Pharmacology: Heart Failure PHPP 515 (IT-I) Fall …...2. Preload This is STRESS in the ventricles...

Pharmacology: Heart Failure

JACOBS Monday, Oct. 14 3:00 – 4:50 PM

PHPP 515 (IT-I) Fall 2013

Required Reading (via Access Pharmacy) • Katzung: Chapters 13

Recommended Reading (via Access Pharmacy) • Goodman and Gilman: Chapter 28

1

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

Heart Failure: The heart cannot pump enough blood to meet the demands of the body (low cardiac output*)

Basic Concepts

PULMONARY

SYSTEMIC

RV LV

LV Cardiac Output Systemic Venous Return

RV Cardiac Output Pulmonary Venous Return

Backup = Pulmonary Edema

Backup = Peripheral Edema

*high CO is seen in some rare cases 3

Basic Concepts

EDV ESV

In DIASTOLIC HF EDV and SV are PROPORTIONALLY reduced. Therefore, Ejection Fraction (EF = SV/EDV) DOES NOT CHANGE.

DISATOLIC VS SYSTOLIC HF

SV Normal

EDV’ ESV’

SV’ SV’ EDV’

SV EDV

= Diastolic HF

4

Basic Concepts

DISATOLIC VS SYSTOLIC HF

EDV ESV

SV

In SYSTOLIC HF SV is REDUCED for a given amount of EDV. Therefore, Ejection Fraction (EF = SV/EDV) IS REDUCED.

Normal

EDV’ ESV’

SV’ SV’ EDV’

SV EDV

< Systolic HF

5

Basic Concepts

Most patients have BOTH types of HF

EDV’ ESV’

SV’

EDV’ ESV’

SV’

REDUCED EF (SYSTOLIC HF)

REDUCED EDV (DIASTOLIC HF)

EDV’ ESV’

SV’

6

FOUR FACTORS DETERMINE CO:

1. Heart rate (HR)

2. Preload 3. Contractility 4. Afterload

Influence Stroke Volume (SV)

1. Heart Rate

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.

Cardiac Output (CO = SV x HR) i.e. Stroke Volume x Heart Rate The amount of blood pumped in 1 min (units = liters/min)

Basic Concepts

7

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

Basic Concepts

8

Volume

Pressure

END DIASTOLE

END SYSTOLE

SV

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)

Basic Concepts

Ventricles emptying (systole)

Ventricles filling (diastole)

Cardiac Pressure-Volume Loop

9

Volume

Pressure Ventricles filling (diastole) while muscle relaxed

Basic Concepts

SV

2. Preload

During filling there is no muscle contraction. The rise in pressure during filling is relative to the COMPLIANCE of the ventricles (i.e. “stretchiness”)

10

Basic Concepts

Volume

Pressure

SV

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

SV

Effect of Preload

2. Preload

11

Volume

Pressure

Basic Concepts

Normal SV

Diastolic Heart Failure

Leftward Shift in Diastolic PV Curve (caused by reduced chamber compliance) SV

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.

Preload EDP

2. Preload

12

Volume

Pressure

Basic Concepts

SV

To COMPENSATE for the reduction in SV caused by reduced compliance, the body will increase preload How? By increasing venous pressure (water retention – edema)

Preload

Effect of Preload

2. Preload

Diastolic HF is typically associated with elevated preload, which helps to compensate for less heart compliance

13

Basic Concepts

2. Preload In DIASTOLIC HF, the heart still contracts strongly (ejects blood), but on a smaller volume and is less compliant (stretchy)

Volume

Pressure

END DIASTOLE

END SYSTOLE

SV

14

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)

Basic Concepts

15

3. Contractility

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

Basic Concepts

16

3. Contractility

Partially Stretched (more pre-load)

More myosin heads touching actin, less crowded

Few myosin heads touching actin, ALSO: too crowded!

Basic Concepts

17

3. Contractility

Fully stretched (even more pre-load)

Lots of myosin heads touching actin

Over-Stretched (too much!)

Basic Concepts

18

Stroke Volume

Frank-Starling Curve

more preload (i.e. Venous Return)

= more SV (i.e. Cardiac Output)

This is the heart’s intrinsic way of matching cardiac output to venous return.

Ventricular End Diastolic Volume (EDV)

3. Contractility

Basic Concepts

19


Stroke Volume

overloaded (CONGESTION)

RIGHT VENTRICLE FAILURE • Peripheral edema,

ascites LEFT VENTRICLE FAILURE

• Pulmonary edema, dyspnea

underloaded • Dehydration • Shock (sepsis)

Relationship of BLOOD VOLUME to cardiac contractility

3. Contractility

Basic Concepts

Frank-Starling Curve

Apex

20

Stroke Volume

A. In SYSTOLIC HF the ventricles are less contractile, so are less effective at ejecting blood for a given amount of fill (preload) Normal

Systolic Heart Failure

B. SV in HF is also WORSENED by the increased preload (cardiac stretch) caused by edema (because CO < venous return)


3. Contractility

Basic Concepts

Apex

21

4. Afterload

This is PEAK STRESS in the ventricles during SYSTOLE (i.e. ventricular contraction).

