Vilasinee Hirunpanich B.Pharm, M.Sc In Pharm (Pharmacology)

1. Drugs treatment in heart failure Vilasinee Hirunpanich B.Pharm, M.Sc In Pharm (Pharmacology)

2. Congestive heart failure • Definition • Systolic dysfunction ผลจากการที่กล้ามเนื้อหัวใจไม่สามารถสูบฉีดเลือดไปเลี้ยงเนื้อเยื่อต่างๆ ได้เพียงพอกับความต้องการของร่างกาย • Diastolic dysfunction กล้ามเนื้อหัวใจไม่สามารถคลายตัวรองรับเลือดเข้าสู่หัวใจได้ดีพอ

3. อาการแสดง Dypnea Fatigue Fluid retention Shortness of breath

4. สาเหตุของการเกิด heart failure Decrease cardiac output

5. Compensatory mechanisms 1. Extrinsic compensatory 2. Intrinsic compensatory

6. Extrinsic compensatory • Increase the sympathetic system HR, contraction • Stimulate renin-angiotensin system aldosterone • Sodium and Water retention

7. Intrinsic compensatory • Frank-Starling mechanism • Myocardial hypertrophy • remodeling

8. Left Ventricular cannot pump blood ลด Cardiac output Intrinsic compensatory Extrinsic compensatory เพิ่มsympathetic discharge ลดrenal perfusion เพิ่มcontractility vasoconstriction HR เพิ่มการหลั่ง renin AT II aldosterone เพิ่ม afterload Fluid retention Ventricular hypertrophy เพิ่ม preload

9. Failure compensatory mechanism Congestive heart faliure

10. อาการที่เกิดขึ้นหากเกิดการล้มเหลวของ compensatory mechanism

11. Management of heart failure • Prevention of initial causative • Pharmacological treatment

12. increase contractility Treatment Conventional drugs Diuretic Digitalis vasodilators Progressive remodeling with impaired myocardial performance Treatment Conventional drugs Decreasing the process of cardiac remodeling (ACEI, -blocker, nitrate) Neurohormone blockers ACEI (RAAS) Spironolactone (aldosterone) -blocker (renin) Digoxin (renin) • Neurohormone model (1980-2000) • Hemodynamic model • (1950-1980)

13. Treatment of CHF • Goal: to relief symptom 1. Control salt and water retention (diuretic) 2. Increase myocardial contractility (inotropic drugs) 3. Reduce work load of heart by Preload: Diuretic, Nitrate, ACEI Afterload: Direct vasodilator Decrease activation of neurohormone: ACEI, -blocker, spironolactone

14. Heart failure Positive inotropic vasodilator Decreased cardiac output Increased venous volume and pressure Decreased tissue perfusion Neuroendocrine system activation Congestion and edema Dysnea and orthopnea Sympathetic activation RAS Na retention vasoconstriction Increased afterload

15. Positive inotropic drugs

16. Positive inotropic drugs • Cardiac glycoside Digitalis, digoxin, quabain • Non-cardiac glycoside • Phosphodiesterase inhibitors (PDEI) • Catecholamine (Dopamine, Dobutamine)

17. Cardiac glycoside • Digoxin is the prototype. • Digitalis lanata, Digitalis purpurea • Digoxin, digitoxin, quabain

18. structure • Lactone ring and steroid nucleus are essential for activity • sugar molecule influence pharmacokinetic

19. Pharmacological effects 1. Positive inotropic effect Glycoside  Inh. Of Na+/K+ ATPase  Decrease Na+/Ca2+ exchange  Increase cardiac [Ca2+]  Increase contraction

21. Positive inotropic effect (cont) • Binding with Na+/K+ ATPase thus inhibit Na+ pump • 20-40 % inhibition therapeutic • >50 % inhibition toxic Increase the force of contraction of both normal and failure heart. Improvement hemodynamic in failure heart.

22. 2.Sensitized baroreceptor reflex • Parasympathetic activation AV-node inhibition, increase refractory period • Sympathetic inhibition • Inhibit sympathetic discharge • Inhibit renin release

23. 3. Decrease electrical activity • Decrease action potential depolarization • Decrease conduction velocity

24. 4. Other effects • Muscle • Slightly increase Ca2+ in muscle • GI • N/V, stimulate CTZ (vomiting center) • CNS • Disorientation, hallucination, convulsion

25. Pharmacokinetics Absorption • Variable oral bioavailability depend on dosage form • 70% tablet • 85% elixir • 95% capsule 10% of pts. metabolism by Eubacterium lentum

26. Distribution • Vd 7-8 L/kg • Little affinity for distribution into fat (dosing should base on ideal body weight) • Myocardial/serum digoxin concentration ratio are approximately 30:1. • Hypokalemia increase the binding of digoxin to heart.

