2. PROF. AZZA El-Medany Department of Pharmacology

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

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

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

6. CAUSES OF HEART FAILURE CAUSES OF HEART FAILURE

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

9. Tachycardia Decreased exercise tolerance (rapid fatigue). Dyspnea ( pulmonary congestion) Peripheral edema. Cardiomegaly.

10.  Dyspnea  Oedema of lower limbs

11. Cardiac contractility Preload Afterload Heart rate.

12. Drugs that increase contractility Cardiac glycosides Phosphodiesterase inhibitors β- adrenoceptor agonists

13. Drugs that decrease preload Diuretics Venodilators

14. Drugs that decrease afterload Arteriolodilators

15. Drugs that decrease preload & afterload ACEI & ARB α 1 -adrenoceptor antagonists Directly-acting vasodilators

16. Cardiac glycosides Phosphodiesterase inhibitors β- adrenoceptor agonists

17. CARDIAC GLYCOSIDES Digoxin / Digitoxin / Ouabain Digitalis Lanata Sugar &ste roid like

18. PHARMACOKINETICS 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, t 1/2 40 hrs Drug has narrow therapeutic index

19. Mechanism of action Inhibits Na + / K + ATP ase

20. MECHANISM OF ACTION

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

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

23. Therapeutic uses Congestive heart failure Atrial flutter / Atrial fibrillation

24. adverse effects adverse effects CARDIAC Arrhythmias

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

26. Factors increase digitalis toxicity Small Lean body mass Renal diseases Hypokalemia Hypomagnesemia Hypercalemia

27. Treatment OF ADVERSE EFFECTS HEART CNS Vision GIT AAtropine AAntiarrythmics KK supplements  FAB fragment life saving Digoxin

28. Contraindications Toxic myocarditis Constrictive pericarditis

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

30. Dopamine :Acts on: α,β 1 and dopamine receptors. Uses: acute H.F. mainly in patients with impaired renal blood flow. Dobutamine : More Selective β 1 agonist acute heart failure & Cardiogenic shock

31. Bipyridines :(Amrinone,Milrinone ) only available in IV form. Half-life 3-6hrs. Excreted in urine.

32. Mechanism 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.

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

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

35. Drugs used to reduce preload Diuretics Venodilators

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

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

38. 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.

39. Reduction of Afterload Arteriolodilators Hydralazine reduce after-load in CHF. Used when the main symptom is rapid fatigue due to low cardiac output.

40. Reduction of afterload & preload

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

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

43. Angiotensin receptor blockers Mechanism of action Block AT 1 receptors  decreasing the action of angiotensin 11 e.g. losartan ( ARB) e.g. captopril ( ACEI)

44.  Peripheral resistance ( Afterload )  Venous return ( Preload)  sympathetic activity  cardiac remodeling  mortality rate

45. Sodium nitropruside given I.V. in acute or severe refractory heart failure, acts immediately and effects lasts for 1- 5 minutes.

46. 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

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

48. Management of chronic heart failure (Cont.)  Digitalis  β- blockers  Vasodilators

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