Pharmacology: Congestive Heart Failure

Front 1

Epidemiology of HF:

Back 1

*Approximately 5 million patients in this country have heart failure (HF).

*Over 550,000 patients are diagnosed with HF for the first time each year.

*Over 1 million hospitalizations per year.

*20% of admissions of patients over age 65 are due to HF.

*In 2001, nearly 53,000 patients died of HF as a primary cause.

Front 2

Definition of HF:

Back 2

Heart Failure is a clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood at normal filling pressures.

Front 3

Pressure/Volume loops of HF with systolic and diastolic function:

Back 3

In systolic dysfunction, left ventricular contractility is depressed, and the end-systolic pressure-volume line is displaced downward and to the right (Panel A, black arrow); as a result, there is a diminished capacity to eject blood into the high-pressure aorta.

In diastolic dysfunction, the diastolic pressure-volume line is displaced upward and to the left (Panel C, black arrow); there is diminished capacity to fill at low left-atrial pressures.

In systolic dysfunction, the ejection fraction is depressed, and the end-diastolic pressure is normal (Panel A, open arrow); in diastolic dysfunction, the ejection fraction is normal and the end-diastolic pressure is elevated (Panel C, open arrow).

Front 4

Heart Failure vs. Congestive Heart Failure:

Back 4

*“Congestive Heart Failure” usually denotes a volume overloaded status.

*Because not all patients have volume overload at the time of the evaluation, “congestive heart failure” should be distinguished from the broader term “heart failure.”

Front 5

NYHA Functional Classification of HF: 4 classes--

Back 5

Class I – No limitation during ordinary activity
Class II – Slight limitation with moderate exertion
Class III – Symptoms with minimal exertion
Class IV – Inability to carry out any physical activity

Front 6

How does NYHA Functional Classification work? What does it describe?

Back 6

*Characterizes the CURRENT state of a patient with heart failure.

*Class can change depending on fluid status.

*Useful in describing the acuity of a patient that presents to the hospital or clinic complaining of symptoms.

*Not as useful in guiding preventive therapy.

Front 7

ACC/AHA Stages of Heart Failure:

Back 7

*At Risk for Heart Failure (no symptoms):

-STAGE A: High risk for developing HF, but no structural heart disease.
-STAGE B: Structural heart disease is present, but no symptoms, e.g. asymptomatic LV dysfunction.

*Symptomatic Heart Failure:
-STAGE C: Past or current symptoms of HF.
-STAGE D: End-stage HF.

Front 8

How do the ACC/AHA Stages of Heart Failure work? What do they describe?

Back 8

*Designed to emphasize PREVENTABILITY of symptomatic HF.

*Designed to recognize the PROGRESSIVE NATURE of LV dysfunction.

*Has direct implications on the therapy of HF.

*Distinguish from NYHA classification, which is dynamic and reversible.

*DON'T ALWAYS CORRELATE WITH NYHA CRITERIA*

Front 9

OUTLINE slide of ACC/AHA Stages of Heart Failure and treatment recommendations for each stage:

Back 9

Front 10

Discuss ACC/ACA Stage A in detail.

Back 10

*Stage A: Risk Factors with Normal EF

*Hypertension
*Hyperlipidemia
*Diabetes Mellitus
*Atherosclerosis -CAD*
*Metabolic syndrome
*Tachyarrhythmias
*Cardiotoxic drugs
*Familial dilated cardiomyopathy

Front 11

Risk Factors for Heart Failure by prevalence:

Back 11

Front 12

Treatment strategies of risk factors for heart failure:
HTN--
Lipids--
Glucose--
Behaviors--

Back 12

*Hypertension: optimal blood pressure is 130/80 mm Hg or less.

*Lipid reduction therapy: lower LDL levels as per ATP III guidelines.

*Optimize blood glucose control.

*Modify behavior to reduce risk of CAD in general (smoking, lack of exercise, poor diet).

Front 13

Stage A – Drug Therapy: 2

Back 13

*Focus is to slow the progression of disease:
1) Angiotensin Converting Enzyme inhibitors (ACE-i)
2) Angiotensin Receptor Blockers (ARBs)

Front 14

How do ACE-is work?

Back 14

Front 15

Is there any Mortality Reduction with ACE-is?

Back 15

Yes, they've been around a long time and the evidence indicate they are very good agents at reducing mortality from HF.

Front 16

Side Effects of ACE- is:

Back 16

*Dry cough 15% of patients.
*Risk of angioedema (0.1 – 1%).
*Renal excretion -> dose adjustment in renal failure [Except: fosinopril (hepatic)].

*May cause hypotension:
-Initiation: start with low doses.
-Volume depleted patients, especially After diuretics.

