Drugs Used in Drugs Used in Heart FailureHeart Failure

M Shafiei, PhD

Department of Pharmacology

Case StudyCase Study A 50-year-old man has developed dyspnea with

exertion several weeks after a viral illness. This is accompanied by swelling feet and ankles and some increasing fatigue. On physical examination he is found to be mildly short of breath lying down, but feels better sitting upright. Pulse is 105 and regular, and blood pressure is 90/60 mm Hg. An echocardiogram shows a LVEF of about 25%. The diagnosis is dilated cardiomyopathy secondary to viral infection. What treatments are available for the patient?

Congestive Heart Failure (CHF)Congestive Heart Failure (CHF)

Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body.

A 5-year mortality rate is about 50%. The most common cause is coronary

artery disease, with hypertension also an important factor.

Types of Heart FailureTypes of Heart Failure

1) Low output failure Systolic failure

(EF < 40-45%) Diastolic failure

2) High output failure

Heart FailureHeart Failure

A progressive disease that is characterized by a gradual reduction in cardiac performance.

It is also punctuated in many cases by episodes of acute decompensation, often requiring hospitalization.

Heart FailureHeart Failure

Treatment is therefore directed at two somewhat different goals:

1) Reducing symptoms and slowing progression during stable periods

2) Managing acute episodes of decompensated failure

Pathogenesis of Heart FailurePathogenesis of Heart Failure

Primary defect in early systolic HF resides in excitation-contraction coupling machinery

Clinical condition also involves many other organs, including:

a) Baroreceptor reflex

b) Sympathetic nervous system

c) Kidneys

d) Angiotensin II and other peptides (eg, ANP, ET)

e) Aldosterone

f) Apoptosis of cardiac cells

Drug Groups Commonly Used in Drug Groups Commonly Used in Heart Failure Heart Failure

Diuretics Aldosterone receptor antagonists Angiotensin-converting enzyme (ACE) inhibitors Angiotensin receptor blockers (ARBs) blockers Cardiac glycosides Vasodilators agonists Bipyridines Natriuretic peptide

Treatment of Heart FailureTreatment of Heart Failure

Extensive trails have shown that just the following drug groups actually prolong life in patients with chronic heart failure:

ACE inhibitorsARBs blockersAldosterone receptor antagonistsCombined hydralazine-nitrate therapy

Treatment of Heart FailureTreatment of Heart Failure

Positive inotropic drugs can be helpful in acute failure.

Cardiac glycosides also reduce symptoms in chronic systolic heart failure.

Other positive inotropic drugs have consistently reduced survival in chronic failure.

Control of Normal Cardiac ContractilityControl of Normal Cardiac Contractility

Pathophysiology of Heart Pathophysiology of Heart FailureFailure

Extrinsic Compensatory ResponsesExtrinsic Compensatory Responses

Cardiac output

Carotid sinus firing Renal blood flow

Sympathetic discharge Renin release

Angiotensin II

Preload Afterload

Remodeling

Force

Rate

Cardiac Output(via compensation)

Intrinsic Compensatory Intrinsic Compensatory MechanismMechanism

Myocardial hypertrophyRemodeling is the term applied to dilation

& other slow structural changes in the stressed myocardium.

Ultimately, myocytes die through apoptosis.

Cardiac Performance in Heart Cardiac Performance in Heart FailureFailure

Time

Cardiac performance↓CO

↑NE, AgII, ET

↑Afterload

↓EF

↓CO

↑ NE, AgII, ET

↑Afterload

↓EF

↓CO

①

②

③

Pathophysiology of Cardiac Pathophysiology of Cardiac PerformancePerformance

Cardiac performance is a function of:

a) Preload

b) Afterload

c) Contractility

d) Heart rate

Frank-Starling Relation

Basic Pharmacology of Drugs Basic Pharmacology of Drugs Used in Heart FailureUsed in Heart Failure

1) Drugs with Positive Inotropic Effect

DigitalisDigitalis

William Withering (18th century) Chemistry of cardiac glycosides

Activity

Lactone ring

Steroid

Digoxin

Pharmacokinetics of DigoxinPharmacokinetics of Digoxin

Is 65-80% absorbed after oral administration.

Is excreted mostly unchanged by the kidneys.

Its renal clearance is proportionate to creatinine clearance.

Na-K ATPase Na-Ca Exchanger

Ca2+3 Na+2 K+

3 Na+Myofilaments

CONTRACTILITY

Ca2+

Digital Mechanical EffectsDigital Mechanical Effects

Digital Electrical EffectsDigital Electrical Effects

Direct electrical actions: An early, brief prolongation followed by

shortening of action potential occurs (contributes to the shortening of refractoriness).

At higher concentration, resting membrane potential is reduced.

Slows conduction in such depolarized cardiac tissues.

Normal

Digital

Digital Electrical Effects Digital Electrical Effects

Direct electrical actions: As toxicity progress oscillatory delayed

afterdepolarizations appear (digitalis-induced bigeminy).

Ventricular tachycardia

Ventricular fibrillation

Digital Indirect Electrical EffectsDigital Indirect Electrical Effects (Autonomic Actions)(Autonomic Actions)

Parasympathetic effects (in lower doses):

1) Sensitization of baroreceptors

2) Facilitation of muscarinic transmission at the cardiac muscle (SA & AV nodes are more affected)

3) …..

