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Biomedical subjects

D R Stanski

Publications and source records attributed to D R Stanski.

At least 91 records · Page 5Linked to original sources
PubMed1985

The effect of increasing age on thiopental disposition and anesthetic requirement.

The dose of thiopental required to induce anesthesia in adults decreases with age. The pharmacokinetic and pharmacodynamic properties of thiopental were studied in two groups of surgical patients to determine the mechanism of this decrease. In one group (29 patients 19-88 yr of age), thiopental was infused at a rate of 75-150 mg/min until the electroencephalogram (EEG) demonstrated early burst suppression (phase III). Arterial blood samples were obtained frequently during and after the infusion to measure serum thiopental concentrations, and power spectral analysis was used to calculate the spectral edge (Hz), defined as the frequency below which 95% of the EEG power is located. Pharmacodynamic modeling was used to relate the serum thiopental concentrations to the spectral edge in order to estimate the individual patient's brain sensitivity to thiopental. In a second group (28 patients 24-88 yr of age), pharmacokinetics were determined after a bolus or rapid infusion of thiopental. Arterial blood samples were obtained frequently to characterize the initial distribution phases, sampling continued for 24-48 h to characterize elimination processes. The dose of thiopental required to achieve early burst suppression on the electroencephalogram (EEG) decreased linearly and significantly with age. Pharmacodynamic modeling also demonstrated that brain sensitivity to thiopental does not change with age. The age-related decrease of the thiopental dose requirement is due to a change in the initial distribution of the drug. That is, the initial distribution volume (central compartment, or V1) of thiopental decreases exponentially with age. This smaller initial distribution volume in the elderly results in higher serum levels after a given dose of thiopental.

Adult↗
PubMed1984

Pharmacodynamic modeling of thiopental anesthesia.

We have pharmacodynamically modeled the relationship between the thiopental serum concentration and its effects on the electroencephalogram (EEG). Power spectral analysis was used to calculate the spectral edge, a measure of the underlying EEG frequency that characterizes the progressive slowing of the EEG induced by thiopental. Eight male volunteer subjects had venous thiopental serum concentrations measured, and 10 surgical patients had arterial serum concentrations measured. Thiopental was infused at a rate of 75 to 150 mg/min until a burst suppression EEG pattern was evident. Frequent blood samples were obtained during and after the infusion for measurement of serum thiopental concentrations, and the EEG was recorded for subsequent off-line power spectral analysis to calculate the spectral edge. With venous blood sampling, it was not possible to demonstrate significant hysteresis between the thiopental serum concentration and the spectral edge, allowing thiopental concentrations to be directly related to the spectral edge. With arterial blood sampling, significant hysteresis was present, requiring an effect compartment to relate concentration to effect. The half-time for equilibration (mean +/- SD) between concentration and response for the arterial data was 1.2 +/- 0.30 min. This value for Keo is consistent with known values for cerebral blood flow and thiopental brain: blood partition coefficient. Arterial-venous concentration differences cause the apparent lack of hysteresis with venous blood sampling. An inhibitory sigmoid Emax pharmacodynamic model optimally characterized the relationship between thiopental concentrations and the spectral edge. This model allows estimation of the thiopental serum concentration that causes one-half of the maximal EEG slowing (IC50), which is a measure of an individual's sensitivity to thiopental. Except for the hysteresis, there was no statistical difference in the parameters of the inhibitory sigmoid Emax pharmacodynamic model when venous and arterial blood samplings were compared. Arterial blood sampling offers some distinct advantages when pharmacodynamically modeling continuous, rapidly changing measures of drug effect, such as the EEG.

Adult↗
PubMed1984

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.

Adult↗
PubMed1983

Pharmacokinetics and anesthetic potency of a thiopental isomer.

In developing a high-performance liquid chromatographic assay for thiopental [5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid], a thiopental isomer [5-ethyl-5-(1-ethylpropyl)-2-thiobarbituric acid] was found. This isomer occurs (6-7%) in supposedly pure thiopental and in the commercially available thiopental sodium administered to patients for induction of anesthesia. A similar type of isomer also occurs in pentobarbital, the oxybarbiturate analogue of thiopental. Because the disposition and anesthetic potency of the isomer is unknown, its pharmacokinetic properties were determined in humans and its anesthetic potency in mice. In five surgical patients, the terminal elimination half-life, clearance, and volume of distribution at steady state of the isomer were not statistically different from those of thiopental. In mice, the isomer proved to be as effective as thiopental for induction of anesthesia. The LD50 and sleep time at one-half the LD50 did not statistically differ between the two compounds in mice. The close structural similarity of thiopental and the isomer results in similar pharmacokinetic and anesthetic properties. It does not appear critical that the isomer be separated from thiopental in subsequent pharmacological research.

