Pharmacokinetics Of Alfentanil Research Articles

Pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane‐anesthetized cats

The aim of this study was to compare the pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats. Six adult cats were used. Anesthesia was induced and maintained with isoflurane in oxygen. End-tidal isoflurane concentration was set at 2% and adjusted as required due to spontaneous movement. Fentanyl (10 μg/kg), alfentanil (100 μg/kg), or sufentanil (1 μg/kg) was administered intravenously as a bolus, on separate days. Blood samples were collected immediately before and for 8 h following drug administration. Plasma drug concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to concentration-time data. A 3-compartment model best fitted the concentration-time data for all drugs, except for 1 cat in the sufentanil group (excluded from analysis). The volume of the central compartment and the volume of distribution at steady-state (L/kg) [mean ± SEM (range)], the clearance (mL/min/kg) [harmonic mean ± pseudo-SD (range)], and the terminal half-life (min) [median (range)] were 0.25 ± 0.04 (0.09-0.34), 2.18 ± 0.16 (1.79-2.83), 18.6 ± 5.0 (15-29.8), and 151 (115-211) for fentanyl; 0.10 ± 0.01 (0.07-0.14), 0.89 ± 0.16 (0.68-1.83), 11.6 ± 2.6 (9.2-15.8), and 144 (118-501) for alfentanil; and 0.06 ± 0.01 (0.04-0.10), 0.77 ± 0.07 (0.63-0.99), 17.6 ± 4.3 (13.9-24.3), and 54 (46-76) for sufentanil. Differences in clearance and volume of distribution result in similar terminal half-lives for fentanyl and alfentanil, longer than for sufentanil.

Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life

Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine. A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.

Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture

Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture

THIS MONTH IN ANESTHESIOLOGY

THIS MONTH IN ANESTHESIOLOGY

Elimination of alfentanil delivered by infusion is not altered by the chronic administration of atorvastatin

Background and objective: Statins are prescribed for patients with hypercholesterolemia. Atorvastatin is metabolized by cytochrome P4503A4 and inhibits P4503A4 activity in vitro. Alfentanil is a potent opioid used in clinical anaesthetic practice and is also metabolized by P4503A4. This study tested the hypothesis that chronic atorvastatin administration inhibits the metabolism of alfentanil. Methods: Sixteen patients undergoing elective surgery were studied as matched pairs. One member of each pair was maintained on standard doses of atorvastatin for at least 4 months. Each patient received an alfentanil bolus (80 μg kg−1) intravenously (i.v.), followed by an alfentanil infusion (0.67 μg kg−1 min−1) for 90 min. Serial plasma alfentanil concentrations were measured using gas chromatography-nitrogen phosphorous detection. Pharmacokinetic parameters were calculated using two-compartment linear modelling. Results: One patient and the corresponding match were excluded from the analysis. The elimination half-life of alfentanil was similar in the control and atorvastatin groups (98.8 ± 12.4 versus 98.3 ± 11.3 min, respectively). The clearance (Cl), volume of distribution at steady-state (Vdss) and area under the curve (AUC) were similar in the two groups (Cl = 0.20 (±0.06) and 0.22 (±0.04) L min−1, Vdss = 0.38 (±0.07) and 0.39 (±0.07) L kg−1, AUC = 0.05 (±0.02) and 0.04 (±0.01) mg min mL−1). Conclusions: Concurrent atorvastatin administration does not alter the pharmacokinetics of alfentanil in patients undergoing elective surgery.

Concurrent ketamine and alfentanil administration: pharmacokinetic considerations

