Inotropes & Beta Blockers in Congestive HF

Question 1

What are the four factors that determine cardiac output?

Answer 1

Heart rate
Contractility
Preload
Afterload

Question 2

What are the two major compensatory mechanisms in systolic heart failure?

Answer 2

Activation of RAAS

Sympathetic system activation

Question 3

What occurs when RAAS is activated as a compensatory mechanism in systolic heart failure?

Answer 3

Decreased renal perfusion pressure due to heart failure activates RAAS
Angiotensin II –> vasoconstriction –> increased afterload
Aldosterone –> Na+/water retention –> edema

Question 4

What occurs when sympathetic system is activated as a compensatory mechanism in systolic heart failure?

Answer 4

Sympathetic activation increases plasma NE
Increases HR
Increases contractility

Question 5

What are the long term effects of sympathetic stimulation in heart failure?

Answer 5

Maladaptive proliferation (hypertrophy, fibrosis)
Myocyte apoptosis
Worsening LV dysfunction and HF symptoms

Question 6

Which beta blockers have been documented to have a survival benefit in HF?

Answer 6

Metoprolol
Bisoprolol
Carvedilol

Question 7

What are the acute effects of beta blockers in HF?

Answer 7

Decrease contractility (attenuated adenylyl cyclase, PKA)
Negative chronotropy (reduced SA activity, slowed conduction in AV, increased refractory period in AV)

Overall, acutely causes further decrease in CO

Question 8

What occurs on Day 1 of beta blocker use?

Answer 8

Significant decrease in ejection fraction

Must make sure patient can tolerate this

Question 9

What are the long term effects of beta blockers in HF?

Answer 9

Improved survival
Improved LV ejection fraction
Decrease in sudden death events

Question 10

What is the mechanism for the improved survival in HF with use of beta blockers?

Answer 10

Unknown! Maybe just protecting heart from sympathetic overstimulation

Question 11

What are guidelines for beta blocker use in systolic dysfunction HF?

Answer 11

Initiate beta blockers at low dose, then increase slowly
Class III and IV patients approached with caution
Patients with new onset should only be treated once stabilized

Question 12

When should inotropes be used as opposed to beta blockers?

Answer 12

Beta blockers - patient is stable, need to chronically manipulate receptors, short term pain for long term good

Inotropes - patient is decompensated, need to acutely manipulate receptors

Question 13

What catecholamines are used as inotropes?

Answer 13

Dobutamine

Dopamine

Question 14

What phosphodiesterase Type 3 inhibitors are used as inotropes?

Answer 14

Milrinone

Question 15

How do catecholamines result in greater force of contraction?

Answer 15

NE, Epi stimulate Beta receptor, increase cAMP, activate PKA

PKA
Phosphorylates Ca channel, more Ca in cell
Phosphorylates phospholamban, more uptake of Ca into SR
Phosphorylates Troponin, enhanced binding of Ca to myofilaments

Overall, greater Ca transient release and greater force of contraction at myofilament level
Also get quicker relaxation, better filling of ventricle for next systole

Question 16

What is the mechanism of action of Dobutamine/Dopamine?

Answer 16

Stimulates beta adrenergic receptors (primarily Beta 1), resulting in increased Calcium and better force of contraction

Question 17

What is the mechanism of action of Milrinone?

Answer 17

Blocks PDE type III that converts cAMP to AMP

This allows for sustained levels of cAMP, resulting in increased Calcium and better force of contraction

Question 18

How do inotropes change the Starling curve?

Answer 18

Decreases LV filling pressure

Increases CO

Question 19

What is a negative effect of Beta1 receptor activation in the heart?

Answer 19

Increased automaticity - can lead to ventricular arrhythmias

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Question 20

What non-cardiac effects does dopamine have?

Answer 20

Vasodilation of splanchnic and renal artery beds

Question 21

Which inotrope is preferred: dobutamine or dopamine?

Answer 21

Dobutamine

Dopamine will increase HR (not desired since inotrope already increases contractility and increasing HR as well would increase cardiac work too much)
Dopamine will increase TPR via alpha1 effects (not desired since it will increase afterload)
Dopamine will increase preload

Question 22

What is the mechanism of action of digitalis as an inotrope?

Answer 22

Inhibition of membrane Na/K-ATPase
Increased intracellular Na leads to increased intracellular Ca via Na-Ca exchanger
Increased cellular Ca is sequestered into SR, allows for greater release of Ca with next depolarization
More SR calcium released = greater force of contraction

Question 23

What are the non-inotropic effects of digitalis?

Answer 23

Improved carotid baroreflex sensitivity –> Decreased sympathetic tone
Increased cholinergic receptor sensitivity –> Increased vagal tone

Question 24

When used at therapeutic levels, will digitalis produce an inotropic effect?

Answer 24

No
Inotropic effects at levels near 1.4 ng/ml
Dosage recommendations are <1 ng/ml

Question 25

What is the current therapeutic window of digitalis?

Answer 25

0.5-0.9 ng/ml

Question 26

What are toxic effects of digitalis?

Answer 26

Excessively slow HR
Arrhythmias
Hypokalemia --> increased binding to Na/K ATPase --> increased chance of toxic arrhythmias
GI abdominal cramping
Ophthalmology: yellow-green halos

Question 27

What are clinical uses of digitalis?

Answer 27

Treatment of rapid heart rate due to atrial fib or flutter

Treatment of HF patients in normal rhythm who are still symptomatic on standard therapy