Drugs Used for the Treatment of Congestive Heart Failure

Compensatory Mechanisms in Heart Failure:

1. Neurohumoral activation
♦ Sympathetic nervous system
- Baroreceptor reflex
- Frank Starling’s Mechanism
♦ Renin-Angiotensin Aldosterone system
2. Myocardial remodeling
♦ a process that leads to maladaptive changes in the structure and function of the ventricles
 increase heart size
 dilatation of chambers
♦ initial beneficial effect
♦ contribute to maintenance of normal stroke volume
♦ hallmark of progressive heart failure

The New York Heart Association Functional Classification of Congestive Heart Failure
Class Classification
I No limitation of physical activity. No shortness of breath, fatigue, or heart palpitations with ordinary physical activity.
II Slight limitation of physical activity. Shortness of breath, fatigue, or heart palpitations with ordinary physical activity,
but patients are comfortable at rest.
III Marked limitation of activity. Shortness of breath, fatigue, or heart palpitations with less than ordinary physical activity,
but patients are comfortable at rest.
IV Severe to complete limitation of activity. Shortness of breath, fatigue, or heart palpitations with any physical exertion
and symptoms appear even at rest.

Goals of Treatment of Heart Failure

♦ Relief of symptoms
♦ Improve quality of life
♦ Prevent complications
♦ Attenuate disease progression
♦ Reduce mortality

Non-Pharmacologic Measures: Pharmacologic Treatment of Heart Failure

1.Decrease physical activity ♦ Diuretics
2.Sodium and fluid restriction ♦ Vasodilators
♦limit sodium intake to 2 g or less per day ♦ Beta Blockers
♦in advance heart failure: limit fluid intake to1500-2000 mL /day ♦ Inotropic Agents
3.Control risk factors
♦Management of co-morbid conditions
♦Smoking cessation
♦Alcohol avoidance

Current Approach to Treatment of Heart Failure

♦Preload and After load reduction
Diuretics
Vasodilators
♦Attenuate Neurohumoral Activation
Angiotensin Inhibitors
Beta Blockers
♦Enhancement of Ventricular Efficiency
Positive Inotropic Agents
CLASSIFICATIONS

DIURETICS VASODILATORS Beta Blockers Inotropic Agents

Thiazides ACE Inhibitors Metoprolol Cardiac Glycosides
Hydrochlorthiazide Captopril (2nd generation b1 selective Digoxin Digitoxin
Loop Diuretics Enalapril antagonist)
Furosemide AT1 Receptor Antagonists Bisoprolol Adrenergic Agonists
Potassium Sparing Losartan (2nd generation b1 selective Dobutamine Dopamine
Spironolactone Irbesartan antagonist)
Hydralazine Carvedilol Phosphodiesterase Inhibitors
Organic Nitrates (3rd generation Non-b selective Inamrinone Milrinone
1.Rapid –acting and a1 antagonist)
-Nitroglycerin Sublingual
Tablets/Spray
-Intravenous Nitroglycerin
2.Short-acting (Oral)
-Isosorbide dinitrate
3.Long-acting
-Isosorbide mononitrate
4.Topical
-Nitroglycerin ointment
-Nitroglycerin Transdermal
patches
Parenteral Vasodilators
Nitroprusside
Intravenous Nitroglycerin
Nesiritide

Diuretics in Heart Failure

Actions: Effects: Pharmacologic Effects:

♦retention of fluid and water
expands the extracellular fluid
volume
♦elevated filling pressure result
in pulmonary congestion and
peripheral edema
♦reduce extracellular fluid
volume
♦reduce ventricular filling
pressure
♦improve cardiac efficiency
♦alleviate congestive symptoms Diuretics: A double-edged
♦improve exercise tolerance sword
òNot shown to reduce ♦Increase water and sodium
mortality in heart failure excretion
♦Volume depletion
♦Decrease renal perfusion
♦RAAS Activation
♦SNS activation
♦Electrolyte excretion (K+, Ca++
and Mg++)

