Drug Heart Failure m

8/13/2019 Drug Heart Failure m

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DEFINITION

Congestive heart failure is a condition in which the heart is unable toto pump sufficient blood to meet the needs of the body.

It can be caused by an impaired ability of the heart muscle to

contract or an increased workload imposed on the heart.

CONGESTIVE HEART FAILURE

A clinical syndrome caused by an accumulation of fluid peripherally

(right ventricular failure) or in the lungs (left ventricular failure), or

both, from inadequate functioning of the heart. Congestive heart failure

is a complication of an underlying disease process.

Systolic heart failure (the more common form) is due to impaired

systolic pumping action of the heart. Diastolic heart failure occurs when

the systolic function is normal but the filling of the heart is impaired.


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Types of heart failure

Systolic dysfunction or systolic heart failure:

The ventricles are dilated and unable to develop

sufficient wall tension to eject adequate quantityof blood.

Diastolic dysfunction or diastolic heart failure:

The ventricular wall is thickened and unable to

relax properly during diastole, ventricular filling isimpaired and output is low.


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Signs & symptoms of congestive heart failure

heart rate.

Rapid muscular fatigue.

Short breath due to pulmonary edema Myocardial hypertrophy (size of heart)

Renal output

Congestion (excessive amount of fluid) in thechest

Poor exercise tolerance.

Tachycardia.


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Prevalence and incidence

It is currently approximated that about 23 million people are suffering from

CHF globally.

In developed countries between 1% and 2% of the adult population have CHF.

It particularly affects the elderly (>65 years) and in this age group 6-10%

suffer from CHF.

Each year CHF is diagnosed in about 3 per 1000 in the population, but the

incidence is much higher (10 per 1000) in the elderly.

The lifetime risk of developing heart failure is one in five for a person at the

age of 40 years.

In 2010,estimated total cost of heart failure in the United States was $39.2billion, representing 1-2% of all health care expenditures.

Mortality is greater than 50% for patients in USA.


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Factors aggravating heart failure (Risk factor)

Myocardial ischemia or infarction

Dietary sodium excess

Excess fluid intake

Arrhythmias

Conditions associated with increased metabolic demand (eg pregnancy,

thyrotoxicosis, excessive physical activity) Administration of drug with negative inotropic properties or fluid retaining

properties (e. NSAIDs, corticosteroids)

Alcohol

Advancing age

Coronary artery disease and previous heart attacks

High blood pressure Diabetes

High cholesterol

Thyroid disease

Kidney disease


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Preventive measures:

Tobacco cessation and avoidance of smoke.

Limit alcohol consumption.

Increase daily activity.

Decrease emotional stress.

A diet high in vegetables and fruits isrecommended.


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Management

Drug therapy: vasodilators, ACE inhibitors, Diuretics,Anti-arrhythmic drug therapy, blockers, Cardiac glycosides

Treat the cause/aggravating factors Supportive oxygen, bed rest, elevation of

head of bed

Surgery revascularization to treat ischemia


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Four classes of drugs are currently recommended to manage

congestive heart failure:

1. Angiotensin-converting enzyme (ACE) inhibitors

2. Diuretics

3. Cardiac glycosides

4. Nitrates or direct vasodilators.

A stepwise approach is often used.

Step 1:ACE inhibitors (e.g., captopril

Step 2:Diuretics (e.g., furosemide)

Step 3:Cardiac glycosides (e.g., digoxin)

Step 4: Nitrates or vasodilator (e.g., topical nitroglycerin)

Pharmacologic Interventions


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Diet ensure adequate general nutrition and, in obese patients,

weight reduction

Salt advise patients to avoid high salt content foods and not to

add salt (particularly in severe cases of congestive heartfailure)

Fluid urge overloaded patients and those with severe

congestive heart failure to restrict their fluid intake

Alcoho l advise moderate alcohol consumption (abstinence in

alcohol related cardiomyopathy)

Smoking avoid smoking (adverse effects on coronary disease)

Exercise regular exercise should be encouraged

Non-pharmacological measures for the

management of heart failure


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Drugs for congestive heart failure

1. Vasodilators

Captoprol Enalapril

Fosinopril

Lisinopril

Hydralazine

Sodium nitroprusside

2. Diuretics

Bumetanide

Furosemide

Hydrochlorothiazide

Metolazone3. Inotropic agents

Digitoxin

Digoxin

Dobutamine b-adrenergic agonist Amrinone

Milrinone

ACE inhibitors

Cardiac glycosides

Phosphodiesterase inhibitor


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Three main sites of pharmacological attackPre-load - reduce venous pressure

After-load reduce peripheral resistance

Drug treatment of heart failure

Pre-load:is the volume of blood that fills the ventricle during diastole.

