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Flashcards in Ostrom Deck (53):
1

What factors determine heart work and O2 supply?

- Work: heart rate, cardiac contractility, wall tension (afterload) 

- O2 supply: coronary vascular resistance, perfusion pressure, collateral blood flow, heart rate and mechanics 

- Therapies can either decrease demand, increase supply, or both

3

What does combo diuretic therapy typically look like? What are the associated toxicities and interactions?

- Combo: loop diuretic + metolozone, loop + spirono 25-50mg/day 

Toxicity: electrolyte disturbances, hypokalemia, hyponatremia, hypochloremic metabolic alkalosis, azotemia (abnormally high levels of nitrogen-containing compounds, i.e., urea, creatinine, etc.), dehydration, hypotension, ototoxicity (tinnitus, hearing loss; loop diuretics)

- Interaxns: NSAID's reduce efficacy of diuretics by promoting fluid retention 

3

What is Nesiritide? What are its benefits and MOA's?

- Recombinant human BNP; FDA approved for IV tx of decompensated Class IV CHF 

- MOA's: binds BNP receptor in vascular smooth muscle, veno- and vasodilation (via cGMP) -> reduces preload and afterload 

1. Dilation of afferent renal glomerular arterioles INC GFR, filtration fraction, and DEC sodium reapsorption (natriuresis) 

2. Suppresses renin-angiotensin and SNS 

- Benefit comparable to IV nitroglycerine, but hypotension may persist longer -> use should be limited to those who do not respond to nitroglycerine

3

Which drugs decrease preload?

- Furosemide

- Nitrates 

- ACEI (also DEC afterload) 

- ARB (also DEC afterload)

- Spironolactone 

- Nesiritide (also DEC afterload)

4

Which drugs are anti-mitogenic?

- ACEI 

- ARB 

- Spironolactone 

- Nesiritide 

- B-blocker 

4

What are the general approaches to treating angina?

- Increase coronary blood flow

- Reduce myocardial oxygen consumption (mvo2) by:

1. NEGATIVE CHRONOTROPIC EFFECT *HR

2. NEGATIVE INOTROPIC EFFECT *contractility

3. Decreased ventricular workload (wall stress):

a. Reduced preload (venodilation)

b. Reduced afterload (vasodilation)

- Prevent platelet deposition/aggregation: ASA

4

What drugs are effective in preventing CHD, MI death in patients with angina?

- BB: reduce CHD events

- CCB: variable effect

- Aspirin: all patients w/CHD should receive ASA tx unless contraindicated -> reduces reinfarction, CHD, and stroke after unstable angina or MI 

ACEI: improve survival post-MI w/LV dysfunction; reduce MI in high-risk pts

Thrombolytic therapy: DEC mortality in first year post-MI (can also do revascularization)

- Statins: reduce recurrent MI; may acutely stabilize coronary plaque 

- HDL/TG drugs: reduce recurrent CHD/MI 

5

What are the ACA/NYHA stages?

- Stage A: preventive measures + ACEI/ARB

- Stage B (NY 1): preventive measures + ACEI/ARB + beta blocker 

- Stage C (NY 2, 3): PM + ACEI/ARB + BB + diuretic (2)/ Digoxin/ Spironolactone 

- Stage D: PM + ACEI/ARB + BB + diuretic/ Digoxin/ Spironolactone + transplant/IV inotropes 

5

What are the deleterious effects of chronically high levels of NE, E?

- BB's attenuate deleterious effects of chronically high levels of NE and E, which cause: 

1. B-AR down-regulation 

2. Arrhythmias (leading cause of death in class II, III CHF) 
3. INC myocardial O2 consumption/ischemia 

4. Myocyte apoptosis, followed by cardiac fibrosis 

6

What are the effects of Spironolactone in CHF?

- DEC preload 

- Anti-mitogenic 

- Secondary diuresis 

- Survival benefit 

7

What vasodilators are NOT effective in CHF?

- Prazosin

- Minoxidil 

- Dihydropiridine Ca-channel blockers 

8

Why are nitrates used in advanced CHF?

- EX: Nitroprusside 

- IV: veno- and vasodilation reduces preload and afterload (alone, or with vasodilator) 

- Reduce pulmonary artery pressure and pulmonary congestion (via reduced preload)

- Reduce left ventricular filling pressure and wall stress

 

8

Which drugs increase inotropy?

