6 cvs lecture 5 - drugs for heart failure

7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure

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Congestive Cardiac Failure

Dr. E. McIntosh

October 2011


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Introduction to Heart Failure

Heart unable to provide adequate perfusion

of peripheral organs to meet their metabolic

requirements

Characterized by:

1. Reduction in cardiac output

2. Increased TPR

Progressing to congestive heart failure (CHF) isaccompanied by peripheral and pulmonary

edema.


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Acute Vs Chronic HF

In a patient with acute heart failure, theshort-term aim is stabilization by providingsymptomatic treatment through intravenousinterventions.

Management ofchronic heart failure ismultifaceted, with the long-term aims of: relieving symptoms

improving hemodynamics

improving quality of life and decrease mortality.


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Cardiac Vs Noncardiac targets

Conventional belief that the primary

defect in HF is in the heart

Reality is that HF involves many otherprocesses and organs

Research has shown that therapy

directed at noncardiac targets are morevaluable than cardiac targets


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Compensation in HF

Heart failure is usually accompanied by anincrease in:

1. Sympathetic nervous system (SNS)

2. Chronic up-regulation of the renin-angiotensin-aldosterone system (RAAS)and effects ofaldosterone on heart,vessels, and kidneys.

CHF should be viewed as a complex,interrelated sequence of events involvinghemodynamic, and neurohormonal events.


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Compensation contd..

In a failing heart, the loss of contractile function leadsto a decline in CO and a decrease in arterial BP.

Baroreceptors sense the hemodynamic changes andinitiate countermeasures to maintain support of the

circulatory system. Activation of the SNS serves as a compensatory

mechanism in response to the earlier

This helps maintain adequate cardiac output by:

1. Increasing myocardial contractility and heart rate (1-adrenergic receptors)

2. Increasing vasomotor tone (1-adrenergic receptors)to maintain systemic blood pressure


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Consequences of hyperadrenergic

state

Over the long term, this hyperadrenergic stateleads to irreversible myocyte damage, cell death, andfibrosis.

In addition, the augmentation in peripheral vasomotortone increases LV afterload

This places an added stress upon the left ventricleand an increase in myocardial O2 demand(ventricular remodeling).

The frequency and severity of cardiac arrhythmiasare enhanced in the failing heart


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Figure p.203 kat


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Therapeutic Overview

Problem

Reduced force of contraction

Decreased cardiac output

Increased total peripheral resistance Inadequate organ perfusion

Development of edema

Decreased exercise tolerance

Ischemic heart disease

Sudden death

Ventricular remodeling and decreased function


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Goals and drug therapy

Goals

Alleviation of symptoms, improve quality of life

Arrest ventricular remodeling

Prevent sudden death

Nondrug therapy Reduce cardiac work; rest, weight loss, low Na+ diet

Drug therapy

Chronic heart failure ACE-I, -blockers, ARB, aldosterone antagonists, digoxin, diuretics

Acute heart failure Intravenous diuretics, inotropic agents, PDE inhibitors, vasodilator


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Drugs for CCF


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Drugs for CCF

Diuretics :

These are useful in reducing the

symptoms of volume overload by decreasing the extra cellular volume

decreasing the venous return


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Drugs for CCF

Diuretics :

Loop diuretics like furosemide and

bumetanide are the most effective andcommonly used.

Thiazides are effective in mild cases

only.


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Drugs for CCF

Diuretics :Adverse effects :

Loop diuretics and thiazides cause

hypokalemia. Potassium sparing diuretics help in

reducing the hypokalemia due to these

diuretics.


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Drugs for CCF

Potassium Sparing Diuretics :Spironolactone :

Aldosterone inhibition minimizepotassium loss, prevent sodium andwater retention, endothelial

dysfunction and myocardial fibrosis.


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Drugs for CCF

Spironolactone : Aldosterone antagonist

Spironolactone can be added to loop

diuretics to modestly enhance thediuresis; more importantly, improvesurvival.


