Transcript Congestive heart failure

Vilasinee Hirunpanich
B.Pharm, M.Sc In Pharm (Pharmacology)
Congestive heart failure
Definition
 Systolic dysfunction ผลจากการที่กล้ามเนื้อหัวใจไม่
สามารถสูบฉีดเลือดไปเลี้ยงเนื้อเยือ่ ต่างๆ ได้เพียงพอกับความ
ต้องการของร่ างกาย
 Diastolic dysfunction กล้ามเนื้อหัวใจไม่สามารถ
คลายตัวรองรับเลือดเข้าสู่หวั ใจได้ดีพอ
อาการแสดง
Dypnea
Fatigue
Fluid retention
Shortness of breath
สาเหตุของการเกิด heart failure
Decrease cardiac output
Compensatory mechanisms
1. Extrinsic compensatory
2. Intrinsic compensatory
Extrinsic compensatory
 Increase the sympathetic system
HR, contraction
 Stimulate renin-angiotensin system
aldosterone
 Sodium and Water retention
Intrinsic compensatory
 Frank-Starling mechanism
 Myocardial hypertrophy
 remodeling
Left Ventricular cannot pump blood
ลด Cardiac output
Intrinsic compensatory
Extrinsic compensatory
เพิ่มcontractility
เพิ่มsympathetic
discharge
vasoconstriction
เพิม่ afterload
Ventricular
hypertrophy
HR
ลดrenal
perfusion
เพิ่มการหลัง่ renin
AT II
aldosterone
Fluid retention
เพิ่ม preload
Failure compensatory
mechanism
อาการที่เกิดขึน้ หากเกิดการล้ มเหลวของ
compensatory mechanism
Management of heart failure
 Prevention of initial causative
 Pharmacological treatment
Hemodynamic model
(1950-1980)
 increase contractility
 Treatment
– Conventional drugs
• Diuretic
• Digitalis
• vasodilators
Neurohormone model
(1980-2000)
 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)
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
Heart failure
vasodilator
Decreased cardiac output
Increased venous volume and pressure
Decreased tissue perfusion
Neuroendocrine system
activation
Congestion and edema
Dysnea and orthopnea
Positive inotropic
Sympathetic
activation
RAS
vasoconstriction
Na retention
Increased afterload
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 effect
Glycoside

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
– >50 % inhibition
therapeutic
toxic
Increase the force of contraction of
both normal and failure heart.
Improvement hemodynamic in failure
heart.
2.Sensitized baroreceptor reflex
 Parasympathetic activation
AV-node inhibition, increase refractory
period
 Sympathetic inhibition
– Inhibit sympathetic discharge
– Inhibit renin release
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
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.
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)
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
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
เพิ่ม Ca2+ influx
เพิ่ม Ca2+ efflux
ลด 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
Diuretic
Goal: decrease edema and pulmonary congestion
 เพิ่มการขับน้ าออกจากร่ างกาย, ลด blood volume
 Thiazide diuretic, loop diuretic, K+
sparing diuretic
 Loop diuretic ใช้ในกรณี ที่มี CO ลดลงรุ นแรงและใช้
thiazide ไม่ได้ผลแล้ว (GFR <30 ml/min)
 Diuretic+ACEI/-blocker > monotherapy
(will stimulate RAAS)
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
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.