Congestive Heart Failure PDF - KYCO Pharm I 2020

Congestive Heart Failure Amanda Blankenship, MD, PharmD, RPh KYCO Pharm I 2020 Objectives: • Diagnose and recognize main causes of CHF • List targets for CHF drugs • List main categories of CHF drugs • Explain mechanism of action for CHF drugs • List primary side effects for CHF drugs • List comorbi...

Congestive Heart Failure Amanda Blankenship, MD, PharmD, RPh KYCO Pharm I 2020 Objectives: • Diagnose and recognize main causes of CHF • List targets for CHF drugs • List main categories of CHF drugs • Explain mechanism of action for CHF drugs • List primary side effects for CHF drugs • List comorbid conditions where CHF drugs are commonly used • List contraindications or drug interactions for selected CHF drugs Heart failure is a common condition in the U.S., especially in older adults. It is the primary diagnosis in over 1 million hospitalizations each year. Heart failure occurs when the heart is not able to supply sufficient oxygen rich blood to the body, because of impaired ability of the ventricle to either fill or eject blood. Heart failure (HF) is commonly classified as either ischemic (due to decreased blood supply, such as from an MI) or non-ischemic (due to long-standing uncontrolled hypertension). Less common causes include valvular disease, excessive alcohol intake, illicit drug use, congenital heart defects, viral infections, diabetes, autoimmune disorders, genetic heart disease, heart rhythm related, and cardiotoxic drugs/chest radiation. Bottom line: heart muscles less effective at pumping. This causes a back-up within the closed system of circulation. The chambers of the heart stretch and thicken to hold more blood (this weakens the heart) Then kidneys compensate to hold more Na+ and water. And the cycle continues. Signs and Symptoms: Symptoms of HF are usually related to fluid overload, which commonly presents as shortness of breath (SOB) and edema. Symptoms can occur due to problems with systolic (contraction) or diastolic (relaxation/filling) functions of the heart. Patients can experience periods of stability and exacerbation. Exacerbations frequently result in hospitalization and negatively impact quality of life Diagnosis: Ultrasound of the heart (echocardiography or ECHO) is performed when HF is suspected (Symptomatic and natriuretic peptide labs are elevated). It provides an estimate of left ventricular ejection fraction (LVEF) LVEF is a measurement of how much blood is pumped out of the left ventricle with each contraction. The term LVEF is used interchangeably with ejection fraction (EF). Classification Systems: Two classification systems are recommended for HfrEF, The American College of Cardiology and the American Heart Association (ACC/AHA) recommend categorizing patients by HF stage. The staging system used to guide treatment in order to slow progression of structural heart disease in asymptomatic patients (stages A and B) or symptomatic patients (stages C and D). HF patient can also be classified by the level of limitation in physical functioning using the New York Heart Association (NYHA) classification system. These classifications remain extremely relevant to drug therapy decisions. Concepts: Cardiac Output: depends on stroke volume and heart rate. It is the volume of blood that is pumped by the heart in one minute. CO = SV X HR Stroke Volume depends on: • Preload: volume of blood received by the heart (stretch) • Afterload: pressure or resistance the heart has to overcome to eject blood (squeeze) • Resistance / pressure at which the heart must pump blood • Contractility: Cardiac performance Pathology: • Heart is not able to pump blood to meet body’s demands or… • Cardiac output is inadequate to provide the oxygen needed by the body • Myocyte loss and fibrosis Compensatory mechanisms: HFrEF is a low cardiac output state, which the body compensates for by activating neurohormonal pathways to increase blood volume or the force or speed of contractions. This can temporarily increase CO, but chronically leads to myocyte damage and cardiac remodeling. This causes changes in the size, composition, and shape of the heart (hypertrophy, dilation) The main pathways activated in HF are the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and vasopressin. The neurohormones that normally balance these systems (ex. Natriuretic peptides) become deficient. ANP and BNP (Atrial Natriuretic Peptide and Brain Natriuretic Peptide: • Hormones produced by the cardiomyocytes in response to stretching o Works to widen blood vessels o BNP produced by the lower champers and ANP by the upper • BNP: Blood test that aids in diagnosis and