Pharmacology: Heart Failure PHPP 515 (IT-I) Fall JACOBS Monday, Oct. 14 3:00 4:50 PM

Transcription

1 Pharmacology: Heart Failure PHPP 515 (IT-I) Fall 2013 JACOBS Monday, Oct. 14 3:00 4:50 PM Required Reading (via Access Pharmacy) Katzung: Chapters 13 Recommended Reading (via Access Pharmacy) Goodman and Gilman: Chapter 28 1

2 Basic Concepts Lecture Outline: Heart Failure Definition Diastolic vs. Systolic Heart Failure Determinants of Cardiac Output: Heart rate Preload Contractility Afterload Hormonal and Sympathetic Activation in HF HF Drugs Diuretics RAA system inhibitors Beta blockers Vasodilators Inotropic agents (chronic and acute) 2

3 Basic Concepts Heart Failure: The heart cannot pump enough blood to meet the demands of the body (low cardiac output*) PULMONARY RV Cardiac Output Pulmonary Venous Return Backup = Peripheral Edema RV LV Backup = Pulmonary Edema Systemic Venous Return LV Cardiac Output SYSTEMIC *high CO is seen in some rare cases 3

4 Basic Concepts DISATOLIC VS SYSTOLIC HF SV Normal EDV ESV In DIASTOLIC HF EDV and SV are PROPORTIONALLY reduced. Therefore, Ejection Fraction (EF = SV/EDV) DOES NOT CHANGE. SV SV SV = Diastolic HF EDV EDV EDV ESV 4

5 Basic Concepts DISATOLIC VS SYSTOLIC HF SV Normal EDV ESV In SYSTOLIC HF SV is REDUCED for a given amount of EDV. Therefore, Ejection Fraction (EF = SV/EDV) IS REDUCED. SV SV SV < Systolic HF EDV EDV EDV ESV 5

6 Basic Concepts Most patients have BOTH types of HF SV SV EDV ESV EDV ESV REDUCED EF (SYSTOLIC HF) REDUCED EDV (DIASTOLIC HF) SV EDV ESV 6

7 1. Heart Rate FOUR FACTORS DETERMINE CO: 1. Heart rate (HR) 2. Preload 3. Contractility 4. Afterload Basic Concepts Cardiac Output (CO = SV x HR) i.e. Stroke Volume x Heart Rate The amount of blood pumped in 1 min (units = liters/min) Influence Stroke Volume (SV) Taken independently (i.e., if you think about the heart as a mechanical pump, not considering effects of HR on other cardiovascular factors) increasing heart rate will proportionally increase cardiac output. 7

8 Basic Concepts 2. Preload This is STRESS in the ventricles at the end of diastole (just before ventricular contraction). At this time, the ventricles are at their greatest stretch. For the RIGHT ventricle, preload is proportional to central venous pressure (CVP), which is the same as Right ventricular end-diastolic pressure (RV-EDP). Normal CVP is quite low, around 3-8 mmhg. For the LEFT ventricle, preload is also known as left ventricular end diastolic pressure (LV-EDP). An estimate of this value is provided by measuring pulmonary capillary wedge pressure (PCWP). Normally, LV-EDP is around 6-12 mmhg. END DIASTOLE 8

9 Basic Concepts 2. Preload It is easiest to visualize the effect of preload on cardiac output (via SV) by looking at only the diastolic filling part of the P-V Loop (green line) Pressure END SYSTOLE Ventricles emptying (systole) SV Cardiac Pressure- Volume Loop END DIASTOLE Ventricles filling (diastole) Volume 9

10 2. Preload Basic Concepts During filling there is no muscle contraction. The rise in pressure during filling is relative to the COMPLIANCE of the ventricles (i.e. stretchiness ) Pressure Ventricles filling (diastole) while muscle relaxed SV Volume 10

11 2. Preload Basic Concepts Preload is proportional to end diastolic pressure (EDP) By increasing preload, you can increase the stroke volume (SV) For RV, preload is increased by increasing CVP For LV, preload is increased by increasing PCWP Pressure Effect of Preload SV SV Volume 11

