Pharmacology: Heart Failure

Transcription

1 Pharmacology: Heart Failure PHPP 515 (IT I) Fall 2014 Monday, Oct. 13 3:00 4:50 PM Dr. Jacobs Required Reading (via Access Pharmacy) Katzung: Chapters 13 Recommended Reading (via Access Pharmacy) Goodman and Gilman: Chapter 28 1

2 Lecture Outline: Heart Failure Overview Cardiac Output: (Heart rate, Preload, Contractility, Afterload) Hormonal and Sympathetic Activity in HF HF Drugs Diuretics RAA system inhibitors Beta blockers Vasodilators Inotropic agents (chronic and acute) 2

3 PULMONARY VASCULATURE RV Cardiac Output Basic Concepts LV failure: Pulmonary Edema Pulmonary Return RV failure: Peripheral Edema RV Systemic Venous Return SYSTEMIC LV LV Cardiac Output DIASTOLIC HF: Ventricles LESS COMPLIANT SYSTOLIC HF: Ventricles LESS CONTRACTILE 3

4 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) Stroke Volume x Heart Rate Or, the amount of blood pumped in 1 min (units = liters/min) Influence Stroke Volume (SV) Taken independently (not considering effects of HR on other cardiovascular factors) heart rate will proportionally cardiac output. 4

5 Basic Concepts 2. PRELOAD PRELOAD = STRESS on the walls 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 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). Normal LV EDP is around 6 12 mmhg. END DIASTOLE 5

6 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) Cardiac Pressure Volume Loop SV END DIASTOLE Ventricles filling (diastole) Volume 6

7 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 7

8 2. PRELOAD Basic Concepts Preload is proportional to end diastolic pressure (EDP) If you Preload, then you Stroke Volume (SV) For RV, preload is increased by CVP For LV, preload is increased by PCWP Pressure Effect of Preload on Stroke Volume Higher SV Normal SV Volume 8

9 2. PRELOAD Basic Concepts In DIASTOLIC HF (red line) the heart is STIFFER (less compliant) So if you keep end diastolic pressure (EDP) the same, then SV in Diastolic HF. Pressure Low SV Diastolic HF Leftward Shift in Diastolic PV Curve (caused by reduced compliance) Same EDP Normal SV Volume 9

10 2. PRELOAD Basic Concepts To COMPENSATE for the SV in diastolic HF, the body will Preload. How does it do this? By Venous Pressure (water retention, edema) Pressure Preload Increased SV SV Higher EDP (w/ edema) Diastolic HF is typically associated withelevated preload, which helps to compensate for less heart compliance Volume 10

11 2. PRELOAD Pressure Basic Concepts In DIASTOLIC HF, the heart still contracts strongly but on a SMALLER VOLUME and is less compliant (less stretchy) END SYSTOLE SV END DIASTOLE Reduced End Diastolic Volume Volume 11

12 3. CONTRACTILITY Basic Concepts This is FORCE 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) 12

13 3. CONTRACTILITY Basic Concepts The FRANK STARLING LAW simply states: Preload (i.e. EDV) causes Contractility (up to a point) How? Let s re visit cardiac muscle contraction Sarcomere Z line M line Sarcomere I band A band 13

14 3. CONTRACTILITY Basic Concepts Few myosin heads touching actin, ALSO: too crowded! Partially Stretched (more pre load) More myosin heads touching actin, less crowded 14

15 3. CONTRACTILITY Basic Concepts Fully stretched (even more pre load) Optimal # of myosin heads touching actin Over Stretched (too much!) 15

16 3. CONTRACTILITY Stroke Volume Basic Concepts Frank Starling Law = 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 End Diastolic Volume (EDV) 16

17 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 End Diastolic Volume (EDV) 17

18 3. CONTRACTILITY Stroke Volume Basic Concepts Normal Apex A. In SYSTOLIC HF the ventricles are less contractile, so are less effective at ejecting blood at a given EDV Systolic Heart Failure B. SV in HF is also WORSENED by the increased preload (cardiac stretch) caused by edema (because CO < venous return) End Diastolic Volume (EDV) 18