- Digoxin 

- Milrinone 

- Dobutamine 

- Beta-blockers (INC and DEC)

9

What are the three types of angina?

- Unstable (pre-infarction, crescendo) angina

1. Recurrent angina assoc with minimal exertion

2. Prolonged and frequent pain

3. Due to fissuring of atheroscelortic plaques, and subsequent platelet aggregation

4. High correlation with myocardial infarction

- Variant (vasospastic, Prinzmetal's) angina

1. Direct result of reduction in coronary flow due to vasospasm, not an increase in myocardial oxygen demand

2. Normal coronary angiograms – Excellent prognosis

- Exertional (exercise-induced) angina

1. Due to fixed coronary vascular obstruction (sx revascularization, angioplasty may be beneficial) 

10

How do CCB's treat angina?

- Non-dihydropyridine: Verapamil, Diltiazem

1. Direct effects to reduce heart work (demand): DEC HR & contractility, slowed AV conduction

2. Prevents, reverses vasospasm (coronary vasodilation)

- Dihydropyridine: Nifedipine, Felodipine, etc

1. Potent vasodilation, reduces MvO2 by reducing afterload

2. Coronary vasodilation (increased supply)

3. Reflex cardiac stimulation: HR, contractility can increase reflexively

4. AV node conduction unaffected

5. Only use in combination with ß-blocker!

11

What are the contraindications for BB use in CHF?

- Heart block 

- Bradycardia 

- Decompensated CHF/need for IV inotropes (i.e., dobutamine) 

- Volume overload 

12

What are the effects of the beta-blockers in CHF?

- DEC/INC inotropy 

- Anti-mitogenic 

- Secondary natriuresis 

- Survival benefit 

12

Why does it matter that the heart is perfused during diastole (for drug therapy)?

- Any therapy that reduces contractility will reduce the amount of squeezing during systole 

- Decreasing HR will increase amount of time spent in diastole, increasing amount of blood delivered to myocardium

15

What is aldosterone escape?

- Inability of ACEI therapy to reliably suppress aldosterone release

- Usually manifested by increased salt and water retention (refractory hyperaldosteronism)

16

What are ANP and BNP? What are their hemodynamic effects?

- Released from atria (ANP) and ventricles (BNP) in response to volume/pressure expansion 

- Naturally elevated in CHF 

- Promote vaso/venodilation and natriuresis 

- Hemodynamic effects

1. Reduce ventricular filling pressure (preload) 

2. Inhibit renin/aldosterone release 

3. Inhibit Na reabsorption in proximal convoluted tubule 

4. Selective afferent arteriolar vasodilation 

17

What are the effects of the nitrates in CHF?

DEC preload

18

What are the hemodynamic effects of BB's in CHF?

- Short-term: reduced CO, BP 

- Long-term: increased CO, decreased LVEDP 

- May see initial worsening of symptoms, then improvement (dose up slowly) -> overall improved function in CHF 

1. Benefits class II-IV (start low, then titrate up slowly)

18

What are the effects of Nesiritide in CHF?

- DEC preload AND afterload 

- Anti-mitogenic 

- Natriuretic 

- Survival benefit?

19

Which drugs impart a survival benefit?

- Digoxin (not overall disease course, but helps prevent sudden decline)

- Hydralazine 

- ACEI 

- ARB 

- Spironolactone 

- B-blocker 

- Nesiritide??

21

Which drugs decrease afterload?

- Milrinone 

- Hydralazine 

- ACEI (also DEC preload)

- ARB (also DEC preload)

- Dobutamine (increases and decreases) 

- Nesiritide (also DEC preload) 

23

Are ACEI's or ARB's better?

- Currently, ACEI's preferred unless patient can't tolerate side effects 

- Combining ACEI and ARB showed no increased benefit 

25

What effects do spironolactone and eplerenone have beyond their diuretic effects?

- Aldosterone inhibition: 

1. Aldosterone has mitogenic and fibrogenic effects on myocardium (combines with AngII to stimulate fibrosis) 

2. Increased aldosterone may lead to worsened LV function 

- Reduce mortality/improve survival 

26

Know this.

Good job!

27

Which BB's are approved for treatment of CHF?

