prof. azza el-medany department of pharmacology objectives at the end of lectures the students...
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PROF.
AZZA El-Medany
Department of Pharmacology
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OBJECTIVES
At the end of lectures the students should
Describe the different classes of drugs used for treatment of acute & chronic heart failure
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OBJECTIVES ( cont.)
Describe the mechanism of action , therapeutic uses , side effects & drug interactions of individual drugs used for the treatment of heart failure
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HEART FAILUREHEART FAILUREHEART FAILUREHEART FAILURE
Inability of the heart to maintain an adequate cardiac output to meet the metabolic demands of the body.
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CAUSES OF HEART FAILURECAUSES OF HEART FAILURECAUSES OF HEART FAILURECAUSES OF HEART FAILURE
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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
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Tachycardia
Decreased exercise tolerance (rapid fatigue) .
Dyspnea ( pulmonary congestion)
Peripheral edema.
Cardiomegaly.
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Dyspnea
Oedema of lower limbs
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Cardiac contractility
Preload
Afterload
Heart rate.
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Drugs that increase Drugs that increase contractilitycontractility
Cardiac glycosides
Phosphodiesterase inhibitors
β- adrenoceptor agonists
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Drugs that decrease Drugs that decrease preloadpreload
Diuretics
Venodilators
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Drugs that decrease Drugs that decrease afterloadafterload
Arteriolodilators
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Drugs that decrease Drugs that decrease preload & afterloadpreload & afterload
ACEI & ARB
α1-adrenoceptor antagonists
Directly-acting vasodilators
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Cardiac glycosides
Phosphodiesterase inhibitors
β- adrenoceptor agonists
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CARDIAC GLYCOSIDES
Digoxin / Digitoxin / Ouabain Digitalis Lanata
Sugar &steroid like
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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
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Mechanism of action
Inhibits Na+ / K+ ATP ase
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MECHANISM OF ACTION
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CARDIAC GLYCOSIDESPHARMACOLOGICAL ACTIONS:
CARDIAC:
1- Increase the force of myocardial contraction ( +ve inotropic) Marked increase in CO .
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Continue
2- Slow heart rate
Mediated through vagal nerve stimulation.
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Therapeutic uses
Congestive heart failure
Atrial flutter / Atrial fibrillation
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adverse effectsadverse effects
CARDIAC
Arrhythmias
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Extra -cardiac adverse Extra -cardiac adverse effectseffects
GIT upset : The earliest signs of digoxin toxicity
(Anorexia ,nausea)
C.N.S. :Headache, visual disturbances, drowsiness
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Factors increase Factors increase digitalis toxicitydigitalis toxicity
Small Lean body mass
Renal diseases
Hypokalemia
Hypomagnesemia
Hypercalemia
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Treatment OF ADVERSE EFFECTS
HEART CNS
Vision
GIT
AtropineAntiarrythmicsK supplements FAB fragment life saving
Digoxin
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ContraindicationsContraindications
Toxic myocarditis
Constrictive pericarditis
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Drug interactionsDrug interactions
Diuretics hypokalemia (arrhythmia)
Quinidine : plasma level of digitalis
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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
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Bipyridines :(Amrinone ,Milrinone )
only available in IV form.
Half-life 3-6hrs.
Excreted in urine.
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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.
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Therapeutic uses Therapeutic uses
For short -term management of heart failure
{ acute heart failure }
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Adverse effectsAdverse effects
Nausea ,vomiting
Arrhythmias (less than digitalis )
Thrombocytopenia
Liver toxicity
Milrinone less toxic than amrinone.
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Drugs used to reduce preload
Diuretics
Venodilators
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Among First-line therapy of heart failure
Remove the signs and symptoms of
volume overload (pulmonary congestion/ peripheral edema ).
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Reduce salt and water
retentionventricular preload and venous pressure.
Reduction of cardiac size improve cardiac performance
e.g. Furosemide , Hydrochlorothiazide , spironolactone
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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.
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Reduction of AfterloadArteriolodilators
Hydralazine reduce after-load in CHF.
Used when the main symptom is rapid fatigue
due to low cardiac output.
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Reduction of afterload & preload
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ACE Inhibitors & Angiotensin Receptor
Blockers
Along with digitalis and diuretics are now considered as first –line drugs for heart failure therapy
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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.
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Angiotensin receptor blockers
Mechanism of action
Block AT1 receptors decreasing the action of angiotensin 11
e.g. losartan ( ARB)
e.g. captopril ( ACEI)
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Peripheral resistance ( Afterload )
Venous return ( Preload)
sympathetic activity
cardiac remodeling mortality rate
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Sodium nitropruside given I.V. in acute or severe
refractory heart failure, acts immediately and effects lasts for 1-5 minutes.
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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
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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
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Management of chronic Management of chronic heart failure (Cont.)heart failure (Cont.)
Digitalis
β- blockers
Vasodilators
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Management of acute heart Management of acute heart failurefailure
Volume replacement
Diuretics
Positive inotropic drugs
Vasodilators
Antiarrhythmic drugs
Treatment of myocardial infarction
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