A ketamine-alfentanil combination has been suggested for total i.v. anaesthesia. We determined the pharmacokinetics of ketamine and alfentanil, alone and together, in three groups of adult male rats, to assess any pharmacokinetic interaction. Group 1 animals were infused with i.v. ketamine for 5 min; in group 2, constant low plasma concentrations of alfentanil were maintained by computer-controlled infusion; in group 3, the treatments were combined. Serial plasma and terminal tissue concentrations were measured by high performance liquid chromatography or gas chromatography-mass spectrometry. In the presence of alfentanil, the mean plasma ketamine concentration-time area under the curve (AUC) value was significantly lower (by 13%, P<0.05), while clearance (CIT) and volume of distribution (Vss) were significantly higher (by 16 and 28%, respectively, both P<0.05). Tissue:plasma distribution coefficients for ketamine in the presence of alfentanil were significantly higher in forebrain (by 128%, P<0.005), hindbrain (by 207%, P<0.01), gut (by 254%, P<0.005), and fat (by 344%, P<0.0001). Mean AUC values for alfentanil did not differ significantly in the presence of ketamine, but alfentanil tissue concentrations were significantly lower in forebrain (by 77%, P<0.0001), hindbrain (by 28%, P<0.01), heart (by 33%, P<0.01), lung (30%, P<0.05), and gut (by 21%, P<0.05). Corresponding tissue:plasma distribution coefficients were significantly lower for forebrain (by 69%, P<0.0001) alone. The finding that the distribution of ketamine into the brain was increased by low plasma concentrations of alfentanil could have important clinical applications for pain management.

Pharmacokinetic-pharmacodynamic analysis of the EEG effect of alfentanil in rats following beta-funaltrexamine-induced mu-opioid receptor "knockdown" in vivo.

The objective of this investigation was to determine the influence of pre-treatment with the irreversible mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) on the pharmacokinetic-pharmacodynamic (PK/PD) relationship of alfentanil in rats. The PK/PD correlation of alfentanil (2 mg x kg(-1) intravenously in 20 min) was determined in chronically instrumented rats using amplitudes in the 0.5-4.5 Hz frequency band of the EEG as pharmacodynamic endpoint. Beta-FNA was administered intravenously (10 mg x kg(-1)) either 35 min or 24 h prior to the PK/PD experiments. Pre-treatment with beta-FNA had no influence on the pharmacokinetics of alfentanil. The in vivo concentration-EEG effect relationships, however, were steeper and shifted towards higher concentrations with no difference between the 35-min and the 24-h pre-treatment groups. Analysis of the data on basis of the operational model agonism revealed that the observed changes could be explained by a 70-80% reduction in alfentanil efficacy in beta-FNA pre-treated rats. This is consistent with results from an in vitro receptor bioassay showing a 40-60% reduction in the number of specific mu-opioid binding sites in the brain. This investigation confirms the validity of a previously postulated mechanism-based PK/PD model for the effect of synthetic opiates in rats.

Recirculatory and compartmental pharmacokinetic modeling of alfentanil in pigs: the influence of cardiac output.

Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models. Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution. The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO. Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.

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

1. The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological effect 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(-1) 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 x min(-1) x kg(-1), 0.91+/-0.09 l/kg(-1) 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 effect relationships of alfentanil were derived which were successfully quantified by the sigmoidal Emax pharmacodynamic model. When the results of the first of the two consecutive infusions were compared, no systematic differences in the pharmacodynamic parameters were observed for the different infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean+/-s.e., n=20): E0=56+/-3 microV, Emax=93+/-8 microV, EC50=235+/-27 ng x ml(-1) and Hill factor=1.6+/-0.1, respectively. For the second of the two consecutive infusions a significantly higher value of the EC50 of 404+/-56 ng x ml(-1) was observed (P < 0.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration effect relationship can be explained by a 40% loss of functional mu-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 effect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

Application of physiologic models to predict the influence of changes in body composition and blood flows on the pharmacokinetics of fentanyl and alfentanil in patients.

The influence of changes in the physiologic state of a patient on the disposition of fentanyl and alfentanil is poorly understood. The aims of this study were to determine whether physiologic pharmacokinetic models for fentanyl and alfentanil, based on data from rats, could predict plasma concentrations of these opioids in humans and to determine how changes in physiology would influence the predictions of their disposition. The predictions of the models were tested against plasma concentration data from published pharmacokinetic studies. The influences of changes in body composition, cardiac output, and regional blood flows on the disposition of the opioids were simulated. The models could predict independently measured plasma concentrations of the opioids after short infusions in humans. Simulations then predicted that differences in body composition between men and women would have little influence on the pharmacokinetics of the opioids. Changes in cardiac output would affect drug redistribution, and consequently the early decay of the plasma concentrations, but not markedly influence rates of elimination. Further, the clearance of the opioids would decrease and their volumes of distribution increase with the age of the patient, but this would only marginally affect the early disposition of the drugs. Even large fluctuations in peripheral or hepatic blood flows would have modest effects on arterial plasma concentrations of the opioids, and sudden "postoperative" increases in peripheral blood flows would cause minor secondary plasma concentration peaks. The ability of the physiologic models to predict plasma concentrations of fentanyl and alfentanil in humans was confirmed. When changes in physiologic condition were simulated, effects on the pharmacokinetics of the opioids with possible implications for dosing were obtained only if cardiac output was varied over a wide range.