Front 17

Discuss Angiotensin Receptor Blockers:

Back 17

*Selective and more complete Angiotensin II receptor blockade.
-Due to non-ACE related mechanisms of Ang II generation.

*Do not affect bradykinin levels.

*Similar mechanism of action than ACE-i:
-Vasodilation.
-Decrease sympathetic output.
-Natriuresis.

*We prefer to use ACEi first; will use ARB if adverse effects from ACEi.

Front 18

How do ARBs work?

Back 18

Front 19

Discuss effectiveness of ARBs:

Back 19

*Similar or less effective than ACE-i for treatment of HF depending on the ARB.

*In general, should be used as an alternative heart failure therapy in patients who cannot tolerate ACE-i.

*May use in combination with ACE-i for heart failure.

**Proven efficacy in heart failure: valsartan, candesartan.
**Questionable efficacy: losartan at low doses.

Front 20

Side effects of ARBs:

Back 20

*Similar side effect profile as in ACE-i

*Better tolerated than ACE-i in general

*Do not produce cough (bradykinin related)

*Can still cause angioedema

*Similar contraindications as with ACE-i:
-pregnancy
-bilateral renal artery atenosis
-severe renal failure
-hyperkalemia

Front 21

Discuss stage B HF in detail:

Back 21

*Stage B – Asymptomatic Structural Heart Disease

*General Measures as advised for Stage A.

*Coronary revascularization in appropriate patients.

*Valve replacement or repair in appropriate patients.

*Drug therapy for all patients:
1) ACE-i and/or ARBs
2) Beta-Blockers

Front 22

How do ß-blockers work?

Back 22

*Act through neurohormonal antagonism:
-Sympathetic output: renin, NE, epinephrine
-Local cardiac receptors: heart rate, contractility
-Antihypertensive
-Antiarrhythmic
-Antioxidant, Antiproliferative

*Improves symptoms (at long term) and survival in heart failure.

*Improve ventricular remodeling in systolic dysfunction.

Front 23

Side effects of ß-blockers:

Back 23

*Side Effects:
-Hypotension
-Fluid retention / worsening heart failure
-Fatigue
-Bradycardia / heart block

*Reduce dose if needed:
-Consider cardiac pacing only if necessary.
-Discontinue beta blocker only in severe cases.

Front 24

Relative contraindications for ß-blockers:

Back 24

*Heart rate < 60 pm

*SBP < 100 mm Hg

*PR > 0.24 s or 2nd or 3rd AV block

*Severe COPD or asthma

*Severe peripheral vascular disease

Front 25

What happens to many patients after initiating or adding a ß-blocker to their drug regimen?

What ß-blockers have proven efficacy in HF? 3
Which ones are unproven? 4

Back 25

*May worsen symptoms in the first 4-10 weeks

*Start at low doses, and double the dose every 2-3 weeks until target

*Proven efficacy in heart failure:
-carvedilol, metoprolol XL 75 mg, bisoprolol.

*Unproven efficacy in heart failure:
-Short-acting metoprolol, atenolol, propanolol, bucindolol.

Front 26

Considerations for patients who have just begun taking a ß-blocker:

Back 26

*Patients should weigh themselves daily and call if >1-1.5 kg of weight gain

*Weight gain can be treated with diuretics

*Dose reduction or transient cessation may be necessary in severe decompensation

Front 27

Summary of Aims of Pharmacologic Therapy in Stages A and B:

Back 27

*Risk Factors
-Prevention
-Correction

*Therapy to slow disease progression
-ACE-inhibitors
-Angiotensin Receptor Blockers
-Beta-blockers

Front 28

Discuss Stage C HF therapy:

Back 28

*General measures as advised for Stages A and B.

*Drug therapy for ALL patients:
-Diuretics for fluid retention.
-ACE-i.
-Beta-blockers.

*Drug therapy for SELECTED patients:
-Aldosterone antagonists.
-Digitalis.
-Hydralazine/nitrates.
-ARBs (in addition to ACE-i).

Front 29

How do you treat Hypotension in stage C HF?

How do you treat congestion in stage C HF?

Back 29

*Sx: Hypotension, fatigue
-Rx: Increase Cardiac Output
-Increase contractility: Inotropes
-Decrease afterload:
-ACE-i/ARB’s
-Hydralazine

*Sx: Water retention, pulmonary congestion
-Rx: Decrease preload
-Nitrates
-Diuretics
-ACE-i/ARB’s

**MAINTAIN EUVOLEMIA** BIG GOAL HERE

Front 30

How do diuretics work?

survival benefits?

Back 30

*Decreases preload.
*Ultimately decreases afterload by decreasing blood pressure.