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Renin angiotensin system

Baroreceptor mediated activation of the SNSleads to an increase in renin release and

formation of angiotensin II

Angiotensin II acts through AT1 and AT2

receptors (most of its actions occur throughAT1 receptors)

This causes vasoconstriction and stimulates

aldosterone production

RAS remains the most important target of

chronic CHF therapy


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Effects of AT-II


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MOA

ACE-Inhibitors and ARBs Blockade of ACE

Decreased AT-II

Decreased aldosterone

Decreased fluid retention

Vasodilation

Reduced preload and afterload

Slows cardiac remodeling


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Advantages

Improves symptoms significantly

Improves exercise tolerance

Slows progression of the disease Prolong survival in established cases


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ADR

What are the ADR of ACEIs?

Cough (why?)

Hyperkalemia (possible Druginteractions?)

Contraindicated in pregnant women (1sttrimester)

Rare: angioedema


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Other Vasodilators:

Mechanism 2:

Direct smooth muscle relaxants

Nitrates Venous dilators

Reduce preload

Eg: sodium nitropruside

Nit t i CCF


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Nitrates in CCF


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Inotropes

Increase force of contraction

All increase intracellular cardiac Ca++

concentration Eg:

Digitalis (cardiac glycoside)

Dobutamine (-adrenergic agonist) Amrinone (PDE inhibitor)


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Cardiac glycosides

Digitalis

Sourced from foxglove plant

1785, Dr. William Witheringsmonograph on digitalis

Has a profound effect on the cardiac

contractility


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Pck

Two drugs (digoxin, digitoxin)

Well absorbed orally

10% of population have bacteria in the gut,which inactivate digoxin, needing an

increased dose in such

Beware of using antibiotics in such patients

Digoxin has a very narrow ther. Margin


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Pck

Taken orally

Enters CNS (so what?)

Renal clearance proportional toCreatinine Clearance

To be used with extreme caution in

patients suffering from renalimpairment


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MOA

Regulation of cytosolic Ca metabolism:

Reversibly combine with sodium-potassiumATPase of the cardiac cell membrane

Results in inhibition of pump activity This leads to in intracellular Na conc.

This favors Ca ions in the cell

Ca levels result in increased systolic force ofcontraction


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Digoxin MOA


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Na/K ATPase inhibition


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Additional MOA

Force of contraction resembles that of thenormal heart

Improved circulation leads to reduced

sympathetic activity This reduces PVR

All this leads to reduction in HR

Vagal tone is enhanced

Finally myocardial O2 demand is reduced


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Electrophysiological effects on the

heart

Direct Indirect (increased vagal tone)

SA Node No effect at therapeutic dose No effect at therapeutic dose

Atrial muscle High dose increases rate ofspontaneous depolarization High dose decreases rate ofspontaneous depolarization

AV node Increased refractory period Decreased conduction velocity

Decreased conduction velocity Increased refractory period

His-Purkinje

system

Increased refractory period Increased refractory period

Decreased conduction velocity Decreased conduction velocity

High dose increases triggered

activity

None

Toxic doses enhance pacemaker


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Uses

Severe LV systolic dysfunction

Only after initiation of diuretics andvasodialtor therapy

Management of patients with chronic atrialfibrillation

Cannot arrest the progression of pathologicalchanges causing heart failure, and does not

prolong life in patients with CHF


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ADR

Digitalis toxicity is one among most

commonest encountered (why?)

Therapeutic concentration- 0.5-1.5 ng/ml

Often the first step is discontinuation of Rx

Digoxin levels must be monitored closely


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Signs of digoxin toxicity

CNS: Malaise, confusion, depression,vertigo, vision (abnormalities in colorvision)

GI: Anorexia, nausea, intestinalcramping, diarrhea

Cardiovascular: Palpitations, syncope,

arrhythmias, bradycardia, AV nodeblock, tachycardia


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Factors increasing the possibility of

digoxin toxicity

Pharmacological and toxic effects are greaterin hypokalemic patients.

K+-depleting diuretics are a majorcontributing factor to digoxin toxicity.