Pharmacokinetics of opioids in renal dysfunction.

Patients with renal insufficiency commonly require the administration of an opioid analgesic to provide adequate pain relief. The handling of morphine, pethidine (meperidine) and dextropropoxyphene in patients with renal insufficiency is complicated by the potential accumulation of metabolites. While morphine itself remains largely unaffected by renal failure, accumulation, as denoted by an increase in both mean peak concentrations and the area under the concentration-time curve, of both the active metabolite (morphine-6-glucuronide) and the principal metabolite (morphine-3-glucuronide, thought to possess opiate antagonist properties) have been reported. The increased elimination half-lives of the toxic metabolites norpethidine and norpropoxyphene in patients with poor renal function administered pethidine and dextropropoxyphene, respectively, makes their routine use ill advised. Case reports of prolonged narcosis associated with the use of both codeine and dihydrocodeine in patients with renal insufficiency call for care to be used when prescribing these agents under such conditions. Although the pharmacokinetics of buprenorphine, alfentanil, sufentanil and remifentanil change little in patients with renal failure, the continuous administration of fentanyl can lead to prolonged sedation.

The Pharmacokinetics of Alfentanil After Normothermic and Hypothermic Cardiopulmonary Bypass

PETROS, ANDY; DUNNE, NUALA; MEHTA, RAJ; DORE, CAROLINE; PEER, ACHIEL VAN; GILLBE, CHARLES; MACRAE, DUNCAN Author Information

The Pharmacokinetics of Alfentanil After Normothermic and Hypothermic Cardiopulmonary Bypass

The Pharmacokinetics of Alfentanil After Normothermic and Hypothermic Cardiopulmonary Bypass

Pharmacokinetics of Alfentanil in Patients Treated with either Cimetidine or Ranitidine

KIENLEN, J.; LEVRON, J. -C.; AUBAS, S.; ROUSTAN, J. -P.; CAILAR, J. DU Author Information

Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models

The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a wholebody model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans.

Effect of xylazine and ketamine on the pharmacokinetics of alfentanil during halothane anaesthesia

We measured plasma concentrations of alfentanil in two horses after three different randomly ordered treatments. Each horse received halothane in oxygen by mask followed by a bolus dose of alfentanil 60 micrograms kg-1 i.v., halothane in oxygen by mask followed by an i.v. alfentanil infusion for 120 min and xylazine and ketamine followed by halothane and a bolus dose of alfentanil 60 micrograms kg-1 i.v. Halothane was maintained at 1.05-1.07% end-tidal concentration with a PaCO2 of 6-7.3 kPa. The plasma concentration-time curves were similar after bolus and infusion doses of alfentanil with halothane and could be fitted to a two-compartment open model. A plateau was noted in the plasma concentration-time curve in the presence of xylazine-ketamine which could not be modelled adequately, but suggested a three-compartment open model with an additional input component.

Alfentanil Pharmacokinetics in Cardiac Surgical Patients

There is growing interest in early tracheal extubation and intensive care unit. (ICU) discharge of cardiac surgical patients. Among the opioids currently available, alfentanil seems to be particularly suited to these goals because of its pharmacokinetic and pharmacodynamic characteristics. However, the pharmacokinetics of alfentanil after cardiopulmonary bypass (CPB) have not been fully characterized. Eight patients undergoing coronary artery bypass grafting (CABG) with hypothermic CPB received alfentanil 125 micrograms/kg intravenously (IV) at the induction of anesthesia and again 5 h later after the completion of CPB. Arterial blood samples were analyzed for alfentanil (n = 8) and for plasma proteins (n = 3). Arterial blood samples were obtained from another six patients for measurements of the concentrations of plasma proteins at various stages of the perioperative period. Compared to the pre-CPB period as well as to patients not exposed to CPB, CABG patients after CPB exhibited an increased elimination half-time (t1/2 beta = 180 +/- 55 min SD), central distribution volume (Vc = 0.25 +/- 0.07 L/kg), and total volume of distribution (Vdss 0.63 +/- 0.08 L/kg; Vd area 0.92 +/- 0.23 L/kg) which reflected a 33%-50% decrease in alpha 1-acid glycoprotein, the principal plasma protein to which alfentanil is bound. There was no substantial change in the concentration of free alfentanil at the start of CPB. The clearance of total alfentanil was not affected significantly by CPB. We conclude: 1) Alfentanil pharmacokinetics in CABG patients before CPB are similar to those found in noncardiac surgical patients and volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