Furosemide Spironolactone Thiazides

♦Loop Diuretic
Mechanism of Action:
Inhibits the Na+K+Cl- symporter in the apical
membrane of renal epithelial cells in the
ascending limb of the Loop of Henle
effects:
♦efficacy dependent on renal blood flow
and tubular secretion
♦prevent the reabsorption of about 25% of
Na+
♦increase delivery of Na+ and water to the
distal nephron markedly enhances K+
secretion
Use:
♦Diuretic of choice in majority of patients
with heart failure
♦starting dose is 40 mg once or twice a
day, and gradually increased until
adequate diuresis is achieved
♦need to monitor serum electrolytes and
renal function regularly
♦Aldosterone antagonist
Mechanism of Action: Mechanism of Action:
♦counteract the increase in aldosterone ♦site of action is the Na+Cl- co-transporter
concentration (>20 times) in patients with of the epithelial cells in the distal
heart failure convoluted tubules
♦acts principally in the collecting ducts
effects:
♦improvement in survival is due to
mechanisms independent of diuretic effect;
possibly due to attenuation or reversal of
cardiac remodeling
♦additive beneficial effects with ACE
Inhibitors
Use: Use:
♦useful in patients with moderate to ♦most frequently used in the treatment of
severe heart failure systemic hypertension
♦significant reduction (~30%) in mortality ♦limited use in the treatment of heart
and hospitalization in patients with heart failure
failure ♦not effective in patients with significant
♦decrease mortality is attributed to a renal dysfunction
reduction in the progression and sudden
cardiac death
VASODILATORS
ACE (Angiotensin Converting
Enzyme ) Inhibitors
Captopril
Enalapril
♦relieves symptoms and
prolongs exercise tolerance
♦reduce risk of death
♦prevent the progression of
heart failure after MI by
preventing adverse
ventricular remodeling
♦improvement of over all
clinical outcomes
1. Inhibit production of
Angiotensin II
♦ vasodilatation
♦ inhibit Aldosterone
secretion
2. Increase concentration of
Bradykinin
♦vasodilatation
♦play a role in the
hemodynamic and anti-
remodeling effects of ACE
inhibitors
1. Decrease Afterload
♦ by decreasing total
peripheral resistance
2. Decrease Preload
♦ by decreasing salt and
water retention
♦ increase venous
capacitance
●May produce Angiotensin II
“escape”
♦a phenomenon wherein the
Angiotensin II levels return to
baseline following chronic
treatment with ACE
Inhibitors
♦partly attributed to
production of Angiotensin II
through ACE-independent
enzymes such a Chymase, a
tissue protease
Adverse Effects:
1.Hypotension
2.Non productive cough
3.Hyperkalemia
4.Acute renal failure
5.Angioedema
6.Fetopathic potential
♦IUGR, fetal death
AT1 Receptor Hydralazine Organic Nitrates Parenteral Vasodilators
Antagonists 1.Rapid –acting Nitroprusside
Losartan -Nitroglycerin Sublingual IV Nitroglycerin
Irbesartan Tablets/Spray Nesiritide
-Intravenous Nitroglycerin
2.Short-acting (Oral)
-Isosorbide dinitrate
3.Long-acting
-Isosorbide mononitrate
4.Topical
-Nitroglycerin ointment
-Nitroglycerin Transdermal patches
♦used initially for the ♦an arteriolar ISOSORBIDE DINITRATE SODIUM NITROPRUSSIDE
treatment of dilator ♦is the only nitrate used in the long ♦parenteral vasodilator
hypertension ♦also used as term management of CHF ♦used in ICU for rapid
♦an alternative to antihypertensive ♦improve exercise capacity and management of:
ACE inhibitors in the ♦useful in patients reduce symptoms when acutely decompensated
treatment of heart with HF with renal administered chronically in patients heart failure & severe
failure dysfunction who with heart failure hypertension
♦provide comparable cannot tolerate ACE ♦combination with Hydralazine
mortality benefits in inhibitors produce sustained improvement in
heart failure with ACE ♦combination with hemodynamics and reduction in over
inhibitors Isosorbide dinitrate all mortality
♦additive therapeutic increased survival in
benefit when patients with heart
combined with ACE failure
inhibitors
♦attenuates the ♦appears to have ♦relatively safe and effective ♦venular and arteriolar
hemodynamic and moderate “direct” ♦produce preload reduction by dilator
vascular effects of positive inotropic increasing peripheral venous ♦metabolized in the liver to
activation of RAA activity unrelated to capacitance cyanide and nitric oxide
System in patients afterload reduction ♦increase coronary blood flow that ♦rapid onset of action (2-5
with heart failure ♦decrease Nitrate may enhance both systolic and minutes)
♦provides a more tolerance by an diastolic ventricular function ♦cyanide is metabolized to
potent reduction of antioxidant effect thiocyanate
Angiotensin II effects
♦results in greater AT2
receptor activation
♦reduce the ♦reduces right and
phenomenon of left ventricular
Angiotensin II afterload by
“escape” that occurs decreasing
with ACE inhibitors pulmonary and
systemic vascular
resistance
♦less likely to induce limitations as monotherapy in CHF: Adverse effects:
bradykinin adverse ● limited effects on systemic vascular 1.Hypotension
effects e.g. cough, resistance 2.Cyanide or Thiocyanate
angioedema ● dilate arteries at higher doses toxicity
● pharmacologic tolerance ♦uncommon but may occur ff
prolonged high-dose
infusion or in the presence of
hepatic or renal dysfunction
♦unexplained abd pain,
mental status changes
♦convulsion , actic acidosis
3. Methemoglobinemia
Beta Blockers
Metoprolol
(2nd generation b1 selective antagonist)
Bisoprolol
(2nd generation b1 selective antagonist)
Carvedilol
(3rd generation Non-b selective and a1 antagonist)

