vilasinee hirunpanich b.pharm, m.sc in pharm (pharmacology)
TRANSCRIPT
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Vilasinee Hirunpanich
B.Pharm, M.Sc In Pharm (Pharmacology)
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Congestive heart failure
Systolic dysfunction ผลจากการที่�กลามเนื้��อหั�วใจไม�สามารถส�บฉี�ดเล�อดไปเล��ยงเนื้��อเย�อ
ต่�างๆ ไดเพี�ยงพีอก�บความต่องการของร�างกาย Diastolic dysfunction กลามเนื้��อหั�วใจไม�สามารถคลายต่�วรองร�บเล�อดเขาส��หั�วใจไดด�พีอ
Definition
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อาการแสดง
Dypnea
Fatigue
Fluid retention
Shortness of breath
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สาเหัต่%ของการเก&ด heart failure
Decrease cardiac output
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Compensatory mechanisms
1. Extrinsic compensatory
2. Intrinsic compensatory
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Extrinsic compensatory
Increase the sympathetic systemHR, contraction
Stimulate renin-angiotensin systemaldosterone
Sodium and Water retention
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Intrinsic compensatory
Frank-Starling mechanism
Myocardial hypertrophy
remodeling
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ลด Cardiac output
เพี&มsympathetic discharge
ลดrenal perfusion
เพี&มการหัล�งrenin
เพี&มcontractility
HRvasoconstriction
เพิ่� มafterload
Ventricular hypertrophy
AT II
aldosterone
Fluid retention
Left Ventricular cannot pump blood
Intrinsic compensatory Extrinsic compensatory
เพี&ม preload
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Failure compensatory mechanism
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อาการที่�เก&ดข'�นื้หัากเก&ดการลม เหัลวของ compensatory
mechanism
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Management of heart failure
Prevention of initial causative
Pharmacological treatment
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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)
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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, ACEIAfterload: Direct vasodilatorDecrease activation of neurohormone: ACEI, -blocker, spironolactone
Goal: to relief symptom
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Heart failure
Decreased cardiac output
Increased venous volume and pressureCongestion and edemaDysnea and orthopnea
Decreased tissue perfusionNeuroendocrine system activation
Sympathetic activation
RAS
vasoconstriction
Na retentionIncreased
afterload
Positive inotropicvasodil
ator
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Positive inotropic drugs
Cardiac glycoside
Digitalis, digoxin, quabain Non-cardiac glycoside
– Phosphodiesterase inhibitors (PDEI)– Catecholamine (Dopamine, Dobutamine)
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Cardiac glycoside
Digoxin is the prototype. Digitalis lanata, Digitalis purpurea Digoxin, digitoxin, quabain
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Lactone ring and steroid nucleus are essential for activity
sugar molecule influence pharmacokinetic
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Pharmacological effects
1. Positive inotropic effectGlycoside
Inh. Of Na+/K+ ATPase
Decrease Na+/Ca2+ exchange
Increase cardiac [Ca2+]
Increase contraction
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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.
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Parasympathetic activation
AV-node inhibition, increase refractory period
Sympathetic inhibition– Inhibit sympathetic discharge– Inhibit renin release
2.Sensitized baroreceptor reflex
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3. Decrease electrical activity
Decrease action potential depolarization Decrease conduction velocity
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4. Other effects
Muscle– Slightly increase Ca2+ in muscle
GI– N/V, stimulate CTZ (vomiting center)
CNS– Disorientation, hallucination, convulsion
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Pharmacokinetics
Absorption Variable oral bioavailability depend on
dosage form– 70% tablet– 85% elixir– 95% capsule
10% of pts. metabolism by Eubacterium lentum
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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.
Distribution
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Metabolism
Enterohepatic recycling Gut bacterial enzyme conjugation
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Excretion
Renal route T1/2
1.6 day
Pts with renal disease increase T1/2 3.5-4.5 d.
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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)
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ADRGI N/V, vomiting, diarrhea, abdominal pain,
constipationNeurologic Headache, fatigue, insomnia, vertigoVisual Color vision (green or yellow), colored halos
around the subjectMiscellenoues Allergic, thrombocytopenia, necrosis
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ADR (cont)
Heart SA and AV node suppression AV block Atrial arrhythmia Ventricular arrhythmia
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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.
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Clinical Use
To improve clinical status of the patient Combination with -blocker, diuretic,
ACEI
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1.catecholamine
2. PDEI
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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
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PDEI (phosphodiesterase enzyme inhibitor)
Bipyridine derivatives– Amrinone, milrinone, vesnarinone
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Pharmacological actions
Positive inotropic effect
Peripheral vasodilation
Coronary vasodilation
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Mechanism of PDE inhibitors
Drug inhibit PDE enz.
Increase cAMP
heart Vascular smooth muscle
เพี&ม Ca2+ influx
ลด Ca2+ efflux
เพี&ม Ca2+ efflux
ลด Ca2+ influx
HR vasodilation
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ADR
Cardiac arrhythmia Hypotension N/V Amrinone………. Thrombocytopenia,
liver enzyme Milirinone…….. Bone marrow
suppression, liver toxicity
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Vasodilators
Reduce preload/afterload Venodilator…Isosorbide, nitroglycerine Vasodilator….hydralazine, minoxidil, Ca2+
channel blocker Both Venodilator and Vasodilator……
ACEI, prazosin
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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
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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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เพี&มการข�บนื้(�าออกจากร�างกาย, ลด blood volume
Thiazide diuretic, loop diuretic, K+ sparing diuretic
Loop diuretic ใช้ในื้กรณี�ที่�ม� CO ลดลงร%นื้แรง และใช้ thiazide ไม�ไดผลแลว (GFR <30 ml/min)
Diuretic+ACEI/-blocker > monotherapy
(will stimulate RAAS)
DiureticGoal: decrease edema and pulmonary congestion
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ขอควรระว�งในื้การใช้ diuretic ในื้ การร�กษา CHF
Electrolytes depletion Serious cardiac arrhythmia Add K+ sparing diuretic Neurohormonal activation increase activation of RAAS Add ACEIHypotension Excessive use Worsening heart failure
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beta-blockers Effect in CHF
– Block SNS effects – Block renin
Improve symptoms and clinical status Combination with diuretic, ACEI, digoxin,
vasodilators Bisoprolol, metoprolol, Carvedilol
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Risk of treatment
Hypotension Fluid retention & worsening CHF Bradycardia & heart block Contraindication in pts with CHF
exacerbation
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Aldosterone antagonist
Spironolactone Research study indicate that spironolactone
reduce mortality and morbidity in CHF. Monitor K+ level.