Pharmacology of Congestive Heart Failure (CHF) Lecture PDF

Pharmacology of Congestive Heart Failure (CHF) Maria A. Pino, Ph.D Department of Clinical Specialties [email protected] Office of Academic Affairs  Session Objectives 1. Describe the specific goals of congestive heart failure (CHF) management. 2. Correlate the pathophysiology of CHF with the d...

Pharmacology of Congestive Heart Failure (CHF) Maria A. Pino, Ph.D Department of Clinical Specialties [email protected] Office of Academic Affairs  Session Objectives 1. Describe the specific goals of congestive heart failure (CHF) management. 2. Correlate the pathophysiology of CHF with the drugs used for treatment. 3. Explain how these drugs benefit the CHF patient. 4. Examine the pharmacological mechanism of these drugs. 5. Describe specific drug adverse effects. Source: Course Syllabus Pathophysiology of CHF  CHF Inability of ventricle to pump blood into circulation Causes: recent MI, uncontrolled hypertension, arrhythmia. Drugs: Doxorubicin (intercalating agent, chemotherapeutic). Thiazolidinediones “glitazones” (PPAR γ agonists for type II diabetes). Pioglitazone, Rosiglitazone NSAIDs (vasoconstriction in kidney by prostaglandin blockade in the afferent arteriole) Results in cardiac remodeling  Cardiac Remodeling Post MI Stretch of muscle fibers Results in fibrosis, collagen, and myocyte hypertrophy Consequences: Reduced stroke volume and cardiac output, increased ventricle stiffness, decreased contractility Increase in sympathetics and renin-angiotensin-aldosterone axis (benefit of beta blockers, ACEI/ARBS/ARNI/spironolactone)  CHF Left ventricular failure Right ventricular failure Heart can’t maintain Right ventricle can’t pump to body’s blood flow lungs. Fluid build-up needs Ankle edema Pressure in pulmonary Hepatojugular congestion circulation increases “nutmeg liver” Edema, dyspnea, orthopnea, fatigue, hypoxia, organ dysfunction CHF Frank-Starling http://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of_heart_failure  CHF Management Diet, exercise, sodium restriction guidelines Decrease preload: diuretics, ACEIs/ARBS, venodilators Decrease afterload: ACEIs/ARBS, arteriodilators Improve contractility: digoxin, B1 agonists, PDE3 blockers Decrease remodeling: ACEIs/ARBS, spironolactone, beta blockers. Other drugs: Antiplatelet or anticoagulants, antidiabetics, antihyperlipidemics, etc  Positive Inotropic Drugs Increase contractility Digoxin (digitalis, foxglove plant) Dobutamine (B1 agonist, Gs mechanism). Dopamine (maintains GFR and renal blood flow) Milrinone (PDE-3 blocker) Digoxin http://www.cvpharmacology.com/cardiostimulatory/digitalis  Digoxin Long t1/2 Negative chronotropic: increases parasympathetic tone (vagal) Increased afterdepolarizations (monitor K+)  Digoxin Increases PR (reduced AV node) ST depression (hockey stick configuration)  Digoxin N/V/D, anorexia Ventricular arrhythmias: High Ca, low K, Mg (monitor diuretic use) Yellow vision (halos) Gynecomastia (estrogenic) DI: antacids, cholestyramine (absorption) amiodarone (CYP inhibition), verapamil and quinidine (elimination) Renal impairment (reduced digoxin elimination) Antidote: DigFab, manage electrolytes. Give magnesium (torsades) Dobutamine-Milrinone (increase cAMP) Teerlink JR - Heart Fail Rev (2009)  Vasodilators Angiotensin-converting enzyme inhibitors (ACEI, -prils) and Angiotensin II receptor blockers (ARBS, -sartans). **Chronic CHF****** Hydralazine Nitric oxide donors (nitroglycerin, isosorbide dinitrate, nitroprusside) Nesiritide Renin-Angiotensin-Aldosterone System  RAAS Adverse Effects First-Dose Phenomenon Aldosterone absence: Hyperkalemia Bradykinin: Cough, angioedema. Specific to ACEI. Replace with ARBs Drug interactions (K+ sparing diuretics or supplements), NSAIDs. Renal artery stenosis (contraindication). But used to reduce proteinuria in type II diabetics Fetal renotoxicity (not in pregnancy) Aliskiren: direct