Beta Blockers in Heart Failure

Rationale:
♦ improve symptoms and functional status
♦ improve survival
♦ slow disease progression
♦ reduce risk of hospitalization due to worsening heart failure by 32%
♦ decrease all-cause mortality by 34%

ß-ADRENERGIC BLOCKERS
Indication:
Mild to moderate heart failure
♦ Ejection fraction <35%
♦ NYHA class II and III
symptoms in
conjunction with ACE
inhibitors or AT1
Receptor Blockers and
Diuretics
♦blocks the catecholamine-
induced effects on the
myocardium and blood vessels
♦Anti-remodeling action
●improvement in left
ventricular structure and
function
●decrease chamber size
●increase ejection fraction
♦start with very low doses
♦gradually increase dose over
weeks under careful
supervision
♦ patients with CHF
classification NYHA class III-B
and IV, should be approached
with high level of caution
Contraindications:
♦acute decompensated heart
failure
♦ patients with significant fluid
retention requiring intensive
diuresis
♦patients receiving intravenous
therapy for heart failure or
require hospitalization for heart
failure

Inotropic Agents
• drugs that increase the force of myocardial contraction by altering mechanisms that control the concentration of intracellular Calcium
Review of Cardiac Physiology: Cardiac Contraction = directly related to the concentration of intracellular Calcium

Cardiac Glycosides
Digoxin Digitoxin
Adrenergic Agonists
Dobutamine Dopamine
Phosphodiesterase Inhibitors
Inamrinone Milrinone

DIGOXIN DOBUTAMINE DOPAMINE

Mechanism of action: Mechanism of action:
Inhibition of Na+K+ ATPAse

Increase intracellular Sodium

Decrease Calcium efflux via
Na+ Ca++ exchange mechanism

Increase Intracellular Calcium
♦agonist at 1 receptor ♦immediate metabolic precursor of NE
♦ does not cause endogenous ♦acts on dopaminergic, 1 and 1
release of NE receptors
♦ does not activate dopaminergic ♦negligible effect on 2 receptors
receptors ♦Pharmacologic and hemodynamic effects
are dose-related