12 2. Preload Pressure Basic Concepts The heart is STIFFER (less compliant) with DIASTOLIC HF (red line). If preload is kept the same (i.e. same EDP) as a normal heart then SV will decrease. Diastolic Heart Failure SV Leftward Shift in Diastolic PV Curve (caused by reduced chamber compliance) Preload EDP Normal SV Volume 12

13 2. Preload Basic Concepts To COMPENSATE for the reduction in SV caused by reduced compliance, the body will increase preload How? By increasing venous pressure (water retention edema) Pressure Effect of Preload Preload SV Diastolic HF is typically associated with elevated preload, which helps to compensate for less heart compliance Volume 13

14 Basic Concepts 2. Preload In DIASTOLIC HF, the heart still contracts strongly (ejects blood), but on a smaller volume and is less compliant (stretchy) Pressure END SYSTOLE SV END DIASTOLE Volume 14

15 Basic Concepts 3. Contractility This is FORCE of Contraction generated by the ventricles during systole. This is affected by various factors, including preload More Preload = More Contractility This is the Frank-Starling Law of the heart Frank (German) Starling (English) 15

16 3. Contractility Basic Concepts The Frank-Starling Law simply states that an increase in preload (which is proportional to EDV) will cause an increase in contractility (up to a certain point). How? Let s re-visit cardiac muscle contraction Sarcomere Z-line M-line Sarcomere I-band A-band 16

17 3. Contractility Basic Concepts Few myosin heads touching actin, ALSO: too crowded! Partially Stretched (more pre-load) More myosin heads touching actin, less crowded 17

18 Basic Concepts 3. Contractility Fully stretched (even more pre-load) Lots of myosin heads touching actin Over-Stretched (too much!) 18

19 3. Contractility Stroke Volume Basic Concepts This is the heart s intrinsic way of matching cardiac output to venous return. more preload (i.e. Venous Return) = more SV (i.e. Cardiac Output) Frank-Starling Curve Ventricular End Diastolic Volume (EDV) 19

20 3. Contractility Basic Concepts Relationship of BLOOD VOLUME to cardiac contractility Stroke Volume underloaded Dehydration Shock (sepsis) Apex overloaded (CONGESTION) RIGHT VENTRICLE FAILURE Peripheral edema, ascites LEFT VENTRICLE FAILURE Pulmonary edema, dyspnea Frank-Starling Curve Ventricular End Diastolic Volume (EDV) 20

21 3. Contractility Stroke Volume Basic Concepts Normal Apex A. In SYSTOLIC HF the ventricles are less contractile, so are less effective at ejecting blood for a given amount of fill (preload) Systolic Heart Failure B. SV in HF is also WORSENED by the increased preload (cardiac stretch) caused by edema (because CO < venous return) Ventricular End Diastolic Volume (EDV) 21

22 4. Afterload Basic Concepts This is PEAK STRESS in the ventricles during SYSTOLE (i.e. ventricular contraction). It can be thought of as the stress encountered by ventricular myofibrils as they contract against the volume of blood in the heart. You can also think of this as the force that the heart needs to generate in order to pump blood. END SYSTOLE 22

23 4. Afterload Stroke Volume Basic Concepts increasing afterload will decrease stroke volume Afterload Curve Afterload (peak systolic stress) 23

24 4. Afterload Stroke Volume Basic Concepts With SYSTOLIC HF, for a given afterload (i.e. pulmonary artery or aortic pressure) the stroke volume is reduced (the heart can t push as strongly against that pressure) Systolic Heart Failure Normal Afterload Curve Afterload (peak systolic stress) 24

25 4. Afterload LaPlace Equation = Pr 2w Basic Concepts r w = Stress (afterload) P = systolic pressure* r = ventricular diameter w = wall thickness *For R Ventricle, P = pulmonary artery pressure *For L Ventricle, P = aortic pressure 25

26 4. Afterload Pr = 2w Basic Concepts High Systolic BP and Ventricular Dilation MAY CONTRIBUTE to HF and will affect the AFTERLOAD in the ventricles. HOW? HIGH SYSTOLIC PRESSURE (P) = HIGHER Afterload ( ) DILATED HEART (r) = HIGHER Afterload ( ) seen in 1/3 of HF The heart may COMPENSATE by increasing wall thickness (w) through cardiac HYPERTROPHY because THICKER VENTRICLE WALL (w) = LOWER Afterload ( ) which should INCREASE CO......BUT this doesn t really help because cardiac hypertrophy eventually causes REDUCED CHAMBER COMPLIANCE, causing LESS Preload which will LOWER CO 26

