Chronic alcohol intake does not change thiopental anesthetic requirement, pharmacokinetics, or pharmacodynamics.

The anesthetic requirements of chronic alcoholics for induction of anesthesia with thiopental were investigated using an electroencephalographic (EEG) measure of thiopental's CNS drug effect and pharmacodynamic modeling to relate thiopental serum concentrations to drug effect. Eleven patients with a history of excessive alcohol intake were studied from an inpatient alcohol rehabilitation program and compared with nine control patients or volunteers who were social drinkers. The alcoholic population had consumed ethanol 9-17 days prior to the study. They had no evidence of acute intoxication or acute withdrawal at the time of the study. Five of the 11 alcoholic patients were restudied after 1 month of abstinence from alcohol consumption. Each study consisted of a thiopental infusion until EEG burst suppression (1-3 s of isoelectric signal) was achieved. Timed arterial and then venous blood samples were obtained for measurement of thiopental serum concentrations for up to 36 h. Pharmacokinetic differences between groups were analyzed using a three-compartment model. Power spectral analysis of the EEG allowed determination of spectral edge frequency. An inhibitory sigmoid Emax pharmacodynamic model combined with an effect compartment was used to analyze concentration-response relationships and to provide an estimate of brain sensitivity to thiopental in the study populations. The thiopental anesthetic dose requirement using the EEG was not different between alcoholics and nonalcoholics. The mean dose requirement (+/- SD) of alcoholics was 823 +/- 246 mg and the mean dose requirement of nonalcoholics was 733 +/- 218 mg. There were no differences in thiopental pharmacokinetic and pharmacodynamic parameters between alcoholics and nonalcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodynamics of constant-rate i.v. and transdermal delivery.

We have investigated the use of constant-rate delivery of fentanyl by i.v. and transdermal routes for the treatment of pain after major surgery. Forty-five males, ASA I-III, received in a double-blinded fashion either placebo (n = 6) or fentanyl (n = 39) i.v. at one of four dose rates (25, 50, 100 or 125 micrograms h-1). Stable serum concentrations of fentanyl were produced by the end of surgery and were maintained for a total of 24 h. Calculated clearance of fentanyl was 1.05 +/- 0.38 litre min-1 and was not related to weight or age. Both the 100- and 125-micrograms h-1 dose rates produced significant analgesic efficacy as assessed by postoperative morphine requirements. Mean serum concentrations of fentanyl in these groups were 1.42 +/- 0.14 (SD) and 1.90 +/- 0.30 ng ml-1, respectively. One of 10 patients receiving fentanyl 100 micrograms h-1 and three of nine patients receiving 125 micrograms h-1 had evidence of respiratory depression. Eight additional patients were treated with a transdermal drug delivery system containing fentanyl (TTS-fentanyl). Steady-state serum concentrations in this group were 2.15 +/- 0.92 (SD) ng ml-1. Post-operative morphine requirements were minimal (less than 0.5 mg h-1) and PaCO2 remained acceptable in all patients. Serum concentrations of fentanyl increased slowly (15 h to plateau) and decreased slowly (apparent half-life, 21 h). We conclude that delivery of analgesic doses of fentanyl is feasible by the transdermal route.

Intravenous anaesthetic agents. Pharmacokinetic-pharmacodynamic relationships.

The number and variety of intravenous anaesthetics available has increased dramatically in recent years. In order to administer these agents safely and rationally in the operating theatre, the anaesthesiologist needs to have a detailed understanding of their dose-response behaviour. The pharmacokinetic and pharmacodynamic profiles of these anaesthetics underlie this behaviour. In understanding and applying this information, an integrated approach involving combined pharmacokinetic and pharmacodynamic modelling has proved tremendously helpful. This approach has provided significant insight into the pharmacology of these drugs under conditions of normal and abnormal physiology. Intravenous anaesthetics may be classified as hypnotics, narcotics, or muscle relaxants. Through quantitative measures or drug effect, as provided by the electroencephalogram (EEG) in the former two classes or electromyography in the latter class, precise measures of end-organ (brain or neuromuscular junction) sensitivity have been generated using integrated modelling techniques. These values not only allow for dose potency comparisons within an anaesthetic class but, furthermore, may explain changes in drug response with ageing and disease. Incorporation within these models of an effect compartment, characterised by a rate constant for equilibration with plasma (keo), has proved to be essential in accurately describing the temporal lag between drug administration and effect. Quantitating the size of this lag has direct implications for the design of anaesthetic bolus and infusion regimens. Combined pharmacokinetic and pharmacodynamic modelling of intravenous anaesthetics provides a precise, rational basis for the clinical use of these classes of drugs.

Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response.

