Principles of Pharmacotherapy in Chronic Heart Failure .. ....,, PPhhaarrmm..DD..,, PPhh..DD.. 1. 2. 3. (chronic heart failure) (acute exacerbation of chronic heart failure decompensated heart failure)4. (indication) (contraindication) (optimal dosing) (monitoring) (patient counseling) 5. digoxin digoxin 6. (goals of care) 7. 2. 2 | pageCardiac output cardiac output (/) stroke volume /Cardiac output (L/min) = heart rate x stroke volumeStroke volume stroke volume 1. Preload or Venous return Frank-Starlings law of the heart (Stroke volume) (venous return) (force of contraction) (preload or venous return) preload (cardiac myocyte) (stretching) preload hemodynamic preload left ventricular end-diastolic volume (LVEDV) left ventricular end-diastolic pressure (LVEDP) stroke volume preload 12. Cardiac contractility Inotropic state preload ( Frank-Starling) Contractility inotropy state sympathetic nervous system (SNS), catecholamines , digoxin, dopamine, dobutamine contractility Contractility stroke volume ventricular function curve 2. 3. 3 | page3. Afterload (Ventricular wall stress) 3 :a. (intravenricular size radius ) (Cardiac chamber enlargement)b. (ventricular wall thickness)c. (intraventricular systolic pressure) total peripheral vascular resistance afterload Afterload Parameters Afterload = Intraventricular systolic pressure x radiusEjection fraction (EF) (eject) systole (left ventricular systolic function) diastole EF = Stroke volume x 100End-diastolic volume EF 50-60Ventricular wall thickness 1 Frank-Starling Mechanism 2 Cardiac function curve 4. 4 | page (Heart failure) (clinical presentation) oxygen (dyspnea onexertion) (orthopnea) (peripheral edema) (interstitium) oxygen 1. 3 a. Systolic heart failure (contraction or inotropy) (cardiac output) systolic dysfunction systolic heart failure ejection fraction 40% (EF< 40%) EF 40-60% mild systolic dysfunctionb. Diastolic heart failure (relaxation or lusitropy) ( ) (ventricular filling preload) cardiac output FrankStarling diastolic heart failure normal ejection fraction (EF > 60%) 1 3 diastolic heart failure systolic heart failurec. Combination of systolic and diastolic heart failure EF echocardiography2. (functional classification) New York Heart Association (NYHA) New York Heart Association Functional Classification of Heart Failure 4 5. 5 | pagea. NYHA funcional class I (ordinary physicalactivity) b. NYHA functional class II (slight limitation) c. NYHA functional class III (no symptoms at rest)d. NYHA functional class IV (symptoms at rest)3. (staging of disease progression) American Heart Association (AHA) American College of Cardiology (ACC) a. Stage A hypertension, atherosclerotic diseases ( ), diabetes, obesity, metabolic syndrome cardiomyopathyb. Stage B (structural abnormalities) (left ventricular hypertrophy) ejection fraction c. Stage C d. Stage D refractory heart failure ventricular assisted device,chronic inotropes therapy 6. 6 | page (Causes) 3 1. a. Ischemic heart disease myocardial infarction systolic heart failure diatolic heart failureb. (cardiomyopathies) (1) Dilated cardiomyopathy systolic heartfailure(2) Hypertrophic cardiomyopathy (disarray) diastolic heart failure.(3) Restrictive cardiomyopathy diastolic heart failurec. (myocarditis) 2. valvular stenosis regurgitation (aortic, pulmonic,mitral, tricuspid valve) a. stenosis ( mitral tricuspid valve stenosis) preload diastolic heart failure ( pulmonicvalve stenosis) ( aortic valve stenosis) systolic heart failure b. regurgitation insufficiency ( mitral regurgitation tricuspid regurgitation), pulmonary artery right ventricle ( pulmonic valve regurgitation) aorta ( aorticregurgitation) left ventricle (volume overload) 7. 