receiving ACE inhibitors and
other standard therapy.

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 Diuretics in clinical practice
 To maintain euvolemia in patients with
clinically evident fluid retention.
Monitor serum electrolytes and renal
function
 If present, hypokalemia from therapy: -
– may be corrected by oral or IV K+
supplementation or by the addition of a
K+-sparing diuretic.
– When appropriate, diuretics are decreased
to the minimum effective concentration for
maintaining euvolemia.
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 Diuretics in the decompensated
patient
Repetitive IV administered boluses or a
constant infusion titrated to achieve a
desired response may be needed to provide
expeditious (and reliable) diuresis.
Advantage to IV infusion is that:
sustained natriuresis is achieved.
the risk of ototoxicity is reduced by
continuous infusion when compared to
repetitive, intermittent intravenous dosing

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 Diuretic Resistance
Causes of diuretic resistance in heart failure
 Noncompliance _ excess dietary Na+ intake.
 Decreased renal perfusion and GFR due to:
– Excessive vascular volume depletion and
hypotension due to aggressive diuretic or
vasodilator therapy
– Decline in cardiac output due to worsening
heart failure, arrhythmias, or
– Selective reduction in GFR _ following initiation
(or dose increase) of ACE-inhibitor therapy.


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  Options to manage diuretic resistance:
– Bed rest _ improve the renal circulation.
– Increase in dose of loop diuretic up to ceiling
dose
– Frequent administration of smaller doses or a
continuous IV infusion of a loop diuretic.
– Use of combination therapy to have
synergistic.
– Reducing salt intake
– Scheduling of diuretic administration
shortly before food intake
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 ACE inhibitors
 ACE inhibitors are preferential arterial
vasodilators __ decreases in LV afterload result
in increased stroke volume and cardiac
output.
 Initiated at a low dose (e.g., 6.25 mg of
captopril, 5 mg of lisinopril) to avoid
iatrogenic hypotension __
 If possible, drug doses are targeted in practice
to match those affording maximum clinical
benefit in controlled trials: (captopril, 50 mg
three times daily, enalapril, 10 mg twice daily;
23 lisinopril, 10 mg once daily).
  ACE Inhibitors and Survival in CHF:
Improve survival by preventing post-
infarction-associated adverse ventricular
remodeling.
 In the event of acute renal failure or a
decrease in the glomerular filtration rate
by >20%, ACE-inhibitor dosing should be
reduced or the drug discontinued.

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 AT1-Receptor Antagonists
(ARBs)
– Substantially decreases the probability of
developing bradykinin-mediated side effects
associated with ACE inhibition.
– Rare angioedema
– Excellent alternative in CHF patients
intolerant of ACE inhibitors

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 β-Adrenergic Receptor Antagonists
The benefit of β-blockers to HF is by:
 Preventing the changes that occur
because of the chronic activation of the
sympathetic nervous system, including:
– Decreasing the heart rate and
– Inhibiting the release of renin
– prevent the direct deleterious effects
of norepinephrine on the cardiac
muscle fibers, decreasing remodeling,
hypertrophy, and cell death.
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 – Decreasing the frequency of unstable
tachyarrhythmias to which CHF patients
are particularly prone.
– Influence survival by favorably affecting
LV geometry, specifically by decreasing LV
chamber size and increasing LV ejection
fraction.
 Three β-blockers have been shown to
significantly reduce mortality compared
with placebo: carvedilol, metoprolol
succinate (CR/XL), and bisoprolol.
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 Clinical Use of beta blockers in Heart
Failure
 All patients with symptomatic heart failure
(stage C, NYHA II–IV)
 all patients with left ventricular dysfunction
(stage B, NYHA I) after myocardial infarction
 Therapy must be initiated in a clinically
stable condition and at very low doses (1/8
of target), and dose escalation requires time
(e.g., doubling every 4 weeks in ambulatory
settings; “start low, go slow”).
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  The improvement of left ventricular
function generally takes 3–6 months.
 The β blockers should not be
administered in
– new-onset or acutely decompensated
heart failure
– Asymptomatic LV dysfunction

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 Cardiac Glycosides__ Digoxin,
Often called
digitalis or digitalis
glycosides,
because most of
the drugs come
from the digitalis
(foxglove) plant.

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 Pharmacokinetics
– 65–80% absorbed after oral
administration
– Widely distributed to tissues, including
the CNS.
– t1/2 is 36–40 hours_ permitting once-
daily dosing.
– A loading dose regimen is used when
acute digitalization is needed.
– Excreted by the kidney
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– Digoxin is available for IV administration
 Mechanism of the Positive Inotropic Effect

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 Mechanism of action of cardiac
glycosides
1. Inotropic action
Through the action of Na/K/ATP ion pump
blockade
↓Na exits the cell
↑Intracellular Na
↓Na electrochemical gradient for Na-Ca
exchanger
↓Ca exits the cell
↑Intracellular Ca

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The ↑in IC Ca _ ↑ed contractility, and CO
 The benefits of cardiac glycosides in CHF:
– A positive inotropic effect on the failing
myocardium.
– Regulation of downstream deleterious effects
of sympathetic nervous system over-
activation.
– In patients with moderate-to-advanced CHF,
cardiac glycoside infusion increases forearm
blood flow and cardiac index and decreased
heart rate
– Suppression of rapid ventricular rate
response in CHF-associated atrial fibrillation.
– Does not reduce all-cause mortality
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 Digoxin use is usually limited to:
• CHF patients with LV systolic dysfunction
in atrial fibrillation_ the common
indication
• To patients in sinus rhythm who remain
symptomatic despite maximal therapy
with ACE inhibitors and β adrenergic
receptor antagonists.
• Not indicated in pts with diastolic or
right-sided HF