27 Basic Concepts CO = SV x HR Stroke Volume, SV = EDV ESV CO = (EDV ESV) x HR End Diastolic Volume (EDV) EDV Preload affects End Diastolic Volume (EDV) ESV SV Higher Preload means Bigger EDV, means Bigger SV, means More CO 27

28 Basic Concepts CO = SV x HR Stroke Volume, SV = EDV ESV CO = (EDV ESV) x HR End Systolic Volume (ESV) EDV Contractility and Afterload affect End Systolic Volume (ESV) ESV SV Contractility (force) Afterload (pulmonary artery or aortic pressure) More Contractility means Smaller ESV, means Bigger SV, means More CO Smaller Afterload means Smaller ESV, means Bigger SV, means More CO 28

29 Heart Failure Hormonal Activation in HF CO Renal Perfusion CO CVP (preload) (blood volume) Na +, H 2 O uptake JGA Renin Angiotensinogen Angiotensin I Aldosterone Principal Cells (distal tubule, collecting ducts) + ACE Angiotensin II Adrenal cortex 29

30 Heart Failure Hormonal Activation in HF CO Renal Perfusion CO JGA Angiotensinogen Renin Angiotensin I Afterload (arterial BP) + ACE Angiotensin II arteriole vasoconstriction 30

31 Heart Failure Sympathetic Activation in HF CO Arterial Baroreceptor Firing Cranial nerve IX Sympathetic activity (NE) Inotropy EPI, NE Adrenal Stimulation Vasoconstriction SVR (Afterload) CVP (Preload) Cardiac Remodeling (Hypertrophy) Vagal activity Chronotropy (HR) (parasympathetic, ACh) 31

32 Inotropy Vent. Compliance HF is a Complex Web Renin CO SNS (NE, EPI) Inotropy HR Angiotensin I Afterload CO Angiotensin II Vasoconstriction CVP Aldosterone Na +, H 2 O retention Preload 32

33 Inotropic Agents Inotropy Vent. Compliance Drug Therapy for HF Renin CO SNS (NE, EPI) Inotropy Renin inhibitors -blockers HR Angiotensin I Afterload ACE inhibitors Vasodilators CO Angiotensin II AT 1 antagonists Vasoconstriction CVP Aldosterone Na +, H 2 O retention Preload K+ sparing diuretics Loop and Thiazide diuretics 33

34 Drug Therapy for HF In summary, to increase CO (CO = SV x HR) I. Increase HR II. Increase SV a. Decrease Preload see next page Diuretics RAA system inhibitors b. Decrease Afterload Vasodilators RAA system inhibitors -blockers c. Increase Contractility Inotropic agents 34

35 Drug Therapy for HF Why Decrease Preload? Stroke Volume Normal Apex Treated Systolic Heart Failure EDV In a normal person, decreasing preload will REDUCE SV But in a person with HF, decreasing preload INCREASES or MINIMALLY AFFECTS SV because they often are AT OR NEAR the right side of the Frank-Starling Curve 35

36 Stroke Volume Drug Therapy for HF Over-Treated Apex Systolic Heart Failure EDV CO RAA activation Afterload Cardiac Remodeling Worsening of HF However, TOO MUCH diuresis (or too quickly) can lead to volume reduction and ACTIVATION of RAA system. 36

37 Diuretics Drug Therapy for HF LOOP DIURETUCS [the mainstay of CHF therapy] Furosemide (Lasix ) Bumetanide (Bumex ) Torsemide (Demadex ) Ethacrynic Acid (Edecrin ) THIAZIDE DIURETICS [can be added on for refractory CHF, refer to diuretics pharmacology lectures Dr. Connelly] Chlorothiazide (Diuril ) Chlorothalidone (Hygroton ) Hydrochlorothiazide (Microzide, Hydrodiuril ) K + SPARING DIURETICS [discussed later in this lecture] Amiloride Triamterene (Dyrenium ) Spironolactone (Diuril ) Eplerenone (Aldactone ) 37