7 | page(increased preload) (cardiac dilatation) systolicheart failure3. () (increasedcardiac workload) 2 (pressure overload) (volume overload) a. (systemic hypertension) heart failureb. (pulmonary hypertension) c. shunt patent ductus arteriosus (PDA), atrial septal defect (ASD), ventricular septaldefect (VSD) 4. a. ventricular fibrillation or tachycardiab. atrial fibrillation or tachycardiac. bradycardiad. complete heart block (Precipitating factors) (compensated state) cardiac output (acute exacerbation decompensation ) pulmonary hypertension 8. 8 | page corticosteroids NSAIDs afterload myocardial contractility beta-blocker propranolol, metoprolol non-dihydropyridine calcium channel antagonists verapamil, diltiazem(Compensatory mechanisms to increase cardiac output) cardiac output (compensatory mechanisms) cardiac output compensated state cardiac output decompensated stateCompensatory mechanisms cardiac output 1. (heart rate) (contractility) sympathetic (activation of autonomic sympatheticnervous system SNS) catecholamines 2. (increased preload) 2 a. (vasoconstriction) (Non-vital organs) redistribute preload. neurohormones norepinephrine, angiotensin II, endothelin-1, B-type natriuretic peptide (BNP) argininevasopressin preload afterload (total peripheral resistance) b. (increased renal reabsorption of water andsodium chloride) (renal hypoperfusion) cardiac output redistribute 9. 9 | page (1) (2) renin juxtaglomerular cells renin angiotensinogen angiotensin I, angiotensin I angiotensin II angiotensin converting enzyme (ACE),angiotensin II aldosterone aldosterone sodium chloride (increased intravascular volume) (increased preload) Frank-Starling cardiac output preload cardiac output ( Frank-Starling curve) preload cardiac output preload stroke volume ( Frank-Starling curve) leftventricular end-diastolic volume left ventricular end-diastolic pressure (pulmonary congestion) (systemic venous congestion) renin SNS renin -1 receptor SNS renin angiotensin II3. / (ventricular dilation and/orhypertrophy) preload, afterload cardiaccontractility / cardiac output neurohormones catecholamines, angiotensin II, aldosterones sympathetic nervous system ventricular remodeling hypertrophy angiotensin II ( ACEIs), (-receptorantagonists), aldosterone ventricular remodeling hypertrophy - ischemic heart disease oxygen demand - (ventricular relaxation) diastolic heart failure- ventricular systolic function 10. 10 | page- cardiac arrhythmias Compensatory mechanisms (vicious cycle) (Continued worsening and downward spiraling of the heart failure state) (1) (2) 3 (CLINICAL PRESENTATION OF DECOMPENSATED HEART FAILURE) (right-sided heart failure) cardiac output cardiac output 11. 11 | page (increased right ventricular end-diastolic pressure) (venous return) (systemic venous congestion) (liver) : (peripheral edema) interstitial fluid cardiac output oxygen carbon dioxide (engorged and elevated neck vein) (hepatomegaly hepatic enlargement) (jugular vein) (hepatojugular reflux) (anorexia) (abdominal fullness) (nausea) (left-sided heart failure) cardiac output cardiac output (increased left atrial and ventricle end-diastolicpressure) (pulmonary congestion) : (dyspnea) (orthopnea) (paroxysmal nocturnal dyspnea) (pulmonary edema) (fatigue) (right-sided heart failure) pulmonary vascular resistance systemic venous congestion 12. 