Pharmacokinetics of computer-controlled alfentanil administration in children undergoing cardiac surgery.

BACKGROUND: Cardiopulmonary bypass (CPB) induces changes in the pharmacokinetics of drugs. The purpose of this study was to model the pharmacokinetics of alfentanil in children undergoing cardiac surgery to provide accurate dosage titration intraoperatively as well as in the postoperative period. METHODS: Fourteen children (aged 3 months to 8 yr) undergoing cardiac surgery with CPB were administered alfentanil via a computer-controlled infusion pump. During surgery, the computer-controlled infusion pump was set to target plasma alfentanil concentrations of 500-2500 micrograms/ml. After surgery, the computer-controlled infusion pump was set to target plasma concentrations of 200-500 micrograms/ml. Parameters for children previously published by Goresky et al. were programmed into the device. Arterial blood samples were taken throughout the infusion. Plasma samples were assayed by radioimmunoassay. Alfentanil pharmacokinetics were estimated using a pooled-data approach with a simple weight-proportional, three-compartment mamillary model with parameters expressed in volumes and clearances as well as a CPB-adjusted, three-compartment model in which the parameters were allowed to change before, during, and after CPB. The accuracy of the three models was compared using cross-validation. RESULTS: Plasma alfentanil concentrations during computer-controlled infusion pump administration exceeded target concentrations for the first 10 min of drug administration, and from 300 min to the end of the study. The median absolute performance error was 33%. Pharmacokinetic modeling estimated a set of parameters for a simple three-compartment model with a median absolute weighted residual of 18.4%. A CPB-adjusted model nominally decreased the median absolute weighted residual to 17.0%. The performance of these models as measured by cross-validation performance was 18.9% median absolute performance error for the simple model and 18.4% median absolute performance error for the CPB-adjusted model. Parameters for the simple three-compartment model are: V1 = 19.2 ml.kg-1; V2 = 99 ml.kg-1; V3 = 2344 ml.kg-1; Cl1 = 2.5 ml.kg-1.min-1; Cl2 = 38 ml.kg-1.min-1; and Cl3 = 15 ml.kg-1.min-1. In the CPB-adjusted model V1, V2, and Cl2 changed with the onset of CPB. After CPB, V1 and Cl2 returned to the initial values, while V2 was described by a third value. CONCLUSIONS: The population pharmacokinetics of alfentanil in children undergoing cardiac surgery were well described by both a simple weight-proportional, three-compartment model and a weight-proportional, CPB-adjusted three-compartment model. Cross-validation estimated an expected median inaccuracy of approximately 18-20% with the estimated models in identical experimental circumstances. The flexible CPB-adjusted pharmacokinetic model could be used for modeling any drug with linear pharmacokinetics given in the context of CPB.

Biopharmaceutics of a new transdermal fentanyl device.

BACKGROUND: Compared with conventional routes of delivering potent analgesics to postoperative patients, transdermal administration of fentanyl offers the advantages of simplicity and noninvasive delivery. The only available form of transdermal fentanyl, the Duragesic system, has been implicated in preventable patient deaths when used for postoperative analgesia and is contraindicated in the management of postoperative pain. We examined the biopharmaceutics of a new transdermal fentanyl device developed by Cygnus and intended for use as a postoperative analgesic to see whether the new formulation offers pharmacokinetic advantages that might permit safe use in postoperative patients. METHODS: We studied 15 consenting male adult surgical patients. Patients received 650 or 750 micrograms intravenous fentanyl as part of the induction of anesthesia. Plasma fentanyl concentrations were measured over the following 24-h period. On the first postoperative day, 24 h after the intravenous dose of fentanyl, a transdermal fentanyl device was placed on the upper torso of the patient for 24 h and then removed. Plasma fentanyl concentrations were measured for 72 h after application of the transdermal fentanyl device. From the concentration versus time profile for the 24 h after intravenous fentanyl administration we determined each patient's clearance and unit disposition function by moment analysis and constrained numeric deconvolution, respectively. From the concentration versus time profile for the 72 h after application of the transdermal device we determined the amount of fentanyl absorbed and the rate of absorption, again by moment analysis and constrained numeric deconvolution. The residual fentanyl in the transdermal fentanyl device was measured, permitting calculation of the absolute bioavailability of transdermally administered fentanyl. RESULTS: Of the 14 subjects who received transdermal fentanyl, 3 had clinically significant fentanyl toxicity, mandating early removal of the device. The range during the plateau from 12 to 24 h in subjects still wearing the device was 0.34-6.75 ng/ml, a 20-fold range in concentration. In subjects wearing the device for 24 h, the terminal half-life of fentanyl after removal of the device was 16 h. The bioavailability of transdermally administered fentanyl was 63 +/- 35% coefficient of variation. The rate of fentanyl absorption from 12-24 h ranged from 10 to 230 micrograms/h in subjects still wearing the device. In two subjects, the rate within the first 6 h briefly exceeded 300 micrograms/h. Both of these subjects demonstrated fentanyl toxicity, requiring early removal of the device. CONCLUSIONS: The Cygnus transdermal fentanyl device shows great variability in the rate of fentanyl absorption, resulting in highly variable plasma fentanyl concentrations. Some persons may rapidly absorb fentanyl from the device in the first few hours after application, leading to fentanyl toxicity. The variability in effect of the Cygnus transdermal fentanyl device is appreciably greater than that reported for the currently available Duragesic transdermal fentanyl device, which is contraindicated for postoperative analgesia.