*Relieves symptoms of congestion:
-Dyspnea, orthopnea, paroxysmal nocturnal dyspnea.
-First line therapy in acute decompensation.

*NO proven survival benefits in heart failure.

Front 31

Examples of diuretics we use in HF:

Back 31

*Loop diuretic: furosemide, bumetanide, torsemide
-especially furosemide and bumetanide.

*Thiazides: HCTZ, metolazone, ethacrinic acid.

*Aldosterone antagonists: spironolactone, eplerenone.

Front 32

Compare Loop diuretics and Thiazides:

Back 32

Front 33

Goal of volume reduction in diuretic use?

Back 33

*Goal of volume reduction is 0.5-1.0 kg/day.

*"It is an art rather than science."

Front 34

How do ACEi and ARBs interact with diuretics?

Back 34

*Antagonism of the Renin-Angiotensin Aldosterone System is essential for symptom relief and diuresis:
-ACE- inhibition
-Angiotensin Receptor Blockade
-Either will potentiate diuretic effect

*If using a diuretic, you want to also have an ACEi/ARB on board. Note aldosterone secretion blockage by ACEi/ARB.

Front 35

Discuss Aldosterone Antagonists as therapy in Stage C HF:

which ones have proven efficacy?

Back 35

*Competitive antagonist of the aldosterone receptor:
-Myocardium
-Arterial walls
-Kidney

*Weak diuretic effect

*Proven efficacy: Aldactone, Eplerenone

Front 36

How do aldosterone inhibitors work?

Back 36

Front 37

Who are aldosterone inhibitors good for?

Contraindications?

Back 37

*Mortality benefit in patients with advanced heart failure (NYHA C III-IV), if given in addition to ACE-I, beta blockers and diuretics.

*Useful when patient also has hypokalemia.

*Do not use if hyperkalemia (K > 5.0 mEq/L), or worsening renal insuficiency (Cr > 2.5 mg/dL).

*Monitor serum K at “frequent intervals.”

Front 38

What is digoxin?

Back 38

*Purified cardiac glycoside extracted from the Foxglove plant.

*One of the oldest drugs we have. Van Gogh took it.

Front 39

How does digoxin work?

Back 39

*Mechanical Effect: Inhibits Na/K ATPase

*Increases Na/Ca exchange

*Increase Ca uptake by Sarcoplasmic Reticulum (SR)

*Increase Ca release by SR during depolarization

*Increase Ca-troponin C reaction -> Actin-Myosin Interaction

Front 40

Electrical and Clinical effects of Digoxin?

mortality reduction %?

Back 40

*Electrical Effect:
-Enhance vagal tone.
-Slows conduction, mostly AV node.

*Clinical Effect:
-Fewer hospitalizations for patients with EF <45%.
-No reduction in overall mortality.
-Benefits people who keep coming back to the hospital. Keeps them away from the hospital.

Front 41

Discuss dosing of digoxin:

Back 41

*Usual dose: 0.125 to 0.25 mg QD or QOD

*T ½ = 40 h

*Want to achieve levels of 0.5-0.8 ng/ml.

*Excreted by the kidney; maintenance dose depends on the patient's kidney function.

*Narrow therapeutic range: 0.3 ng/mL range.

*Toxicity enhanced by quinidine, amiodarone*, Low K- Mg, High Ca.

Front 42

Digoxin-Side Effects related to the heart:

Back 42

*Arrhythmias: Brady and Tachy
-Enhanced automaticity

-Decreased action potential duration -> prone for propagation of arrhythmias

-Less negative resting potential -> volt-dep partial inactivation of fast Na channels ->slow conduction velocity -> Reentry

*“Scooped out” appearance of ST segments (pic).

Front 43

Digoxin- Other Side Effects:

What do you use if there's a digoxin overdose?

Back 43

*CNS: dizziness, confusion, visual disturbances.
-Xanthopsia, blurry vision, “halo” effect around lights.

*GI: anorexia, nausea, vomiting, diarrhea. These are the most common dig side effects.

*Gynecomastia.

*Rx: K, lidocaine, antibodies (digibindR) for emergency use (life threatening arrhythmias refractory to conventional therapy).

Front 44

Discuss Hydralazine and Nitrates in HF:

Back 44

*Isosorbide: nitric oxide (NO) producer--
-NO produces vasodilation through increase in cyclic GMP.
-Long-term use may induce tolerance.
-Reduces preload (mainly) and afterload.

*Hydralazine (T1/2: 2-4h, Effect 12h)
-Metabolism and toxicity depends on rate of
Acetylation.
-Causes reflex tachycardia, lupus, headache, flushing; administration with beta-blocker helps mitigate these effects.
-Reduces afterload.