You can also think of this as the force that the heart needs to generate in order to pump blood.

END SYSTOLE

Basic Concepts

It can be thought of as the stress encountered by ventricular myofibrils as they contract against the volume of blood in the heart.

22

4. Afterload

Stroke Volume

Afterload (peak systolic stress)

Afterload Curve

Basic Concepts

23

will decrease stroke volume

increasing afterload

4. Afterload

Stroke Volume

Afterload (peak systolic stress)

Basic Concepts

Normal Systolic Heart Failure

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)

Afterload Curve

24

4. Afterload

LaPlace Equation

= Stress (afterload) P = systolic pressure* r = ventricular diameter w = wall thickness

*For R Ventricle, P = pulmonary artery pressure *For L Ventricle, P = aortic pressure

Basic Concepts

r w

2w Pr

=

25

4. Afterload

2w Pr

=

• 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

Basic Concepts

High Systolic BP and Ventricular Dilation MAY CONTRIBUTE to HF and will affect the AFTERLOAD in the ventricles. HOW?

26

End Diastolic Volume (EDV)

Preload affects End Diastolic Volume (EDV)

CO = SV x HR Stroke Volume, SV = EDV – ESV CO = (EDV – ESV) x HR

EDV ESV

SV

Higher Preload means Bigger EDV, means Bigger SV, means More CO

Basic Concepts

27

End Systolic Volume (ESV)

Contractility and Afterload affect End Systolic Volume (ESV)

Afterload (pulmonary artery or aortic pressure)

Contractility (force)

CO = SV x HR Stroke Volume, SV = EDV – ESV CO = (EDV – ESV) x HR

More Contractility means Smaller ESV, means Bigger SV, means More CO

Smaller Afterload means Smaller ESV, means Bigger SV, means More CO

EDV ESV

SV

Basic Concepts

28

CO

Angiotensinogen

Angiotensin I

Renal Perfusion

CVP (preload) (blood volume)

Heart Failure

Renin JGA

Aldosterone

Adrenal cortex

Principal Cells (distal tubule, collecting ducts)

Na+, H2O uptake

CO Hormonal Activation in HF

Angiotensin II

ACE +

29

CO

Angiotensin II

ACE

Angiotensinogen

Angiotensin I

Renin

Renal Perfusion

Heart Failure

JGA

CO

Hormonal Activation in HF

arteriole vasoconstriction

Afterload (arterial BP)

+

30

Adrenal Stimulation

EPI, NE Heart Failure

Sympathetic Activation in HF

CO

Arterial Baroreceptor Firing

Cranial nerve IX

Vagal activity (parasympathetic, ACh)

Sympathetic activity (NE)

Chronotropy (HR)

Cardiac Remodeling (Hypertrophy)

Vasoconstriction

SVR (Afterload) CVP (Preload)

Inotropy

31

CO Renin

Angiotensin I

Angiotensin II

Aldosterone

Afterload

HF is a Complex

Web Inotropy

Na+, H2O retention Preload

CO

Vasoconstriction CVP

Vent. Compliance

SNS (NE, EPI) Inotropy

HR

32

Inotropy

CO Renin SNS (NE, EPI)

Angiotensin I

Angiotensin II

Aldosterone

Vasoconstriction

Na+, H2O retention Preload

Afterload

Drug Therapy for HF Vent. Compliance

CO

CVP

Inotropy

HR -blockers

K+ sparing diuretics

AT1 antagonists

ACE inhibitors

Renin inhibitors

Loop and Thiazide diuretics

Inotropic Agents

Vasodilators

33

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

Drug Therapy for HF

34

Drug Therapy for HF

Stroke Volume

Normal


Apex

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

Treated

EDV

Why Decrease Preload?

35

Drug Therapy for HF

However, TOO MUCH diuresis (or too quickly) can lead to volume reduction and ACTIVATION of RAA system.

Stroke Volume


Apex

Over-Treated

EDV

Afterload Cardiac Remodeling

Worsening of HF

CO RAA activation

36

Drug Therapy for HF Diuretics

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

Loop Diuretics

Drug Therapy for HF

Loop of Henle Ascending Limb Capillary blood Tubular Lumen

K+

2Cl-

2 K+

K+

Most powerful diuretics. Why? About 25% of the filtered sodium re-uptake happens here.

