hi...i just learn TIVA now...i am confuse about this...
if The t1/2 ke0 (0.693/ke0) is : the time it takes for half of the equilibration to occur between the biophase and the plasma concentration , and...
the time to peak effect is: when there is equilibration between effect site and the plasma concentration..
so,why the t1/2 ke0 for some drugs is longer than the time to peak effect(as example: fentanyl = time to peak effect is 3.6min and its t1/2keO is 4.7 min, and propofol and midazolam is also like this) ?
am i having something wrong perception about this pharmacokinetics?
please help explain it to me ...thx u
regards,Ketap🙂
I wonder where you got your numbers from? That's a very fast time to peak effect for fentanyl.
You also need to check your definitions: time to peak effect is NOT the time to equilibration with plasma. Think of morphine - plasma concentrations of morphine DO NOT correlate with analgesic effect achieved. At peak effect for a standard receptor based competitive agonist that ceases to have effect following dissociation from the receptor there should be maximal concentration of the drug at the effect site, but that doesn't necessarily mean that it is at equilibrium with plasma. Time to equilibrium is ~5 half lives (or 3 time constants). So for TIVA if you start an infusion of say fentanyl and the t1/2keo you are using is 6.8 min (which is the numbers I have) then at constant infusion it will take 34min for plasma and effect site to be equilibrated. Clearly it doesn't take 34min for fentanyl to have its peak effect.
Anyway, these numbers are all part of models, yes there is experimental evidence behind them but you can't expect to combine data from one experiment (pharmacokinetic describing keo) with data from another experiment (pharmacodynamic describing time to peak effect) and expect to get coherent data. For example there are several different keo values for propofol around. In particular it is worth noting that the Marsh and Schneider TCI models use different keo values, because the data was derived from different studies.
Secondly, there are different methods of determining keo and peak effect (and it depends what effect you are interested in eg for an induction agent are you interested in LOC or maximal EEG depression or maximal depression of evoked potentials or failure to move in response to surgical stimulus). As I understand it (and I'm not an expert in any of this), some methods of determining keo link pharmacokinetics and pharmacodynamics (ie they use time to peak effect to help determine keo) and older (but more longer established) methods (which I don't understand the detail of) that didn't like peak effect with keo.
Thirdly consider what we see in clinical practice. Consider propofol again (cause it's easy to see an estimate of peak effect at induction): certainly we know that the dose of propofol required to induce a 50kg 80yo woman is different from that required to induce a 50kg 20yo woman. But not only is the dose different, we expect that the drug will take longer to reach the effect site due to altered initial Vd and altered cardiac output, so when titrating to effect we wait longer in between doses. keo is not the only thing that effects time to peak effect. Drug can't equilibrate with the brain unless it is present in capillaries in the brain. Got to get there first.
So to summarise my answer is that I don't think there is a problem at all.
Check your data comes from the same source, not two different sources; and remember that these are models, not reality.