12 | page (Complications)a. Cardiac arrhythmia and sudden cardiac deathb. Ischemic heart failurec. Acute renal failure (Prerenal)d. Thromboembolism1. (medical history) a. b. c. d. 2. (physical examination)a. b. (fluid retention status) (peripheral edema) pitting edema ( 1 ) (gut edema) ( hepatic enlargement, hepatojugular reflux positive) ( jugular venous distention engorged neck vein) (pulmonary edema) (dyspnea) (tachypnea) 13. 13 | page (crepitation) rales crackles chest radiography (chest-x-ray) (interstitial infiltrate)c. (tissue perfusion status) cyanosis (mental confusion) urine output3. (Echocardiography with Doppler flow study) (systolic diastolic heart failure) systolic heart failure (myocardialwall motility during diastole and systole) (ejection fraction)4. electrolytes B-type natriuretic peptide echocardiography5. (hemodynamicmonitoring) pulmonary artery catheter (atrial ventricular pressure), (pulmonar capillary wedge pressure) ventricular end-diastolic pressure ventricular preload, systemicvascular resistance, central venous pressure cardiac index 6. ECG , myocardial biopsy 14. 14 | page(ACUTE EXACERBATION OF CHRONIC HEART FAILURE DECOMPENSATED HEART FAILURE)1. (respiratoryfailure) (cardiogenic shock) (suddencardiac death)2. (optimization of cardaic contractility and fluid status) (optimization of cardiac output and preload)1. (non-pharmacological therapy)a. NSAIDs, corticosteroids, negative inotropic drugs calcium channel blockers beta-blockers b. sympathetic nervous systemc. oxygen oxygen d. sodium 2 e. 0.5 1.0 fluid output fluid input = 0.5 1.0 fluid balance intravascular volume depletion () preload tissue hypoperfusion ( volume overload tissue hypoperfusion) fluid output fluid inputf. ultrafiltrationg. shock h. (respiratory failure) (mechanical ventilation) respiratory failure O2 / 15. 15 | page CO2 severe pulmonary edema, 2. (pharmacological therapy)a. b. (critical care unit) (hemodynamic monitoring) pulmonary artery catheter c. pulmonary aretery catheter 2 cardiac index ( cardiac output/body surface area) L/min/m2pulmonary capillary wedge pressure (PCWP) mm Hg left ventricularend-diastolic pressure preloadd. cardaic index (CI) tissue perfusion 2.2 L/min/m2 (tissue hypoperfusion) cardiac output preload Frank Starling PCWP heart failure 8-12 mmHg preload cardiac output intravascular volumedepletion PCWP 12-20 mmHg intravascular volume overload pulmonary congestion cardiac output preload PCWP PCWP 15 18 mmHg e. 1. CI > 2.2 L/min/m2 PCWP 12-20 mmHg cardiac output ventricular filling pressure (preload) 2. CI > 2.2 L/min/m2 PCWP > 20 mmHg intravascularvolume overload preload (diuretics vasodilators) sympathetic nervous system renin-angiotensin-aldosterone system (1) cardiac index (2) intravascular volume depletion 16. 16 | page3. CI < 2.2 L/min/m2 PCWP > 20 mmHg hypoperfusion intravascular volume overload preload (diuretics vasodilators) cardiaccontractility vasodilators afterload cardiac contractility inotropic agent afterload reducer vasodilator vasodilators cardiac output vasodilators afterload 4. CI < 2.2 L/min/m2 PCWP 12-20 mmHg hypoperfusion intravascular volume overload cardiac contractility vasodilators afterload, vasodilator vasodilators cardiac output vasodilators afterload preload vasodilators afterload preload ACEIs, IV nitroprusside, IV nitroglycerin vasodilators IV fluid preload (PCWP 18-20) hypoperfusion preload cardiac output intravascular volume overload .f. pulmonary artery catheter cardiac contractility tissue perfusion narrow pulse presssure hypoperfusion cardiac output preload volume status (pulmonary congestion) chest radiography rales, S3, volume overload overload tachycardia intravascular volumedepletion tachycardia CI PCWP hypoperfusion ( cardiac output) intravascular volume overload (preload) preload (diuretics vasodilators) cardiac contractility afterload (3) g. 17. 