Transdermal fentanyl disposition in elderly subjects.

The pharmacokinetic characteristics of a 20-cm2 fentanyl 24-hour transdermal patch were compared between 10 healthy elderly subjects 67-87 years and 6 young subjects 19-27 years. All 10 elderly subjects required patch removal prior to 24 h due to adverse effects versus none of the young subjects. The mean patch duration (PD) in elderly subjects was 11.7 +/- 4.9 h, yielding a mean area under the curve from 0 to 60 h (AUC0-60) of 20.4 +/- 10.3 ng h/ml versus a mean AUC0-60 of 21.0 +/- 10.4 ng h/ml in young subjects. Correcting AUC0-60 for PD (AUC0-60/PD) gave a mean value of 2.05 +/- 1.10 ng/ml for elderly subjects, which was significantly greater than the AUC0-60/PD of 0.88 +/- 0.44 ng/ml in young subjects (p = 0.034, Student's t test). The higher serum concentrations reflect increased absorption and/or decreased clearance in the elderly.

The activation of the sodium pump in pig red blood cells by internal and external cations.

A study has been made with pig red blood cells of the activation of the sodium pump by internal and external cations. Cell Na and K concentrations were altered using a PCMBS cation loading procedure. The procedure was characterised for resultant ionic conditions, maintenance of ATP levels and fragility. The activation of the sodium pump by external K was measured in cells suspended in choline (Na-free) solutions. External Cs was used as a substitute for K and elicited lower rates of pump activity. Both the Vmax and apparent Km for 42K influx and 134Cs influx increased as internal Na concentration was raised (within the non-saturating range). Vmax/apparent Km ratios for cation influx were constant. Raising external Cs concentration exerted a similar influence on pump activation by internal Na: both the maximum pump velocity and the apparent Na-site dissociation constant (K'Na) increased. The results provide evidence for a transmembrane connection between cation binding sites on opposite faces of the membrane and are consistent with a consecutive model for the sodium pump in pig red blood cells.

The change from symmetry to asymmetry of a sodium transport system in red cell membranes.

A study has been made with human red cells of sodium movements that are sensitive to the drug furosemide. The aim was to see if furosemide-sensitive movements that are symmetrical (exchange) became asymmetrical (net transport) on replacement of chloride with nitrate as the major external anion. Cells were incubated for 4 h at 37 degrees C with 140 mM sodium, and chloride or nitrate as the principal anion. Under a variety of conditions (presence and absence of ouabain or furosemide, or both) the cell sodium concentration was always higher when chloride was replaced with nitrate. The cells became leakier to sodium. Tracer studies indicated that, in contrast to the results in chloride medium, the decrease in sodium influx was greater than the fall in efflux when furosemide was added to cells in nitrate medium. The results confirm that the sensitivity of sodium efflux to furosemide depended on chloride. However, influx showed a different sensitivity in that furosemide still inhibited in cells incubated in nitrate medium. The stimulation of sodium influx with nitrate medium was independent of external potassium (10-50 mM) and the furosemide-sensitive influx was also constant. It is concluded that symmetrical transmembrane sodium movements with cells in chloride medium became downhill asymmetrical in nitrate medium, giving a net gain of cell sodium that was insensitive to ouabain and sensitive to furosemide. The drug thus partly retarded the gain of cell sodium that otherwise occurred in the somewhat leaky cells.

The effect of furosemide on sodium movements in human red blood cells.

A study has been made of Na movements in human red blood cells in order to test their sensitivity to inhibition by furosemide or bumetanide. Net changes as well as influx and efflux were measured. Unidirectional Na influx and efflux values confirmed previous evidence for components of both these fluxes sensitive to inhibition by furosemide or bumetanide. The difference between furosemide-sensitive unidirectional influx and efflux was determined at [Na]o 140 mM and shown to be non-significant, even when [Na]i was raised to about 45 mumol ml cells-1. No evidence was found for an influence of furosemide on net movements of Na in cells of either slightly elevated or physiological [Na]i incubated in a 140 mM-Na medium over 4 h. Incubation of cells, under similar conditions, for 12 h did not reveal a bumetanide-sensitive net Na movement. The results suggest that cells with normal or slightly elevated [Na]i, incubated in media of physiological Na concentration, do not possess a mechanism sensitive to inhibition by the loop diuretics that operates to regulate cell Na.