Pharmacology of Inotropes

Question 1

Explain Phase 0 of Myocardial Cell Action Potential

Answer 1

Na+ entry into the cell

Question 2

Explain Phase 2 of Myocardial Cell Action Potential

Answer 2

Ca2+ entry through voltage gated L-type calcium channels is essential for actin-myosin cross bridge formation resulting in myocyte contraction

Question 3

What effects the force of contraction?

Answer 3

total Ca2+

Question 4

Explain Phase 3 of Myocardial Cell Action Potential

Answer 4

K+ leaves the cell, some Cl- leaves the cell

Question 5

Explain Phase 4 Myocardial Cell Action Potential

Answer 5

Na+/K+ ATPase is used to maintain resting membrane potential, driven by [Na+] gradient
note: used ATP for energy which requires oxygen so ischemia decreases ATP availability

Question 6

Positive inotropic drugs can increase/improve myocardial contractility- HOW?

Answer 6

1. increase availability of free cytoplasmic Ca2+
2. produce a strong actin-myosin complex
3. increase sensitivity of myofibrils to Ca2+

Question 7

What is the MOA of Digoxin (LANOXIN)?

Answer 7

inhibits Na+/K+ ATPase to reduce the exchange of Ca2+ with Na+= increased intracellular Ca2+= enhanced contraction process (+ inotropic effect)

Question 8

Where does increased intracellular Ca2+ go?

Answer 8

stored within endoplasmic reticulum of the cell

Question 9

How does hypokalemia effect Digoxin’s effects?

Answer 9

enhances the effects

Question 10

What are some other MOA/indirect effects of Digoxin?

Answer 10

-decreased automaticity of the SA node= slows HR (neg chronotropic effects)
-increased/prolonged refractory period of the AV node (used in AFib due to this MOA)

Question 11

What are the therapeutic uses of Digoxin?

Answer 11

-systolic ventricular failure (HFrEF < 40%)
-AFib or flutter

Question 12

What are the monitoring parameters of Digoxin?

Answer 12

serum concentration (narrow therapeutic window)

Question 13

What are the adverse effects of DIgoxin?

Answer 13

-enhanced automaticity= arrhythmias (due to Ca2+ overload)
-decreased resting membrane potential= arrhythmias (due to inhibition of Na+/K+ ATPase
-nodal block aka heart block (due to atrial excitability), characteristic of digoxin toxicity
-CNS toxicity (hallucinations, changes in color perception (yellow-green), haloing around lights)
-gynecomastia (increased breast tissue in men due to stimulation of estrogen receptors)

Question 14

What is the MOA of Dobutamine?

Answer 14

selective beta1-adrenoreceptor agonist

Question 15

What are the unique pharmacokinetics of Dobutamine?

Answer 15

function is limited due to desensitization (decreased effects) of surface receptors (48-72h), half life= 12 minutes

Question 16

What is the MOA of Mlirinone?

Answer 16

phosphodiesterase (type 3) inhibitor (PDE3)= inhibits degradation of cAMP in cardiac myocytes (increased mobilization of intracellular Ca2+)

Question 17

What are the adverse effects of Mlirinone?

Answer 17

-long term use is associated with increased mortality in HF (oral use discontinued)
-excessive cardiac stimulation-ectopic beats, ventricular and supraventricular arrhythmias

Question 18

What is the MOA of Omecamtiv Mecarbil?

Answer 18

cardiac specific myosin activator

Question 19

What are the physiological effects seen with Omecamtiv Mecarbil?

Answer 19

-increased force production, systolic ejection fraction, stroke volume
-no increase in myocyte Ca2+ concentration, HR, velocity of contraction