Myocardial Inotropic Agents I and II Flashcards
By what mechanism do all FDA approved inotropes act?
by increasing intracellular calcium and cAMP
How does beta receptor modulation affect calcium levels in myocytes?
agonist activity at beta receptor can increase cAMP which increases calcium via PKA-mediated phosphorylation of phospholamban
How does PDE modulation affect calcium levels in myocytes?
PDE-3 inhibitors block degradation of cAMP to AMP allowing for greater PKA-mediated phosphorylation of phospholamban to increase calcium stores
What does addition of an inotrope do the starling curve (stroke volume vs. EDV/preload)?
moves curve up and to the left (improves contractility)
What does addition of a vasodilator do the starling curve (stroke volume vs. EDV/preload)?
moves curve up and to the left (improves contractility by reducing afterload)
What does addition of a vasodilator and inotrope do the starling curve (stroke volume vs. EDV/preload)?
moves curve up and to the left b/c of synergistic contractility improving effects of both drugs
What does addition of a diuretic do the starling curve (stroke volume vs. EDV/preload)?
shift along curve to left b/c reducing volume
What is the most commonly prescribed heart failure medicine and how does it work?
digoxin –> binds to Na/K atpase –> increases intracellular Na –> increased action by Na/Ca exchanger –> increased intracellular calcium causing increased inotropy without increasing HR
*upward and left shift of starling curve)
What do normal levels of extracellular potassium do to efficacy of digoxin?
reduces –> competitively decreases digoxin binding and may be protective in digoxin toxicity
What does hypokalemia do to efficacy of digoxin?
unlike at higher levels/normal potassium which is protective, hypokalemia may increase both effect and toxicity of digoxin
What is the concern with desensitization/tolerance of digoxin?
none –> it’s pretty unique in that you don’t get desensitized
How do low doses of digoxin affect mortality risk?
does not at LOW doses
How is digoxin administered and how is it cleared?
oral administration, renal elimination
What is the therapeutic level of digoxin?
.5-1 (some textbooks say up to 2 but that is dangerous) –> keep levels low!
Hemodynamic effects of digoxin
increased cardiac output, increased LV ejection fraction, increased exercise tolerance, increased natriuresis
decreased LVEDP/preload, decreased neurohormonal activation (reduce norepi, RAAS activity, increased vagal tone/normalization of baroreceptors)
Adverse effects of digoxin
- increased vagal tone reducing AV node automatcity leading to bradycardia and heart block
- at toxic doses, increase sympathetic tone and directly increase automaticity and delayed after polarizations leading to ventricular tachycardia and fibrillation
What was the main lesson from the dig trial?
you have to control digoxin dose for body surface area or you end up with lots of toxic side effects
Clinical uses of digoxin
a-fib with rapid ventricular response, CHF symptoms despite medical therapy
Why must we exercise caution when using digoxin with a beta blocker?
risk of bradycardia and heart block
Does the factor predispose or protect against digoxin toxicity? hypokalemia
predispose
Does the factor predispose or protect against digoxin toxicity? hypokalemia
predispose
Does the factor predispose or protect against digoxin toxicity? hyperkalemia
predispose
Does the factor predispose or protect against digoxin toxicity? hypomagnesia
predispose
Does the factor predispose or protect against digoxin toxicity? hyperkalemia
protect
Contraindications to digoxin use
- toxicity
without pacemakers:
- advanced av block
- bradcardia or sick sinus syndrome
- ventricular arrhythmias
- marked hypokalemia
- wolf-parkinson-white w/ afib
Classic rhythm of digoxin toxcity
atrial tachycardia w/ av block
Tx of digoxin toxicity
antibody to digoxin, increase potassium
Does the factor predispose or protect against digoxin toxicity? hypoxia and acidosis
predispose
Does the factor predispose or protect against digoxin toxicity? hypoxia and acidosis
predispose
Contraindications to digoxin use
- toxicity
without pacemakers:
- advanced av block
- bradcardia or sick sinus syndrome
- ventricular arrhythmias
- marked hypokalemia
- wolf-parkinson-white w/ afib
Classic rhythm of digoxin toxcity
atrial tachycardia w/ av block
Tx of digoxin toxicity
antibody to digoxin, increase potassium
Side effects of dopamine
dose dependent tachycardia, htn, nausea, iv site necrosis/gangrene due to alpha vasoconstriction
Dopamine antidote
phentolamine
What is the problem with continuous administration of dopamine or dobutamine?
desensitization
How do beta blockers interact with dobutamine and dopamine?
beta blockers inhibit these drugs –> need higher doses of dobutamine/dopamine to overcome effect but also increase side effect risk
Are dobutamine/dopamine short/long half life? is this good or bad?
short half life –> advantage b/c allows for real time monitoring/modulation
Side effects of dobutamine
arrhythmia, ischemia/angina, hypOtension, tachycardia, rapid ventricular response in afib due to increase in AV conduction, nausea, headache
Why is epinephrine not commonly used in heart failure therapy?
it is non selective and can lead to tachyphylaxis
How does PDE3I differ in peripheral arterial system and in myocytes?
in myocytes–> upregulates cAMP to increase contractility but in peripheral arterial system cAMP reduces contractility/increases vasodilation
How is the parameter affected by PDE3I? cardiac index
increased
How is the parameter affected by PDE3I? SVR/MAP
decreased
How is the parameter affected by PDE3I? PAWP/LVEDP
decreased
How is the parameter affected by PDE3I? heart rate
not much change
How is the parameter affected by PDE3I? ventricular dP/dT/performance
increased
Side effects of PDE3I
hypotension if filling pressures are not elevated due to venodilator properties of inhibitors which drop pre/afterload simultaneously
Main risk associated with amrinone
causes thrombocytopenia in pts with advanced heart failure
Administration of milrinone
bolus + infusion but risk of bolus is acute hypotension
Elimination of milrinone
kidney –> bad renal clearance in heart failure patients can reduce infusion rate
How do oral PDE3I affect mortality?
increase mortality despite great hemodynamic effects in hospital