Na+ (H2O)

K+

Cl-

CAUSE LOSS OF: 3 Na+

Na+

38

Site of Action: Na-K-Cl cotransporter (NKCC2)

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

Loop Diuretics

Drug Therapy for HF

Half-life: Furosemide: 0.5-2 h Bumetanide: 1-1.5 h Torsemide: 3.5 h Ethacrynic acid: 2-4 h

Duration: ORAL: 4-6 h (typical), except ethacrynic acid (12 h) IV: 2-3 h (although often given by continuous admin)

40

Loop Diuretics

Drug Therapy for HF

Route of Elimination:

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

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

Loop Diuretics

Drug Therapy for HF

Drug Interactions:

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 AT1 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

Drug Therapy for HF

Loop Diuretics

Diuretic Resistance:

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

Thiazide Diuretics

Drug Therapy for HF

Early Distal Tubule Capillary blood Tubular Lumen

Cl-

2 K+

K+

Na+ (H2O)

K+ (indirect) Cl-

CAUSE LOSS OF: 3 Na+

Na+

45

Site of Action: NaCl Symporter (SLC12A3)

K+ Sparing Diuretics

Drug Therapy for HF

3 Na+

2 K+

Late Distal Tubule + Collecting Ducts Capillary blood Tubular Lumen

Na+ Na+

Na+ (H2O)

CAUSE LOSS OF:

Site of Action: Aldosterone (mineralcorticoid) Receptor, MR

Spironolactone, Eplerenone (aldosterone antagonists)

46

MR


Drug Therapy for HF

3 Na+

2 K+

Late Distal Tubule + Collecting Ducts Capillary blood Tubular Lumen

Na+ Na+

Na+ (H2O)

CAUSE LOSS OF:

Amiloride, Triamterene (Na+ channel blockers)

Site of Action: Sodium channel

47


Drug Therapy for HF

Administration: ORAL

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


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


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

Drug Therapy for HF

Stroke Volume

Normal


Apex

Treated

EDV

RAA System Inhibitors (ACE inhibitors, Renin inhibitors, AT1 antagonists)

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

Drug Therapy for HF

RAA System Inhibitors (ACE inhibitors, Renin inhibitors, AT1 antagonists)

Stroke Volume

Afterload

Normal


Treated

Inhibition of the RAA system also causes arteriolar vasorelaxation (decreasing arterial BP and afterload, thus increasing CO)

52

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®)

AT1 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

Drug Therapy for HF

RAA System Inhibitors: ACE inhibitors

ACE

Vasoconstriction (endothelin, TxA2)

Vasorelaxation (NO, EDHF, PGI2)

Bradykinin

Inactive peptides Angiotensin I

Angiotensin II ACE

inhibitors

arterioles (resistance arteries) Effect of drug: drop in systemic vascular resistance (BP)

+

54

Drug Therapy for HF


ACE

Angiotensin II

Angiotensin I

ACE inhibitors

+

adrenal glands (zona glomerulosa)

Aldosterone Sodium and water reabsorption

Effect of drug: natriuresis, diuresis

55

Drug Therapy for HF



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

Metabolism: Almost all ACE-I are prodrugs (rapid hydrolysis to active metabolites) Captopril and lisinopril are NOT prodrugs

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)

Drug Therapy for HF


prodrug active metabolite

Esterase

57

Drug Therapy for HF


Adverse Effects: • Dry Cough (caused by bradykinin increase) • Hypotension • Hyperkalemia • Renal function deterioration • Angioedema (rare) • Contraindicated in pregnancy

58

Drug Therapy for HF

RAA System Inhibitors: AT1 antagonists (angiotensin II receptor blockers, ARBs)

Vasoconstriction (endothelin, TxA2)

Angiotensin II arterioles

(resistance arteries)

AT1 receptor AT1 receptor

adrenal glands (zona glomerulosa)

Aldosterone

Sodium and water reabsorption

Effect of drug: natriuresis, diuresis

Effect of drug: drop in systemic vascular resistance (BP)

59

Drug Therapy for HF


Absorption: incomplete

Oral Bioavailability: LOW

Candesartan (15%) Losartan (33%) Valsartan (25%)

Effect of Food:

Drugs may be taken with or without food

RAA System Inhibitors: AT1 antagonists

OK +/-

60

Metabolism: Candesartan cilexetil is a prodrug

Losartan is a prodrug

Valsartan is NOT a prodrug

Drug Therapy for HF

Candesartan cilexetil

Candesartan (active)

Intestinal Esterase


Losartan EXP-3174

CYP2C9, 3A4

61

Drug Therapy for HF


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

Drug Therapy for HF


Another benefit of AT1 antagonists

HF angiotensin II AT1 receptors cell enlargement

Ventricular Hypertrophy (VH) Atrial Enlargement

Candesartan, Losartan, Valsartan

Also, by reducing BP these drugs help prevent VH, since afterload also promotes cardiac remodeling

