Cardiac Inotropes (1 and 2)

Question 0

What are 4 key proteins that control myocyte Ca++ levels?

Answer 0

L-type Ca++ channels (LCC)
Ryanodine Receptor (RyR)
Na+ Ca++ exchanger (NCx) - moves Na+ in, Ca++ out.
SERCA

Question 1

What mechanistic endpoint do all FDA-approved inotropes have?

Answer 1

Increased intracellular Ca++.

Question 2

What do inotropes do to the Starling curve (which relates EDV with SV)?

Answer 2

They shift the curve upward, so that there’s more CO for any given EDV.
This helps avoid low CO symptoms, but sometimes the addition of a vasodilator and/or diuretic helps to get out of the “volume overload” area (EDV’s that are too high).

Question 3

What does digoxin target? How does this help heart failure?

Answer 3

The Na+/K+ ATPase is inhibited.
With less Na+ being pumped out, it builds up in the cell.
High Na+ activates the Na+/Ca++ exchanger to bring Na+ out of the cell, and Ca++ in.
More Ca++ -> more contractility -> upward shifted Starling curve.

Question 4

Does digoxin use create “tolerance” to its effects?

Answer 4

Nope. In contrast to some inotropes that act on proteins that function endogenously as receptors, the Na+/K+ pump doesn’t get downregulated in response to something binding it.

Question 5

What ion can greatly affect the efficacy / toxicity of digoxin?

Answer 5

Extracellular K+.
High extracellular K+ will compete for digoxin binding the pump -> reduced efficacy.
Low extracellular K+ -> increased risk of digoxin toxicity.

Question 6

How is digoxin excreted?

Answer 6

Renally.

If people have renal failure, digoxin buildup can be a real problem.

Question 7

Does digoxin affect HR?

Answer 7

Nope, just contractility.

Question 8

What’s the key to not killing somebody with digoxin?

Answer 8

Keep the dose low so you have wiggle room if something happens that will increase its levels.

Question 9

For each of the following, does digoxin increase or decrease it: CO, LVEF, LVEDP, Exercise tolerance, Natriuresis, Neurohormonal activation.

Answer 9

CO: increased
LVEF: increased
LVEDP: decreased
Exercise tolerance: increased
Natriuresis: increased
Neurohormonal activation: decreased
(basically, digoxin shuts off some of the maladaptive compensatory processes, esp. symp driven stuff, RAAS, etc.)

Question 10

What does digoxin do the AV node? If levels get too high?

Answer 10

It delays conduction through it, prolonging the PR interval.
If digoxin gets too high, it can cause bradycardia and AV block.
(When I shadowed in the ER last year, the resident told me she could tell instantly if a patient is on “didge” by looking at the ECG. Now I know what she meant.)

Question 11

What does digoxin do the ventricles?

Answer 11

It can increase automaticity, and high levels cause ventricular tachycardia and fibrillatiion.
(most digoxin deaths are due to arrhythmia)
(this makes more sense after the mechanisms of tachycardia lecture)

Question 12

5 ECG changes seen with digoxin?

Answer 12

Prolonged PR interval.
ST depression (elevated resting potentials, except during ST).
Inverted T wave.
Shortened QT.
P wave changes.

Question 13

Why did early trials with digoxin show increased mortality in women?

Answer 13

They didn’t adjust the dose for smaller body weights.

Question 14

2+ current uses for digoxin?

Answer 14

A fib with rapid ventricular response (because it slows AV conduction).
CHF symptoms refractory to other treatments. (it doesn’t improve CHF mortality, but improves QoL… which is quite important)
Can be combined with some drugs…

Question 15

4 factors predisposing to digoxin toxicity?

Are drug interactions common?

Answer 15

Hypokalemia.
Hypomagnesemia.
Hypothyroidism.
Hypoxia and acidosis.
Drug interactions are very common.

Question 16

3 aspects of the cardiac toxicity of digoxin?

Answer 16

Arrhythmias - essentially too much excitement in the atria and ventricles -> premature contractions and fibrillation.
Block - in the SA and/or AV nodes.
Exacerbation of HF - due to heart block/bradycardia.

Question 17

4 extra-cardiac systems that are affected by digoxin toxicity?

Answer 17

GI - nausea, vomiting, diarrhea.
Nervous - depression, disorientation, seizures.
Visual - blurred vision, scotomas, yellow-green vision.
Endocrine - Hyperestrogenism -> gynecomastia and galactorrhea.

Question 18

Treatment for digoxin overdose?

Answer 18

Anti-digoxin antibody (Fab) - soaks up digoxin, complexes peed out.
Avoiding hypo/hyperkalemia. (note that digoxin can actually make K+ look high because cells can’t take it up)

Question 19

In the ICU/CCU, do you prefer drugs with a short or long half-life?

Answer 19

Short half-lives are great: you can quickly titrate it to the steady state that you want, and you can reverse its effects quickly if you don’t like them.