38 Loop Diuretics Capillary blood Drug Therapy for HF Loop of Henle Ascending Limb 2Cl - K + 3 Na + Na + 2 K + K + Tubular Lumen Site of Action: Na-K-Cl cotransporter (NKCC2) CAUSE LOSS OF: Na + (H 2 O) Cl - K + Most powerful diuretics. Why? About 25% of the filtered sodium re-uptake happens here. 38

39 Loop Diuretics Drug Therapy for HF Administration: ORAL (maintenance), IV (decompendated) Oral Bioavailability: Furosemide 40-70% (variable absorption) Bumetanide >80% Torsemide 80-90% Ethacrynic Acid: ~100% Drug absorption may be REDUCED by edema in the gut wall Protein binding: All are HIGHLY protein bound (>90%) They reach their site of action (luminal surface of ascending Loop of Henle) after secretion of the free drug from the plasma into the proximal tubule. 39

40 Loop Diuretics Half-life: Furosemide: h Bumetanide: h Torsemide: 3.5 h Ethacrynic acid: 2-4 h Drug Therapy for HF Duration: ORAL: 4-6 h (typical), except ethacrynic acid (12 h) IV: 2-3 h (although often given by continuous admin) 40

41 Loop Diuretics Route of Elimination: Drug Therapy for HF Furosemide and Bumetanide Urinary excretion (slower elimination with renal disease) Torsemide Hepatic metabolism (slower in hepatic disease, cirrhosis) Mainly by CYP2C9 Only 20% excreted in urine as parent drug Ethacrynic acid Urinary AND Biliary excretion (as cysteine conjugate) 41

42 Loop Diuretics Drug Therapy for HF Adverse Effects: Furosemide, Bumetanide and Torsemide have sulfonylurea moieties. They can cause hypersensitivity reactions in sensitive patients. Ethacrynic Acid is NOT a sulfonylurea. However, ethacrynic acid is MORE likely to cause ototoxicity All loop diuretics can cause K+ wasting (hypokalemia): muscle weakness, fatigue, severe cramps constipation hyperglycemia, hyperlipidemia (low insulin) abnormal heart rhythms Too aggressive therapy can lead to circulatory volume reduction (and lower CO) which may be mistaken for worsening of heart function 42

43 Loop Diuretics Drug Interactions: Drug Therapy for HF NSAIDs (aspirin, ibuprofen, etc.) Block prostaglandin biosynthesis (COX-1, COX-2) This decreases renal blood flow (and diuresis) ACE inhibitors (captopril, enalapril, lisinopril, etc.), OR AT 1 antagonists (azilsartan, losartan, valsartan, etc.) Both of these classes will reduce glomerular pressure. This causes a drop in GFR (filtration rate), and increase in renin secretion (leading to Na + reabsorption) Negative interaction with loop diuretics is typically short-lived and occurs during initiation of drug therapy or dose-escalations. 43

44 Loop Diuretics Diuretic Resistance: Drug Therapy for HF Caused by compensatory increase in renal Na + reabsorption (decrease in GFR leading to activation of RAA system). Reduction in dosing intervals or adding/switching diuretic class can sometimes overcome resistance. 44

45 Thiazide Diuretics Capillary blood Drug Therapy for HF Early Distal Tubule Cl - 3 Na + Na + 2 K + K + Tubular Lumen Site of Action: NaCl Symporter (SLC12A3) CAUSE LOSS OF: Na + (H 2 O) Cl - K + (indirect) 45

46 K+ Sparing Diuretics Drug Therapy for HF Spironolactone, Eplerenone (aldosterone antagonists) Capillary blood Late Distal Tubule + Collecting Ducts Tubular Lumen Site of Action: Aldosterone (mineralcorticoid) Receptor, MR 3 Na + MR CAUSE LOSS OF: Na + Na + Na+ (H 2 O) 2 K + 46

47 K+ Sparing Diuretics Drug Therapy for HF Amiloride, Triamterene (Na + channel blockers) Capillary blood Late Distal Tubule + Collecting Ducts Tubular Lumen 3 Na + CAUSE LOSS OF: Na + Na + Na+ (H 2 O) 2 K + Site of Action: Sodium channel 47