27. Metabolism • Enterohepatic recycling • Gut bacterial enzyme • conjugation

28. Excretion • Renal route • T1/21.6 day • Pts with renal disease increase T1/2 3.5-4.5 d.

29. Therapeutic concentration • Drug has narrow therapeutic index. • Therapeutic range 0.5-2 ng/ml (after 4-5 T1,/2) • Dose adjustment when drug reach to steady State. (equilibrium between heart and serum)

30. ADR GI • N/V, vomiting, diarrhea, abdominal pain, constipation Neurologic • Headache, fatigue, insomnia, vertigo Visual • Color vision (green or yellow), colored halos around the subject Miscellenoues • Allergic, thrombocytopenia, necrosis

31. ADR (cont) Heart • SA and AV node suppression • AV block • Atrial arrhythmia • Ventricular arrhythmia

32. Risk of treatment • Serum digoxin level > 2 ng/ml • Cardiac arrhythmia • GI symptom • Neurogenic compliant • Lower digoxin level is toxic if hypokalemia, hypomagnesemia and hypercalcemia. • Comcomittent use of quinidine, verapamil, flecainide and amiodarone which increase digoxin level.

33. Clinical Use • To improve clinical status of the patient • Combination with -blocker, diuretic, ACEI

34. Non cardiac glycoside 1.catecholamine 2. PDEI

35. Catecholamine • Dopamine  1, 1 DA receptor Increase NE… tachycardia • Dobutamine • synthetic analoge of dopamine • Stimulate 1> 2 receptor and >  receptor (not DA receptor) • positive inotropic • Use in refractory HF, sever acute MI, cardiotonic shock

36. PDEI (phosphodiesterase enzyme inhibitor) • Bipyridine derivatives • Amrinone, milrinone, vesnarinone

37. Pharmacological actions • Positive inotropic effect • Peripheral vasodilation • Coronary vasodilation

38. Mechanism of PDE inhibitors Drug inhibit PDE enz. Increase cAMP Vascular smooth muscle heart เพิ่ม Ca2+ influx ลด Ca2+ efflux เพิ่ม Ca2+ efflux ลด Ca2+ influx HR vasodilation

39. ADR • Cardiac arrhythmia • Hypotension • N/V • Amrinone………. Thrombocytopenia, liver enzyme • Milirinone…….. Bone marrow suppression, liver toxicity

40. 2.vasodilators

41. Vasodilators • Reduce preload/afterload • Venodilator…Isosorbide, nitroglycerine • Vasodilator….hydralazine, minoxidil, Ca2+ channel blocker • Both Venodilator and Vasodilator……ACEI, prazosin

42. ACEI • ACEI in CHF • Report that reduce remodeling • Reduce aldosterone from the compensatory mechanism • Vasodilate (Preload/after load) • Improve symptoms and clinical status and decrease the risk of death and hospitalization in mild, moderate, severe heart failure. • Decrease risk of HF in pts with LV-dysfunction

43. ACEI in CHF Contraindicated in • Angioedma • Anuric renal failure • Pregnancy Use with caution in pts with • Serum K+> 5.5 mmole/L

44. 3.Diuretic

45. Diuretic Goal: decrease edema and pulmonary congestion • เพิ่มการขับน้ำออกจากร่างกาย, ลด blood volume • Thiazide diuretic, loop diuretic, K+ sparing diuretic • Loop diuretic ใช้ในกรณีที่มี CO ลดลงรุนแรงและใช้ thiazide ไม่ได้ผลแล้ว (GFR <30 ml/min) • Diuretic+ACEI/-blocker > monotherapy (will stimulate RAAS)

46. ข้อควรระวังในการใช้ diuretic ในการรักษา CHF Electrolytes depletion • Serious cardiac arrhythmia • Add K+ sparing diuretic Neurohormonal activation • increase activation of RAAS • Add ACEI Hypotension • Excessive use • Worsening heart failure

47. Other drugs

48. beta-blocker

49. beta-blockers • Effect in CHF • Block SNS effects • Block renin • Improve symptoms and clinical status • Combination with diuretic, ACEI, digoxin, vasodilators • Bisoprolol, metoprolol, Carvedilol

50. Risk of treatment • Hypotension • Fluid retention & worsening CHF • Bradycardia & heart block • Contraindication in pts with CHF exacerbation