Drugs Used in HF II

7/31/2019 Drugs Used in HF II

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Drugs Used in Heart FailureWawaimuli Arozal, MD, D.Pharm

1. Introduction

2. Cardiac Contractility

3. Pathophysiology of heart failure4. Pathophsiology of cardiac performance

5. Basic pharmacology of drugs used in

heart failure


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Introduction

Heart failure (HF): is a complex clinical syndrome thatcan result from any functional or structural cardiacdisorder that impairs the ventricles ability to fill with oreject blood cardiac output is inadequate to provide the

oxygen needed a systemic response attempting tocompensate for the inadequacy

Diagnosis based on careful history and physicalexamination and supported by ancillary tests such aschest radiograph, electrocardiogram, and

echocardiography 2 mechanisms of reduced cardiac output and HF:

systolic dysfunction and diastolic dysfunction


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Introduction

Systolic dysfunction : defined by a left-ventricularejection fraction of < 50%

Most common causes : ischemic heart disease,idiopathic dilated cardiomyopathy, hypertension,

and valvular heart disease Diastolic dysfunction: defined as dysfunction of

left-ventricular filling with preserved systolicfunction.

Causes: hypertension, ischemic heart disease,hypertrophic cardiomyopathy, and restrictivecardiomyopathy


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Introduction

Modified Framingham Criteria for the Diagnosis ofCHF :

Major Criteria : Neck-vein distention, orthopnea or

paroxysmal nocturnal dyspnea, cardiomegaly onchest radiograph, S3 gallop, Central venouspressure >12 mmHg, LV dysfunction on echo,weight loss >4.5 kg, acute pulmonary edema

Minor criteria: bilateral ankle edema, night cough,dyspnea on exertion, hepatomegaly, pleuraleffusion, tachycardia (>120 beats/min)


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Introduction

New York Heart Association Classificationon CHF :

I (none) No symptoms from ordinary

activitiesII (mild) comfortable at rest or during mild

exertion

III (moderate) symptomatic with any activityIV (severe) symptomatic at rest, confined to

bed or chair


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Cardiac contractility

Contraction results from the interaction ofactivator calcium (during systole) with theactin-troponin-tropomyosin system, there

by releasing the actin-myosin interaction.The calcium released from sarcoplasmicreticulum (SR) ; see figure


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Pathophysiology of heart failure


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Intrinsic compensatory mechanism

1. myocardial hypertrophy ischemicchanges, impairment of diastolic filling,and alteration ventricular geometry

2. Remodeling proliferation of connectivetissue


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Heart Failure

Cardiac output

Symphatetic nervoussystem activation

Vasoconstriction

Cardiac

remodeling

Elevatedcardiac filling

pressures

Na+ and waterretention

Renin

Angiotensin I

Angiotensin II

Aldosterone

X

X

X

X

X X

X

X

X

X

X

X

ARBs Diuretics

Inotropic agents, digoxin

DigoxinB-blockers

Renininhibitors

ACE-I

Vasodilators

Spironolactons


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Pathophsiology of cardiac

performance

Determinants of cardiac output

Cardiac Output

Strokevolume

Preload Contractility Afterload

Heart rate


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Pathophsiology of cardiac

performance

Preload : the volume that enters the left ventricle(LV)

Afterload : the impedance of the flow from LV;resistance against which the heart must pump

bloodCardiac contractility : muscular pumping of the

heart = ejection fractionHeart rate: major determinant of cardiac output

(CO); increase in heart rate through sympatheticactivation of B-adrenoreceptors is the firstcompensatory mechanism to maintain CO


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Basic pharmacology of drugs used in heart failure

I. Digitalis

prototype: digoxinMechanism of action: inhibit membrane-bound alpha subunits of Na-K ATPase

(sodium pump) promotes Na-Ca exchange increases theintracellular Ca concentration contractile proteins resulting anincrease in the force of myocardial contraction

Baroreceptor function: improvement in baroreceptor function that results indecreased activation of the sympathetic nervous system (decreasessinoatrial and atrioventricular conduction)

Vagomimetic effect : increase vagal tonesCirculating neurohormones: decrease the serum NE concentration and plasma

renin activityPharmacokinetics : bioavailability 60-80 %; 6-8 hours tissue distribution phase.

