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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)

2 Congestive heart failure  Systolic dysfunction ผลจากการที่ กล้ามเนื้อหัวใจไม่สามารถสูบฉีดเลือดไป เลี้ยงเนื้อเยื่อต่างๆ ได้เพียงพอกับความ ต้องการของร่างกาย  Diastolic dysfunction กล้ามเนื้อหัวใจไม่ สามารถคลายตัวรองรับเลือดเข้าสู่หัวใจได้ ดีพอ Definition

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 ลด Cardiac output เพิ่ม sympatheti c discharge ลด renal perfusion เพิ่มการหลั่ง renin เพิ่ม contractilit y  HR vasoconstriction เพิ่ม afterload Ventricular hypertrophy AT II aldosterone Fluid retention Left Ventricular cannot pump blood Intrinsic compensatoryExtrinsic compensatory เพิ่ม preload

9 Failure compensatory mechanism

10 อาการที่เกิดขึ้นหากเกิดการ ล้มเหลวของ 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) Hemodynamic model (1950-1980) Neurohormone model (1980-2000)

13 Treatment of CHF 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 Goal: to relief symptom

14 Heart failure Decreased cardiac output Increased venous volume and pressure Congestion and edema Dysnea and orthopnea Decreased tissue perfusion Neuroendocri ne system activation Sympath etic activatio n RAS vasoconstri ction Na retenti on Increased afterload Positive inotropic vasodila tor

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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  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 + /Ca 2+ exchange  Increase cardiac [Ca 2+ ]  Increase contraction

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

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

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

24 4. Other effects  Muscle – Slightly increase Ca 2+ 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  V d 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. Distribution

27 Metabolism  Enterohepatic recycling  Gut bacterial enzyme  conjugation

28 Excretion  Renal route  T 1/2 1.6 day  Pts with renal disease increase T 1/2 3.5-4.5 d.

29 Therapeutic concentration  Drug has narrow therapeutic index.  Therapeutic range 0.5-2 ng/ml (after 4-5 T 1,/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 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 heart Vascular smooth muscle เพิ่ม Ca 2+ influx ลด Ca 2+ efflux เพิ่ม Ca 2+ efflux ลด Ca 2+ influx  HR vasodilation

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

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41 Vasodilators  Reduce preload/afterload  Venodilator…Isosorbide, nitroglycerine  Vasodilator….hydralazine, minoxidil, Ca 2+ 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

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

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

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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

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


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