A rule-based postoperative pain controller: Simulation results

We describe a system for controlling postoperative pain, a phenomenon that is difficult to treat by conventional control methods due to interpatient variability, interferences, non-linearity and the lack of a plausible, well-defined mathematical model. The system consists of two phases. In Phase 1 a closed-loop fuzzy controller implementing a suitable control strategy brings the patient to a zero-pain state. In Phase 2, an open-loop computer-assisted continuous infusion controller maintains a constant concentration of the analgesic (alfentanil) in plasma, subject to an upper safety limit on infusion rate; the setpoint of this controller is periodically revised (either maintained or reduced) on the basis of feedback on the duration of zero pain (setpoint reduction is necessary because the open-loop system has no means of knowing whether analgesic is accumulating in the patient). Pain is quantified by the patient on a numerical scale of 1 to 10 at 1.5-min intervals during Phase 1 and 9-min intervals during Phase 2. In simulation trials in which a fixed approximate model was used for the effect of sedation on pain while the pharmacokinetics of alfentanil were varied from one simulated patient to another, zero pain was achieved in under 15 min with minimal overshoot in plasma drug concentration and was maintained, with only minor deviation, by means of low drug concentrations.

Pharmacokinetics of Alfentanil in Patients Treated with Either Cimetidine or Ranitidine

The pharmacokinetics of alfentanil were studied after single dose intravenous administration of 125 μg/kg to 19 intensive care unit patients who were divided into 3 groups. Group I was given oral antacid, and groups II and III were given, respectively, cimetidine 1200 mg/day IV and ranitidine 300 mg/day IV for 48 hours before administration of alfentanil. Alfentanil plasma concentrations were determined over the 8 hours following drug administration using a radio-immunoassay. Pharmacokinetic parameters were calculated using a noncompartmental analysis. In group II, alfentanil plasma concentrations were significantly higher than in the other groups. In addition, significant changes involving the elimination half-life (142.3 ± 35 vs 81.14 ± 11 and 88.1 ± 33 minutes), total clearance (1.27 ± 0.5 vs 3.56 ± 1.17 and 2.74 ± 1 ml/kg/min) and total volume of distribution related to the pseudo distribution phase (226 ± 73 vs 336 ± 76 and 271 ± 61 ml/kg) were found in group II vs groups I and III. These results suggest that pretreatment with cimetidine alters alfentanil pharmacokinetics after single dose administration. In contrast, ranitidine does not appear to have a significant effect.

Patientengesteuerte Applikation von Alfentanil bei interventioneilen Maßnahmen - eine Alternative zur Allgemeinanästhesie

In 360 patients undergoing extracorporal shock wave lithotripsy (ESWL) the effects of an opioid analgesia with alfentanil (Rapifen) were investigated. Starting with an intravenous bolus injection of 30 micrograms/kg repetitive injections of 15 micrograms/kg were administered when pain recurred. In 12 patients arterial blood samples were taken to determine alfentanil serum concentrations and blood gases. The pharmacokinetics of alfentanil were described by an open two-compartment model. In spite of multiple applications of the opioid no relevant cumulation could be seen. Although the patients received 3 l/min of oxygen via nasal tube, a significant decrease in paO2 was observed. pH was decreased and there was a significantly increased paCO2. No significant changes in arterial blood pressure were observed. Two patients developed rigidity of the chest wall. For short operations with only mild noxious stimuli opioid analgesia with alfentanil is a suitable procedure if applied by an experienced anaesthesiologist.