Dose Implications of the Biophase

The delay in onset has important clinical implications. After a bolus, the plasma concentration peaks nearly instantly and then steadily declines. The effect-site concentration starts at zero and increases over time until it equals the descending plasma concentration. The plasma concentration continues to fall, and after that moment of identical concentrations, the gradient between plasma and the effect site favors drug removal from the effect site, and effect-site concentrations decrease. The rate at which the effect-site concentration rises toward the peak after a bolus dictates how much drug must be injected into plasma to produce a given effect. For alfentanil, the rapid plasma effect-site equilibration (large k_e0 ) causes the effect-site concentration to rise rapidly and produce a peak in about 90 seconds. At the time of the peak, about 60% of the alfentanil bolus has been distributed into peripheral tissues or has been eliminated from the body. For fentanyl, the effect-site concentration rises much more slowly and peaks 3 to 4 minutes after the bolus.^[34] At the time of the peak, more than 80% of the initial bolus of fentanyl has been distributed into tissues or eliminated. As a result of the slower equilibration with the effect site, relatively more fentanyl than alfentanil must be injected into plasma, which makes the rate of drug offset after a fentanyl bolus slower than after an alfentanil bolus.

This variability in achieving peak effect-site concentration suggests that k_e0 must be incorporated into dosing strategies. For a rapid onset of effect, a drug with a large k_e0 (short t½k_e0 ) should be chosen. For example, for rapid-sequence induction, alfentanil or remifentanil may be the opioid of choice because the peak opioid effect-site concentration coincides with endotracheal intubation. However, for a slower induction in which a nondepolarizing neuromuscular blocking drug is used, it may be appropriate to choose an opioid with a slower onset of drug effect to coincide with the peak effect of the muscle relaxant. In this case, a bolus of fentanyl or sufentanil at the time of induction may be appropriate. The time to peak effect for the commonly used opioids is shown in

Figure 12-6 Simulated onset and time to peak effect of commonly used opioids based on their k_e0 and pharmacokinetic parameters. k_e0 , rate constant for transfer of drug from the site of drug effect to the environment.