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 Adverse effects:
In CG overdosing,
– Arrhythmias (90%),
– GI symptoms (~55%), and
– Neurotoxic symptoms (~12%).
– Renal insufficiency and overdosing
 Cardiac effects__
– In healthy persons presents as extreme
bradycardia, atrial fibrillation, and AV block

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  In patients with structural heart
disease
– ventricular extra-systoles
– Bigeminy (premature beat)
– Ventricular tachycardia, and fibrillation
 Gastrointestinal effects__
– anorexia, nausea, vomiting, and diarrhea

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 Digoxin Toxicity
Ectopic beats originating from the AV
junction or ventricle, first-degree AV block,
abnormally slow ventricular rate response
to atrial fibrillation, or an accelerated AV
junctional pacemaker__ the more common
electro-physiologic manifestations.
Sinus bradycardia, SA arrest or exit block,
and second- or third-degree AV conduction
delay requiring atropine or temporary
ventricular pacing__ uncommon
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 Management for digoxin toxicity:
 Extreme sinus bradycardia, sinoatrial block,
or AV block grade II or III: Atropine (0.5–1
mg) IV. If not successful, a temporary
pacemaker may be necessary
 Tachycardic ventricular arrhythmias and
hypokalemia: K+ infusion (40–60 mmol/d).
Consider that high K+ can aggravate AV
conduction defects
 Purified Fab fragments (anti-digoxin
immunotherapy)_ for life-threatening digoxin
(or digitoxin) toxicity.
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 Class activity
1. A 72-year-old man with atrial brillation is hospitalized
because o severe pulmonary and peripheral edema
that is not adequately treated by his current
medications that include losartan, carvedilol, and
furosemide. During his stay in the hospital, his
edema is controlled by aggressive intravenous (IV)
furosemide administration and a strict low-salt diet.
He is also started on digoxin and spironolactone.
a) What is the rationale or adding digoxin?
b) What are the risks o digoxin therapy in this patient?
c) What are the symptoms of digoxin toxicity?
d) What is the rationale or adding spironolactone?
e) What are the side effects of spironolactone?

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 Drug Treatment of Acutely
Decompensated Heart Failure

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 Vasodilators
Vasodilators decrease cardiac preload
(venous dilators ) and afterload
(arterial dilators ) for patients with
congestive HF.
Nitrovasodilators
Nitrovasodilators are nitric oxide (NO)
donors __ leading to vasodilation.

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 a) Organic Nitrates
Available formulations include:
i. Rapid-acting nitroglycerin tablets or spray
for sublingual administration,
ii. short-acting oral agents such as
isosorbide dinitrate
iii. long-acting oral agents such as isosorbide
mononitrate
iv. topical preparations such as nitroglycerin
ointment and transdermal patches, and
v. Intravenous nitroglycerin
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  Their principal action in HF is by reducing
LV filling pressure _ by decreasing
preload.
 Additional effects include:
Pulmonary and systemic vascular
resistance reduction __ but do not
substantially influence __ due to tolerance.
Epicardial coronary artery vasodilation
 Outcome of these effect is __ improved
exercise capacity and CHF-symptom
reduction.
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 b) Parenteral Vasodilators
Sodium Nitroprusside
It is a direct NO donor and potent
vasodilator
Onset to activation is rapid (2-5 minutes)
 Effective in treating critically ill
patients with CHF who have elevated
systemic vascular resistance

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 Intravenous Nitroglycerin
It is a vasoactive NO donor that is
commonly used in the intensive care
unit setting.
Use in CHF
LV dysfunction due to an acute
myocardial ischemia
Non-ischemic cardiomyopathy when
expeditious LV filling pressure
reduction is desired.
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β-Adrenergic and Dopaminergic Agonists
They increase myocardial contractility __ in
pts with severely decompensated CHF
from reduced cardiac output.
Provide short-term circulatory support in
advanced CHF via stimulation of cardiac
myocyte dopamine (D1) and β-adrenergic
receptors
Restricted to patients with critically low
cardiac output and perfusion of vital organs
These includes:
Isoproterenol, epinephrine, and
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norepinephrine
 Dopamine
Limited utility in the treatment of most
patients with cardiogenic circulatory failure
Low-dose dopamine infusion ((2 µg/kg
lean body mass/min)
Often is used to increase renal blood
flow __ to maintain an adequate GFR in
hospitalized CHF patients with impaired
renal function refractory to diuretics

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  At higher infusion rates (5-15
g/kg/min):
– α-adrenergic receptor stimulation–
mediated peripheral arterial and venous
constriction occurs.
– Beneficial for reduced arterial pressure
or in those with circulatory failure from
severe vasodilation (e.g., sepsis,
anaphylaxis).
– Little role for cardiac contractile
dysfunction.
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 Dobutamine
 It is the β-agonist of choice for the
management of CHF patients with systolic
dysfunction.
 It stimulates both β-1 and β-2 receptor
subtypes.
 Increase in stroke volume from positive
inotropy.
 Major side effects
tachycardia and
supraventricular or ventricular arrhythmias.

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 Principal hemodynamic effect of
dobutamine is an

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 THE END

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