- Metoprolol 

- Bisoprolol 

- Carvedilol 

- Nebivolol (in Europe): potentiates NO in vasculature, but only approved for HTN in US 

28

What are the IV inotropic agents used to manage advanced CHF?

- Beta-agonists: DOBUTAMINE 

1. B1 > B2, and A1; + inotrope, vasodilator 

2. Short-term IV bridge or intermittent therapy 

3. Limited by B-rec desensitization, arrhythmias 

4. BB therapy prevents vasodilatory effect of DOBU, and can even cause vasoconstriction (via unopposed A1 agonism) 

- Phosphodiesterase inhibitors: MILRINONE 

1. Short-term IV use (long-term use of PDE inhibitors in CHF increases mortality!) 

- NESIRITIDE: B-type natriuretic peptide 

- NOTE: cardiac transplantation, extracorporeal bridging devices in severe cases

28

What are the effects of Furosemide in CHF?

- DEC preload 

- Natriuretic 

29

What are the effects of Hydralazine in CHF?

- DEC afterload 

- Survival benefit 

30

What is hydralazine? What are its limitations?

- Vasodilator that acts directly on arterial smooth muscle 

- Effective in CHF, but: 

1. Variability in effective dose (300-1200mg/day)

2. Stimulates RAS: peripheral edema, circulatory congestion 

3. Toxicity: nausea, anorexia, +FANA (freq), drug-induced lupus (rare), can exacerbate angina (coronary steal/reflex tachycardia) 

4. Use limited to patients unable to tolerate ACEI (e.g., due to renal insufficiency, angioedema) 

31

What is the drug of first choice in angina treatment?

- Beta-blockers 

- CCB's reserved for patients unable to tolerate BB, or as add-on therapy for angina uncontrolled by BB + nitrate 

- NOTE: CCB's may inhibit apoptosis (affect cancer cell growth); data inconclusive

32

What are the effects of Milrinone in CHF?

- INC inotropy 

- DEC afterload 

- Secondary natriuresis 

33

How do BB's treat angina?

- Blunt HR and inotropic response to exercise

- Reduce afterload (CNS)

- Do not reduce preload (may paradoxically increase short term)

- Do not prevent coronary vasospasm 

35

What are the effects of Digoxin in CHF?

- INC inotropy 

- Secondary natriuretic and survival benefit

36

What are the hemodynamic consequences of the admin of vasodilators in CHF?

- REDUCE AFTERLOAD

- Reduced resistance to outflow of blood from LV improve ventricular performance, increasing CO

- Improved ventricular emptying also reduces LV pressure during diastole (preload) but effect is relatively modest alone

- Need to combine arterial vasodilator w/venodilator (nitrate) to reduce both preload and afterload

37

Which drugs are natriuretic?

- Digoxin 

- Milrinone 

- Furosemide (+)

- ACEI

- ARB 

- Spironolactone 

- Dobutamine 

- Nesiritide (+) 

- B-blocker 

38

How do nitrates treat angina?

- Venodilation = decreased preload 

1. DEC pressure in diastole in ventricles of heart

2. Reduced wall stress and MvO2 (myocardial O2 consumption)

3. Subendocardial blood flow is increased

- Coronary vasodilation

1. Redistribution of BF to areas of ischemia

2. Selective dilation of epicardial and collateral coronary vessels

3. Prevents or reverses coronary vasospasm

- Overall effect on hemodynamics

1. BP: unchanged or slight decrease

2. HR: unchanged or slight increase

3. Pulmonary vascular resistance decreased

4. Cardiac Output reduced (slight) 

39

What is Ranolazine?

- Reduces amount of metabolic demand in heart via unknown MOA

1. Partial FA oxidase inhibitor, INC glu oxidation and efficiency of O2 utilization in the heart

2. Late sodium current inhibitor

3. No effect on HR and BP

- Indications: chronic stable angina in combo with amlodapine, BB's or nitrates -> basically, use when everything else is not enough

- Will not relieve acute angina attacks

- Pregnancy category C

41

What is bradykinin?

A vasodilator and anti-fibrotic mediator (increased by ACEI's; NOT increased by ARB's)

42

What is the spectrum of action of BB's in angina?