17 | page1. preloada. DiureticsDiuretics sodium intravascular volume preload fluid overload loop diuretics (1) Thiazides thiazide-like diuretics hydrochlorothiazide, chlorothalidone,metolazone loop diuretics (creatinine clearance < 30 ml/min) thiazides loopdiuretics diuretic resistance loop diuretics thiazides loop diuretics 30 (2) Loop diuretics furosemide, bumetanide, torasemide thiazide diuretics creatinine clearance ~ 10 ml/min (Henles loop) heart failure (gut edema) (urine output) 1 furosemide 240 mg/ diuretics hydration intravascular volume hypoperfusion prerenal acute renal failure intravascular volume depletion baroreceptor reflex sympathetic nervous system renin-angiotensin-aldosterone system tachycardia myocardial infarction cardiac arrhythmia b. vasodilatorsVasodilators acute heart failure ACEIs (PO IV), IV nitroglycerin, IV sodiumnitroprusside, nitrates PO isosorbide dinitrate, hydralazine PO or IV(1) ACEIs preload afterload IV enalaprilat active metabolite enalapril acute renal failure ACEIs 18. 18 | page(2) Sodium nitroprusside preload afterload sodium nitroprusside cyanide (cyanide toxicity) cyanide lactic acidosis thiocyanate cyanide thiosulfate thiocyanate thiocyanate 24-48 thiocyanate IV nitroglycerin(3) IV nitroglycerin Nitrates preload afterload IV nitroglycerin vasodilator of choice intravascular volumeoverload (4) Hydralazine afterload preload reflex tachycardia vasodilators :(1) IV decompensation (2) preload vasodilators cardiac output cardiac output intravascular volume preload reflex tachycardia cardiac output afterload 2 tissue hypoperfusion diuretics preload reducer 2. cardiac contractility (positive inotropic agents) positive inotropic agents (myocardial infarction) myocardial oxygen demand ventriculartachycardia 19. 19 | pagea. Digoxin Na-K ATPase calcium ion myocardial contractility loading dose maintenance dose positive inotropic b. Catecholamines dopamine dobutamine norepinephrine epinephrine systemic vascular resistance afterload (1) Dopamine 5 mcg/kg/min dopamine-1 receptor renal perfusion 5-10mcg/kg/min beta-1 receptor cardiac contractility heart rate cardiacoutput 10 mcg/kg/min alpha-1 receptor blood pressure afterload cardiac output renal ischemia dopamine renal perfusion 10 mcg/kg/min cardiac contractility (2) Dobutamine beta-1 alpha-1 beta-2 cardiac contractility heart rate sympathetic nervous system 1-10 mcg/kg/min tachycardia hypotensionc. Phosphodiesterase inhibitors phosphodiesterase isozyme III cAMP cardiac contractility cardiac output contractility afterload amrinone milrinone cardiac contractility dopamine dobutamine ventricular tachycardia beta-blockers dobutamine dopamine phosphodiesterase inhibitors d. Nesiritide 20. 