Elevated pre-load causes overfilling of the heart which increases the workload

of heart

After-load: is the pressure (due to increased PR) that must be overcome for

the heart to pump blood into the arterial system.

Elevated after-load causes the heart to work harder to pump blood into the

arterial system.


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P th l f H t F il & D T t


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Pre-load After-loadHeart disease

Renin release

Angiotensin II

Aldosterone

Edema

Na+& H2Oretension

+

+

Tissue perfusionC.O.-

-

Diuretics -

Positive

inotropes-

ACEinhibitor

Renal blood flowVenous pressure+

-

-Vasodilator +

Pathology of Heart Failure & Drug Target


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Diuretics

Loop diuretics (eg frusemide): mainly act on ascending loop

of Henle (powerful diuretic): acute heart failure, severechronic heart failure (CHF).

Thiazide diuretics (eg hydrochlorothiazide): act on early

distal tubule: suitable alternative for mild to moderate CHF.

Spironolactone (aldosterone antagonist): given in

combination with above diuretics reduces K+ loss. Improvessurvival in severe heart failure.

Drugs that reduce pre-load

Veno-dilator pre-load reducersTherapeutic use: Sodium nitroprusside particularly appropriate if

acute failure associated with acute ischaemia.

M/A: Dilatation of arterioles and venules, so peripheralresistance and venous pressure, preload.effective in heartfailure.


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Angiotensin convert ing enzyme inhib i tors (ACEI)

- reduce peripheral resistance through blocking

formation of angiotensin II and cause natiuresis

through inhibition aldosterone production and

prolong life in CHF patients.

AII recepto r blo ckers

- may be alternative if ACEI not tolerated

because of cough.

Reduction of after-load


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Increase myocardial contraction

Inotropic drugs

Cytoplasmic Ca2+ concentration

Cardiac muscle contractility

Cardiac output

Inotropic agents

Digitoxin

Digoxin

Dobutamine -adrenergic agonist

Amrinone

Milrinone

Cardiac glycosides

Phosphodiesterase inhibitor


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M/A of Digoxin

Digitalis

Inhibition of Na+-K+ATPase

N

Na+-K+pump

Intracellular Na+

Inhibition of Na+/Ca2+exchange

Intracellular Ca2+

Interaction of actin and myosin

cardiac contractility

Heart size & HR


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M/A of Digoxin

Na+

Na+

K+

K+

ATPase

Na+

Na+Ca2+

Ca2+

Ca2+

Ca2+

SR

Ca2+

Digoxin-


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Adverse effects Nausea, vomiting

Cardiac arrythmias

Confusion

Hypokalemia

Skin rash

Gynecomastia (due to prolong use)

Digoxin

Therapeutic uses

1. Congestive heart failure

2. Left vetricular failure

Contraindication

Arrhythmia

Heart block

Ventricular tachycardia

Renal failure

Hypokalemia

Hypercalcemia

Pharmacokinetics

Route of admn: oral

Plasma t1/2: 5-7 days (digitoxin)40 hrs (digoxin)

Plasma protein binding: 95%(digitoxin)

25% (digoxin)

Metabolized by liver and excreted with

bile in the gut, thus has longer t1/2


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-adrenergic agonist(Dobutamine)

Dobutamide is the most commonly used inotropic

agent other than digitalis.

It is given by intravenous infusion and primary used

in the treatment of acute heart failure in hospitalsetting.


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M/A of -adrenergic agonist(Dobutamine)

-adrenergic agonist

Binds to -adrenergic receptor

Activates adenylyl cyclase

Catalyzed ATP to produce cAMP

cAMP activates protein kinase which phophorylates

Ca2+channel and Ca2+flow into cell

force of contraction of heart muscle

AMPPDE

PDE inhibitor

M/A f d i i t &


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M/A of -adrenergic agonist&

PDE inhibitor

Ca2+

Ca2+

SR

Ca2+

Adenynyl

cyclase

-adrenergicreceptor

ATP cAMP AMPPDE

Protein kinase A

(Active)

activatesPhosphorylates Ca-channel

& Ca2+ flow into cell

Ca2+channel

Binding of -adrenergic

agonist activates adenynyl

cyclase which produce cAMP

PDE: phosphodiesterase inhibitor

Amrinone-


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-adrenergic agonist(Dobutamine)Therapeutic uses

Congestive heart failure

Acute myocardial infarction

Cardiac decompensation that may occur

after cardiac surgery

Pharmacokinetics

Plasma t1/2: 2 min

Route of admin: IV

Adverse effect

Increase BP and HR

Increase Myocardial infarction

by increasing oxygen demand

Drug Heart Failure m

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