- Unstable angina: use w/nitrates, ASA, and Heparin

- Exertional angina: DEC HR, myocardial contractility

- Vasospastic angina: ineffective (may block B-2)

- MI: reduce chest pain, and ST, cardiac enzyme elev

1.  Reduced ventricular ectopy (PVB) and vfib

2. Reduced re-infarction and ischemic episodes during hospitalization

3. Reduced mortality during 2-3 years post-MI

- RECOMMENDATION: in acute MI/unstable angina, give BB IV, then PO provided no CHF, hypotension, or sinus bradycardia/heart block 

43

What are the effects of Dobutamine in CHF?

- INC/DEC afterload 

- INC inotropy 

- Secondary natriuresis

44

What are the mitogenic effects of Angiotensin II?

- Hypertrophy of cardiac myocytes 

- Hypertrophy of vascular smooth muscle 

- Cardiac and vascular fibrosis, remodeling 

- Atherosclerosis 

46

What are the diuretic effects of ACEI's and ARB's?

- Reduce sodium retention by preventing aldosterone release 

- Effect not always sufficient to prevent edema 

- Dose of diuretic should be reduced (azotemia)

47

What is angina and why does it happen?

- Lack of sufficient oxygen (ischemia) to the heart causes pain, angina 

- WHY?

1. Coronary artery obstruction limits blood supply to part of the myocardium

2. Atherosclerosis and thrombosis blocks blood flow (unstable angina)

3. Vasospasm blocks blood flow (variant or Prinzmetal’s angina)

4. Coronary circulation can meet O2 demands of myocardium at rest, but not when heart work INC by exercise (exertional angina) due to atherosclerosis

48

What is the effect of arterial vasodilators on cardiac output?

- Increase cardiac output by decreasing afterload

- Improve cardiac performance by reducing the resistance to outflow of blood from left ventricle -> shifts pressure-volume curve upward and to the left

- Preload is reduced to varying degree depending on agent

49

How does diuretic therapy improve CHF? What diuretics are commonly used?

- Reduce preload (cardiac output NOT increased)

1. Do NOT improve survival or prognosis, except for spironolactone/eplerenone, which block effects of aldosterone 

- "High ceiling" diuretics commonly used: Furosemide (loop), Bumetanide 

1. Potassium-sparing diuretics (i.e., spirono) commonly used in combo with loop diuretics 

50

What are the AE's and contraindications for Ranolazine?

- Adverse reactions:

1. Dizziness, headache, constipation, nausea 

2. Sm, reversible INC in serum creatinine, BUN

3. Syncope and weakness; NO torsade 

- Contraindications:

1. Use w/CYP3A4 INH (verapamil, diltiazem, cyclosporine, quinolone, macrolide antibiotics, protease inhibitors, azole antifungals, grapefruit)

2. Existing long QT or class Ia, III antiarrhythmics

3. Hepatic impairment 

- Digoxin conc INC 40-60% via P-GP inhibition

51

What are the situations favoring CCB use in angina?

- Highly effective for relief of symptoms in exertional and vasospastic angina; do not use in patients with coronary heart disease

- Dihydropyridine-type (Nifedipine; Procardia XL®)

1. Combo w/ß-Blocker for coronary vasodilation, reduced afterload (avoid Verapamil/Diltiazem + β- Blocker -> AV block)

2. Sinus bradycardia, SA/AV block

3. Valvular insufficiency (A or M): DEC afterload

- Non-Dihydropyridine- type (provided no significant LV dysfunction -> INC morbidity and mortality)

1. Asthma/Bronchospastic COPD

2. Severe peripheral vascular disease with rest pain Depression

3. Labile (variable glu levels) insulin-dependent diabetes 

4. Vasospastic angina (b/c BB contraindicated and dihydros need admin w/BB)

52

Why are BB's used in combos?

- Rationale for combining β-Blockers with:

1. Nitrates: reduces LVEDP, LV volume, dilates coronary arteries

2. CCB’s (dihydropyridine type): prevent coronary vasospasm, reduce systemic vascular resistance

- β-blockers prevent reflex tachycardia and positive inotropic effect of nitrates and dihydropyridine CCB’s

53

What are the effects of the ACEI/ARB's in CHF?

- DEC preload AND afterload 

- Anti-mitogenic 

- Secondarily natriuretic 

- Survival benefit