Goals of Heart Failure Therapy:

-Reduce symptoms: dyspnea (Backward failure: Fluid backs up in pulmonary circulation) and fatigue (forward failure: Reduced CO->less perfusion)

-Counter maladaptive compensatory responses: baroreceptor reflex, SNS activation, RAAS activation; Myocyte Death from necrosis (Ca overload from NE stimulation) or apoptosis (programmed cell death by Ang II)

-Counter progressive cardiac remodeling: Dilation, Hypertrophy, Transformation to spherical shape, Mitral regurgitation; Wall stress is a major stimuli for remodeling

-Extend Life

Oral drugs to manage heart failure:

1. Diuretics and Aldosterone Antagonists: Furosemide

2. Vasodilators: ACE-I, ARB's, ACE-I/ARB, nitrovasodilator/hydralazine

3. B-Blocker: Increases EF

4. Cardiac glycosilides (digitalis, digoxin): + inotropic effect

5. Anti-arrhythmics: 50% die of arrhythmia (other 50% from pump failure)

Parenteral drugs for acute heart failure:

1. Nitruprusside: Donates NO

2. Furosemide (IV)

3. B-receptor agonist: Dobutamine-increases contractility and CO

4. Phosphodiesterase Inhibitors: Milrinone-Vasodilation and positive inotropic effects (but fatal arrhythmias)

5. Nesiritide: Smooth muscle relaxation

Heart Failure:

Systolic: Ventricular dilation; Weakened muscle->Decreased EF

Diastolic: Pathologic Hypertrophy prevents filling due to decreased compliance; To treat-prolong time spent in diastole (Ca channel blockers or B-Blockers or Ranolazine)

Fetal Gene Activation: Switch from Alpha Myosin Heavy Chain to Beta Myosin Heavy Chain reduces contractile function

Beta-1: Beta-2 receptor ratio: Changes from 80:20 to 40:60 b/c B-1 receptor is downregulated

Loss of myofilaments, altered cytoskeleton proteins, cardiac fibrosis due to excessive aldosterone, altered excitation-contraction coupling

Catopril Study: Catopril and Enalopril have a protective effect against remodeling, prolong life, and incresed exercise tolerance; Patients with the greater baseline wall motion abnormalities (>30% at the beginning of the study) had more LV dilation over time

Lowers the volume of circulating blood (by blocking NA/K/Cl coransporter) to decrease filling pressure and prevent remodeling

Drugs: Furosemide, Torsemide

By stopping Na/Cl/K gradient, Ca and Mg can't be reabsorbed either

Also a venodilator->decreases preload

SE's: OH DANG - Ototoxicity, Hypokalemia, Dehydration, Allergy, Nephritis, Gout (Hyperurecemia)

Resistance: Patient noncompliance, decereased absorption, renal damage, decreased renal perfusion (from hypotension and volume depletion, decreased CO drug interactions: ACE-I, NSAIDs)

With resistance: Increase dose, add thiazide, or start digoxin therapy

Not #1 for HF: Used in mild HF, patients intolerant to loop diuretics, or to increase effect of loop diuretics by stopping Na reabsorption in DCT

Metolazone: Can be used in HF with renal failure

Decresaes LV volume->decreases end diastolic pressure->decreases congestive symptoms with very little drop in CO

Spironolactone and Eplerenone

Eplerenone: Newer, doesn't block androgen receptors->no gynecomastia and impotence

ACE-I's: Aldosterone drops initially, then begins to rise->aldosterone antagonists are a great combo to stop the aldosterone-mediated effects of long-term ACE-I therapy

Aldosterone in HF: Causes edema from fluid/sodium retention, arrhythmias and death from K and Mg loss, remodeling and ventricular disfunction from myocardial fibrosis, excitability and contractility of myocytes from increased sodium

Results: Aldosterone Antagonists->Incresed survival

Dangerous SE: Hyperkalemia

ACE Inhibitors (1st line):

HTN: Arterial dilation only

CHF: Balanced Vasodilators (veins too), orthostatic HTN, Increases CO and SV (that decreases in response to increased resistance from RAAS and NE increasing in CHF)

ARB's: Newer->not as studies, but seem to be as effective as ACE-I's

Organic Nitrates: Isosorbide dinitrates; A venodilator->decreases preload; NOT alone, used with arterial dilators like hydralazine

Nonselective B-blockers/alpha-1 selective alpha-blocker: Carvedilol

NO donor: Nitroprosside; for acute HF, hyptertensive emergencies; balanced b/c NO is spontanteously made from nitroprusside in arteries and veins