Anesthetics↗
PubMed1983

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.

Administration, Oral↗
PubMed1983

The role of metabolism and protein binding in thiopental anesthesia.

The role of metabolism, relative to redistribution, in the termination of anesthesia was examined in patients receiving a single bolus iv injection of thiopental. Additionally, it was determined if nonlinear protein binding occurs immediately after the bolus iv injection of thiopental, possibly enhancing thiopental effect. Thiopental pharmacokinetics and protein binding were determined in 12 surgical patients with normal hepatic function. Using the pharmacokinetic equations listed in the appendix, plasma concentration over time data were used to quantitate the contribution of metabolism to the early decline of thiopental plasma concentrations after a single iv bolus administration. The fraction of thiopental loss from the central compartment due to metabolism was calculated to be 0.14 +/- 0.06 (mean +/- SD) at 1 min and 0.18 +/) 0.04 at 15 min. These data confirm that metabolism is far less important than distribution in the initial decline of blood and brain concentrations of thiopental, and, therefore, termination of thiopental anesthetic effect. The protein binding of thiopental from 0.5 to 15 min was found to be linear over a concentration range of 93 +/- 60 micrograms/ml to 6.9 +/- 0.62 micrograms/ml. Thus, concentration-dependent or nonlinear protein binding of thiopental after a single iv bolus administration could not be demonstrated and does not enhance thiopental anesthetic effect.

Adult↗
PubMed1982

Morphine pharmacokinetics: GLC assay versus radioimmunoassay.

The validity of a radioimmunoassay (RIA) for research on the pharmacokinetics of morphine has been questioned because of the possible measurement of cross-reactive metabolites. An RIA using antiserum derived from the 3-O-carboxymethylmorphine hapten was compared with a specific GLC assay in the measurement of plasma morphine concentrations in humans. The ratio of values for morphine concentrations measured using RIA and those measured using GLC was determined. The RIA values resulted in a 27% overestimation of this ratio. This overestimation did not significantly affect the values for terminal elimination half-life, volume of distribution at steady state, or total body clearance that were derived using results from each assay and model-independent pharmacokinetic techniques.

Adult↗
PubMed1982

Decreased protein binding and thiopental kinetics.

Thiopental kinetics and protein binding were determined in seven surgical patients with chronic renal failure and a thiopental free fraction of 28.0 +/- 6.5% (SD) and in seven age- and weight-matched normal surgical patients with a thiopental free fraction of 15.7 +/- 2.4%. Thiopental clearance, based upon total plasma concentrations, rose from 3.2 +/- 0.6 ml/kg/min in the normal group to 4.5 +/- 1.1 ml/kg/min in the chronic renal failure group. Volume of distribution at steady state, also based on total drug concentrations, rose from 1.9 +/- 0.5 l/kg in the normal group to 3.0 +/- 1.0 l/kg in the chronic renal failure group. These changes in clearance and volume of distribution at steady state are secondary to changes in free drug distribution and elimination. When kinetics were calculated from free drug concentrations, the intrinsic clearance, unbound volume of distribution at steady state, and free fraction in tissues in the normal and renal failure groups did not differ substantially. These data suggest that the kinetic changes based on total drug concentrations are secondary to changes in free fraction in plasma. In chronic renal failure patients, the underlying rate and extent of thiopental distribution and elimination are much the same as in normal patients.

Blood Proteins↗
PubMed1982

Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults.