20 | page 1 55 2 PMH: Chronic heart failure x 5 Chronic stable angina x 5 Hypertension x 10 All: NKDAMeds: Aspirin 80 mg PO AMCarvedilol 6.25 PO BIDIsosorbide mononitrate 60 mg PO AMEnalapril 10 mg PO BIDFurosemide 20 mg PO AMPE: BP 180/100 mmHg , P 100 , RR 22, T 38.6, wt 65 kg, ht 174 cmalert & oriented, anxious, dyspneic man(+) neck vein engorgement(+) S1 S2, (+) S3 , no systolic murmur(+) crepitation bilaterally(+) hepatojuxgular reflux, (-) bowel sound(+) pitting edema 4+CXR: interstitial infiltration both lungLabs: Na 136 K 4.8 Cl 98 CO2 24 BUN 20 Scr 1.2 Ca 9.7 Mg 2.1 Alb 4.1WBC 11 HGB 15 HCT 44 PLT 347UA: (+) WBC , (+) bacteria, (-) protein, (-) glucose acute exacerbation of chronic heart failure (CHRONIC SYSTOLIC HEART FAILURE)1. 2. 21. 21 | page chronic heart failure1. Non-pharmacologic therapya. coronary artery bypass graft myocardial contractility b. afterload, c. sodium 3 intravascular volume overloadd. decompensation 4 American Heart Association/American College ofcardiology 2009 22. 22 | page2. Pharmacologic therapya. Vasodilators preload / afterload cardiac output(1) angiotensin-converting enzyme inhibitors (ACEIs) captopril, enalapril, lisinopril preload afterload sympathetic nervous system angiotensin II ventricular hypertrophy ACEIs AHA/ACC stage A (JNC7 thiazides ) stage B, C D ACEIs ACEIs hypoperfusion preload cardiac output tissue hypoperfusion hypotension serum creatinine serum potassium ACEIs perfusion pressure glomerular filtration acute renal failure intravascular volumedepletion diuretics ( diuretics ACEIs diuretics volume depletion) GFR < 30 ml/min/1.73 m2, NSAIDs, atherosclerosis renal artery stenosis (2) Angiotensin receptor blockers (ARBs) losartan, valsartan, candesartan ACEIs angioneurotic edema ACEIs ARBs ACEIs ARBs chronic heart failure stage C ACEIs, diuretics beta-blockers ARBs ARBs ACEIs hyperkalemia worsening renal function rennin-angiotensin-aldosterone system serum creatinineAHA/ACC ARBs ACEIs aldosterone antagonist ( 3 ) hyperkalemia (3) Hydralazine oral nitrate hydralazine oral nitrates ACEIs ACEIs hydralazine nitrate combination hydralazine +oral nitrate ACEIs hydralazine oral nitrate clinical trials hydralazine oral nitrates ARBs 23. 23 | pagehydralazine + oral nitrate clinical trial 2 regimens ARBs ACEIs ARBs ACEIs hypertension, prevention of systolic dysfunction post-MI,prevention of coronary heart disease in high risk patients heart failure hydralazine nitrate stage C ACEIs, beta-blocker diuretics (adherence) b. Diuretics preload diuretics diuretics intravascular volume depletion tissuehypoperfusion, prerenal renal failure, reflex tachycardia myocardial infarction ACEIs beta-blocker stable thiazide loop diuretics (thiazides creatinine clearance < 30 ml/min)c. Beta-blockers sympathetic nervous system renin-angiotensin-aldosterone system ejection fraction carvedilol, metoprololsuccinate SR bisoprolol AHA carvedilol 3.125 mg BID metoprolol 12.5 mg BID hypotension , beta-blockers (decompensatedheart failure) myocardial contractility decompensation blood pressure, heart rate, worsening heart failured. Digoxin cardiac contractility sympathetic system preload digoxin stage C ACEIs diuretics beta-blocker narrow therapeutic index 24. 24 | pagee. Spironolactone Eplerenone aldosterone antagonist aldosterone ventricular wall remodeling heart failure ( stage C NYHA functional class III-IV) EF 2.5 mg/dL >2.0 mg/dL ) hyperkalemia (serum potassium > 5.0mEq/L) potassium ventricular tachycardia fibrillation f. Calcium channel blockers systolic heart failure calcium channel antagonist heart failure sympathetic nervous system stimulation ischemic heart disease calcium channel antagonists systolic heart failure amlodipine systolic heart failure ischemic heart disease diastolic heart failure non-dihydropyridines verapamil diltiazem 2 heart rate ventricular filling time preload ( diastolicheart failure beta-blocker calcium channel antagonist cardiac contractility) 2 62 8/1/xyHPI: 2-3 2 PMH: Chronic heart failureOsteoarthritis x 5 Type 2 Diabetes x 5 Hypertension x 10 Meds: 8/1/xy Diltiazem 180 mg AM PO AJ8/1/xy Glibenclamide 5 mg BID PO AJ8/1/xy Aspirin 80 mg AM PO AJ 25. 