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PROF. AZZA El- Medany Department of Pharmacology

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.).

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PROF. AZZA El- Medany Department of Pharmacology

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  1. PROF. AZZA El-Medany Department of Pharmacology

  2. OBJECTIVES • At the end of lectures the students should • Describe the different classes of drugs used for treatment of acute & chronic heart failure

  3. OBJECTIVES ( cont.) • Describe the mechanism of action , therapeutic uses , side effects & drug interactions of individual drugs used for the treatment of heart failure

  4. HEART FAILURE ? Inability of the heart to maintain an adequate cardiac outputto meet the metabolic demands of the body.

  5. CAUSES OF HEART FAILURE

  6.  Force of contraction Low C.O.  Carotid sinus firing  Renal blood flow Activate sympathetic system  Sympathetic discharge Activate renin-angiotensin- Aldosterone system ALDOST. Ag. II Remodeling Salt & Water Retention Volume expansion Vasoconstriction  Force of Cardiac .cont.  HR . Venous VC Arterial VC  Preload  Preload  After load  C.O. Via compensation Pathophysiology of CHF

  7. Heart failure symptoms • Tachycardia • Decreased exercise tolerance (rapid fatigue) . • Dyspnea ( pulmonary congestion) • Peripheral edema. • Cardiomegaly.

  8. Dyspnea l l l l l l • Oedema of lower limbs

  9. Factors affecting cardiac output and Heart Failure • Cardiac contractility • Preload • Afterload • Heart rate.

  10. Drugs used in the treatment of heart failure Drugs that increase contractility • Cardiac glycosides • Phosphodiesterase inhibitors • β- adrenoceptor agonists

  11. Drugs that decrease preload • Diuretics • Venodilators

  12. Drugs that decrease afterload • Arteriolodilators

  13. Drugs that decrease preload & afterload • ACEI & ARB • α1-adrenoceptor antagonists • Directly-acting vasodilators

  14. Drugs That Increase Contractility • Cardiac glycosides • Phosphodiesterase inhibitors • β- adrenoceptor agonists

  15. CARDIAC GLYCOSIDES Digoxin / Digitoxin / Ouabain Digitalis Lanata Sugar &steroid like

  16. CARDIAC GLYCOSIDES Digoxin / PHARMACOKINETICS Drug has narrow therapeutic index 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

  17. Mechanism of action • Inhibits Na+ / K+ ATP ase

  18. MECHANISM OF ACTION

  19. CARDIAC GLYCOSIDES PHARMACOLOGICAL ACTIONS: CARDIAC: 1-Increase the force of myocardial contraction ( +ve inotropic) Marked increase in CO .

  20. Continue • 2- Slow heart rate Mediated through vagal nerve stimulation.

  21. Therapeutic uses • Congestive heart failure • Atrial flutter / Atrial fibrillation

  22. adverse effects CARDIAC • Arrhythmias

  23. Extra -cardiac adverse effects • GITupset : The earliest signs of digoxin toxicity (Anorexia ,nausea) • C.N.S. :Headache, visual disturbances, drowsiness

  24. Factors increase digitalis toxicity • SmallLean body mass • Renal diseases • Hypokalemia • Hypomagnesemia • Hypercalemia

  25. Treatment OF ADVERSE EFFECTS HEART CNS Vision GIT ??? • Atropine • Antiarrythmics • K supplements • FAB fragment life saving Digoxin

  26. Contraindications • Toxic myocarditis • Constrictive pericarditis

  27. Drug interactions • Diuretics hypokalemia (arrhythmia) • Quinidine : plasma level of digitalis

  28. β-Adrenoceptor agonists Dopamine :Acts on: α ,β1 and dopamine receptors. Uses: acute H.F. mainly in patients with impaired renal blood flow. Dobutamine : MoreSelective β1 agonist acute heart failure & Cardiogenic shock

  29. Phosphodiesterase Inhibitors • Bipyridines :(Amrinone ,Milrinone ) • onlyavailable in IV form. • Half-life 3-6hrs. • Excreted in urine.

  30. Mechanism of action • Inhibit phosphodiesteraseisozyme 3 in cardiac & smooth muscles → :↑ cAMP In the heart : Increase myocardial contraction In the peripheral vasculature : Dilatation of both arteries & veins →↓ afterload & preload.

  31. Therapeutic uses • For short -term management of heart failure { acute heart failure }

  32. Adverse effects • Nausea ,vomiting • Arrhythmias (less than digitalis ) • Thrombocytopenia • Liver toxicity • Milrinone less toxic than amrinone.

  33. Drugs used to reduce preload • Diuretics • Venodilators

  34. Diuretics • Among First-line therapy of heart failure • Remove the signs and symptoms of volume overload (pulmonary congestion/ peripheral edema ).

  35. Diuretics • Reduce salt and water retentionventricular preload and venous pressure. • Reduction of cardiac size improve cardiac performance e.g. Furosemide , Hydrochlorothiazide , spironolactone

  36. Venodilators • 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.

  37. Reduction of Afterload Arteriolodilators • Hydralazine reduce after-load in CHF. • Used when the main symptom is rapidfatigue due to low cardiac output.

  38. Reduction of afterload & preload

  39. ACE Inhibitors & Angiotensin Receptor Blockers • Along with digitalis and diuretics are now considered as first –line drugs for heart failure therapy

  40. Angiotensin converting enzyme inhibitors MECHANISM OF ACTION VASOCONSTRICTION VASODILATATION ALDOSTERONE VASOPRESSIN SYMPATHETIC Angiotensinogen RENIN BRADYKININ Angiotensin I A.C.E. Inhibitor INACTIVATION ANGIOTENSIN II

  41. Angiotensin receptor blockers Mechanism of action Block AT1 receptors decreasing the action of angiotensin 11 e.g. losartan ( ARB) e.g. captopril ( ACEI)

  42. Effects of converting enzyme inhibitors & angiotensin receptor blockers in heart failure • Peripheral resistance ( Afterload ) • Venous return ( Preload) • sympathetic activity • cardiac remodeling mortality rate

  43. Direct acting vasodilators • Sodiumnitropruside • given I.V. in acute or severe refractory heart failure, acts immediately and effects lasts for 1-5 minutes.

  44. Uses of β-adrenoceptor blockers in heart failure • Reduce catecholamine myocyte toxicity ( remodeling) • Decrease mortality rate • Decrease heart rate • Inhibit renin release e.g. Carvedilol , Metoprolol ,bisoprolol

  45. Management of chronic heart failure • Reduce work load of the heart • Limits patient activity • Reduce weight • Control hypertension • Restrict sodium • Diuretics • ACEI or ARBs

  46. Management of chronic heart failure (Cont.) • Digitalis • β- blockers • Vasodilators

  47. Management of acute heart failure • Volume replacement • Diuretics • Positive inotropic drugs • Vasodilators • Antiarrhythmic drugs • Treatment of myocardial infarction

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