J.C. Levron

Alfentanil Pharmacokinetics in Patients with Cirrhosis

The pharmacokinetics of alfentanil were studied in 11 patients with alcoholic cirrhosis and 10 control patients during general anesthesia. All patients received 50 μg·kg−1 alfentanil as an intravenous bolus injection. Plasma concentrations were measured acintervals up to 10 h, using a specific radioimmunoassay technique. Protein binding was measured by equilibrium dialysis. Patients with cirrhosis had a significantly lower (P < 0.01) plasma clearance of alfentanil of 1.6 ± 1.0 ml·min−1·kg−1 (mean ± SD) instead of 3.1 ± 1.6 ml · min−1 · kg−1 in the controls. The total apparent volume of distribution was similar in the two groups. The elimination half-life was prolonged from 90 ± 18 min in the controls to 219 ± 128 min in the cirrhotics (P < 0.01). Patients with cirrhosis had a higher (P < 0.01) alfentanil plasma-free fraction (18.6 ± 9.4%) compared with the control patients (11.5 ± 3.9%). When kinetic parameters were corrected for protein binding, the unbound volume of distribution and the free drug clearance were decreased significantly in patients with cirrhosis. Since the concentration α1-glycoprotein to which alfentanil mainly is bound in plasma did not differ in the two groups, it is suggested that the increase in the free fraction is caused by an alteration of binding sites of this protein in patients with cirrhosis. Owing to its delayed elimination and increased free fraction, alfentanil will exert a prolonged and pronounced effect in patients with cirrhosis.

OXYGEN UPTAKE AFTER MAJOR ABDOMINAL SURGERY : EFFECT OF CLONIDINE

To examine the effect of an alpha-2 agonist, clonidine, on oxygen uptake and on the incidence of postoperative shivering, 28 patients presenting for major abdominal surgery were randomly assigned in a double-blind manner to one of two groups. Intraoperatively, 14 patients received 5 micrograms.kg-1 clonidine infused over 3 h (clonidine group), and 14 patients received placebo (placebo group). Oxygen uptake was measured continuously over the first 3 postoperative hours with a mass spectrometer system. Circulatory variables, esophageal temperature, and skin temperature were measured over the first 6 postoperative hours. Heart rate, mean arterial pressure, rate pressure product, and norepinephrine concentration were decreased in the clonidine group (P less than 2 x 10(-4)). There were no differences among groups in the incidence of shivering and in the rate of increase of esophageal temperature. By contrast, oxygen uptake was lower in the clonidine group (P = 4 x 10(-4)). This contrasting pattern may be secondary to a reduction in the intensity of mean muscular tremor in the clonidine group.

Pharmacokinetics of alfentanil in chronic renal failure.

The pharmacokinetics of alfentanil were studied during general anesthesia in nine patients with renal failure and in ten patients with normal renal function. All patients received 0.05 mg/kg alfentanil as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 8 hr, using a specific radioimmunoassay technique. Protein binding was measured by equilibrium dialysis. Elimination half-life and plasma clearance were similar in both groups. The volume of distribution at steady state was greater (P < 0.02) in patients with renal failure (405 ± 86 ml/kg) than in patients with normal renal function (281 ± 97 ml/kg). Patients with renal failure had a higher (P < 0.01) alfentanil plasma free fraction (0.19 ± 0.06) than patients with normal renal function (0.11 ± 0.03). When kinetic parameters were corrected for protein binding, the unbound volume of distribution and the free drug clearance were unchanged in patients with renal failure. These results suggest that the modification of alfentanil free fraction in renal failure does not induce any change in elimination but may influence the distribution of alfentanil.

Sufentanil pharmacokinetics in patients with cirrhosis.

