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
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
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
Which drugs decrease preload?
- ACEI (also DEC afterload)
- ARB (also DEC afterload)
- Nesiritide (also DEC afterload)
Which drugs are anti-mitogenic?
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
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
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
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
What are the effects of Spironolactone in CHF?
- DEC preload
- Secondary diuresis
- Survival benefit
What vasodilators are NOT effective in CHF?
- Dihydropiridine Ca-channel blockers
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
Which drugs increase inotropy?
- Beta-blockers (INC and DEC)
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)
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!
What are the contraindications for BB use in CHF?
- Heart block
- Decompensated CHF/need for IV inotropes (i.e., dobutamine)
- Volume overload
What are the effects of the beta-blockers in CHF?
- DEC/INC inotropy
- Secondary natriuresis
- Survival benefit
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
What is aldosterone escape?
- Inability of ACEI therapy to reliably suppress aldosterone release
- Usually manifested by increased salt and water retention (refractory hyperaldosteronism)
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
What are the effects of the nitrates in CHF?
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)
What are the effects of Nesiritide in CHF?
- DEC preload AND afterload
- Survival benefit?
Which drugs impart a survival benefit?
- Digoxin (not overall disease course, but helps prevent sudden decline)
Which drugs decrease afterload?
- ACEI (also DEC preload)
- ARB (also DEC preload)
- Dobutamine (increases and decreases)
- Nesiritide (also DEC preload)
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
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
Which BB's are approved for treatment of CHF?
- Nebivolol (in Europe): potentiates NO in vasculature, but only approved for HTN in US
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