Front 45

Why are Hydralazine and Nitrates combined in HF?

Back 45

*Combination is known to improve survival and symptoms specifically in African American patients** with heart failure. Unclear if benefit translates to other races.

*Regardless, the combo should be considered as an alternative therapy in all other patients who are:
-Persistently symptomatic despite ACE-i and beta-blocker.
-Intolerant to ACE-i or ARB’s (e.g. RENAL FAILURE).

Front 46

Discuss the use of ARB in combination with ACE-i:

Back 46

*May be considered in persistently symptomatic patients with reduced LV function who are already being treated with conventional therapy.

*Usually reserved when first and second-line therapies have failed.

*This combo DOES NOT prolong survival any further than what ACE-i/ARB does individually.

Front 47

IN STAGE C HF, what drugs and drug combinations should NEVER be used? 5

Back 47

*Routine combined use of an ACE-i, ARB, and aldosterone antagonist is not recommended.

*Long-term use of an infusion of a positive inotropic drug.

*Use of nutritional supplements.

*Calcium channel blockers with negative inotropic effects may be harmful: nifedipine, verapamil, diltiazem.

*Hormonal therapies other than to replete deficiencies are not recommended and may be harmful.

Front 48

What non-pharmacologic therapies may be helpful in Stage C HF therapy?

Back 48

*ICDs in appropriate patients

*Cardiac resynchronization in appropriate patients

*Exercise Testing and Training

Front 49

Summary chart of Stages A-D HF:

Back 49

Front 50

Goals for treatment of Stage D HF:

Back 50

*Relief of Symptoms: Control of fluid retention.

*Referral to a HF program for appropriate pts.

*Discussion of options for end-of-life care.

*Device use in appropriate patients.

Front 51

Discuss surgical and drug therapies for Stage D HF:

Back 51

*Surgical therapy:
-Cardiac transplantation.
-Mitral valve repair or replacement.

*Drug Therapy:
-Previously mentioned measures.
-Positive inotrope infusion as palliation--can't just continuously infuse, though.

Front 52

Pharmacologic Therapy summary:
Which drugs improve symptoms?
Which drugs improve survival?

Back 52

*Improvement in Sx: Diuretics, beta blockers, ACE inhibitors, inotropes, ARBs.

*Prolongation of survival: ACE inhibitors, ARBs, Beta blockers, aldosterone inhibitors (aldosterone, eplerenone), hydralazine+Isosorbide (especially in black patients).

Front 53

List the inotropic drugs:

How are they ideally used?

Back 53

*Cardiac glycosides: Digoxin, Digitoxin.

*Phosphodiesterase Inhibitors: Amrinone, milrinone.

*Sympathomimetic amines: Dopamine, dobutamine, norepineprine, epinephrine, isoproterenol.

*Ideally, short term. Get their blood pumping in the ICU (you want renal perfusion), and get them off the drugs as soon as possible. Doesn't always happen that way.

Front 54

Discuss Sympathomimetic Amines:
What are they good for?
How are they given?
How do they work?

Back 54

*Short term relief of symptoms.
*No survival benefit (may worsen survival).
*Given as IV infusion.
*Bind to cardiac B1-receptors -> Increase cAMP -> Ca entry (slow Ca channels) -> Ca release from SR.
*Increase contractility.
*Tachycardia – may predispose to arrhythmias.
*The longer the pt is on the drug, the more trouble you're asking for.

Front 55

Sympathomimetic Amines: Talk about Dopamine considerations:

Back 55

*<2 ug/kg/min: increase renal perfusion.
*2-10 ug/kg/min: release of NE and stimulation of B1 -> Increase C.O.

*>10 ug/kg/min: alpha -> vasoconstriction.
-Used for Shock.
-Not recommended for CHF.

Front 56

Sympathomimetic Amines: Talk about Dobutamine:

Back 56

*B1: Greatly increases Contractility.

*Balance of B2 and alpha stimulation ->
-Does not change Periph Vasc Resistance.
-Useful in ABSENCE of hypotension.
-Sometimes may CAUSE hypotension.
-Causes a lot of ectopy.

*No survival benefit. Good for the short term if the pt can tolerate it.

Front 57

Discuss Phosphodiesterase Inhibitors:

Back 57

*Inhibits cAMP degradation (increases cytosolic Ca++)
-Inotropism, reduces afterload.

*Vasodilator.
*Short term relief of symptoms.
*No survival benefit.

*Side effects: hypotension, ventricular arrhythmias (less than dobutamine though), thrombocytopenia (amrinone).

Front 58

Nasty side effect of aldosterone antagonism (for men):

Back 58

GYNECOMASTIA. BOARD QUESTION?

Be suspicious of spironolactone and eplerenone for this.