1. The inhibition of Na+/K+-ATPase induces a rise in

sodium concentration inside cells.
2. Increased sodium induces in turn an increase in
the intracellular calcium concentration, via the
sodium-calcium exchanger.
3. The rise in intracellular calcium increases the force
of myocardial contraction
DIGOXIN DOBUTAMINE DOPAMINE
Pharmacologic Actions: Pharmacologic actions: Three General Infusion Ranges:
1. Mechanical ♦increase force of myocardial 1. Low dose: ≤ 2.0 ug/kg/min
Increase the force of myocardial contraction contraction ♦activate Dopaminergic receptors in
 ♦ minimal increase in heart rate peripheral, splanchnic and renal beds 
Increase Cardiac Output ♦modest decrease in systemic Vasodilatation
vascular resistance and venous ♦activate D2 receptors in sympathetic
filling pressure nerves that inhibit NE release and reduce
♦minimal effect on mean arterial a adrenergic stimulation of vascular
pressure smooth muscles
2. Medium dose: 2 - 5 ug/kg/min
♦dose used in heart failure
♦activate Beta adrenoceptors in the heart
to enhance contractility and induce
release of NE
♦serious adverse effects: arrhythmias
3. High dose: 5-15 ug/kg/min
♦ vasoconstriction of peripheral blood
vessels due to 1 receptor activation
♦ dose used in patients in shock
2. Electrophysiologic actions: ♦ increase TPR, increase BP
At therapeutic blood conc. (1-2 ng/ml) ♦ serious adverse effects: tachycardia,
♦ increase vagal tone ischemia
♦ prolongation of effective refractory period
♦ decrease conduction velocity in AV nodal tissue
At Higher concentrations:
♦ increase automaticiyy
♦ depress conduction in the His-Purkinje and
ventricular muscle fibers = atrial and ventricular
arrhythmias
Pharmacokinetics: Pharmacokinetics:
♦oral and parenteral route ♦given by continuous IV infusion
♦60 - 80% bioavailability ♦half-life 2.5 minutes
♦half-life 36-48 hours ♦hepatic metabolism
♦steady-state 5-7 days ♦maximum hemodynamic effects
♦not extensively metabolized in 2 hrs.; with 33% reduction in 72
♦metabolized in the GIT in about 10% of patients by hrs.
Eubacterium lentum
♦20-40% bound to plasma proteins
♦large volume of distribution
♦peripheral tissue reserve is skeletal muscle
♦dose should be based on lean body mass
♦2/3 excreted unchanged in thekidneys
♦narrow margin of safety
♦minimal variations in dose can either cause serious
toxic effects or loss of efficacy
♦therapeutic range: 0.5 - 1.5 ng / ml
♦serum levels >1.5 ng/ml is associated with
increased mortality
Therapeutic effects: DOC in the treatment of
1. Improve hemodynamics thru a acute heart failure
(+) inotropic effect on failing myocardium
2. Efficacy in controlling the response of the
ventricular rate to atrial fibrillation

DIGITALIS TOXOCITY* DOBUTAMINE

Adverse Effects:
1.excessive tachycardia,
arrhythmias
2. hypotension
3. anginal pain
Current Status of the Clinical Use of DIGOXIN in Heart Failure
♦no longer considered as first line drug in the treatment of heart failure
♦used in patients who remain symptomatic despite treatment with ACE Inhibitors and Beta Blockers
♦also used in patients with HF associated with atrial fibrillation
♦Maximal increase in contractility at serum Digoxin levels of 1.4 ng/ml
♦exhibit neurohumoral efffects at serum levels of 0.5-1 ng/ml such as
* attenuation of sympathetic activation
* reduction of renin release
♦no effect on over all survival
♦reduce risk of hospitalization