renin inhibitor (similar adverse effects)  ACEI-induced Angioedema Remove offending drug Treatment: epinephrine, glucocorticoids Icatibant: a synthetic bradykinin receptor antagonist for hereditary angioedema??? Nitric oxide (NO) donors Nitroglycerin, Isosorbide Sildenafil Hydralazine, Nesiritide http://cvpharmacology.com/vasodilator/nitro Nitric oxide (NO) donors Act at the venule Decrease preload Decrease O2 consumption Adverse effects: tolerance, headache hypotension (avoid PDE-5 inhibitors)  Nitroprusside NO donor, but also dilates arterioles. Decrease preload and afterload Cyanide toxicity (hydroxycobalamin is the antidote)  Hydralazine Arteriole (decrease afterload) Severe hypertension in pregnancy Acetylated (procainamide, isoniazid, sulfonamides) Adverse effects: headache, flushing, dizziness, hypotension, tachycardia, fluid retention. Lupus-like syndrome (slow acetylators) Antihypertensives Basic & Clinical Pharmacology, 16e Bertram G. Katzung, Anthony J. Trevor  Beta-adrenergic antagonists Beta 1: decrease HR, CO, and renin from JXA Use: hypertension, MI, and, CHF Beta 1: (atenolol, metoprolol) Beta 1, 2: (nadolol, propranolol, timolol). Bronchoconstriction, hypoglycemia, PVD (Beta 2) Labetalol and Carvedilol (alpha and beta blocker, antioxidant potential) Pindolol and Acebutolol (ISA) Worsen!!! Esmolol (ultrashort acting) Nebivolol (nitric oxide effect)  AV nodal suppressants Calcium channel blockers (Class IV) Verapamil and Diltiazem. (Not for CHF, negative inotropic). Adenosine (Gi mechanism, for PSVT) Digoxin (vagus, parasympathetic) Beta adrenergic antagonists (Class II) Diuretics: Sites of Action Aldosterone Blockers (MRA) Spironolactone, Eplerenone Antagonizes aldosterone receptors Spironolactone (androgen blocker) Use: high aldosterone/ CHF, acne, hirsutism Adverse effects: Hyperkalemia, acidosis Spironolactone: gynecomastia, impotence. Drug interactions: Digoxin, “renin” drugs, NSAIDs Aldosterone Blockers: Collecting Tubule  Loop Diuretics Furosemide, Bumetanide, Torsemide, Ethacrynic acid (no sulfur) Inhibit Na/K/2Cl- cotransport in thick ascending Loop of Henle (TAL). “High ceiling” diuretics Reduce preload Loop Diuretics: TAL  Loop Diuretics Loss of Na, Cl, K, Ca, and Mg Increases PGE2 (vasodilation) Use: CHF, pulmonary edema, hypercalcemia, hyperkalemia, hypertension, acute renal failure Adverse effects: hypokalemia, hypomagnesemia, hypocalcemia, hyperuricemia, metabolic alkalosis. Ototoxicity (especially with ethacrynic) hypersensitivity (except ethacrynic acid) Drug interactions: NSAIDS, digoxin, overlap ototoxicity (cisplatin, gentamicin, vancomycin) Thiazide Diuretics: DCT  Thiazide Diuretics Hydrochlorothiazide, Chlorthalidone, Indapamide Use: hypertension, CHF, kidney stones, and nephrogenic diabetes insipidus Adverse effects: Hypokalemia, alkalosis, hyperglycemia, hypercalcemia, hyperlipidemia, hyperuricemia, hypovolemia, hyponatremia, sulfa sensitivity. Drug Interactions: digoxin, NSAIDs, lithium  Ivabradine Selective If inhibitor (“funny channel” blocker) Inhibits action in the SA node without affecting the duration of the action potential Use: CHF and stable angina, especially those who can’t tolerate or be managed with beta antagonist Adverse effects: bradycardia, vision changes, not in pregnancy. Caution with CYP 3A4 inhibitors  Other Drugs Angiotensin receptor/neprilysin inhibitor (ARNI): Sacubitril: (prodrug) inhibits neprilysin to enhance natriuretic peptides. Combined with Valsartan. Adverse effect: hypotension, hyperkalemia. Sodium-glucose cotransporter 2 inhibitor (SGLT2): dapagliflozin Conivaptan: blockade of V1a receptor decreases PVR. V2 blockade causes water secretion. Subtype 2 sodium-glucose transport protein (SGLT2) inhibitors Canagliflozin, dapagliflozin, empagliflozin Glucose excreted by kidney via proximal tubule CHF management: promotes diuresis. ~ 1% A1c reduction Adverse Effects: UTIs, monitor GFR (not for CrCl