Pharmacological Management of Congestive Heart Failure PDF

Pharmacological Management of Congestive Heart Failure  Learning outcomes List major drug groups used in treatment of heart failure Explain mechanism of action of digitalis and its major effects Explain the nature and mechanism of digitalis toxic effects Describe the clinical impl...

Pharmacological Management of Congestive Heart Failure  Learning outcomes List major drug groups used in treatment of heart failure Explain mechanism of action of digitalis and its major effects Explain the nature and mechanism of digitalis toxic effects Describe the clinical implications of diuretics, vasodilators, ACE inhibitors and other drugs that lack positive inotropic effects in heart failure Describe the strategies used in the treatment of heart failure The amount of blood at any time pumped to your body is sort of based on this demand that your body has for blood  What is heart failure Condition in which heart is unable to pump sufficient amounts of blood to meet the metabolic demands of the body (systolic heart failure) or not enough blood fills into the ventricles during diastole, called diastolic heart failure In both Systolic and diastolic, blood backs up into the lungs, causing congestion or fluid buildup, which is why it’s also often known as congestive heart failure. Due to any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.  Heart failure (HF) Pulmonary hypertension Myocardial infarction Cardiac output Body demand www.dreamstime. com Chronic systemic Valvular heart hypertension disease Dilated cardiomyopathy 6  Cardiac output mL/min Beat/min mL/beat Ejection fraction  Definitions Stroke Volume (SV): the amount of blood pumped by one contraction of the heart Cardiac Output (CO): the volume pumped out in one minute (SV x heart rate) Preload: is the amount of blood in the left ventricle waiting to be pumped out to the body, or the volume in the ventricle at the end of diastole. It's mainly dependent on the venous return of blood from the body 9  Cardiac output-example For example, in an adult, The heart might beat (HR) = 70 times per minute The left ventricle might squeeze out (SV) = 70ml per beat So 70 x 70 equals a cardiac output of 4900 ml per minute, which is almost 5 liters per minute. So notice that not all the blood was pumped out right? And the stroke volume is only a fraction of the total volume. The total volume might be closer to 110 ml, and 70ml is the fraction that got ejected out with each beat, the other 40ml kind of lingers in the left ventricle until the next beat.  Cardiac output-example In this example, the ejection fraction would be 70ml divided by 110 ml or about 64%, a normal ejection fraction is around 50-70%, between 40-50% would be considered borderline, and anything about 40% or less would indicate systolic heart failure because the heart is only squeezing out a little blood each beat. So in our example, if the total volume of the left ventricle was 110 ml, but only 44 ml was pumped out with each beat (then you have 44 ml divided by 110 ml which is 40%), and we would say that this person is in systolic heart failure.  Cont.. Now in addition to systolic heart failure, you’ve also got diastolic heart failure, which is where the heart’s squeezing hard enough but not filling quite enough. In this case again the stroke volume is low, but the ejection fraction’s normal...how’s that? Well it’s not filling enough so there’s a low total volume, say about 69 mL, well even though both are low, 44 ml divided by 69 ml is still 64%. In this situation, the failure’s caused by abnormal filling of the ventricle so that the chamber doesn’t get fully loaded or stretched out in the first place. Another term for this is having a reduced “preload” which is the volume of blood that’s in the ventricle right before the ventricular muscle contracts. Cardiac muscle contraction  Compensatory responses during heart failure Heart failure ↑ Sympathetic ↓ FOC ↓ COP ↓ Renal perfusion discharge Ventricular Vasoconstriction dilation ↑ Renin ↓ GFR β1 activation release Cardiac Na & remodelling ↑ AT-1 ↑ preload ↑ FOC water ↑ afterload ↑ HR ↑ AT-II retention Back pressure (Oedema) Initially ↑CO ↑ Aldosterone Later ↓ CO Oedema  Cardiac remodeling Hypertrophy of cardiomyocytes Necrosis and apoptosis of cardiomyocytes Cardiac fibroblasts differentiation into myofibroblasts, which proliferate and displace the dead cells, and deposit great amounts of extracellular matrix resulting in progressive cardiac fibrosis 1 8 Compensated vs. decompensated (acute) HF Compensated HF: if the adaptive mechanisms restore cardiac output. Decompensated HF: when these mechanisms fail, resulting in worsening HF symptoms: - Dyspnea on exertion - Orthopnea - Paroxysmal nocturnal dyspnea - Fatigue - Peripheral edema 19  Goal of heart failure treatment Alleviate symptoms Slow disease progression Improve survival 20  Therapeutic strategies in HF Fluid limitation (less than 1.5 – 2 L/day) Low dietary intake of sodium (less than 2000 