Digital Indirect Electrical EffectsDigital Indirect Electrical Effects (Autonomic Actions)(Autonomic Actions)

Sympathetic effects (at toxic levels): Sensitizes the myocardium, leading to:

ventricular tachycardia & fibrillation

Effects on Other Organs Effects on Other Organs

Inhibition of Na+/K+ ATPase results in depolarization.

Thus, increases spontaneous activity in excitable tissues, i.e., neurons and smooth muscle cells.

Effects on Other OrgansEffects on Other Organs

GI tract (direct & indirect): Anorexia, nausea, vomiting & diarrhea CNS:a) Vagal & CTZ

b) Disorientation & hallucinations

c) Visual disturbances Gynecomastia in men (rare)

Chemoreceptor Trigger Zone (CTZ)Chemoreceptor Trigger Zone (CTZ)

Interaction with KInteraction with K++ Potassium and digitalis:

a) They inhibit each other’s binding to Na+/K+ ATPase.

b) Abnormal cardiac automaticity is inhibited by hyperkalemia.

Interaction with CaInteraction with Ca2+2+ & Mg & Mg2+2+

Calcium and digitalis:Hypercalcemia accelerates the

overloading of intracellular calcium. Magnesium and digitalisMay inhibit Ca2+ inward current.

Indications of DigoxinIndications of Digoxin

In patients with :

1) heart failure and atrial fibrillation

2) a dilated heart and third heart sound It is usually given only when diuretics &

ACE inhibitors have failed to control symptoms.

Digitalis in CHF Digitalis in CHF

It reduces the death rate from progressive CHF (Cp < 0.9 ng/ml).

Also increases the sudden death (Cp > 1.5 ng/ml).

Digitalis has no net effect on mortality

Management of Toxicity of DigitalisManagement of Toxicity of Digitalis

During therapy of significant toxicity the followings should be monitored :

TDM Electrolyte status ECG

Management of Toxicity of Management of Toxicity of DigitalisDigitalis

In very severe intoxication:

a) No use of antiarrhythmic drug

b) Insertion of a temporary cardiac

pacemaker

c) Administration of digoxin antibody

(digoxin immune fab)

Other Positive Inotropic DrugsOther Positive Inotropic Drugs

Phosphodiesterase inhibitors (parenteral)Bipyridines: Inamrinone & Milrinone

cAMP AMP

cGMP GMPIncrease myocardial contractility.Have an important vasodilating effect.Used in acute heart failure.

PDE

PDE

Other Positive Inotropic DrugsOther Positive Inotropic Drugs

Beta-adrenoceptor stimulantsDobutamine Dopamine

2) Drugs without Positive 2) Drugs without Positive Inotropic EffectInotropic Effect

DiureticsDiuretics

Mainstay of heart failure management Reduction of preload results in reduction

of:

1) Edema

2) Cardiac size

DiureticsDiuretics

Aldosterone antagonist diuretics reduce myocardial & vascular fibrosis caused by aldosterone:

Spironolactone Eplerenone (less androgenic side effects)

Aldosterone antagonist diuretics reduce morbidity & mortality

Renin-Angiotensin System InhibitorsRenin-Angiotensin System Inhibitors

ACE Inhibitors ACE Inhibitors

a) Reduce peripheral resistance reduce afterload

b) Reduce salt & water retention reduce preload

c) Reduce sympathetic activity

d) Reduce long-term remodeling of the heart & vessels

ACE inhibitors reduce morbidity & mortality

Angiotensin II Receptor Blockers Angiotensin II Receptor Blockers (ARBs)(ARBs)

Produce similar but more limited beneficial effects.

Renin InhibitorsRenin Inhibitors

AliskirenApproved for primary hypertension In clinical trails for heart failurePreliminary results suggests an efficacy

similar to that of ACE inhibitors.

VasodilatorsVasodilators

Are effective in acute heart failure. Reduce afterload or preload or both Long-term use of hydralazine and

isosorbide dinitrate can reduce remodeling.

Hydralazine-isosorbide dinitrate reduce morbidity & mortality

VasodilatorsVasodilators

Nesiritide (a synthetic form of endogenous “brain natriuretic peptide” (BNP) causes:a) venous & arteriolar dilation b) diuresis

Approved for use in acute heart failure.

Beta-Adrenoceptor BlockersBeta-Adrenoceptor Blockers

Studies with bisoprolol, carvedilol & metoprolol have shown a reduction in mortality in patient with stable severe CHF (class II-IV).

-Blockers reduce morbidity & mortality

Metoprolol & CHFMetoprolol & CHF

Beta-Adrenoceptor BlockersBeta-Adrenoceptor Blockers

The suggested mechanisms include:

a) Attenuation of the adverse effects of high level of catecholamines (including apoptosis and remodeling)

b) Up-regulation of beta-receptors

c) Decreased heart rate

Case StudyCase Study A 50-year-old man has developed dyspnea with

exertion several weeks after a viral illness. This is accompanied by swelling feet and ankles and some increasing fatigue. On physical examination he is found to be mildly short of breath lying down, but feels better sitting upright. Pulse is 105 and regular, and blood pressure is 90/60 mm Hg. An echocardiogram shows a LVEF of about 25%. The diagnosis is dilated cardiomyopathy secondary to viral infection. What treatments are available for the patient?

Case StudyCase Study

The patient is placed on a low-sodium diet. He was treated with: furosemide 40 mg twice dailydigoxin 0.25 mg daily enalapril 20 mg twice daily