Flashcards in Cardiac Inotropes (1 and 2) Deck (40)
What mechanistic endpoint do all FDA-approved inotropes have?
Increased intracellular Ca++.
What are 4 key proteins that control myocyte Ca++ levels?
L-type Ca++ channels (LCC)
Ryanodine Receptor (RyR)
Na+ Ca++ exchanger (NCx) - moves Na+ in, Ca++ out.
What do inotropes do to the Starling curve (which relates EDV with SV)?
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).
What does digoxin target? How does this help heart failure?
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.
Does digoxin use create "tolerance" to its effects?
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.
What ion can greatly affect the efficacy / toxicity of digoxin?
High extracellular K+ will compete for digoxin binding the pump -> reduced efficacy.
Low extracellular K+ -> increased risk of digoxin toxicity.
How is digoxin excreted?
If people have renal failure, digoxin buildup can be a real problem.
Does digoxin affect HR?
Nope, just contractility.
What's the key to not killing somebody with digoxin?
Keep the dose low so you have wiggle room if something happens that will increase its levels.
For each of the following, does digoxin increase or decrease it: CO, LVEF, LVEDP, Exercise tolerance, Natriuresis, Neurohormonal activation.
Exercise tolerance: increased
Neurohormonal activation: decreased
(basically, digoxin shuts off some of the maladaptive compensatory processes, esp. symp driven stuff, RAAS, etc.)
What does digoxin do the AV node? If levels get too high?
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.)
What does digoxin do the ventricles?
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)
5 ECG changes seen with digoxin?
Prolonged PR interval.
ST depression (elevated resting potentials, except during ST).
Inverted T wave.
P wave changes.
Why did early trials with digoxin show increased mortality in women?
They didn't adjust the dose for smaller body weights.
2+ current uses for digoxin?
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...
4 factors predisposing to digoxin toxicity?
Are drug interactions common?
Hypoxia and acidosis.
Drug interactions are very common.
3 aspects of the cardiac toxicity of digoxin?
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.
4 extra-cardiac systems that are affected by digoxin toxicity?
GI - nausea, vomiting, diarrhea.
Nervous - depression, disorientation, seizures.
Visual - blurred vision, scotomas, yellow-green vision.
Endocrine - Hyperestrogenism -> gynecomastia and galactorrhea.
Treatment for digoxin overdose?
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)
In the ICU/CCU, do you prefer drugs with a short or long half-life?
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.
Review: How does dopamine receptor specificity vary across concentrations?
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
What's the major local side effect of dopamine, and how do you avoid this?
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)
How is dobutamine helpful for diagnosis?
It can be used to stimulate exercise for stress tests.
Does do people on dobutamine develop tolerance?
Yes, because chronic stimulation leads to beta-1 receptor downregulation.
Major side effect of epinephrine?
Platelet aggregation and infarction.
(If a tiger is chasing you, the body anticipates some bleeding.)
Utility of NE?
Mainly as a pressor / vasoconstrictor (similar to high dose dopamine).
Two uses of isoproterenol?
Driving a dennervated transplanted heart.
In emergencies, to increase HR if a pacemaker can't be quickly placed.
What do inhibitors of phosphodiesterase type III do? (not to be confused with PDE5 inhibitors)
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))
Aside from direct effects on the heart, how are PDE3 inhibitors beneficial in decompensated HF?
Venodilation and pulmonary vasodilation.
Inhibits platelet aggregation.
May inhibit pro-inflammatory cytokine formation.