63

Drug Therapy for HF

RAA System Inhibitors

Aldosterone breakthrough (several possible mechanisms)

Angiotensinogen

Angiotensin I

Angiotensin II

Renin

ACE

• tissue plasminogen activator • Cathepsin G

• Chymase • Cathepsin G

Aldosterone

Aldosterone antagonists spironolactone eplerenone

AT1 Receptor

ACE inhibitors

Renin inhibitors

AT1 antagonists

fluid retention 64

Drug Therapy for HF

Beta blockers

• Bisoprolol* (Zebeta®)

• Carvedilol (Coreg®)

• Metoprolol succinate ER (Toprol XL®)

HF indications in bold, blue * = 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)

65

Drug Therapy for HF Beta blockers

CO SNS (NE, EPI)

Vasoconstriction

Afterload

-blockers

On the arterial side -blockers should have a beneficial effect (reducing afterload)

Preload

CO

CVP On the venous side -blockers should have a (modest) beneficial effect (lowering preload)

Inotropy

HR

In the heart they lower oxygen demand (good) but also lower CO (bad)

Beta blockers are a “mixed bag” of effects in HF

66


Clinical trials have shown three -blockers to benefit survival in patients with chronic HF:

• bisoprolol • carvedilol • metorpolol ER

TRENDS in Pharmacological Sciences 67


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

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

SV SV EDV

EF1 = EDV


Normal

SV’ SV’ EDV’

EF2 =

LOW EF EDV’

Enlarged Ventricle

EF2 < EF1

69

Drug Therapy for HF

Beta blockers


Absorption: well absorbed

Oral Bioavailability: bisoprolol (80%) – 20% lost in 1st pass to CYP3A4 carvedilol (25%) – 75% lost in 1st pass to CYP2D6 (carvedilol ER has much higher bioavailability) metoprolol (50%) – 75% lost in 1st 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

Adverse Effects: • Bradycardia • Syncope • Dizziness • Fatigue • Masking signs of hypoglycemia (preventing rapid HR) • Abrupt withdrawal/withdrawal syndrome:

acute tachycardia hypertension ischemia

Drug Therapy for HF

Beta blockers

71

Drug Therapy for HF

Vasodilators

RAA system inhibitors have vasodilatory actions by blocking angiotensin II production (blocking vasoconstriction)

ACE inhibitors (also increase bradykinin) AT1 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

72

chronic management

acute decompensation

Drug Therapy for HF

Inotropic Agents

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

Drug Therapy for HF

Inotropic Agents: cardiac glycosides

3 Na+

2 K+

Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Ca2+ SR

(OUT) Na+ Ca2+

Ca2+ (IN) Na+

Ca2+

Na+

Ca2+ = Inotopy Digoxin (competes with K+ for K+ binding site)

Intracellular calcium levels (and SR stores) are increased 74

Drug Therapy for HF


Digitalis

75

Stroke Volume



Normal

Drug Therapy for HF


Effect on Frank-Starling Curve

Treated

76

Drug Therapy for HF


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: 36-48 hr (3-5 days with renal failure) Excretion: Urine (80-90% as parent drug)

77

Drug Therapy for HF


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

Drug Therapy for HF


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: LD50 = 10-15 mg oral

79

Drug Therapy for HF


Supportive care: Arrhythmias: magnesium, lidocaine, phenytoin Bradycardia: atropine, isoprenaline

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

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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 O2 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.

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Drug Therapy for HF


Dopamine: • D1 and D2 > receptors

(but also causes NE release) • strong (+) inotropy • moderate (+) chronotropy • D2 = 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)

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Drug Therapy for HF


D1 receptor or 1 receptor

Dopamine, Dobutamine

Gs

AC

ATP

cAMP

EPI, NE, IsoP

PKA

Ca2+ (IN)

Ca2+

SR Ca2+ Stores

CONTRACTION

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Drug Therapy for HF


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)

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Drug Therapy for HF


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

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AC

ATP

cAMP PKA

Ca2+ (IN)

Ca2+

CONTRACTION

PDE3

AMP

Inamrinone, Milrinone

Drug Therapy for HF

Inotropic Agents: PDE3 Inhibitors

SR Ca2+ Stores

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Drug Therapy for HF


Administration: IV bolus followed by infusion

Onset: inamrinone: 2-5 min milrinone: 5-15 min

Duration: 0.5-2 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)

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Drug Therapy for HF


Benefits:

• Do NOT increase heart rate (HR) or myocardial O2 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

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Pharmacology: Heart Failure PHPP 515 (IT-I) Fall …...2. Preload This is STRESS in the ventricles...

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Transcript of Pharmacology: Heart Failure PHPP 515 (IT-I) Fall …...2. Preload This is STRESS in the ventricles...