Drugs Used in Heart Failure

Wawaimuli Arozal, MD, D.Pharm

1. 2. 3. 4. 5.

Introduction Cardiac Contractility Pathophysiology of heart failure Pathophsiology of cardiac performance Basic pharmacology of drugs used in heart failure

Introduction
Heart failure (HF): is a complex clinical syndrome that can result from any functional or structural cardiac disorder that impairs the ventricles ability to fill with or eject blood cardiac output is inadequate to provide the oxygen needed a systemic response attempting to compensate for the inadequacy Diagnosis based on careful history and physical examination and supported by ancillary tests such as chest radiograph, electrocardiogram, and echocardiography 2 mechanisms of reduced cardiac output and HF: systolic dysfunction and diastolic dysfunction

Introduction
Systolic dysfunction : defined by a left-ventricular ejection 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 systolic function. Causes: hypertension, ischemic heart disease, hypertrophic cardiomyopathy, and restrictive cardiomyopathy

Introduction
Modified Framingham Criteria for the Diagnosis of CHF : Major Criteria : Neck-vein distention, orthopnea or paroxysmal nocturnal dyspnea, cardiomegaly on chest radiograph, S3 gallop, Central venous pressure >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, pleural effusion, tachycardia (>120 beats/min)

Introduction
New York Heart Association Classification on CHF : I (none) No symptoms from ordinary activities II (mild) comfortable at rest or during mild exertion III (moderate) symptomatic with any activity IV (severe) symptomatic at rest, confined to bed or chair

Cardiac contractility
Contraction results from the interaction of activator calcium (during systole) with the actin-troponin-tropomyosin system, there by releasing the actin-myosin interaction. The calcium released from sarcoplasmic reticulum (SR) ; see figure

Pathophysiology of heart failure

Pathophysiology of heart failure

Pathophysiology of heart failure

Intrinsic compensatory mechanism 1. myocardial hypertrophy ischemic changes, impairment of diastolic filling, and alteration ventricular geometry 2. Remodeling proliferation of connective tissue

Heart Failure
Inotropic agents, digoxin

X
Cardiac output

B-blockers

Digoxin

X Elevated cardiac filling pressures

Renin
X
Renin inhibitors

Symphatetic nervous system activation

Vasodilators

Angiotensin I X
ACE-I

Vasoconstriction Na+ and water retention

Angiotensin II X Aldosterone ARBs X X Diuretics

X
Spironolactons

Cardiac remodeling

Pathophsiology of cardiac performance

Determinants of cardiac output
Preload Contractility Afterload

Stroke volume

Heart rate

Cardiac Output

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 blood Cardiac contractility : muscular pumping of the heart = ejection fraction Heart rate: major determinant of cardiac output (CO); increase in heart rate through sympathetic activation of B-adrenoreceptors is the first compensatory mechanism to maintain CO

Basic pharmacology of drugs used in heart failure

I. Digitalis
prototype: digoxin Mechanism of action: inhibit membrane-bound alpha subunits of Na-K ATPase (sodium pump) promotes Na-Ca exchange increases the intracellular Ca concentration contractile proteins resulting an increase in the force of myocardial contraction Baroreceptor function: improvement in baroreceptor function that results in decreased activation of the sympathetic nervous system (decreases sinoatrial and atrioventricular conduction) Vagomimetic effect : increase vagal tones Circulating neurohormones: decrease the serum NE concentration and plasma renin activity Pharmacokinetics : 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 normal patients (3.5-5 days in CRF). Oral daily maintenance results in A steady state blood concentration in approximately 7 days

Mechanisms of Action of Digitalis

Inhibition of Na/K-ATPase

Membrane Depolarization
Ca++ channel opening

Na+ int

Na+/Ca++ exchanger

CONTRACTILITY

Ca intracell

Sarcoplasmic reticulum

Ca++-induced Ca++ release

Electrophysiologic effects of Digitalis

Lowers resting potential (phase 4 become less negative Increases the slope of phase 4 otomaticity Produces Delayed after depolarization Shortening of potential action duration arrhythtmogenic

 Direct effects on the heart

Increases automaticity in the atrium, ventricle and Purkinje fibre arrhythmogenic Delays conductivity (AV node, Purkinje) dromotropic (-) Shortens refractory periods in the atrium and ventricle arrythmogenik Prolongs refractory period in AV node
chronotropic (-)
Atrium Automaticity Conductivity Refractory period - AV node Ventricle/Purkinje -- /

 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

Pharmacodynamic effects
1. Direct effects: Positive Inotropism
Improved contractility Improve cardiac output Decrease pulmonary congestion Improved dyspnoe

2. Indirect effects Sympathetic tone

Improved renal circulation

Decrease heart rate Decrease peripheral resistance afterload SRA activity Peripheral resistance Aldosterone salt /water retention edema IMPROVE CARDIAC PERFORMANCE

Digitalis in Atrial Flutter / Fibrillation

Digitalis prolongs refractory period in AV node some impulses from atrium are retained in AV node and not transmitted to ventricle

In other words: Digitalis prevent the transmission of fibrillation from atrium to ventricle
(Not directly eliminate AF)
(Although spontaneous conversion to sinus rhythm frequently occur)