PDE Inhibitors: Milrinone; Inotropic, balanced vasodilator

Not for HF: Alpha-blockers  (prazosin), Ca channel blockers (further depression in the heart), B-agonists (isoproterenol-stimulates heart and decreases diastolic pressure in the struggling heart)

Aldosterone initially decreses, then increases above pre-ACE-I's->use ARB alongside ACE-I's

Captopril and Enopril (more studied b/c it has a better dosing schedule: once or twice a day vs. 3)

HF: Cardiac index is less than 2 (normal=3.5), HR>80, systemic vascular resistance is 1800-2000 (normal=1000), pulmonary wedge pressure, a measure of left atrial pressure, is 27.5-30 (normal is 8)

Effects: Decreases pulmonary wedge pressure (not back to normal levels), degreases afterload from decreased vascular resistance, decreases SNS->venodilation, prolongs life, decreases EDV and increased CO

SE: Orthostatic hypotension, cough, angioedema, hyperkalemia (Can't use K-sparing diureteics with it except spironolactone, b/c the dose of spironolactone in HF only works on heart's aldosterone receptors, not the kidneys)

Losartan, Valsartan

Classwide benefit same as ACE-I's, use if patient can't tolerate ACE-I

Additional benefit and adverse effects (hypotension and renal impairment, may be clinically insignificant) at higher dose (150 vs 50)->Use higher dose when possible

May be a benefit to combining ACE-I and ARB, but may cause more SE, currently not enough evidence to support adding them

Bidil: A combination in 1 pill

Important if patient can't tolerate ACE-I or ARB b/c they have no renal effects

Prolongs life, but not as strongly as ACE-I's

Isosorbide dinitrate alone: Pulmonary wedge pressure decreases but cardiac index doesn't change b/c no arterial effects

Hydralazine alone: Cardiac index increases and pulmnoary wedge pressure doesn't change

African Americans have particular benefit with this combo (they have a harder time releasing NO from damaged endothelium->isosorbide dinitrate works as an NO source; hydralazine acts as an antioxidant to counteract superoxides made when converting nitrates to NO through MAD)

No class effect-only specific ones work

Carvedilol: Most effective to reduce mortality; non-selective coverage of B and alpha-1 receptors; anti-oxidant; Prevents cardiomyocyte remodeling, causes cardiac depression; Highest dose tolerated is 25mg bid

Metoprolol: Selective for B-1; Allows more exercise tolerance, can be used in diabetics

Bisoprolol: Selective for B-1-the most; not lipid soluble

Nebivolol (most cardioselective, but doesn't decrease mortality as much) and Bucindolol (like Cavedilol, but not anti-oxidant) aren't used in HF

ACE-I plus B-Blocker provides the best reduction in mortality

Initially: EF decrease (cardiac depressing-why 1/10th dose given), but within 3 months the B-Blocker changes the biology of the myocardium and there's a significant improvement of LVEF

Other effects: Down regulates fetal beta myosin heavy chain

Alpha-1: Upregulated in HF; Gq->Ca->Increased SNS; Intracellular Ca increases in myocytes->hypertrophy

B-adrenergic receptors: Gs->cAMP->positive chronotropic and inotropic effects; B-1: High NE from excessive SNS stimulation in HF->B-1 receptors are downregulated to compensate; B-2: Inhibit SNS output

When to give B-Blocker: LVEF<35%, Class II or III HF that's being treated w/ ACE-I

Digoxin, Digitoxin, Oubain

Digitoxin: Highest lipid solubility (CNS effects), oral availability, plasma binding, metabolism, long t1/2

Oubain: Lowest values

Digoxin: Middle, only one available in US; Works in narrow therapeutic range->too much causes fatal arrhythmias; Stored in muscle-be careful with low muscle; Eliminated renally

Positive inotropic effect

Normal heart: No change in CO b/c it acts as a vasoconstrictor

HF: TPR decreases b/c it acts as a vasodilator->increases CO->lowers SNS output->lower HR, decreased heart size, lower O2 consumption; Increased diuresis from increased blood flow and incresed PSNS (from sensitizing baroreceptor and acting on vagal center)

Mechanism: Inhibits phosphorylated Na-K ATPase in cardiomyocytes->No extracellular sodium gradient->downstream inhibition of Ca efflux->More intracellular Ca increaes contrctability (inotropy); Build up of intracellular K->hypokalemia->no dephosphorylation of Na-K ATPase->more digoxin can bind receptors->toxicity

Too much intracellular Na->arrhythmias; Hypokalemia causing drugs should be used with caution

No effect on mortality, but patient's HF doesn't worsen in their remaining time