25 | page8/1/xy Furosemide 20 mg AM PO AJ8/1/xy Glucosamine sulfate sachet 1884 mg AM PO AJ8/1/xy Amoxicillin 500 mg TID PO AJ8/1/xy Triprolidine/Pseudoedrine 2.5mg/60mgTID PO AJ10/12/xx Diltiazem 180 mg AM PO AJ10/12/xx Glibenclamide 5 mg BID PO AJ10/12/xx Aspirin 80 mg AM PO AJ10/12/xx HCTZ 25 mg AM PO AJ10/12/xx Glucosamine sulfate sachet 1884 mg AM PO AJ13/11/xx Glibenclamide 2.5 mg BID PO GG13/11/xx Aspirin 80 mg AM PO GG13/11/xx HCTZ 25 mg AM PO GG13/11/xx Glucosamine sulfate sachet 1884 mg AM PO GG17/10/xx Enalapril 10 mg BID PO TB17/10/xx Glibenclamide 2.5 mg BID PO TB17/10/xx Aspirin 80 mg AM PO TB17/10/xx HCTZ 25 mg AM PO TBLABs: Na 144 K 4.2 Cl 98 CO2 24 BUN 19 Scr 1.4 FBS 128 digoxinTherapeutic uses digoxinDigoxin digitalis glycoside Digitalis digoxin 1. Chronic heart failure digoxin Na-K ATPase (myocyte) calcium ion sarcoplasmic reticulum myocytes calcium ion myocardialcontractility (positive inotropic effects)2. Control of ventricular rate in supraventricular tachycardia (e.g. atrial fibrillation) digoxin acetylcholine vagus nerve atrioventricular node (AV node) refractory period digoxin atrial fibrillation 26. 26 | page digoxin digoxin digoxin (1) narrow therapeutic index (2) digoxin renal impairment, drug interactions, (3) digoxin ventricular tachycardia digoxin (Absorption)Digoxin passive non-saturable diffusion (dosage forms) 1 (Tmax) 10 digoxin tablet bioavailability 70-80% (F= 0.7-0.8), digoxin elixir F = 0.75-0.85 F = 1 (Distribution) digoxin 2-compartment model 6 digoxin ATPase digoxin 70 digoxin digoxin lean bodyweight total body weight 20-30 digoxin digoxin 27. 27 | page (Volume of distribution; Vd) digoxin 6-7 1 (L/kg) hemodialysis 5-6 L/kg hemodialysis 4-5 L/kg extracellular fluid, hyperkalemia, Na-K ATPase activity digoxin ( ), , 20 Na-K ATPase activity digoxin digoxin (Metabolism) digoxin (metabolism) metabolites enterohepatic recycling digoxin metabolites chronic heart failure digoxin (drug clearance) heart failure (Excretion) digoxin glomerular filtration active tubularsecretion digoxin creatinine clearance digoxin digoxin 38 creatinine clearance digoxin 106 digoxin heart failure digoxin digoxin 0.8 2.0 ng/mL (g/L) digoxin digoxin 0.8-1.2 ng/mL atrial fibrillation ventricular response 28. 28 | page -blockers non-dihydropyridines calcium channel blockers digoxin atrialfibrillation digoxin therapeutic range digoxin premature ventricular contractions, atrioventricular nodalblock, , , , , , , , , 6 (troughlevel) (steady-state) 7-14 digoxin digoxin 1. 2. 3. digoxin 4. (therapeuticrange) digoxin 1. aluminium magnesium digoxin 252. Cholestyramine digoxin 20-353. penicillins, tetracyclines digoxin digoxin 4. Amiodarone digoxin 70-100 1-7 amiodarone digoxin digoxin 30-50 29. 29 | page digoxin digoxin 7 digoxin loading dose (maintenance dose)Jeliffe Method1. ideal lean body weight (LBW)2. creatinine clearance Cockroft Gault3. loading dose (LD) LD = 10 g/kg x LBW(kg) = total body store (TBS)F bioavailability 0.7-0.8 total body store 10 g/kg LD 3 6 1/4 1/4 6 (1/2 + 1/4 + 1/4)4. (% daily loss) creatinine clearance % Daily loss = 14 + CrCl (ml/min) 14 CrCl/5 (% daily loss digoxin clearance )5. maintenance dose(MD)MD = TBS x % daily loss Jeliffe method 50 chronic heart failure 175 cm. 80 kg Scr 1.1mg/dL LD MD digoxin Jeliffe method1. LBWLBW = 50 + (2.3 x 10) = 73 kg2. CrClF5 30. 