In some patients, oral digoxin is partial inactivated by colonic bacteria.Excreted unchanged in the urine. Half life 36-48 hours in normalpatients (3.5-5 days in CRF). Oral daily maintenance results in Asteady state blood concentration in approximately 7 days


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Mechanisms of Action of Digitalis

Inhibition of Na/K-ATPase

Na+ int

Ca++-induced

Ca++ release

Sarcoplasmicreticulum

MembraneDepolarization

Ca++ channelopening

Ca intracell

Na+/Ca++exchanger

CONTRACTILITY


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Electrophysiologic effects of Digitalis

Lowers resting potential (phase 4 become lessnegative

Increases the slope of phase 4 otomaticity Produces Delayed after depolarization Shortening of potential action duration arrhythtmogenic


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Direct effects on the heart Increases automaticity in the atrium, ventricle and

Purkinje fibrearrhythmogenic

Delays conductivity (AV node, Purkinje)

dromotropic (-)

Shortens refractory periods in the atrium andventriclearrythmogenik

Prolongs refractory period in AV node

chronotropic (-)

Atrium AV node Ventricle/Purkinje

Automaticity

Conductivity --

Refractory

period

-- /


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Indirect effects

Vagal effect: In SA and AV nodes Vagal tone

Incereses sensitivity of heart to acetylcholine

Negative chronotropic

Sympathetic effects: Decreases sympathetic tone

Decreases sensitivity of heart to NE

Decreases sympathetic flow

Negative chronotropic effect

At high/toxic dose : sympathetic flow arrhythitmogenic


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Pharmacodynamic effects

1. Direct effects: Positive Inotropism

Improved contractility Improve cardiac output Decrease pulmonary congestion

Improved dyspnoe2. Indirect effects Sympathetic tone

Decrease heart rate Decrease peripheral resistance afterload

Improved renal circulation SRA activity Peripheral resistance Aldosterone salt /water retention edema IMPROVE CARDIAC PERFORMANCE


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Digitalis in Atrial Flutter / Fibrillation

Digitalis prolongs refractory period in AVnode

some impulses from atrium are retained inAV node and not transmitted to ventricle

In other words:

Digitalis prevent the transmission of fibrillationfrom atrium to ventricle

(Not directly eliminate AF)

(Although spontaneous conversion to sinus rhythm frequently occur)


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Digoxin

Indication:

1. Patients with HF and impaired systolicfunction who are in sinus rhythm andcontinue to have signs and symptomsdespite standard therapy that includesACE-inhibitors and beta-blockers

2. Patients with atrial fibrillation with orwithout HF


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Digoxin

Drug Interactions : Quinidine, verapamil, andamiodarone may significantly increase theconcentration of digoxin dose of digoxin

should reduce; tiazid, furosemid causinghypokalemia increase toxicity

Dose/serum concentration: low dose digoxinresulting in serum concentration less than 1

ng/ml beneficial clinical effect; > 1ng/mlincrease mortality; Usual dose 0.125 mg daily 0.8 ng/ml


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Digoxin

Intoxication- Arrhythmias- Gastrointestinal abnormalities- CNS abnormalitiesIntoxication not only related to dose but also to the concurrent

medication (diuretics) or condition (renal insufficiency, ischemia)Special consideration in the use of digoxin :-Woman-Elderly-Coronary artery disease; myocardial ischemia cause inhibition of

sodium pump myocardial tissue moore sensitive to thearrhythmogenic effects of digoxin should be used very low dose

Precautions:Should not be used in patients with SA or 2nd/3rd AV block; WPW

syndrome, hypertrophic or restrictive cardiomyopathy


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INTOXICATION

Digitalis has a low margin of savety

risk ofintoxication with increasing dose Potassium depletion due to diuretics facilitates

intoxication Symptoms of intoxication sometimes resembles

cardiac worsening.

CAUSES OF INTOXICATION To high doses Hypokalemia/hyperkalemia Hyperkalsemia Hypomagnesemia Myocardial ischemia


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Symptoms of Intoxication GI symptoms (nausea, vomiting, abdominal pain) Neurologic symptoms (dizzy, restlessness,

confusion) Visual dysturbances (blurred, yellow vision) Cardiac: arrhythmia, AV-block

Treatment Stop digitalis and diuretic Electrolyte correction Management of arrhythmia: lidocain, phenitoin Antidigoxin-Antibody

INTOXICATION


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Interaction

Quinidin Verapamil Increases plasma digoxin

Diltiazem

Amiodarone

Phenobarbital

Phenytoin Enzyme inducers metabolism

Fenilbutazon Decrease plasma digoxin

Rifampisin Amphoterisin hypokalemia digitalis toxicity


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Other positive inotropic drugs

I. Inamrinone and milrinone (inhibitor of phosphodiesteraseisoenzyme 3 (PDE-3)

Increase cAMPIncrease myocardial contractility byincreasing inward Ca flux in heart and vasodilating effect

