PROF.

AZZA El-Medany

Department of Pharmacology

OBJECTIVES

At the end of lectures the students should

Describe the different classes of drugs used for treatment of acute & chronic heart failure

OBJECTIVES ( cont.)

Describe the mechanism of action , therapeutic uses , side effects & drug interactions of individual drugs used for the treatment of heart failure

HEART FAILUREHEART FAILUREHEART FAILUREHEART FAILURE

Inability of the heart to maintain an adequate cardiac output to meet the metabolic demands of the body.

CAUSES OF HEART FAILURECAUSES OF HEART FAILURECAUSES OF HEART FAILURECAUSES OF HEART FAILURE

Force of contraction

Low C.O.

Force of Cardiac .cont. HR .

RemodelingSalt & WaterRetention

Volume expansionVasoconstriction

ALD

OS

T.

Ag. II

C.O. Via

compensation

Activate sympathetic system Sympathetic discharge

Carotid sinus firing

Pathophysiology of CHF

Preload

Venous VC Arterial VC

Preload After load

Renal blood flow

Activate renin-angiotensin-Aldosterone system

Tachycardia

Decreased exercise tolerance (rapid fatigue) .

Dyspnea ( pulmonary congestion)

Peripheral edema.

Cardiomegaly.

Dyspnea

Oedema of lower limbs

Cardiac contractility

Preload

Afterload

Heart rate.

Drugs that increase Drugs that increase contractilitycontractility

Cardiac glycosides

Phosphodiesterase inhibitors

β- adrenoceptor agonists

Drugs that decrease Drugs that decrease preloadpreload

Diuretics

Venodilators

Drugs that decrease Drugs that decrease afterloadafterload

Arteriolodilators

Drugs that decrease Drugs that decrease preload & afterloadpreload & afterload

ACEI & ARB

α1-adrenoceptor antagonists

Directly-acting vasodilators

Cardiac glycosides

Phosphodiesterase inhibitors

β- adrenoceptor agonists

CARDIAC GLYCOSIDES

Digoxin / Digitoxin / Ouabain Digitalis Lanata

Sugar &steroid like

PHARMACOKINETICSPHARMACOKINETICS

CARDIAC GLYCOSIDES

Digoxin /

Absorption: orally : 40-80% I.V. : acts within 15 min-3hrs

Distribution & Metabolism: 25% protein bound, cumulative, metabolized in liver to cardioactive metabolite

Elimination; Slow, mainly renal , t1/2 40 hrs

Drug has narrow therapeutic index

Mechanism of action

Inhibits Na+ / K+ ATP ase

MECHANISM OF ACTION

CARDIAC GLYCOSIDESPHARMACOLOGICAL ACTIONS:

CARDIAC:

1- Increase the force of myocardial contraction ( +ve inotropic) Marked increase in CO .

Continue

2- Slow heart rate

Mediated through vagal nerve stimulation.

Therapeutic uses

Congestive heart failure

Atrial flutter / Atrial fibrillation

adverse effectsadverse effects

CARDIAC

Arrhythmias

Extra -cardiac adverse Extra -cardiac adverse effectseffects

GIT upset : The earliest signs of digoxin toxicity

(Anorexia ,nausea)

C.N.S. :Headache, visual disturbances, drowsiness

Factors increase Factors increase digitalis toxicitydigitalis toxicity

Small Lean body mass

Renal diseases

Hypokalemia

Hypomagnesemia

Hypercalemia

Treatment OF ADVERSE EFFECTS

HEART CNS

Vision

GIT

AtropineAntiarrythmicsK supplements FAB fragment life saving

Digoxin

ContraindicationsContraindications

Toxic myocarditis

Constrictive pericarditis

Drug interactionsDrug interactions

Diuretics hypokalemia (arrhythmia)

Quinidine : plasma level of digitalis

Dopamine :Acts on: α ,β1 and dopamine receptors.

Uses: acute H.F. mainly in patients with impaired renal blood

flow.

Dobutamine : More Selective β1 agonist

acute heart failure &

Cardiogenic shock

Bipyridines :(Amrinone ,Milrinone )

only available in IV form.

Half-life 3-6hrs.

Excreted in urine.

Mechanism of actionMechanism of action

Inhibit phosphodiesterase isozyme 3 in cardiac & smooth muscles → :↑ cAMP

In the heart : Increase myocardial contraction

In the peripheral vasculature : Dilatation of both arteries & veins → ↓ afterload & preload.

Therapeutic uses Therapeutic uses

For short -term management of heart failure

{ acute heart failure }

Adverse effectsAdverse effects

Nausea ,vomiting

Arrhythmias (less than digitalis )

Thrombocytopenia

Liver toxicity

Milrinone less toxic than amrinone.

Drugs used to reduce preload

Diuretics

Venodilators

Among First-line therapy of heart failure

Remove the signs and symptoms of

volume overload (pulmonary congestion/ peripheral edema ).

Reduce salt and water

retentionventricular preload and venous pressure.

Reduction of cardiac size improve cardiac performance

e.g. Furosemide , Hydrochlorothiazide , spironolactone

Nitroglycerine is used for short term IV treatment of severe heart failure and relief dyspnea due to pulmonary congestion.

Dilate large capacitance veins and reduce preload.

Reduction of AfterloadArteriolodilators

Hydralazine reduce after-load in CHF.

Used when the main symptom is rapid fatigue

due to low cardiac output.

Reduction of afterload & preload

ACE Inhibitors & Angiotensin Receptor

Blockers

Along with digitalis and diuretics are now considered as first –line drugs for heart failure therapy

Angiotensin converting enzyme inhibitorsAngiotensin converting enzyme inhibitorsMECHANISM OF ACTIONMECHANISM OF ACTION

VASOCONSTRICTIONVASOCONSTRICTION VASODILATATION VASODILATATION

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin IRENINRENIN

INACTIVATIONINACTIVATIONInhibitorInhibitor

ALDOSTERONEALDOSTERONE

SYMPATHETICSYMPATHETIC

VASOPRESSINVASOPRESSIN

ANGIOTENSIN IIANGIOTENSIN II

BRADYKININBRADYKININ

A.C.E.A.C.E.

Angiotensin receptor blockers

Mechanism of action

Block AT1 receptors decreasing the action of angiotensin 11

e.g. losartan ( ARB)

e.g. captopril ( ACEI)

Peripheral resistance ( Afterload )

Venous return ( Preload)

sympathetic activity

cardiac remodeling mortality rate

Sodium nitropruside given I.V. in acute or severe

refractory heart failure, acts immediately and effects lasts for 1-5 minutes.

Uses of β-adrenoceptor blockers in heart

failureReduce catecholamine myocyte toxicity ( remodeling)

Decrease mortality rate

Decrease heart rate

Inhibit renin release

e.g. Carvedilol , Metoprolol ,bisoprolol

Management of chronic Management of chronic heart failureheart failure

Reduce work load of the heart Limits patient activityReduce weightControl hypertension

Restrict sodium Diuretics ACEI or ARBs

Management of chronic Management of chronic heart failure (Cont.)heart failure (Cont.)

Digitalis

β- blockers

Vasodilators

Management of acute heart Management of acute heart failurefailure

Volume replacement

Diuretics

Positive inotropic drugs

Vasodilators

Antiarrhythmic drugs

Treatment of myocardial infarction