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.