The effects of cirrhosis on the elimination kinetics and plasma protein binding of sufentanil were evaluated in 12 anesthetized patients with uncomplicated cirrhosis and these findings were compared with data from age-matdied control anesthetized patients with normal hepatic and renal function. Sufentanil 3 μg/kg was Xiuen intravenously as a bolus injection and venous plasnza concentrations were measured at intervals up to 10 hrs. The average (±SD) elimination half life was 3.5 ± 0.9 lirs in controls and did not differ in cirrhotics: 4.1 ± 0.6 hrs. The plasma clearance did not differ between the two groups: 11.3 ± 2.5 ml·min−1·kg−1 in controls and 10.8 ± 4.6 ml·min−1·kg−1 in cirrhotic patients. The sufentanil free fraction was also similar in controls (8.3 ± 1.590) and in cirrhotic patients (9.6 ± 1.8%). These data suggest that sufentanil in a single dose should hazle a similar duration of action in patients with uncomplicated cirrhosis and in normal patients.

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects.

AbstractObjective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4–5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss · kg–1) 11.2 l ·  kg–1; total clearance (CL) 51.6 h–1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l · h–1) were significantly higher in obese patients. But Vss · kg–1 (9.4 l · kg–1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15–18 l · h–1) and the t1/2 prolonged (32–34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.

Determination of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography with electrochemical detection

A method for the determination of risperidone and its active metabolite 9-hydroxyrisperidone in human plasma has been developed. The procedure involved a multi-step liquid-liquid extraction with an internal standard. The parent drug and its metabolite were separated on a cyano column used in the reversed-phase model. The coulometric detection allows quantification in the range 2-100 ng/ml. The precision, accuracy and specificity have been checked, and show that the method is reliable for clinical studies.

The Influence of Hepatic Plasma Flow on Alfentanil Plasma Concentration Plateaus Achieved with an Infusion Model in Humans: Measurement of Alfentanil Hepatic Extraction Coefficient

In a group of seven patients undergoing intracranial surgery under neurolept anesthesia, an alfentanil infusion was initiated with a loading dose of 235 μg/kg over 5min, followed by a maintenance infusion rate of 1.8 μg/kg−1·min−1 in order to obtain a steady state plasma concentration (Css) of 400 ng/ml−1 according to an infusion model. The mean values of Css (446 ± 209 ng/ml) were close to the predicted ones. Nevertheless, an important intersubject variability in Css values was observed. A positive linear correlation existed between alfentanil steady state clearance and indocyanine green clearance (r = 0.88) and between alfentanil steady state clearance and cardiac index (r = 0.93). In three patients, a catheter was inserted into an hepatic vein to determine the alfentanil hepatic extraction coefficient. Alfentanil plasma clearance did not differ from alfentanil hepatic clearance and alfentanil hepatic extraction coefficient values ranged from 0.32–0.53. We conclude that alfentanil is a drug with an intermediate hepatic extraction coefficient and that alfentanil plasma clearance depends on hepatic plasma flow, which is thus one of the factors accounting for individual variability in plasma concentration plateaus achieved with an infusion model.

Risperidone Drug Monitoring

AbstractBackground: Risperidone is an atypical antipsychotic drug that has been marketed in France since 1996. Therapeutic failures have been observed with risperidone. Objective: To investigate whether interactions with the cytochrome P450 (CYP) isoenzymes implicated in risperidone metabolism could explain these treatment failures. Design and Setting: This was a retrospective study of clinical and drug monitoring data from 50 patients treated by five psychiatrists in northern France. Methods: The concentration of active drug (risperidone + 9-hydroxy-risperidone) in serum was evaluated by high performance liquid chromatography and radio receptor assay. Clinical efficacy was assessed by the global improvement (CGI2) item of the Clinical Global Impression rating scale. Results: Statistical analysis revealed a significant increase in efficacy when the serum concentration of active drug was between 25 and 150 μg/L compared with when it was out of this range. Carbamazepine, a CYP3A4 inducer, dramatically decreased the concentration of the active moiety of risperidone; on the contrary, CYP3A4 inhibitors (alprazolam and valproic acid) increased the concentration of active drug. The metabolism of risperidone by CYP3A4 did not lead to the formation of metabolite(s) with anti-D2 dopaminergic activity. Drugs interacting with CYP2D6 altered the risperidone/9-hydroxy-risperidone ratio but did not change the total amount of active drug. Conclusions: We have established a therapeutic range for risperidone. CYP3A4 is a major pathway for risperidone metabolism. Consideration of these factors in clinical practice should lead to improved outcomes for patients treated with risperidone.