30 | pageCrCl = (140-50) x 73 = 83 ml/min72 x 1.13. LDLD = 10 g/kg x 73 = 913 g ~ 1 mg LD 0.5 mg 0.25 mg 6 0.25 mg 6 1 mg4. % daily loss% daily loss = 14 + 83/5 = 30.6% ~ 31% TBS5. MDMD = 0.913 mg x 0.31 = 0.27 mg digoxin tablet 0.25 mg Volume-Clearance Method Jeliffe method volume of distribution (Vd) (Vd digoxin uremictoxin ) volume-clearance method 1. LBW2. CrCl ml/min/70 kg 140 ( x 0.85 )3. Vd CrCl ( ml/min/70 kg) Vd 70kg LBW Vd/70 kg = 226 + 298 x CrCl CrCl ml/min/70 kg Vd Vd 70 kg4. LDLD = Cp x Vd Cp digoxin g/L (ng/mL)Vd volume of distribution LBW (4) ( Vd/70 kg)F bioavailabilityScr29 + CrClF0.8 31. 31 | page5. Clearance/70 kg digoxin CrCl/70 kg non-renalclearance (Clnon-renal) Clnon-renal chronic heart failure Clnon-renal = 41 ml/min/70 kg CHFClnon-renal = 20 ml/min/70kg CHFClearance digoxin/70 kg (Cldigoxin/70 kg) = (1.303 x CrCl) + Clnon-renal6. MD MD = Cp x Cldigoxin x LBW x MD maintenance dose mgCp digoxin ng/mLCldigoxin clearance digoxin (5) mL/min/kg ( 70 kg)LBW lean body weight kg (dosing interval) 1440 1 F bioavailability 106 ng mg volume-clearance method 50 chronic heart failure 170 cm 73 kg Scr 3.7 mg/dL LD MD volume-clearance method1. LBWLBW = 45.5 + (2.3 x 8) = 63.9 kg2. CrClCrCl = (140-50) X 0.85 = 20.7 ml/min/70 kg3. Vd digoxin CrCl Vd/70 kg = 226 + 298 x 20.7 = 349.9 L/70 kg = 5.0 L/kg Vd = 5.0 x 63.9 = 319 L4. LD106x F3.729 + 20.7 32. 32 | pageLD = 1.5 g/L X 319 L = 598 g = 0.598 mg ~ 0.625 mg () 0.25 mg 6 0.25 mg 6 0.125 mg5. clearance digoxin (Cldigoxin) creatinine clearance chronic heart failureCldigoxin /70 kg = (1.303 x 20.7) + 20 = 47.0 ml/min/70 kg= 0.671 ml/min/kg6. MDMD = 1.5 ng/mL x 0.671 ml/min/kg x 63.4 kg x 1440 min= 0.115 mg 0.125 mg 1 (steady-state) digoxin linear pharmacokinetics steady-state Dose 1 = Dose 2 steady-state digoxin 0.125 mg steady-state 0.8 ng/mL 1. 6 ng/mL 0.125 mg = Dose 2Dose 2 = 0.25 mg 0.25 mg 0.8106x 0.8Cp1 Cp20 .8 ng/mL 1.6 ng/mL 33. 33 | page 31. systolic heart failure diastolic heart failure 1. Ejection fraction2. cardiac output3. . 1 . 1 2 . 2 3 . 1, 2 32. (compensatory mechanisms) cardiac output 1. renin 2. catecholamines3. myocardial contractility. 1 . 1 2 . 2 3 . 1, 2 33. tissue hypoperfusion 1. Pulmonary edema: chest X-ray 2. Mental confusion: 3. Decreased urine output: . 1 . 1 2 . 2 3 . 1, 2 34. (acute heart failure) pulmonary artery catheter PCWP = 8, HR = 110, BP = 100/80 . IV Furosemide. IV nitroglycerin5. (acute heart failure) pulmonary artery catheter PCWP = 28 , HR = 100, BP = 156/100 . IV Furosemide. IV nitroglycerin6. . digoxin . Spironolactone . carvedilol . enalapril 34. 7. ACEIs 1. ACEIs preload afterload 2. ACEIs tissue hypoperfusion acute renal failure , hypotension potassium hypokalemia 3. ACEIs hydralazine oral nitrates angiotensin II receptor antagonists. 1 . 1 2 . 2 3 . 1, 2 38. Beta-blockers 1. sympathetic nervous system heart rate myocardialcontractility renin 2. asthma chronic obstructive pulmonary disease bronchospasm 3. , heart rate, . 1. . 1 2 . 2 3 . 1, 2 39. Spironolactone 1. aldosterone antagonists 2. hyperkalemia 3. 100 mg 1 . 1 . 1 2 . 2 3 . 1, 2 310. Diuretics 1. preload sodium (salt and water retention)2. intravascular volume depletion reflextachycardia renal hypoperfusion3. loop diuretics creatinine clearance 30ml/min. 1 . 