Toxicity : nausea, vomiting, arrhythmias, trombcytopenia,bone marrow toxicity

Only for acute HF or severe exacerbation of CHF

II. Beta adrenoceptor stimulants (dopamine and

dobutamine)Increase cardiac output together with a decrease inventricular filling pressure

Side effect : tachycardia


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Diuretics

Mainstay of HF management No effect on cardiac contractility Major mechanism: reduce venous pressure and ventricular preload Reduction on salt and water retention and edema and its symptoms Loop diuretics : furosemide

Thiazide diuretics : combination with loop diuretics Aldosterone antagonist (AA): spironolactone and eplerenon ; HF

increase circulating plasma aldosterone myocardial and vascularfibrosis and baroreceptor dysfunction. AA decreased morbidity andmortality in patients with CHF who also receiving ACE inhibitors orother standard therapy


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DIURETICS(First line drug for CHF)

(See also diuretics and antihyperensive agents) Furosemide:

Strong diuretic with rapid onset

For acute CHF (and also for chronic)

Mechanism of action: reduceing preload Thiazide: HCT, indapamid

For chronic CHF

Aldosteron Antagonist : spironolaktone

Reduces the risk of furosemide-inducedhypokalemia

To be used for longterm treatment

Prevent myocardial fibrosis


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ACE inhibitors and AT-1 Blockers

ACE inhibitors : captopril, enalapril lisinopril ramipiril

Reduced peripheral resistance reduced afterload

Reduce salt and water retention (by reducingaldosterone secretion) reduce preload

Reduce tissue angiotensin level reduces sympatheticactivity

Reduce longterm remodeling of the heart and vessel

At-1 blockers : losartan, candesartan, valsartan similar

to ACE Inhibitors. Considered with patient intolerant ofACE-I


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ARBs are comparable to ACE inhibitors inreducing all-cause mortality and HF related-hospitalization in patients with NYHA classes II

and III HF ARBs more expensive than ACE-I, but not cause

cough reasonable in patients who are unableto tolerate ACE-inhibitor therapy

Some studies reported that adding an ARB toACE-I provides benefit (reduced hospitalization)compared with ACE-I alone, but the combinationmay cause increase adverse effects (worseningof renal function, hypotension, and

hyperkalemia) combination may be reservedfor patients who remain symptomatic on therapywith ACE-I under strict monitoring


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ACE-I side effects:- elevated bradykinin angioedema, drycough

- elevated serum K+ level low potassium dietor dose adjustment

- hypotensionDirect renin inhibitor (aliskiren) :- Developed for the treatment of hypertension- Appears to exert beneficial effects on myocardial remodeling, by decreasing

LV mass in hypertensive patients- In ALOFT trial (2008) aliskiren (150 mg/day) add on therapy to beta blocker

and ACE-I or ARBs was not associated with a significant increase inhypotension and hyperkalemia

- Not yet studied to analyze the efficacy for CHF

Beta adrenoceptor antagonists in


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Beta-adrenoceptor antagonists in

CHF

-AR antagonist

Blockade of

-adrenoceptor

Prevention of cardiacremodelling

Beneficial effects inchronic heart failure

Anti-arrhythmicaction

EnergyconservationAntioxidantaction

Reduction insymphateticactivity

B t

d t t i t


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Mechanism of action in HF :1. Decreasing the frequency of arrhytmias2. Affecting LV geometry, decreasing LV

chamber size, increasing LV ejection fraction

3. Inhibition of symphatetic nervous systemactivation prevent or delay progression ofmyocardial contractile dysfunction by inhibitingproliferative cell signaling in the myocardium,

reducing cathecholamine inducedcardiacmyocyte toxicity, and decreasingmyocyte apoptosis and fibrosis

Beta-adrenoceptor antagonistsin CHF


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Data from > 15000 patients with mild-moderate CHFproved that B blockers improve disease-associatedsymptoms, hospitalization, and mortality

Recommendation : use in patients with LV ejection


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Non pharmacologic management1. Dietary sodium restriction

Restricting sodium intake to 2 g or less (~0.25 tsp) perday can aid in the control of fluid status and thesymptoms of heart failure

2. Exercise

Moderate exercise (i.e. at 60% of maximum exercise

capacity on a stationary bicycle for 2 or 3 hours perweek) improves quality of life, decrease moratlity, anddecrease hospitality in patient with stable chronic heartfailure (for NYHA class I-III)

3. Smoking cessation, restricting alcohol

4. Patients with renal dysfunction should restrict fluid intaketo 1.5 2.0 L per day

5. Weight monitoring

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Drugs Used in HF II