To determine the effect of aging on the pharmacokinetics and pharmacodynamics of etomidate, we administered etomidate (5 to 10 mg/min) by intravenous infusion to 21 healthy surgical patients, age 22 to 82 yr. Etomidate produced progressive slowing of the EEG to an easily recognized pattern (stage 3) that determined the dosage endpoint. Subsequent power-spectrum analysis of the EEG gave the median frequency. Median frequency values and simultaneous measurements of blood etomidate concentration were incorporated into a sigmoid Emax pharmacodynamic model that permitted an estimate of IC50, the blood etomidate concentration which produced a 50% reduction in the median frequency. The dose of etomidate required to reach the uniform EEG endpoint decreased significantly with increasing age (r2 = .68) as did the dose needed to produce maximal median frequency depression (r2 = .69). None of the parameters of the pharmacodynamic effect model, including IC50, correlated with age, suggesting that increased brain sensitivity in the elderly does not cause the age-related change in dose requirement. The initial distribution volume for etomidate decreased significantly with increasing age (r = .56), implying that a higher initial blood concentration in the elderly following any given dose of etomidate is part of the cause of the lower dose requirement in the elderly patient. A contracted initial distribution volume in the elderly may result from well described physiologic changes of age. Etomidate clearance also decreased with age. Age-dependent changes in etomidate pharmacokinetics rather than altered brain responsiveness may be the basis for the decreased etomidate dose requirement in the elderly.

Effects of cardiac surgery with cardiopulmonary bypass on lidocaine disposition.

We investigated lidocaine kinetics after cardiac surgery to elucidate the effects of cardiopulmonary bypass (CPB) and major surgery on its disposition. In five patients lidocaine kinetics were unchanged 15 min and 1 day after CPB, but lidocaine clearance decreased 42% and volume of distribution was reduced by 40% in eight patients 3 days after surgery. Seven days after surgery lidocaine kinetics had returned to baseline in five patients. These changes correlated with a doubling of the alpha 1-acid glycoprotein concentration and a 46% decrease in lidocaine free fraction on day 3, effects that persisted on day 7. Our results suggest that the use of lidocaine need not be altered in the first day after uncomplicated coronary artery surgery, but, in light of our findings the use of lidocaine and the interpretation of measured total lidocaine concentrations 3 to 7 days thereafter should be reexamined.

Haloperidol kinetics after oral and intravenous doses.

Haloperidol kinetics were determined after oral and intravenous drug doses in 15 men. Mean elimination t1/2 for the subjects was 17.9 +/- 6.4 (SD) hr. After 0.125 mg/kg IV, mean distribution t1/2s in six subjects were 0.19 +/- 0.07 and 2 +/- 1 hr, and in 12 subjects mean clearance was 11.8 +/- 2.9 ml/kg/min and mean steady-state volume of distribution was 17.8 +/- 6.5 l/kg. After 0.50-mg/kg oral doses in eight subjects, mean lag time before drug absorption was 0.82 +/- 0.25 hr. Mean absorption t1/2 was 0.37 +/- 0.18 hr and mean distribution t1/2 was 0.96 +/- 0.20 hr. Bioavailability was 0.65 +/- 0.14 after oral doses. In 14 kinetic studies in nine subjects, data was analyzed by both model-dependent (open two- and three-compartment models using nonlinear regression) and model-independent (AUC and first moment curve) approaches. Results of the two were found to be in close agreement. The long elimination t1/2 of haloperidol is explained by the drug's extensive tissue distribution.

Effect of cardiopulmonary bypass on the pharmacokinetics of drugs.

The cardiopulmonary bypass apparatus must temporarily substitute for the cardiac and pulmonary function of the patient undergoing heart surgery. In order to meet the metabolic needs of the patient and the technical demands of the surgeon, within the limits of engineering technology, a number of major alterations are made in normal physiology. The patient is typically cooled to 27 degrees C and perfused with a non-pulsatile flow of blood which has been diluted with saline to a haematocrit in the mid-20s. Blood flow and pressure are often considerably less than normal. Blood coagulation is prevented by administration of a massive dose of heparin. Central redistribution of blood flow, elaboration of stress-reactant hormones, and fluid and electrolyte shifts occur in response to these changes. In the postoperative period, these alterations are reversed, and normal physiology is restored. Effects upon the pharmacokinetics of drugs are anticipated. The clearance of many drugs may be reduced. Protein binding is diminished by haemodilution, but may rise above normal in the postoperative period for basic drugs which bind to alpha 1-acid glycoprotein. Changes in volume of distribution depend upon the opposing influences of protein binding and reduced peripheral perfusion. Previous studies on the pharmacokinetics of drugs during and after cardiopulmonary bypass illustrate many of these effects. The clearance of digoxin, fentanyl, and the cephalosporins is reduced after cardiopulmonary bypass, and the volume of distribution of cefazolin is increased during cardiopulmonary bypass. Studies of digitoxin and propranolol are also reviewed. Many of the investigations in this area of study have been limited by logistical and methodological factors. Thus, the effects of cardiopulmonary bypass on the pharmacokinetics of drugs are incompletely understood, and the subject merits further attention.