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Management

Arrhythmias may be converted to normalsinus rhythm by K+. when the plasma K+conc. is low or within the normal range.

When the plasma K+ conc. is high,

antiarrhythmic drugs, such as lidocaine,procainamide, or propranolol, can be used.

Severe toxicity treated with Digibind, an anti-

digoxin antibody.


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A 96-year-old AAF was admitted from a nursing home withcomplaints of abdominal pain, N/V, dizziness, confusion anddouble vision for 5 days. She was discharged from thehospital just 4 days ago. Digoxin was started during thatprevious hospitalization for control of tachycardia in atrial

fibrillation. One day prior to discharge, digoxin level was 1.8mg/mL and digoxin dose was decreased to 125 mcg PO Q48 hr.PMHHypertension, atrial fibrillation, coronary artery disease,stroke, congestive heart failure.MedicationsMetoprolol, Digoxin, ASA, lisinopril, Lasix, Coumadin,Nexium

What could it be???


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Dopamine

Dopamine acts at a variety ofreceptors (dose dependant)

Dopamine receptors at low dose

Beta 2 at intermediate dose

Alpha 1 at high dose

Rapid elimination- can only be

administered as a continuous infusion Treatment for acute, severe heart

failure (LVF) esp. with low BP


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Dobutamine

Stimulates beta-adrenergic receptors andproduces a positive inotropic response

Unlike the vasoconstriction seen with high

doses of dopamine, dobutamine producesa mild vasodilatation

Used in acute heart failure with normal or

high BP


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MOA


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PDE inhibitors

Amrinone and Milrinone (bipyridines) Acts by inhibiting the enzyme Phosphodiesterase

Thus lead to increase of intracellularconcentrations of cAMP

cAMP is responsible for the conversion ofinactive protein kinase to active form

Protein kinases are responsible forphosphorylation of Ca channels

Thus causing increased Ca entry into the cell.


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MOA

Increase myocardial contractility by

increasing the Ca influx during AP

Also have vasodilating effect Selective for PDE isoenzyme-3 (found

in cardiac and smooth muscle)


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Current status

Both are orally active

Only available in parenteral forms

Limited efficacy Clinical trials- increased mortality (oral)

Still new drugs are under trial


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ADR

Amrinone: nausea, vomiting,

arrhythmias, thrombocytopenia and liver

enzyme changes

Withdrawn in some countries

Milrinone: arrhythmias, less likely to

cause other ADR


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(BNP)-Niseritide

Brain (B-type) natriuretic peptide (BNP) issecreted constitutively by ventricularmyocytes in response to stretch

BNP binds to receptors in the vasculature,kidney, and other organs, producing potentvasodilation with rapid onset and offset ofaction by increasing levels of cGMP

Niseritide is recombinant human BNP

approved for treatment of acutedecompensated CHF.


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BNP contd..

It reduces systemic and pulmonary

vascular resistances, causing an

indirect increase in cardiac output and

diuresis.

Effective in HF because cause

reduction in preload and afterload

ADR- hypotension


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Beta blockers

Overwhelming evidence to support the use of-blockers in CHF, however

Mechanism involved remain unclear

Part of their beneficial effects may derive fromslowing of heart rate and decreasemyocardial O2consumption.

This would lessen the frequency of ischemic

events and potential for development of alethal arrhythmia.


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Beta blockers

Suggested mechanisms also include reducedremodeling

-Blockers may be beneficial throughresensitization of the down-regulatedreceptor, improving myocardial contractility.

Recent studies with bisoprolol, carvedilol andmetoprolol showed a reduction in mortality inpatients with these drugs

CI in unstable cases


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Management of Chronic HF

(combination of drugs) Limit physical activity Reduce weight

Reduce water intake

Control HT

Na restriction

Diuretics

ACE-Is

Digitalis (ther. margin, DI with quinidine) Beta blockers

Vasodilators


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Management of acute HF

Diuretics

Vasodilators

Inotropic drugs Life support

Treating cause (surgery to correct

valvular disorders)

6 cvs lecture 5 - drugs for heart failure

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