mg/day) Treatment of co-morbid conditions, like diabetes Suitable doses of diuretics ACE-I or ARBs Inhibitors of sympathetic nervous system Inotropic agents should be reserved for acute HF Drugs that precipitate or exacerbate HF should be avoided, like: - NSAIDs - Nondihydropyridine CCB - Alcohol - Some anti-arrhythmic drugs 21 Pharmacological treatment Vasodilators Diuretics Inotropics Drugs Used in Heart Failure Aldosterone b-blockers Antagonists ACE-I/ARBs  Pharmacological treatment Benefits of pharmacological treatment: - Reduce myocardial work load - Decrease extracellular fluid volume - Improve cardiac contractility - Reduce rate of cardiac remodeling 23  Goal of therapy Drain the overload of fluid alleviate symptoms slow disease progression improve survival  Inotropic drugs Cardiac glycosides: Digoxin, digitoxin Sympathomimetic amines: Dopamine , dobutamine Phosphodiesterase inhibitors: Amrinone , milrinone Generally increase cytoplasmic calcium conc. that enhances cardiac contractility Associated with reduced survival With the exception of Digoxin, they are used only for short period and mainly for inpatients  Vasodilators Venodilators (nitrates, e.g. isosorbid dinitrate) increase venous capacitance and reduce preload. Arteriodilators (Hydralazine) reduce systemic arteriolar resistance and reduce afterload. A combination of both is added for patients intolerant of ACE-I, β- blockers or requiring additional vasodilation Side effects: Headache, hypotension & tachycardia. Hydralazine can rarely cause drug-induced lupus.  Diuretics Loop diuretics: furosemide, torsemide Thiazide diuretics: hydrochlorthiazide K+ Sparing diuretics: Spironolactone (Also is aldosterone antagonist) Amiloride – These agents are used for patients who require extensive diuresis and those with renal insufficiency  Role of diuretics in heart failure Almost all symptomatic Patients treated with a diuretic They relieve pulmonary congestion and peripheral edema They alleviate the symptoms of volume overload: orthopnea and paroxysmal nocturnal dyspnea They decrease plasma volume and venous return (reduce preload and afterload), thus decrease cardiac work and oxygen demand. High ceiling diuretics (loop diuretics) preferred – Low dose therapy for maintainence  Beta Blockers They block the effect of chronic sympathetic nervous system activation They decrease HR and Renin release from the kidneys They prevent the damaging effects of NE on cardiac muscle fibers: - Decrease remodeling - Decrease hypertrophy - Decrease cell death Three β-blockers are approved: Carvedilol, Bisoprolol and Metoprolol  β-Blockers They are recommended for all patients with chronic stable HF They reduce morbidity and mortality Normally started at low doses and titrated gradually according to patients tolerance and vital signs. 30  ACE Inhibitors in heart failure Angiotensin converting enzyme inhibitors – Captopril, enalapril, ramipril, lisinopril Act by – Reduction of after load – Reduction of preload – Reversing the compensatory changes ACE inhibitors are the most preferred drugs for treatment of Congestive cardiac failure  Indications of ACE- I/ARBs/Aldosterone antagonists ACE-I are indicated for patients with all stages of HF, whether symptomatic or asymptomatic Depending on the severity of HF, ACE-I can be used in combination with diuretics, β-blockers, Digoxin, Aldosterone antagonists, and Hydralazine/isosorbid dinitrate. ACE-I are beneficial for patients with recent MI 32  Angiotensinogen Renin Synthesis Angiotensin I Blocker Angiotensin Converting Enzyme ACE (ACE) inhibitor Angiotensin II Angiotensin Receptor Blocker AT2 AT1 Receptor Blocker Angiotensin III Angiotensin receptor blockers in heart failure Losartan , candesartan, valsartan, telmisartan Block AT1 receptor on the heart, peripheral vasculature and kidney As effective as ACE inhibitors Used mainly in patients who cannot tolerate ACE inhibitors because of cough, angioedema, neutropenia  Benefits of Inhibitors of Renin-Ang II- Aldosterone system (ACE- I/ARBs/Aldosterone receptor blocker) Vasodilation and reduction of aldosterone secretion Reduce cardiac remodeling and fibrosis Improve clinical signs and symptoms of HF Improve patients survival 35  Indications of ACE- I/ARBs/Aldosterone antagonists Aldosterone antagonists (Spironolactone and Eplerenone) are indicated for patients with severe HF or recent MI Eplerenone have lower affinity for the glucocorticoid receptors compared to Spironolactone. 36  Inotropic Agents Cardiac glycosides: Digoxin William Withering 1785 Foxglove plant Extracted from foxglove plant Enhance cardiac muscle contractility Have low therapeutic index!  