19 3. CONTRACTILITY Basic Concepts In CHRONIC SYSTOLIC HF you have higher preload (giving you EDV), but the pressure it can generate and the volume it can expel are both lower ( EDV, overall SV) Pressure Reduced Peak Systolic Pressure SV Smaller Pulse Pressure Elevated Preload Higher End Systolic Volume Higher End Diastolic Volume Volume 19

20 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. AFTERLOAD is proportional to PEAK SYSTOLIC PRESSURE (similar to how preload is proportional to end diastolic pressure) END SYSTOLE 20

21 4. AFTERLOAD Stroke Volume Basic Concepts increasing afterload will decrease stroke volume Afterload Curve Afterload (peak systolic stress) 21

22 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) 22

23 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 23

24 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 wall thickness (w) through cardiac HYPERTROPHY because: THICKER VENTRICLE WALL (w) = Afterload ( ) which should CO......BUT this doesn t really help for long because cardiac hypertrophy eventually causes REDUCED CHAMBER COMPLIANCE, causing Preload which causes CO 24

25 Basic Concepts CO = SV x HR Stroke Volume, SV = EDV ESV CO = (EDV ESV) x HR EDV ESV SV PRELOAD affects End Diastolic Volume (EDV) Preload means EDV means SV means CO 25

26 Basic Concepts CO = (EDV ESV) x HR Contractility and Afterload affect End Systolic Volume (ESV) Contractility (force) EDV ESV SV Afterload (pulmonary artery or aortic pressure) Contractility means ESV means SV means CO Afterload means ESV means SV means CO 26

27 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 27

28 Heart Failure Hormonal Activation in HF CO Renal Perfusion CO JGA Angiotensinogen Renin Angiotensin I Afterload (arterial BP) + ACE Angiotensin II arteriole vasoconstriction 28

29 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) 29

30 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 30

31 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 (ARB) Vasoconstriction CVP Aldosterone Na +, H 2 O retention Preload K+ sparing diuretics Loop and Thiazide diuretics 31

32 In summary, to CO (CO = SV x HR), we can: I. HR Chronotropic drugs (catecholamines) II. Drug Therapy for HF SV a. PRELOAD see next page Diuretics RAA system inhibitors b. AFTERLOAD Vasodilators RAA system inhibitors blockers c. CONTRACTILITY Inotropic agents 32

33 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 33

34 Stroke Volume Drug Therapy for HF Over Treated Apex Systolic Heart Failure EDV CO RAA activation Afterload Cardiac Remodeling Worsening of HF CAUTION: TOO MUCH DIURESIS (or too quickly) can lead to volume reduction and ACTIVATION of RAA system! 34

35 DIURETICS Drug Therapy for HF LOOP DIURETUCS [the mainstay of CHF therapy] Furosemide (Lasix ) Bumetanide (Bumex ) Torsemide (Demadex ) Ethacrynic Acid (Edecrin ) Choice drugs underlined THIAZIDE DIURETICS [can be added on for refractory CHF, refer to diuretics pharmacology lectures Dr. Connelly] Chlorothiazide (Diuril ) Chlorothalidone (Hygroton ) Metolazone (Zaroxolyn ) K + SPARING DIURETICS [discussed later in this lecture] Amiloride Triamterene (Dyrenium ) Spironolactone (Diuril ) Eplerenone (Aldactone ) 35

36 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. 36

37 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. 37

38 LOOP DIURETICS Half lifes: 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) 38

39 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) 39

40 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 40

41 LOOP DIURETICS Drug Interactions: Drug Therapy for HF NSAIDs (aspirin, ibuprofen, etc.) These block prostaglandin biosynthesis (COX 1, COX 2). Prostaglandins vasodilate afferent arterioles and increase intra glomerular pressure. Therefore, NSAIDs can decrease GFR. ACE inhibitors (captopril, enalapril, lisinopril, etc.), AND AT 1 antagonists (azilsartan, losartan, valsartan, etc.) AT II receptor (AT 1 ) vasoconstricts efferent arterioles and increases intra glomerular pressure. Therefore, ACE I and ARBs can decrease GFR. Negative interactions typically short lived, occurs during initiation of drug therapy or dose escalations. 41

