Pharmacokinetic‐pharmacodynamic modelling of the EEG effect of alfentanil in rats: assessment of rapid functional adaptation

Abstract

1 The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological eect relationship of alfentanil in rats using quantitative EEG parameters as a pharmacodynamic endpoint. Three groups of 6 ± 7 rats received in a randomized fashion two consecutive infusions of 2.00, 3.14, or 4.24 mg/kg 71 of alfentanil in 20, 40 or 60 min, respectively. The EEG was continuously recorded and frequent arterial blood samples were collected for determination of the alfentanil concentration by gas chromatography. 2 The pharmacokinetics of alfentanil were most adequately described by a bi-exponential function. The values (mean+s.e., n=20) of clearance, volume of distribution at steady-state and terminal half-life were 45+3 ml.min and 23+1 min, respectively, and independent of the administered dose. 3 Increase in power in the 0.5 ± 4.5 Hz (delta) frequency band of the EEG was used as the measure of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG eect relationships of alfentanil were derived which were successfully quanti®ed by the sigmoidal E max pharmacodynamic model. When the results of the ®rst of the two consecutive infusions were compared, no systematic dierences in the pharmacodynamic parameters were observed for the dierent infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean+s.e., n=20): E 0 =56+3 mV, E max =93+8 mV, EC 50 =235+27 ng.ml 71 and Hill factor=1.6+0.1, respectively. For the second of the two consecutive infusions a signi®cantly higher value of the EC 50 of 404+56 ng.ml 71 was observed (P50.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration eect relationship can be explained by a 40% loss of functional m-opioid receptors. 4 The results of the present study show that upon the administration of a single intravenous dose, acute functional adaptation does not interfere with the assessment of the concentration-EEG eect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

Concurrent ketamine and alfentanil administration: pharmacokinetic considerations

“…An infusion of ketamine was administered at a constant rate of 10 mg kg ±1 min ±1 over 5 min; serial arterial blood samples were taken before, then at 1. 5,3,5,7,10,15,20,30,40,60,80,100,120,140,160, and 180 min after commencement of the infusion. Group 2.…”

A Processed EEG based Brain Anesthetic Resistance Index Predicts Postoperative Delirium in Older Adults: A Dual Center Study

“…A DARS value <27.0 also remained a significant independent predictor of delirium risk in the derivation cohort (OR 5.4, 95% CI: (1.6, 21.1); p<0.014) while accounting for dosage of other anesthetic drugs that can affect EEG parameters (i.e. opioids, 26 non-depolarizing neuromuscular blockers, 27 ketamine, 28 midazolam and propofol 29 ) and the use of epidural anesthesia 30 and/or nitrous oxide 31 (Table 4). None of these other variables were significantly associated with postoperative delirium risk.…”

“…This robustness of the DARS for predicting delirium, despite varying doses of other drugs that can affect the EEG (i.e. opioids, 26,33 ketamine, 28 non-depolarizing neuromuscular blockers, 27 nitrous oxide, 31 etc), suggests that lower brain anesthetic resistance in response to volatile anesthetics is relatively greater in magnitude than the EEG changes due to these other anesthetic drug adjuncts. Further, the DARS was an independent predictor of delirium in two separate cohorts from two separate institutions, in whom delirium was assessed by two different groups of personnel (geriatricians vs trained research staff) using two different instruments (regular CAM vs CAM-ICU).…”

Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models

“…Classical examples in which a difference in concentration–effect curves was observed after different routes of administration are quinidine [ 26 ], and verapamil [ 27 , 28 ]. Meanwhile, changing the rate and route of administration and characterizing the pharmacodynamics upon the administration of different doses has become an accepted approach in the validation of PK–PD models as is illustrated for midazolam [ 29 ], alfentanil [ 30 ], and N 6 cyclopentyl-adenosine [ 31 ].…”

“…In contrast for the 5-HT 1A receptor agonists buspirone, it was demonstrated that the active metabolite 1-(2-pyrimidinyl)-piperazine contributes significantly to the effect following administration of the parent drug [ 62 ]. Furthermore, for benzodiazepines and 5 HT 1A receptor agonists the role of interactive metabolites was studied by direct administration [ 63 ] [ 64 ], while for synthetic opioids and dopamine D 2 receptor antagonists, the analysis of the effect upon repeated administration enabled the characterization of acute functional tolerance development [ 30 , 61 ].…”