48 K+ Sparing Diuretics Administration: ORAL Drug Therapy for HF Oral Bioavailability: Amiloride: 15-25% (poor absorption) Triamterene: 50% (poor absorption) Spironolactone: around 70% (variable, increased by food) Eplerenone: 70% Metabolism: Amiloride: not metabolized Triamterene: hepatic (CYP1A2 to active metabolite) Spironolactone: hepatic (to active metabolites canrenone and 7-alpha-spirolactone) Eplerenone: hepatic (CYP3A4 to inactive metabolites) Avoid strong CYP3A4 inhibitors (e.g. ritnoanvir, ketoconazole, itraconazole, clarithromycin) 48

49 K+ Sparing Diuretics Drug Therapy for HF Serum half-lives: Amiloride: 6-9 hr Triamterene: 1-2 hr (metabolite: 3 hr) Spironolactone: 1.5 hr (metabolites: 7-23 hr) Eplerenone: 4-6 hr Excretion: Urine and feces 49

50 K+ Sparing Diuretics Drug Therapy for HF Adverse effects: Hyperkalemia (esp. if taking K + supplements) Electrolyte/fluid loss (reduction in CO) Spironolactone, endocrine effects: Gynecomastia Breast tenderness Sexual dysfunction (endocrine effects not as severe with eplerenone b/c it is more selective for the aldosterone (mineralcorticoid) receptor vs. sex hormone receptors MR > AR, ER, PR) 50

51 Stroke Volume Drug Therapy for HF RAA System Inhibitors (ACE inhibitors, Renin inhibitors, AT 1 antagonists) Normal Apex Treated Systolic Heart Failure EDV Inhibition of the RAA system causes natiuresis (Na + loss) and diuresis (water loss) which decreases preload (and lowers EDV) This helps get rid of edema and may also improve cardiac output 51

52 Drug Therapy for HF RAA System Inhibitors (ACE inhibitors, Renin inhibitors, AT 1 antagonists) Stroke Volume Treated Normal Systolic Heart Failure Afterload Inhibition of the RAA system also causes arteriolar vasorelaxation (decreasing arterial BP and afterload, thus increasing CO) 52

53 Drug Therapy for HF RAA System Inhibitors ACE inhibitors Benazepril* (Lotensin ) Captopril (Capoten ) Enalapril (Vasotec ) Fosinopril (Monopril ) Lisinopril (Prinivil, Zestril ) Moexipril (Univasc ) Perindopril* (Aceon ) Quinapril (Accupril ) Ramipril (Altace ) Trandolapril (Mavik ) Renin inhibitors Aliskiren (Tekturna ) AT 1 antagonists Azilsartan (Edarbi ) Candesartan (Atacand ) Eprosartan (Teveten ) Irebesartan (Avapro ) Losartan* (Cozaar ) Olmesartan (Benicar ) Telmisartan (Micardis ) Valsartan (Diovan ) HF indications in bold, blue * = Off-label for HF 53

54 Drug Therapy for HF RAA System Inhibitors: ACE inhibitors Angiotensin I Angiotensin II Vasoconstriction (endothelin, TxA 2 ) + ACE ACE inhibitors Inactive peptides Bradykinin Vasorelaxation (NO, EDHF, PGI 2 ) arterioles (resistance arteries) Effect of drug: drop in systemic vascular resistance (BP) 54

55 Drug Therapy for HF RAA System Inhibitors: ACE inhibitors Angiotensin I Angiotensin II + ACE ACE inhibitors adrenal glands (zona glomerulosa) Aldosterone Sodium and water reabsorption Effect of drug: natriuresis, diuresis 55

56 Drug Therapy for HF RAA System Inhibitors: ACE inhibitors Administration: ORAL Oral Bioavailability: variable Low (<40%): benazepril, fosinopril, lisinopril Caused by poor absorption Good (50-95%): other ACE-I Effect of Food: Food inhibits captopril absorption by 30-40% take at least 1 hr before meals 56