42 LOOP DIURETICS Loop Diuretic Resistance: Drug Therapy for HF Caused by compensatory renal Na + reabsorption ( GFR leading to activation of RAA system). Reduction in dosing intervals or adding/switching diuretic class can sometimes overcome resistance. 42

43 THIAZIDE DIURETICS Capillary blood Drug Therapy for HF Early Distal Tubule Cl 3 Na + Na + Tubular Lumen Site of Action: NaCl Symporter (SLC12A3) CAUSE LOSS OF: 2 K + Na + (H 2 O) K + Cl K + (indirect) 43

44 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 + 44

45 K+ SPARING DIURETICS Drug Therapy for HF Amiloride, Triamterene (Na + channel blockers) Capillary blood Late Distal Tubule + Collecting Ducts Tubular Lumen CAUSE LOSS OF: 3 Na + Na + Na + Na+ (H 2 O) 2 K + Site of Action: Sodium channel 45

46 K+ SPARING DIURETICS Administration: ALL 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) 46

47 K+ SPARING DIURETICS Drug Therapy for HF 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 47

48 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) 48

49 Stroke Volume Drug Therapy for HF RAA 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 49

50 Drug Therapy for HF RAA 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) 50

51 Drug Therapy for HF RAA 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 blue Choice drugs underlined * = Off label for HF 51

52 Drug Therapy for HF RAA 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: Systemic vascular resistance ( BP) 52

53 Drug Therapy for HF RAA INHIBITORS: ACE inhibitors Angiotensin I Angiotensin II + ACE ACE inhibitors Adrenal glands (zona glomerulosa) Aldosterone Sodium and water reabsorption Effect of drug: Natriuresis, Diuresis 53

54 Drug Therapy for HF RAA 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 54

55 Drug Therapy for HF RAA INHIBITORS: ACE inhibitors Metabolism: prodrug Almost all ACE I are prodrugs (rapid hydrolysis to active metabolites) But, Captopril and Lisinopril are NOT prodrugs 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) 55

56 Drug Therapy for HF RAA INHIBITORS: ACE inhibitors Adverse Effects: Dry Cough (caused by bradykinin) Hypotension Hyperkalemia Renal function deterioration Angioedema (rare) Contraindicated in pregnancy 56

57 Drug Therapy for HF RAA 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: Systemic vascular resistance ( BP) AT 1 receptor Aldosterone Sodium and water reabsorption Effect of drug: Natriuresis, Diuresis 57

58 Administration: ORAL Absorption: Incomplete Oral Bioavailability: LOW Candesartan (15%) Losartan (33%) Valsartan (25%) Effect of Food: Drug Therapy for HF RAA INHIBITORS: AT 1 antagonists Drugs may be taken with or without food 58

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

60 Drug Therapy for HF RAA INHIBITORS: AT 1 antagonists Half lives: Candesartan: 9 hr Losartan: 1 2 hr, EXP 3174: 6 9 hr Valsartan: 6 hr Excretion: mainly fecal Adverse Effects: Hypotension Hyperkalemia Reduced renal function Contraindicated in pregnancy 60

61 Drug Therapy for HF RAA 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 61

62 Drug Therapy for HF RAA 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 62

63 BETA BLOCKERS Drug Therapy for HF Bisoprolol* (Zebeta ) Carvedilol (Coreg ) Metoprolol succinate ER (Toprol XL ) HF indications in blue Choice drugs underlined * = Off label for HF 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) Effects of blocking 1: Arterial and Venous Vasodilation Reduced Inotropy (in response to endogenous catecholamines) 63

