Alfentanil infusion as a component of intravenous anaesthesia for coronary artery bypass surgery with "fast-track" recovery.

Alfentanil and propofol total intravenous anaesthesia was assessed in 25 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass (CPB). A manually controlled alfentanil infusion, calculated from estimated lean body mass and published pharmacokinetic data, was effective in achieving target plasma concentrations, while the "Diprifusor" system was used to vary propofol target concentrations according to changes in haemodynamics and anaesthetic requirement. The effects of CPB on alfentanil plasma concentrations were offset by changes in protein binding and free-fraction of the drug. With the use of only two target plasma concentrations for alfentanil (changed after CPB), a pre-determined infusion profile ensured effective plasma concentrations during surgery and concentrations unlikely to inhibit extubation within six hours of sternal closure.

Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein.

BACKGROUND: The efflux transporter P-glycoprotein, a member of the adenosine triphosphate-binding cassette superfamily, is a major determinant of the pharmacokinetics and pharmacodynamics of the opioid loperamide, a well-recognized antidiarrheal agent. Animal studies indicate that P-glycoprotein limits morphine entry into the brain. In this study, the authors examined whether other opioids of importance to anesthesiologists such as fentanyl, sufentanil, and alfentanil, and also morphine-6-glucuronide and morphine-3-glucuronide, are P-glycoprotein substrates and whether, in turn, these opioids act also as P-glycoprotein inhibitors. METHODS: The transcellular movement of the various opioids, including loperamide and morphine, was assessed in L-MDR1 (expressing P-glycoprotein) and LLC-PK1 cell monolayers (P-glycoprotein expression absent). A preferential basal-to-apical versus apical-to-basal transport in the L-MDR cells but not the LLC-PK1 cells is seen for P-glycoprotein substrates. In addition, the effect of the various opioids on the transcellular movement of the prototypical P-glycoprotein substrate digoxin was examined in Caco-2 cell monolayers. IC50 values were calculated according to the Hill equation. RESULTS: Loperamide was a substrate showing high dependence on P-glycoprotein in that basal-apical transport was nearly 10-fold greater than in the apical-basal direction in L-MDRI cells. Morphine also showed a basal-to-apical gradient in the L-MDR1 cell monolayer, indicating that it too is a P-glycoprotein substrate, but with less dependence than loperamide in that only 1.5-fold greater basal-apical directional transport was observed. Fentanyl, sufentanil, and alfentanil did not behave as P-glycoprotein substrates, whereas the morphine glucuronides did not cross the cell monolayers at all, whether P-glycoprotein was present or not. Loperamide, sufentanil, fentanyl, and alfentanil inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells with IC50 values of 2.5, 4.5, 6.5, and 112 microm, respectively. Morphine and its glucuronides (20 microm) did not inhibit digoxin (5 microm) transport in Caco-2 cells, and therefore IC50 values were not determined. CONCLUSIONS: Opioids have a wide spectrum of P-glycoprotein activity, acting as both substrates and inhibitors, which might contribute to their varying central nervous system-related effects.

The in vitro effects of remifentanil, sufentanil, fentanyl, and alfentanil on isolated human right atria.

Because some clinical studies have suggested that opioids used in anesthesia may have different deleterious hemodynamic effects, we compared the direct myocardial effects of cumulative concentrations of remifentanil, sufentanil, fentanyl, and alfentanil on inotropic and lusitropic variables of isolated human myocardium in vitro. Human right atrial trabeculae, obtained from patients scheduled for coronary bypass surgery or aortic valve replacement, were suspended vertically in an oxygenated (95% oxygen/5% CO(2)) Tyrode's modified solution ([Ca(2+)](o) = 2.0 mM, 37 degrees C, pH 7.40, stimulation frequency 1 Hz). The effects of cumulative concentrations (10(-11), 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) M) of remifentanil (n = 8), sufentanil (n = 8), fentanyl (n = 8), and alfentanil (n = 8) on inotropic and lusitropic variables of isometric twitches were measured. Remifentanil, sufentanil, and fentanyl did not modify active isometric force and peak of the positive force derivative as compared with the Control group. Alfentanil induced a dose-dependent decrease in active isometric force and peak of the positive force derivative. This effect was abolished in the presence of [Ca(2+)](o) = 4.0 mM. None of these opioids altered lusitropic variables.

Development of a gas chromatographic-mass spectrometric drug screening method for the N-dealkylated metabolites of fentanyl, sufentanil, and alfentanil.

A sensitive, specific urinary assay for fentanyl, sufentanil, and alfentanil based on their N-dealkylated metabolites is described. Norfentanyl, norsufentanil-noralfentanil, and 2H5-norfentanyl are synthesized and characterized by standard analytical techniques. Derivatization of these secondary amines to yield the pentafluorobenzamides produces stable products with good gas chromatographic properties and unique, high-mass fragments in their mass spectra. These properties are utilized to develop a drug screening procedure based on gas chromatography-mass spectrometry to detect these major metabolites in human urine. The metabolites are isolated from urine samples by a liquid-liquid extraction procedure. The method allows for detection of metabolite concentrations as low as 0.3 ng/mL.

Gas chromatographic-mass spectrometric analysis of alfentanil metabolites. Application to human liver microsomal alfentanil biotransformation.

The short-acting synthetic opioid alfentanil undergoes extensive biotransformation to several metabolites. A gas chromatographic-mass spectrometric assay, using selected-ion monitoring and deuterated internal standards, was developed for quantitating the predominant metabolites of alfentanil. Optimal extraction and derivatization conditions are described. The assay was applied to the analysis of metabolites formed during alfentanil metabolism in vitro by human liver microsomes. Formation of known alfentanil metabolites was confirmed, and formation of a metabolite, not previously detected in vitro, is described. The assay represents a significant improvement over existing methods of alfentanil metabolite analysis, which use HPLC and radiochemical detection.