57 Drug Therapy for HF RAA System Inhibitors: ACE inhibitors Metabolism: Almost all ACE-I are prodrugs (rapid hydrolysis to active metabolites) Captopril and lisinopril are NOT prodrugs prodrug Esterase active metabolite Excretion: Some renal Some renal and fecal Heart Failure Accumulation: Some ACE-I have been shown to accumulate in patients with heart failure (due to lower CO and renal perfusion), take caution: lisinopril, perindopril, quinapril Because these agents are eliminated 100% by kidneys (also take caution in other causes of renal impairment) 57

58 Drug Therapy for HF RAA System Inhibitors: ACE inhibitors Adverse Effects: Dry Cough (caused by bradykinin increase) Hypotension Hyperkalemia Renal function deterioration Angioedema (rare) Contraindicated in pregnancy 58

59 Drug Therapy for HF RAA System Inhibitors: AT 1 antagonists (angiotensin II receptor blockers, ARBs) arterioles (resistance arteries) Angiotensin II adrenal glands (zona glomerulosa) Vasoconstriction (endothelin, TxA 2 ) AT 1 receptor Effect of drug: drop in systemic vascular resistance (BP) AT 1 receptor Aldosterone Sodium and water reabsorption Effect of drug: natriuresis, diuresis 59

60 Drug Therapy for HF RAA System Inhibitors: AT 1 antagonists Administration: ORAL Absorption: incomplete Oral Bioavailability: LOW Candesartan (15%) Losartan (33%) Valsartan (25%) Effect of Food: Drugs may be taken with or without food OK +/- 60

61 Metabolism: Candesartan cilexetil is a prodrug Losartan is a prodrug Drug Therapy for HF RAA System Inhibitors: AT 1 antagonists Intestinal Esterase Candesartan Candesartan cilexetil (active) CYP2C9, 3A4 Losartan EXP-3174 Valsartan is NOT a prodrug 61

62 Drug Therapy for HF RAA System Inhibitors: AT 1 antagonists Half-lives: Candesartan: 9 hr Losartan: 1-2 hr, EXP-3174: 6-9 hr Valsartan: 6 hr Excretion: primarily fecal Adverse Effects: Hypotension Hyperkalemia Reduced renal function Contraindicated in pregnancy 62

63 Drug Therapy for HF RAA System Inhibitors: AT 1 antagonists Another benefit of AT 1 antagonists Ventricular Hypertrophy (VH) Atrial Enlargement HF angiotensin II AT 1 receptors cell enlargement Candesartan, Losartan, Valsartan Also, by reducing BP these drugs help prevent VH, since afterload also promotes cardiac remodeling 63

64 Drug Therapy for HF RAA System Inhibitors Aldosterone breakthrough (several possible mechanisms) Angiotensinogen tissue plasminogen activator Cathepsin G Renin Renin inhibitors Chymase Cathepsin G Angiotensin I ACE ACE inhibitors Angiotensin II Aldosterone antagonists spironolactone eplerenone AT 1 Receptor Aldosterone AT 1 antagonists fluid retention 64

65 Beta blockers Drug Therapy for HF HF indications in bold, blue Bisoprolol* (Zebeta ) * = Off-label for HF Carvedilol (Coreg ) Metoprolol succinate ER (Toprol XL ) Beta blocker classes for HF: bisoprolol, metorpolol succinate ER: Second generation beta blockers ( 1-specific) carvedilol: S(-) carvedilol: nonselective beta blocker ( 1 and 2) R(+) and S(-): selective alpha1 blocker ( 1) 65

66 Beta blockers Drug Therapy for HF Beta blockers are a mixed bag of effects in HF CO Afterload SNS (NE, EPI) -blockers Inotropy HR CO In the heart they lower oxygen demand (good) but also lower CO (bad) Vasoconstriction On the arterial side -blockers should have a beneficial effect (reducing afterload) CVP Preload On the venous side -blockers should have a (modest) beneficial effect (lowering preload) 66

67 Beta blockers Drug Therapy for HF Clinical trials have shown three -blockers to benefit survival in patients with chronic HF: bisoprolol carvedilol metorpolol ER 67 TRENDS in Pharmacological Sciences

68 Beta blockers Drug Therapy for HF What is the pharmacological basis for the beneficial actions (survival benefits) of just these three -blockers in HF? To summarize part of this report: We don t know why they work, But it s probably NOT due to their -blocking effects 68

