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Vilasinee Hirunpanich
B.Pharm, M.Sc In Pharm (Pharmacology)
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
อาการแสดง
Dypnea
Fatigue
Fluid retention
Shortness of breath
สาเหัต่%ของการเก&ด heart failure
Decrease cardiac output
Compensatory mechanisms
1. Extrinsic compensatory
2. Intrinsic compensatory
Extrinsic compensatory
Increase the sympathetic systemHR, contraction
Stimulate renin-angiotensin systemaldosterone
Sodium and Water retention
Intrinsic compensatory
Frank-Starling mechanism
Myocardial hypertrophy
remodeling
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
Failure compensatory mechanism
อาการที่�เก&ดข'�นื้หัากเก&ดการลม เหัลวของ compensatory
mechanism
Management of heart failure
Prevention of initial causative
Pharmacological treatment
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)
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
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
Positive inotropic drugs
Cardiac glycoside
Digitalis, digoxin, quabain Non-cardiac glycoside
– Phosphodiesterase inhibitors (PDEI)– Catecholamine (Dopamine, Dobutamine)
Cardiac glycoside
Digoxin is the prototype. Digitalis lanata, Digitalis purpurea Digoxin, digitoxin, quabain
Lactone ring and steroid nucleus are essential for activity
sugar molecule influence pharmacokinetic
Pharmacological effects
1. Positive inotropic effectGlycoside
Inh. Of Na+/K+ ATPase
Decrease Na+/Ca2+ exchange
Increase cardiac [Ca2+]
Increase contraction
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.
Parasympathetic activation
AV-node inhibition, increase refractory period
Sympathetic inhibition– Inhibit sympathetic discharge– Inhibit renin release
2.Sensitized baroreceptor reflex
3. Decrease electrical activity
Decrease action potential depolarization Decrease conduction velocity
4. Other effects
Muscle– Slightly increase Ca2+ in muscle
GI– N/V, stimulate CTZ (vomiting center)
CNS– Disorientation, hallucination, convulsion
Pharmacokinetics
Absorption Variable oral bioavailability depend on
dosage form– 70% tablet– 85% elixir– 95% capsule
10% of pts. metabolism by Eubacterium lentum
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
Metabolism
Enterohepatic recycling Gut bacterial enzyme conjugation
Excretion
Renal route T1/2
1.6 day
Pts with renal disease increase T1/2 3.5-4.5 d.
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)
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
ADR (cont)
Heart SA and AV node suppression AV block Atrial arrhythmia Ventricular arrhythmia
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.
Clinical Use
To improve clinical status of the patient Combination with -blocker, diuretic,
ACEI
1.catecholamine
2. PDEI
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
PDEI (phosphodiesterase enzyme inhibitor)
Bipyridine derivatives– Amrinone, milrinone, vesnarinone
Pharmacological actions
Positive inotropic effect
Peripheral vasodilation
Coronary vasodilation
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
ADR
Cardiac arrhythmia Hypotension N/V Amrinone………. Thrombocytopenia,
liver enzyme Milirinone…….. Bone marrow
suppression, liver toxicity
Vasodilators
Reduce preload/afterload Venodilator…Isosorbide, nitroglycerine Vasodilator….hydralazine, minoxidil, Ca2+
channel blocker Both Venodilator and Vasodilator……
ACEI, prazosin
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
ACEI in CHF
Contraindicated in Angioedma Anuric renal failure Pregnancy
Use with caution in pts with Serum K+> 5.5 mmole/L
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
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
beta-blockers Effect in CHF
– Block SNS effects – Block renin
Improve symptoms and clinical status Combination with diuretic, ACEI, digoxin,
vasodilators Bisoprolol, metoprolol, Carvedilol
Risk of treatment
Hypotension Fluid retention & worsening CHF Bradycardia & heart block Contraindication in pts with CHF
exacerbation
Aldosterone antagonist
Spironolactone Research study indicate that spironolactone
reduce mortality and morbidity in CHF. Monitor K+ level.