Question 20

Review: How does dopamine receptor specificity vary across concentrations?

Answer 20

Low dose: delta-1 and delta-2 agonism -> increased renal perfusion.
Intermediate dose: mainly beta-1 -> inotrope + renal perfusion
High dose: beta-1 + alpha -> inotrope and pressor

Question 21

What’s the major local side effect of dopamine, and how do you avoid this?

Answer 21

Alpha agonism -> vasoconstriction.
If dopamine leaks out of the IV side, the vasoconstriction of the tissue can lead to necrosis.
This can be avoided by giving via central line.
(and reversed with phentolamine, an alpha antagonist)

Question 22

How is dobutamine helpful for diagnosis?

Answer 22

It can be used to stimulate exercise for stress tests.

Question 23

Does do people on dobutamine develop tolerance?

Answer 23

Yes, because chronic stimulation leads to beta-1 receptor downregulation.

Question 24

Major side effect of epinephrine?

Answer 24

Platelet aggregation and infarction.

If a tiger is chasing you, the body anticipates some bleeding.

Question 25

Utility of NE?

Answer 25

Mainly as a pressor / vasoconstrictor (similar to high dose dopamine).

Question 26

Two uses of isoproterenol?

Answer 26

Driving a dennervated transplanted heart.

In emergencies, to increase HR if a pacemaker can’t be quickly placed.

Question 27

What do inhibitors of phosphodiesterase type III do? (not to be confused with PDE5 inhibitors)

Answer 27

PDE3 breaks down cAMP.
cAMP promotes increased Ca++ in SR (via SERCA?)
Inhibiting PDE3 -> more cAMP -> greater contractility of cardiac myocytes.
(these also cause vasodilation of arterioles))

Question 28

Aside from direct effects on the heart, how are PDE3 inhibitors beneficial in decompensated HF?

Answer 28

Venodilation and pulmonary vasodilation.
Inhibits platelet aggregation.
May inhibit pro-inflammatory cytokine formation.

Question 29

How do PDE3 inhibitors affect:

Cardiac index, SVR/MAP, PAWP/LVEDP, HR, ventricular dP/dT (rate of pressure rise in early systole).

Answer 29

Cardiac index: increased
SVR/MAP: decreased
PAWP/LVEDP: decreased
HR: unchanged
Ventricular dP/dT: increased

Question 30

Major problem with giving someone a PDE3 inhibitor for HF?

Answer 30

If they pt is not volume overloaded, can cause a drop in BP before an increase in inotropy -> distributive shock.
(these drugs are best for pts with HF and volume overload)

Question 31

2 PDE3 inhibitors available?

Answer 31

Amrinone
Milrinone
These are given IV. Oral versions would be nice, but only oral PDE5 inhibitors are currently available (e.g. Viagra).

Question 32

Stuff to know about amrinone?

Answer 32

It’s not really used anymore. Can cause pretty bad thrombocytopenia in HF patients.

Question 33

How is milrinone recommended (by non-Penn people) to be given? Why? Why doesn’t Penn do this?

Answer 33

As a bolus followed by infusion.
Milrinone has a relatively long half life of 2.3 hours, so the bolus helps you get up to steady state more quickly.
Penn doesn’t do this because this bolus can cause hypotension, and it doesn’t produce much benefit to get to steady state more quickly.

Question 34

How is milrinone excreted?

Answer 34

Renally.

HF pts can have changing renal function, so you have to watch the levels of any drugs that are excreted renally.

Question 35

Current state of oral PDE3 inhibitors?

Answer 35

Not going so well. Some trials showed increased mortality (despite improved symptoms) at high doses, others showed lack of efficacy at low doses.

Question 36

5 disadvantages of beta adrenergic inotropes for HF?

How does this compare to phosphodiesterase inhibitors?

Answer 36

Weak vasodilation.
Worsens diastolic function.
Pro-arrhythmia potential.
Tachycardia
Densitization/tachyphylaxis (especially a problem when trying to bridge to transplant)

PDE inhibitors can also cause tachycardia and arrhythmia, but not all the rest of the above disadvantages (they do the opposite), and can be used with beta blockers. PDE inhibitors can cause hypotension, though.

Question 37

Lots of trials have shown increased mortality with long term use of dobutamine and milrinone for HF… should you assume that these drugs are worthless?

Answer 37

Nope.
Need to look at trials in detail: dosages, concomitant drugs, era, pt population.
And in general, improved quality of life may be worth some increased risk of mortality.

Question 38

For what patients should you give inotropes acutely?

Answer 38

Volume overload + inadequate perfusion.
Volume overload + diuretic resistance +/- low CO.
(if only volume overload, just give a diuretic?)

Question 39

For what reasons should you give inotropes chronically?

Answer 39

Patients with decompensated HF that need:
Bridging to transplant.
Palliation for HF refractory to other treatments.
(the bridging part is nice - can allow pts to wait for transplant outside of the hospital)