69 Beta blockers Drug Therapy for HF Normal EDV SV EF 1 = SV EDV Enlarged Ventricle EDV SV LOW EF EF 2 = SV EDV EF 2 < EF 1 In patients with dilated ventricular cardiomyopathy EF is low partly because the volume of the ventricles is abnormally large. (afterload is also high, Law of Laplace) Beta blockers have been shown to decrease chamber size (through cardiac remodeling) and help restore normal EF 69

70 Beta blockers Drug Therapy for HF Administration: ORAL Absorption: well absorbed Oral Bioavailability: bisoprolol (80%) 20% lost in 1 st pass to CYP3A4 carvedilol (25%) 75% lost in 1 st pass to CYP2D6 (carvedilol ER has much higher bioavailability) metoprolol (50%) 75% lost in 1 st pass to CYP2D6 Effect of Food: Drugs may be taken with or without food Half-lifes: bisoprolol: 9-12 hr carvedilol: S(-): 7-10 hr, R(+): 5-9 hr metoprolol: 3-7 hr 70

71 Beta blockers Drug Therapy for HF Adverse Effects: Bradycardia Syncope Dizziness Fatigue Masking signs of hypoglycemia (preventing rapid HR) Abrupt withdrawal/withdrawal syndrome: acute tachycardia hypertension ischemia 71

72 Vasodilators Drug Therapy for HF RAA system inhibitors have vasodilatory actions by blocking angiotensin II production (blocking vasoconstriction) ACE inhibitors (also increase bradykinin) AT 1 antagonists Other vasodilators also have beneficial effects for HF: ARTERIAL vasodilators (reduce AFTERload) Hydralazine (oral, high doses) VENOUS vasodilators (reduce PREload) Nitroglycerin Sodium nitroprusside Isosorbide mono/di-nitrate chronic management acute decompensation 72

73 Inotropic Agents Drug Therapy for HF For management of chronic HF Cardiac Glycosides (digitalis glycosides) Digoxin (Digox, Lanoxin ) For acute decompensated HF with hypotension Catecholamines Dopamine Dobutamine Phosphodiesterase-3 (PDE-3) Inhibitors Inamrinone (Inocor ) Milrinone (Primacor ) 73

74 Drug Therapy for HF Inotropic Agents: cardiac glycosides (OUT) Na + Ca 2+ 3 Na + Na + Na + Ca 2+ (IN) Digoxin (competes with K + for K + binding site) 2 K + Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ SR = Inotopy Intracellular calcium levels (and SR stores) are increased 74

75 Drug Therapy for HF Inotropic Agents: cardiac glycosides Digitalis 75

76 Drug Therapy for HF Inotropic Agents: cardiac glycosides Stroke Volume Normal Treated Systolic Heart Failure Effect on Frank-Starling Curve Ventricular End Diastolic Volume (EDV) 76

77 Drug Therapy for HF Inotropic Agents: cardiac glycosides Administration: ORAL, INJ (for A-Fib) Oral Bioavailability: 60-80% (variable hydrolysis in the stomach and metabolism by intestinal bacteria prior to absorption about 10% of population will lose 40% of the dose to gut bacteria) Effect of Food: food may cause a small decrease in bioavailability: longer retention in stomach = more hydrolysis high fiber diet = more bacterial metabolism However, the effect is not believed to be significant enough to necessitate counselling patients Distribution: ss = 5 L/kg Half-life: hr (3-5 days with renal failure) Excretion: Urine (80-90% as parent drug) 77

78 Drug Therapy for HF Inotropic Agents: cardiac glycosides Therapeutic Window: NARROW typical range for HF: 0.5 and 1.0 ng/ml toxicity is dose-related (rare below 0.8 ng/ml) Common Adverse Effects of digoxin: Nausea, loss of appetite, diarrhea Increased urine output (caused by increased renal perfusion due to enhanced CO) not really an AE because it helps with diuresis More likely in hypokalemia (low K + ) because digoxin is more active (less competition for binding site) 78