Digoxin
Indication: 1. Patients with HF and impaired systolic function who are in sinus rhythm and continue to have signs and symptoms despite standard therapy that includes ACE-inhibitors and beta-blockers 2. Patients with atrial fibrillation with or without HF

Digoxin
Drug Interactions : Quinidine, verapamil, and amiodarone may significantly increase the concentration of digoxin dose of digoxin should reduce; tiazid, furosemid causing hypokalemia increase toxicity Dose/serum concentration: low dose digoxin resulting in serum concentration less than 1 ng/ml beneficial clinical effect; > 1ng/ml increase mortality; Usual dose 0.125 mg daily 0.8 ng/ml

Digoxin
Intoxication - Arrhythmias - Gastrointestinal abnormalities - CNS abnormalities Intoxication 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 the arrhythmogenic 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

INTOXICATION
Digitalis has a low margin of savety risk of intoxication 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

INTOXICATION
Symptoms of Intoxication

GI symptoms (nausea, vomiting, abdominal pain) Neurologic symptoms (dizzy, restlessness, confusion) Visual dysturbances (blurred, yellow vision) Cardiac: arrhythmia, AV-block Stop digitalis and diuretic Electrolyte correction Management of arrhythmia: lidocain, phenitoin Antidigoxin-Antibody

Treatment

Interaction
Quinidin Verapamil Diltiazem Amiodarone Phenobarbital Phenytoin Fenilbutazon Rifampisin Increases plasma digoxin

Enzyme inducers metabolism Decrease plasma digoxin

Amphoterisin hypokalemia digitalis toxicity

Other positive inotropic drugs

I. Inamrinone and milrinone (inhibitor of phosphodiesterase isoenzyme 3 (PDE-3) Increase cAMPIncrease myocardial contractility by increasing 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 in ventricular filling pressure Side effect : tachycardia

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 vascular fibrosis and baroreceptor dysfunction. AA decreased morbidity and mortality in patients with CHF who also receiving ACE inhibitors or other standard therapy

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-induced hypokalemia To be used for longterm treatment Prevent myocardial fibrosis

ACE inhibitors and AT-1 Blockers

ACE inhibitors : captopril, enalapril lisinopril ramipiril Reduced peripheral resistance reduced afterload Reduce salt and water retention (by reducing aldosterone secretion) reduce preload Reduce tissue angiotensin level reduces sympathetic activity Reduce longterm remodeling of the heart and vessel At-1 blockers : losartan, candesartan, valsartan similar to ACE Inhibitors. Considered with patient intolerant of ACE-I

 ARBs are comparable to ACE inhibitors in reducing all-cause mortality and HF relatedhospitalization in patients with NYHA classes II and III HF ARBs more expensive than ACE-I, but not cause cough reasonable in patients who are unable to tolerate ACE-inhibitor therapy Some studies reported that adding an ARB to ACE-I provides benefit (reduced hospitalization) compared with ACE-I alone, but the combination may cause increase adverse effects (worsening of renal function, hypotension, and hyperkalemia) combination may be reserved for patients who remain symptomatic on therapy with ACE-I under strict monitoring

ACE-I side effects: - elevated bradykinin angioedema, dry cough - elevated serum K+ level low potassium diet or dose adjustment - hypotension Direct 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 in hypotension and hyperkalemia - Not yet studied to analyze the efficacy for CHF

Beta-adrenoceptor antagonists in CHF

-AR antagonist Blockade of -adrenoceptor Reduction in symphatetic activity Antioxidant action Prevention of cardiac remodelling Antiarrhythmic action Energy conservation

Beneficial effects in chronic heart failure

Beta-adrenoceptor antagonists in CHF

Mechanism of action in HF : 1. Decreasing the frequency of arrhytmias 2. Affecting LV geometry, decreasing LV chamber size, increasing LV ejection fraction 3. Inhibition of symphatetic nervous system activation prevent or delay progression of myocardial contractile dysfunction by inhibiting proliferative cell signaling in the myocardium, reducing cathecholamine induced cardiacmyocyte toxicity, and decreasing myocyte apoptosis and fibrosis

Beta-adrenoceptor antagonists in CHF

Data from > 15000 patients with mild-moderate CHF proved that B blockers improve disease-associated symptoms, hospitalization, and mortality Recommendation : use in patients with LV ejection <35% and NYHA class II or III symptoms in conjunction with an ACE inhibitor or ARB, and diuretics as required to palliate symptoms Initiated at very low dose, and titrated cautiously upward. Usually used : carvedilol, metoprolol, bisoprolol ( have been shows to reduce mortality in clinical trials), nebivolol

Non pharmacologic management

1. Dietary sodium restriction Restricting sodium intake to 2 g or less (~0.25 tsp) per day can aid in the control of fluid status and the symptoms of heart failure 2. Exercise Moderate exercise (i.e. at 60% of maximum exercise capacity on a stationary bicycle for 2 or 3 hours per week) improves quality of life, decrease moratlity, and decrease hospitality in patient with stable chronic heart failure (for NYHA class I-III) 3. Smoking cessation, restricting alcohol 4. Patients with renal dysfunction should restrict fluid intake to 1.5 2.0 L per day 5. Weight monitoring