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

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Presentation on theme: "Vilasinee Hirunpanich B.Pharm, M.Sc In Pharm (Pharmacology)"— Presentation transcript:

1 Vilasinee Hirunpanich B.Pharm, M.Sc In Pharm (Pharmacology)
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 เพิ่มcontractility ลดrenal perfusion 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 Neurohormone model (1980-2000)
Hemodynamic model ( ) 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)

13 Treatment of CHF 1. Control salt and water retention (diuretic)
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 vasoconstriction Na retention 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

20

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 GI CNS Slightly increase Ca2+ in muscle
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 T1/2 1.6 day
Pts with renal disease increase T1/ d.

29 Therapeutic concentration
Drug has narrow therapeutic index. Therapeutic range 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 เพิ่มการขับน้ำออกจากร่างกาย, ลด blood volume
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 Improve symptoms and clinical status
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

51 Aldosterone antagonist
Spironolactone Research study indicate that spironolactone reduce mortality and morbidity in CHF. Monitor K+ level.


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