1 2 . 2 3 . 1, 2 3 35. 11. 65 hypertension, DM, chronic heart failure , CXR: pulmonary edema , BP 160/100, HR = 110, Pulmonary artery catheter CI = 2.5 L/min/m2, PCWP = 28 . IV furosemide . IV dopamine . IV dobutamine . IV digoxin12. hypertension, DM, chronic heart failure aspirin, furosemide, isosorbide dinitrate enalapril (angioneurotic edema) 140/90 mm Hg, HR 70 bpm . digoxin . valsartan . diltiazem . hydralazine13. 58 hypertension, dyslipidemia, s/p MI, chronic heart failure NYHA class II furosemide 40 mg PO AM, simvastatin 20 mg POHS, enalapril 20 mg PO BID, aspirin 81 mg PO AM 140/86 mm Hg . . metoprolol. hydralazine nitrate . spironolactone14. 64 hypertension, ischemic heart disease, DM, chronic heart failure atenolol, furosemide, aspirin, glibenclamide, digoxin, SLnitrate BUN 24 Scr 1.5 140/90, HR 70 bpm, . . amlodipine. verapamil . lisinopril15. 68 hypertension, DM, chronic heart failure NYHA class III aspirin 325 mg PO AM, furosemide 40 mg PO AM, digoxin 0.125mg PO AM, glimepiride 4 mg PO AM, lisinopril 40 mg PO AM, carvedilol 25 mg PO BID BUN 34 Scr 1.9 140/90, HR 80 bpm . isosorbide dinitrate . spironolactone. hydralazine . metolazone16. Case: 60 PMH: Chronic heart failure x 2 Hypertension x 12 IHD, s/p MI x 2 36. Meds PTA: Nifedipine sustained-release 60 mg PO ODAspirin 325 mg PO ODISDN 5 mg SL PRN for chest painIndomethacin 50 mg PO TID for back pain (from drugstore near pts home)PE: P 110 , BP 145/100, RR 25, Temp 37.6Confused, Drowsy(+) S3(+) Dyspnea, (+) crackles in lung(+) hepatojugular reflux(-) bowel sound3+ pitting edemaskin cold and moist ()Labs: Na 135 K 4.0 Cl 102 CO2 24 BUN 18 Scr 1.2Other labs are within normal limitTnI: negativeCXR (chest x-ray): suggests pulmonary edema, mild cardiomegalyECG: tachycardia, normal rhythmEcho: EF ~ 30% (1 )Impression: acute exacerbation of heart failureMDs order:1. Admit2. Monitor vital sign q 1 h till stable then q 4 h , notify MD if HR 110 OR SBP 1503. O2 by nasal cannula to keep O2 sat >90%4. IV D-5-S/2 to keep vein open5. Draw lipid profile in AM16.1 problem list SOAP 16.2 36 PE: (-) dyspnea, (-) crackles, 1+ pitting edemaCXR: (-) for pulmonary edemaVS: BP 136/86 , HR 80, RR 20, Temp 37.6LABs: All are WNL except Cho 210 LDL 170 TG 130Current meds: IV nitroglycerin 20 mcg/min (on titrate-down schedule)IV furosemide 20 mg IVP OD AMAspirin 150 mg OD AMa. SOAP 37. b. digoxin loading dose maintenance dose Jeliffe volume-clearance16.3 3 16.4 Guideline & Review ArticlesACCF/AHA Task Force on Practice Guidelines. 2009 focused update incorporated into the ACC/AHA 2005guidelines for the diagnosis and management of chronic heart failure in the adult. Circulation 2009; 119:e391-e479.Lindenfeld J, et al. on behalf of the Heart Failure Society of America. Executive Summary: HFSA 2010Comprehensive Heart Failure Practice Guideline. J Card Fail 2010; 16: 475-539.Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure2008. Eur Heart J 2008; 29: 23882442.Mc Murray J, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosteroneantagonists and angiotensin receptor blockers in heart failure: Putting guidelines into practice. TheEuropean. J Heart Fail 2005; 7: 710 721. 60 SOB, fatique, orthopnea at nightPMH: CHF x 2 HTN x 12 IHD, s/p MI x 2 Current Meds: Enalapril 20 mg PO BIDAspirin 160 mg PO AMISDN 5 mg SL PRN for chest painSpironolactone 12.5 mg PO AMFurosemide 20 mg PO AMLabs: all are WNL