*DIGITALIS TOXICITY
1.GIT disturbance Factors that Predispose to Digitalis Diagnosis of Digitalis Toxicity:
♦anorexia, nausea, vomiting, diarrhea Toxicity: ♦Serum Digoxin levels > 1.5 ng/ml
2. Cardiac 1. Elderly
♦ventricular arrhythmias 2. Electrolyte abnormalities ♦Assessment of electrolyte status
♦2nd or 3rd degree A- block, sino-atrial arrest, Hypokalemia Management of Digitalis Toxicity:
sinus bradycardia Hypercalcemia 1. Drug withdrawal
3. CNS Hypomagnesemia 2. Correction of electrolyte abnormalities
♦disorientation, drowsiness, fatigue, weakness 3. Renal dysfunction 3. Control arrhythmias
♦dizziness, confusion, agitation, hallucination ♦Symptomatic bradyarrhythmias
4. Visual disturbances Atropine
♦distortion in yellow and green perception ♦Ventricular tachyarrhythmias
♦Van Gogh’s use of swirling greens and yellows Lidocaine
as toxic visual symptoms of Digitalis Phenytoin
♦appearance of halos around objects ♦K+ supplement with evidences of
increased A-V junctional or ventricular
automaticity
4. Digoxin-specific Antibody fragments (Fab)
♦life threatening arrhythmias
♦refractory hyperkalemia
Note:
♦Full neutralizing dose is based on either estimated total dose of drug ingested or total body Digoxin burden
♦Administered IV in Saline solution for 30-60 minutes
♦Digoxin immune Fab is commercially available in the US as Digibind ® (38-mg vials) and DigiFab® (40-mg vials).
♦the contents of one vial of either preparation neutralizes approximately 0.5 mg of Digoxin in life threatening arrhythmias
♦to reverse most cases of toxicity in adults receiving Digoxin will require 228 or 240 mg of Digoxin Immune Fab (contents of six 38-mg
vials of Digibind® or six 40-mg vials of DigiFab®, respectively)
♦Cost is $727.91/vial; Cost of treatment $4,367.46 or Php 192,168.24

POSITIVE INOTROPIC AGENTS

Beneficial Effects
♦improve hemodynamics and produce relief of symptoms
♦decrease neurohormonal activation

Treatment of Heart Failure. Treatment of Heart Treatment of heart failure.

Nitrates: Hemodynamic effects
At therapeutic doses, nitrates produce venodilatation
that reduces systemic and pulmonary venous
resistances. As a consequence, right atrial pressure,
pulmonary capillary pressure, and LVEDP decrease.
The preload reduction improves the signs of
pulmonary congestion and decreases myocardial wall
tension and ventricular size, which in turn reduce
oxygen consumption. With higher doses, nitrates
produce arterial vasodilatation that decreases
peripheral vascular resistance and mean arterial
pressure, leading to a decrease in afterload, and
thereby reduce oxygen consumption. This arterial
vasodilatation increases cardiac output, counteracting
the possible reduction caused by the reduction in
preload caused by venodilatation. The overall effect
on cardiac output depends on the LVEDP; when LVEDP
is high, nitrates increase cardiac output, while when it
is normal nitrates can decrease cardiac output.
Nitrates can also produce coronary vasodilatation, as
much through reducing preload as through a direct
effect on the vascular endothelium. This
vasodilatation can decrease the mechanical
compression of subendocardial vessels and increases
blood flow at this level. Additionally, nitrates reduce
coronary vascular tone, overcoming vasospasm.
Failure. Inotropes: General problems
Indications for Beta- Positive inotropic drugs which increase cellular levels of
Blocker Therapy cAMP have important proarrhythmic effects and seem to
In spite of more than 20 accelerate the progression of heart failure. Their
years of clinical hemodynamic effects decreased with prolonged treatment
investigation, the which suggests that they should not be used for chronic
indication for beta- treatment. Safety and efficacy increases when they are
blockers in patients with used in low doses, with which the increase in contractility
heart failure has not yet is slight. This points out that their beneficial effects
been precisely probably do not depend on their positive inotropic action.
established. The reduction in neurohumoral activation produced by
Nonetheless, it is digoxin and ibopamine, the antiarrhythmic action of
suggested that treatment Vesnarinone or the vasodilatory effects of dopamine,
be started with doses dobutamine or PDE
much lower than those III inhibitors may be more important than the increase in
used for the treatment of contractility that until recently was though to be their
angina, and the dose utility in the treatment of heart failure. With the exception
should be increased of digoxin, chronic administration of these drugs increases
slowly. mortality, so their use, in low doses, should be restricted
to patients with refractory heart failure, with persistent
symptoms despite treatment with combinations of other
drugs. As it is precisely the sickest patients who manifest
the increase in mortality, treatment with inotropic drugs is
not likely to prolong the survival of these patients.