More epidural than intravenous sufentanil is required to provide comparable postoperative pain relief

The extent to which epidurally administered sufentanil acts directly on spinal opioid receptors remains controversial. We tested the hypothesis that small-dose boluses of sufentanil, given epidurally or IV, provide comparable analgesia at similar plasma sufentanil concentrations. The lipophilicity of sufentanil makes it likely to be absorbed into fat surrounding the epidural space. We therefore also tested the hypothesis that more epidural than IV sufentanil is required to produce comparable analgesia. Analgesia and plasma sufentanil concentrations were evaluated in 20 postoperative patients randomly assigned to patient-controlled epidural or IV sufentanil. Pain was evaluated with visual analog scales by blinded observers. Sufentanil doses and plasma concentrations were measured. Analgesia was similar with epidural and IV sufentanil administration. Plasma sufentanil concentrations were virtually identical in the two groups. However, significantly larger sufentanil doses were required with epidural administration: 238 ± 50 &mgr;g vs 160 ± 32 &mgr;g (P < 0.01). The primary mechanism by which small-dose boluses of epidurally-administered sufentanil produce analgesia seems to be systemic absorption of the drug with subsequent recirculation to the supraspinal opioid receptors. This study demonstrates that the cumulative dose of sufentanil, when administered as a small epidural bolus, is approximately 50% more than that administered IV to provide comparable analgesia. This indicates that the bioavailability of epidurally-administered sufentanil is reduced and suggests that a large proportion of the drug may be absorbed into the epidural fat.

COMPARATIVE PHARMACOKINETIC STUDY OF FENTANYL AND SUFENTANIL AFTER SINGLE HIGH-BOLUS DOSES

AbstractObjective: To investigate and compare the pharmacokinetic parameters of sufentanil and fentanyl during a prolonged period after single bolus administration, and to detect and compare the occurrence of secondary peaks of opioid plasma concentration. Design: This was a prospective, double-blind, randomised study in surgical patients. Patients: Forty-one patients, aged ≥35 years, undergoing coronary artery bypass graft surgery, were randomised to anaesthesia with sufentanil/O2 (n = 20) or fentanyl/O2 (n = 21). Methods: Arterial blood samples were taken up to 24 hours after administration for determination of plasma opioid concentrations, and haemodynamic parameters were monitored during and after the surgical procedure. Pharmacokinetic data were analysed by compartmental analysis and by population analysis using a nonlinear mixed-effect modelling approach. Results: There were no significant differences in demographics, features of the surgical procedure or haemodynamic parameters between the two groups. By population analysis, the terminal elimination half-life (t1/2z) of fentanyl was 20.7 hours, total body clearance (CL) was 4.7 ml/min/kg and volume of distribution at steady state (Vss) was 5.2L/kg. For sufentanil, t1/2z was 37.7 hours, CL was 7.4 ml/min/kg and Vss was 13.9 L/kg. No correlation was observed between demographic data and pharmacokinetic parameters for sufentanil, whereas for fentanyl significant correlations were revealed between age and Vss, t1/2z and the intercompartmental transfer rate constant k21. Significant differences were observed in the occurrence of secondary peaks, which occurred in nine patients receiving fentanyl (with two patients exhibiting double secondary peaks) and in one patient receiving sufentanil (p = 0.02). Conclusions: Our study allowed a better determination of the pharmacokinetic parameters of high-dose sufentanil administered as a single bolus, and we demonstrated a clear pharmacokinetic difference between fentanyl and sufentanil in terms of higher CL and larger Vss for sufentanil. These pharmacokinetic differences have not had clinically relevant consequences in our study. However, the occurrence of secondary peaks, which have been considered as a risk factor in the postoperative period, is significantly reduced with sufentanil compared with fentanyl.