measures improving or worsening HF RAAS and Vasopressin Activation: • Renin converts angiotensinogen to angiotensin I • Angiotensin I (ATI) is converted to angiotensin II (ATII) by angiotensin-converting enzyme (ACE) • ATII causes vasoconstriction and stimulates release of aldosterone from the adrenal gland and vasopressin from the pituitary gland • Aldosterone causes sodium and water retention and increases potassium excretion • Vasopressin causes vasoconstriction and water retention SNS activation: Norepinephrine (NE) and epinephrine (Epi) release causes an increase in HR, contractility (positive inotropy), and vasoconstriction The diagram below reviews the pathophysiology and a summary of current treatment recommendations: SGLT2 inhibitor: Yes; mortality benefit Note: Venous dilators reduce preload; whereas arterial dilators reduce afterload on the left ventricle (enhancing stroke volume and cardiac output, which leads to secondary decrease in ventricular preload) Medications used to treat HF: standard Drugs that reduce cardiac remodeling and decrease mortality: gold • RAAS Inhibitors: o ACE inhibitors (ACEIs): Lisinopril, Prinivil, Enalapril o Angiotensin II Receptor Blockers (ARBs): Losartan, Valsartan, Telmisartan o Aldosterone antagonist (mineralocorticoid receptor antagonist; MRA) (Diuretics): Spironolactone and Eplerenone • Beta Blockers: Metoprolol, Bisoprolol, and Carvedilol: Most Commonly Seen • SGLT2 Inhibitors: Dapagliflozin and Empagliflozin • Vasodilator: Neprilysin Inhibitors: Sacubitril Alphal antagonism Other drugs used to treat HF: • Inotropic agents o Cardiac glycosides: Digoxin o Beta1 agonists: Dobutamine and Dopamine o Phosphodiesterase Inhibitors: Milrinone • Agent with SA node focus: linedrug o If Channel Blocker: Ivabradine last • Other Diuretics o Loop: Furosemide (severe) o Thiazides: HCTZ (mild) • • Other vasodilators: o CCB (mixed dilation): Non-dihydropyridine (Verapamil and Diltiazem) and dihydropyridine (Amlodipine) o Direct acting vasodilator: (use as adjunct in African American patients; shown to reduce mortality and hospitalizations) ▪ Hydralazine (mostly arterial and venous) ▪ Isosorbide dinitrate (mostly venous and some arterial) Vasodilators: Used acutely in hospital setting o Alpha 1 blocker: Prazosin (mixed venous and more pronounced in arterial) o Nitrates: Nitroglycerin (venous, but at high doses can dilate arteries) Vasodilators: (5 Classes) 1. Naprilysin Inhibitor: Sacubitril • The first approved neprilysin inhibitor • MOA: Neprilysin is an enzyme that degrades atrial and brain natriuretic peptide, two blood pressure-lowering peptides that work mainly by reducing blood volume (increases half-life of BNP and ANP); also increases the levels of bradykinin (BK) • • • • • • • • Currently available in combination with valsartan (Entresto) and is an alternative to an ACEI (with the ARB get vasodilation) Referred to as an ARNI (angiotensin II receptor blocker neprilysin inhibitor) In the Paradigm-HF trial, valsartan/sacubitril was compared to enalapril (considered gold standard) and found to reduce cardiovascular death or hospitalization from heart failure (26.5% vs. 21.8%) and all-cause mortality (19.8% vs. 17.0%)..also saw better glycemic control in diabetics SE: hypotension, possible potentiation of dementia and accumulation of amyloid plaques (FDA approved because life expectancy of most HF patients is shorter than the time it takes to develop dementia); risk of cough and angioedema (more BK) RAAS Inhibitors: (2 Classes) 1. ACEI: Enalapril, Lisinopril 2. ARB: Losartan, Valsartan, Telmisartan First-line therapy MOA: • Inhibit vasoconstrictor effects of angiotensin II • Inhibit the retention of sodium and water by indirectly inhibiting aldosterone • Prevent aldosterone-mediated cardiac remodeling; aldosterone may act directly on cardiac muscle to promote increased collagen deposition and fibrosis (remodeling) • Induce venous as well as arterial vasodilation • Preload: reduced by reduction salt and water retention and vasodilation • Afterload: reduced by arterial dilation and improves signs of mitral regurgitation • Reduce the long-term remodeling of the heart and therefore reduce morbidity and mortality (increase survival) SE: Hyperkalemia; dry / non-productive cough and angioedema (Seen more with ACEI) CI: • Do NOT take while pregnant: can cause injury or death to fetus • Bilateral renal artery stenosis (dilates efferent arteriole to dec GFR • • • • • • Beta Antagonists: Metoprolol, Bisoprolol, and Carvedilol MOA: Inhibitor of Beta-adrenergic receptors (depress heart rate and contractility) Improves symptom, exercise tolerance, and ventricular function