Step I Ranolazine mechanism

[stronghold]

I am reading Kaplan lecture notes and it says that ranolazine decreases Na entry to cardiac muscle so decreases intracellular Ca and contractility.
I feel confused since there is an Na/Ca exchanger, so less Na entry means that intracellular Ca conc stays high!!

 

[madchemist89]

I have not seen the Kaplan notes, so I can't comment on what you read there. It is my understanding that ranolazine inhibits the late sodium current. My guess is that this refers to the Na/K pump. By inhibiting the influx of sodium at this pump, the intracellular sodium concentration is reduced in comparison to the extracellular sodium concentration. After administration of the drug, there is a greater sodium concentration gradient directed into the cell that must go down the Na/Ca exchanger. More sodium goes into the cell at this point, so more calcium leaves the cell. Thus, reducing calcium and potential contractile force.

 

[Myxedema]

For understanding why reduced intracellular Na+ decreases intracellular Ca2+, correlate it with the MOA of digoxin.
In addition to what madchemist89 wrote above, ranolazine also shifts cardiac metabolism from oxidation of fatty acids to utilizing glucose, which is thought to increase the efficiency of oxygen utilization. This is why ranolazine is among the partial fatty acid oxidation inhibitors (pFOX inhibitors).

 

[Oh_Gee]

I have not seen the Kaplan notes, so I can't comment on what you read there. It is my understanding that ranolazine inhibits the late sodium current. My guess is that this refers to the Na/K pump. By inhibiting the influx of sodium at this pump, the intracellular sodium concentration is reduced in comparison to the extracellular sodium concentration. After administration of the drug, there is a greater sodium concentration gradient directed into the cell that must go down the Na/Ca exchanger. More sodium goes into the cell at this point, so more calcium leaves the cell. Thus, reducing calcium and potential contractile force.

why is it that Ranolazine does not have an effect on heart rate or contractility if it blocks Ca2+ entry into the cell? isn't Ca2+ needed for both heart rate or contractility?