64 Drug Therapy for HF BETA BLOCKERS Beta blockers are a mixed bag of effects in HF CO Afterload SNS (NE, EPI) blockers Inotropy HR CO In the HEART: O 2 demand (good) Contraction (bad) Vasoconstriction In the ARTERIES: Afterload (good) CVP Preload In the VENOUS RETURN: Preload (good for HF patents) 64

65 BETA BLOCKERS Drug Therapy for HF Clinical trials have shown THREE blockers to benefit survival in patients with chronic HF: Bisoprolol Carvedilol Metorpolol ER 65 TRENDS in Pharmacological Sciences

66 BETA BLOCKERS Drug Therapy for HF What is the MECHANISM for the beneficial actions (survival benefits) of only 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 66

67 BETA BLOCKERS Normal Drug Therapy for HF 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 67

68 BETA BLOCKERS Administration: ORAL Drug Therapy for HF Absorption: all are well absorbed, but... 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 68

69 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 69

70 VASODILATORS Drug Therapy for HF RAA Inhibitors have vasodilatory actions by blocking angiotensin II production (blocking vasoconstriction) ACE inhibitors (also bradykinin) AT 1 antagonists Other vasodilators also have beneficial effects for HF: ARTERIAL Vasodilators ( AFTERLOAD) Hydralazine (oral, high doses) for chronic management VENOUS Vasodilators ( PRELOAD) Nitroglycerin Sodium nitroprusside Isosorbide mono/di nitrate for acute decompensation 70

71 INOTROPIC DRUGS 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 ) 71

72 Drug Therapy for HF INOTROPIC DRUGS: 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 Effect of drug: intracellular calcium levels (SR stores) 72

73 Drug Therapy for HF INOTROPIC DRUGS: Cardiac Glycosides w/digoxin 73

74 Drug Therapy for HF INOTROPIC DRUGS: Cardiac Glycosides Stroke Volume Normal Treated Systolic Heart Failure Effect on Frank Starling Curve Ventricular End Diastolic Volume (EDV) 74

75 Drug Therapy for HF INOTROPIC DRUGS: Cardiac Glycosides Administration: ORAL (CHF), INJ (A Fib, rate control in HF patients) 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) 75

76 Drug Therapy for HF INOTROPIC DRUGS: 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) 76

77 Drug Therapy for HF INOTROPIC DRUGS: 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 77

78 Drug Therapy for HF INOTROPIC DRUGS: 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 Other care (supportive): Arrhythmias: magnesium, lidocaine, phenytoin Bradycardia: atropine, isoprenaline 78

79 Drug Therapy for HF INOTROPIC DRUGS: 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 of an increase in myocardial O 2 consumption than isoproterenol, EPI, or NE and are more frequently used in treating HF. They also have the benefit of causing vasodilation (although, only at low doses for DA) which can GFR and Afterload. 79

80 Drug Therapy for HF INOTROPIC DRUGS: 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) 80

81 Drug Therapy for HF INOTROPIC DRUGS: 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 81

82 Drug Therapy for HF INOTROPIC DRUGS: 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) 82

83 Drug Therapy for HF INOTROPIC DRUGS: Catecholamines Adverse Effects: NOT intended for long term therapy Ventricular arrhythmias (ectopic beats) Low infusion rates: Vasodilation Possible hypotension (although, 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 Diastolic pressure Careful in patients with occlusive vascular diseases atherosclerosis arterial embolism Raynaud disease 83

84 Drug Therapy for HF INOTROPIC DRUGS: PDE3 Inhibitors Ca 2+ ATP Ca 2+ (IN) Inamrinone, Milrinone AC camp PDE3 AMP PKA CONTRACTION SR Ca 2+ Stores 84

85 Drug Therapy for HF INOTROPIC DRUGS: PDE3 Inhibitors Administration: IV bolus followed by infusion Onset: Inamrinone: 2 5 min Milrinone: 5 15 min Duration: hr Metabolism: Hepatic (glucuronidation) Half lifes: (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) 85

86 Benefits: Drug Therapy for HF INOTROPIC DRUGS: PDE3 Inhibitors 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 86