Effective In patients with mild to moderate cardiomyopathies in combo with ACEIs +/- diuretics +/- digoxin Effective at decreasing mortality (decreased remodeling, fewer arrhythmias) Dosage: critical for beta blockers used in CHF • Start low and titrate up for the next 4-6 weeks; high doses could be lethal Extensively studied in HF (first line) Affects SA node: 1. Ivabradine: If (funny Sodium Channel) Blocker: • The first approved pacemaker “funny” sodium channel blocker • The If channel is responsible for the automaticity of the SA node; these channels are upregulated in HF patients • MOA: Decreases the diastolic depolarization slope in the SA node: decreases heart rate without direct effects on contractility or intracardiac conduction • Approved for patients with chronic HF with left ventricular ejection fraction ≤35% who are in sinus rhythm with resting heart rate ≥70 bpm and also taking beta blockers at their highest tolerable dose • SE: bradycardia, blurred vision, increased incidence of atrial fibrillation Diuretics: (3 Classes) 1. Loops: Furosemide (Severe CHF) 2. Thiazides: HCTZ (mild CHF) 3. Aldosterone Receptor Antagonists: Spironolactone, Eplerenone • Not very potent as diuretics (K+ sparing) • Main benefit is blocking the action of aldosterone which decreases cardiac remodeling and improves survival (only diuretics that do this) • MOA: reduce extracellular fluid volume and ventricular filling pressures (preload) but usually do not affect cardiac output as a primary function SGLT2 Inhibitors: Dapagliflozin and Empagliflozin MOA in heart failure: not fully understood but could be explained by the natriuresis and osmotic diuresis that these agents promote. This results in improvement of left ventricular loading conditions by a reduction of preload, without reducing the intravascular volume as much as commonly used diuretics. SGLT2 inhibitors also reduce BP without the reflex tachycardia, so reduce myocardial workload. These meds also improve glycemic control with reduced requirements for insulin, so promote weight loss, which also helps with BP. We need more data on improved left ventricular function and remodeling. FDA approved: • Reduces the risk of hospitalization for heart failure, with or without type 2 diabetes to reduce the risk of hospitalization for heart failure and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF), with or without diabetes SE: Wt loss, Increased Genitourinary infections, Hypotension, hyperkalemia Inotropic Drugs: (3 Classes) 1. Digoxin Cardia: glycosides • MOA: 1. cardiac glycosides bind reversibly to the Na+ –K+ -ATPase of the cardiac cell membrane which blocks the activity of the Na-K-ATPase pump →↑intracellular Na+ which favors transport via the Na+ –Ca++ -exchanger which ↑ intracellular Ca++ (increased Ca++ in sarcoplasmic reticulum)→↑force of contraction and slows HR 2. stimulates the parasympatheitic nervous system to slow electrical conduction through the AV node. This provides decreased ventricular response • Group of compounds derived from the plant digitalis (foxglove) • Uses: o Digoxin is preferred in heart failure with concurrent atrial fibrillation or patients who have not responded to standard therapies not first line o • Patients in sinus rhythm with mild to moderate heart failure will often respond to treatment with ACE inhibitors, diuretics, and β-blockers and do not require Digoxin • Pharmacokinetics (PK): digoxin has a half-life of 36-48 hours and an onset of 20 minutes • SE: digitalis toxicity (common) o Major effect is severe arrhythmias which include complete heart block; v-tach, and v-fib; anorexia, nausea, vomiting, headache, fatigue, confusion, and blurred vision are common Factors predisposing to digitalis toxicity: o Hypokalemia, often caused by potassium depleting diuretics (thiazide or loop), can enhance digoxin toxicity by enhancing the binding of digoxin to the Na+ –K+ ATPase (Dig usually binds to site where K+ binds) and precipitate serious arrhythmia; discontinue dig and give potassium supplement o Drugs: 2 drugs: quinidine and verapamil can displace digoxin from plasma proteins o Treatment of severe Dig Toxicity: anti-digoxin antibodies ▪ Digibind 2. Beta 1 Agonists: Dobutamine and Dopamine • MOA: Binds to B receptor, activates adenylyl cyclase, to produce cAMP from ATP, cAMP phosphorylated calcium channel to cause contraction of cardiac muscle (positive inotrope) • Strong Beta1 agonist; weak B2 agonist/alpha1 antagonist • Improves cardiac performance by positive inotropic effects; only used short-term in acute failure as in cardiogenic shock where organ perfusion is needed, due to tachyphylaxis (rapid tolerance) Questions?