In therapeutic dose leads to partial inhibition of Na+/K+ ATPase enzyme ca  ++ K+ Œ Na+ ATPase Na + /ca + + ca++ exchange Na+ ca++++ca ++ ca++ ca++ ca++ Na+ Na+ ca ca++ ca++ Na + troponin Na+ Na+ Na + Ý intracellular Na+ resulting in: Ž ca++ caca ++ ++ca++ sarcoplasmic reticulum Actin Myosin ÇÇ Force Of Contractility  Digoxin’s Mechanism of action 1. Regulation of cytosolic calcium concentration by Digoxin 39  Digoxin’s Mechanism of action Inhibit Na+/K+-ATPase → ↑Intracellular Na+ → ↓Na+ conc. gradient → ↓ability of Na+/Ca2+ exchanger to move Ca2+ out of the cell → ↑ contractility Na+/K+-ATPase inhibition raises resting membrane potential (-90 to - 70 mV) → excitability →risk of arrhythmias Note: Digoxin competes with K+ for the same binding site at Na+/K+- ATPase, thus hypokalemia enhances the activity of Digoxin 40  Digoxin’s Mechanism of action Digoxin enhances the Vagal tone, thus decreasing HR and myocardial oxygen demand Digoxin slows conduction velocity through AV node, useful for atrial fibrillation treatment Low doses of Digoxin inhibits the sympathetic activity with minimal effects on contractility (unknown mechanism). 41  Therapeutic uses of Digoxin Indicated for patients with severe HF after initiation of other standard drugs. Low doses of Digoxin reduces HF admissions and improve survival High doses prevent admissions but the mortality likely is increased Digoxin is not indicated for patients with diastolic or right sided HF unless atrial fibrillation or flutter coexist Not required for patients with mild to moderate HF (respond to standard therapy) 42  Pharmacokinetics of Digoxin Accumulates in cardiac muscle Has long half life (30-40 hr) Eliminated intact by the kidneys Require dose adjustments in renal dysfunction Digoxin is a substrate for P-gp (P-glycoprotien), thus P-gp inhibitors like Clarithromycin, Amiodarone and Verapamil can elevate Digoxin levels 4 3  Adverse effects of Digoxin At therapeutic plasma conc., Digoxin is well-tolerated Higher plasma conc. may cause: - Anorexia, nausea and vomiting (initial symptoms) - Blurred vision and yellowish vision - Various cardiac arrhythmias Digoxin should be used with caution with other drugs that slow AV- conduction (β-blockers, Verapamil and Diltiazem) 4 4  Management of Digoxin toxicity Discontinue Digoxin Check/correct serum K+ levels (Loop and Thiazide diuretics cause hypokalemia) Ventricular tachycardia should be treated with anti-arrhythmic drugs and antibodies to Digoxin (bind and inactivate Digoxin) 4 5  DD interaction Digoxin toxicity is also worsened by hypokalemia. Because digoxin binds to the K+ site of the Na+/K+-ATPase pump, low serum potassium levels increase the risk of digoxin toxicity. Conversely, hyperkalemia diminishes digoxin's effectiveness.  Cardiac Glycosides (Digitalis) Two glycosides: Used – Short acting Digoxin (t½: 1.5 days) – Long acting Digitoxin (t½: 5 days) Severely limited Use  Uses of digoxin Congestive heart failure Cardiac arrhythmias – Atrial fibrillation – Atrial flutter – Paroxysmal supraventricular tachycardia  Adverse effects of digoxin Extra-Cardiac Cardiac GIT: Nausea & vomiting Bradycardia (first to appear) (first cardiac toxic sign) CNS: Vomiting Pulsus bigemini Restlessness, Atrial extra-systole ® Disorientation, Visual flutter ® fibrillation disturbance Ventricular extra-systole Endocrine: ® tachycardia ® Gynaecomastia fibrillation Partial heart block ® complete block  Treatment of toxicity Stop digitalis Oral or parenteral potassium supplements For ventricular arrhythmias: – Lidocaine IV drug of choice For supraventricular arrhythmia: – Propranolol may be given IV or orally For AV block and bradycardia – Atropine 0.6 -1.2 mg IM Digoxin antibody Phosphodiesterase inhibitors in heart failure Amrinone & milrinone are selective phosphodiesterase III inhibitors ↑ cAMP levels The PDE III isoenzyme is specific for intracellular degradation of cAMP in heart, blood vessels and bronchial smooth muscles. Inodilators IV administration for short term treatment of severe heart failure Milrinone is more potent than amrinone and does not produce thrombocytopenia Preservation of cAMP cAMP Adenylyl cyclase ATP Activation of Phosphdiesterase III Milrinone Protein kinase Myocardial & Vascular smooth muscles Phosphorylation 5’AMP of Ca++ Channels Mechanism of Action Increased of Inodilators Ca++ Flow Positive ­ CO inotropism Elevated Cytosolic Ca++ Inodilatation Relaxation of ¯Pre-load Resistance & Capacitance vessels ¯After-load  Phosphodiesterase inhibitors Milrinone It elevates the level of cAMP Given as IV infusion for short-term treatment of acute HF in hospital setting Long term treatment is associated with high rates of mortality 5 3  Other inotropic drugs Dopamine Dobutamine  β-adrenergic agonists Dopamine and Dobutamine Both can be given as IV infusion for short-term treatment of acute HF in hospital setting 5 5  Approach to the Patient with Heart Failure Assessment of LV function (echocardiogram) EF < 40% Assessment of volume status Signs and symptoms of No signs and symptoms of fluid retention fluid retention Diuretic ACE Inhibitor (titrate to euvolemic state) Digoxin b-blocker  Drugs used in heart failure Chronic heart failure Acute heart failure Diuretics Diuretics Aldosterone receptor Vasodilators antagonist Dopamine, dobutamine ACE inhibitors Amrinone Angiotensin receptor blockers Cardiac glycosides Vasodilators 34