79 Drug Therapy for HF Inotropic Agents: cardiac glycosides Digitalis Toxicity (usually if >2 ng/ml) Nausea, vomiting, diarrhea, hyperkalemia Visual disturbances (yellow/green, halos) CNS: confusion, dizziness, anxiety Cardiac: arrhythmias, heart block Overdose: LD 50 = mg oral 79

80 Drug Therapy for HF Inotropic Agents: cardiac glycosides Toxicity/Overdose treatment: Digoxin immune FAb (DigiFab, Digibind ) For life-threatening digitalis toxicity FAb (fragment, antigen binding) produced in sheep (ovine) Given by IV inj Binds to and neutralizing circulating digoxin Inactive complexes are eliminated renally Supportive care: Arrhythmias: magnesium, lidocaine, phenytoin Bradycardia: atropine, isoprenaline 80

81 Drug Therapy for HF Inotropic Agents: catecholamines Dopamine (DA) and dobutamine are inotropic catecholamines used in acute decomensated HF (low CO). Given IV. They have less chronotropic (HR stimulation) effects and cause less increase in myocardial O 2 consumption than isoproterenol, EPI, or NE and are more frequently used in HF. They also cause vasodilation (only at low doses for DA) which can increase GFR and reduce afterload, while stimulating CO. 81

82 Drug Therapy for HF Inotropic Agents: catecholamines Dopamine: D 1 and D 2 > receptors (but also causes NE release) strong (+) inotropy moderate (+) chronotropy D 2 = vasodilation (low doses) Good for GFR and causing diuresis in acute CHF vasoconstriction at high doses (hypertension, ischemia) Dobutamine: 1 and 2 > D receptors strong (+) inotropy moderate (+) chronotropy 2 = vasodilation Good for GFR and causing diuresis in acute CHF less vasoconstriction than DA (less risk of hypertension) 82

83 Drug Therapy for HF Inotropic Agents: catecholamines Dopamine, Dobutamine Gs D 1 receptor or 1 receptor EPI, NE, IsoP Ca 2+ ATP Ca 2+ (IN) AC camp PKA CONTRACTION SR Ca 2+ Stores 83

84 Drug Therapy for HF Inotropic Agents: catecholamines Administration: IV Infusion Onset: 1-2 min (peak effect 5-10 min) Duration: < 10 min Metabolism: MAO, COMT (O-methylation) Half-life: 2 min Excretion: Urine (inactive metabolites) 84

85 Drug Therapy for HF Inotropic Agents: catecholamines Adverse Effects: NOT intended for long-term therapy Ventricular arrhythmias (ectopic beats) Low infusion rates: vasodilation possible hypotension (although an elevation in BP is usually seen because the BP-lowering effect of vasodilation is offset by the increase in CO) use carefully in hypovolemic patients (correct first) High infusion rates (esp. dopamine): vasoconstriction increased diastolic pressure careful in patients with occlusive vascular diseases atherosclerosis arterial embolism Raynaud disease 85

86 Drug Therapy for HF Inotropic Agents: PDE3 Inhibitors Ca 2+ ATP Ca 2+ (IN) Inamrinone, Milrinone AC camp PDE3 AMP PKA CONTRACTION SR Ca 2+ Stores 86

87 Drug Therapy for HF Inotropic Agents: PDE3 Inhibitors Administration: IV bolus followed by infusion Onset: inamrinone: 2-5 min milrinone: 5-15 min Duration: hr Metabolism: Hepatic (glucuronidation) Half-life: (in HF patients) inamrinone: 6 hr milrinone: 2.5 hr (shorter) Excretion: Urine, active tubular secretion (mostly as parent drug, consider dose reduction in patients with renal impairment) 87

88 Drug Therapy for HF Inotropic Agents: PDE3 Inhibitors Benefits: Do NOT increase heart rate (HR) or myocardial O 2 demand as much as catecholamines do (e.g. DA, IsoP, etc.) Decrease preload (filling pressures) and afterload (SVR) Enhance contractility ( CO) Adverse effects: headache, ventricular arrhythmias, chest pain Drug-specific adverse effects: NOT intended for long-term therapy Inamrinone: thrombocytopenia (10%) (rare with milrinone) Milrinone: vasodilation (reduced MAP), use caution in patients with marginal arterial BP and low CO. Milrinone: hypersensitivity 88