The pharmacokinetics and pharmacodynamics of d-tubocurarine (dTc) were determined in neonates (0-2 months, n = 7), infants (2-12 months, n = 7), children (1-12 years, n = 9), and adults (12-30 years, n = 8) during 70% nitrous oxide, 0.58 MAC halothane anesthesia. dTc was administered by infusion, while blood for determination of plasma dTc concentrations was obtained, and the EMG of the adductor pollicis recorded. The plasma dTc concentration at which 50% depression of EMG twitch height occurs (Cpss(50)) was 0.18 +/- 0.09 micrograms/ml in neonates, and 0.27 +/- 0.06 micrograms/ml in infants, both significantly lower than the values of 0.42 +/- 0.14 and 0.53 +/- 0.14 micrograms/ml for children and adults, respectively. The steady-state distribution volume (Vdss) was 0.74 +/- 0.33 l/kg in neonates, significantly greater than the values of 0.52 +/- 0.22, 0.41 +/- 0.12, and 0.30 +/- 0.10 l/kg in infants, children, and adults, respectively. The elimination half-life (t beta 1/2) was 174 +/- 60 min in neonates, significantly longer than the values of 90 +/- 23 and 89 +/- 18 min in children and adults, respectively. Plasma clearance did not differ with age. We also determined D50, the product of Vdss and Cpss(50). D50, the quantity of drug present at steady-state to produce 50% paralysis, did not differ between groups. The authors conclude that during comparable nitrous oxide-halothane anesthesia, neonates and infants have an increased sensitivity to dTc, as determined by CPss(50). However, because of the larger Vdss in younger patients, dose size should not differ with age. In addition, because of the longer t beta 1/2 in neonates, second and subsequent doses should be required at less frequent intervals.

Adolescent↗
PubMed1981

Pharmacokinetics of edrophonium in anephric and renal transplant patients.

The pharmacokinetics of edrophonium were determined in patients anaesthetized with nitrous oxide and halothane undergoing kidney transplant nephrectomy (n=6) or transplantation of a live related donor kidney (n = 6). Serum concentrations of edrophonium were assayed by high pressure liquid chromatography and pharmacokinetic variables computed using non-compartmental analysis. Patients undergoing transplant nephrectomy had a significant increase in elimination half-life and a significant decrease (67%) in serum clearance when compared with kidney transplant recipients or patients with normal renal function. Pharmacokinetic indices for edrophonium in patients receiving a kidney transplant did not differ from those in patients with normal renal function. We conclude that absence of renal function decrease excretion of edrophonium to an extent similar to that of other acetylcholinesterase inhibitors, neostigmine and pyridostigmine.

Adult↗
PubMed1981

Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man.

The pharmacokinetics and effectiveness of edrophonium antagonism of d-tubocurarine neuromuscular blockade were compared with that of neostigmine in surgical patients anesthetized with halothane and nitrous oxide. After an intravenous (iv) injection of d-tubocurarine (0.3 mg/kg), the single twitch tension was allowed to return to five per cent of the control level. Edrophonium, 0.5 or 1.0 mg/kg (n = 12), or neostigmine, 0.07 mg/kg (n = 6), was then given iv in combination with atropine, 1.0 mg, as a 2-min controlled infusion. Train-of-four and single twitch tension were followed for 60 min in all patients. Twelve patients were monitored for 90 min, six patients for 120 min, four patients for 150 min, and two patients for 240 min. Blood was sampled intermittently for four hours and assayed for edrophonium or neostigmine using high-pressure liquid chromatography. Edrophonium was found to promptly antagonize the d-tubocurarine blockade. Twitch tension rapidly increased to a plateau (a rate of increase in twitch tension of less than 2 per cent of control per min) which was sustained in all cases. The mean time to plateau for edrophonium was 2.9 +/- 0.21 (+/-SE) min as compared to 6.1 +/- 0.75 min for neostigmine. Neuromuscular blockade did not reappear in any patient. The degree of antagonism of the neuromuscular blockade by neostigmine and edrophonium was not significantly different. Except for a longer distribution half-life, the pharmacokinetic variables for edrophonium did not differ significantly from those for neostigmine. The elimination half-lives of edrophonium and neostigmine were 110 +/- 34 min (mean +/- SD) and 77 +/- 47 min, respectively. The authors therefore conclude that edrophonium, 0.5-1.0 mg/kg, has pharmacokinetic variables comparable to neostigmine and produces prompt, sustained, and effective antagonism of d-tubocurarine neuromuscular blockade.

Adult↗
PubMed1980

Pyridostigmine kinetics with and without renal function.

Pyridostigmine kinetics were examined under conditions of clinical use as an antagonist of nondepolarizing neuromuscular blockade in anesthetized patients with and without renal function. Pyridostigmine serum levels were assayed by gas-liquid chromatography, and data were fitted to a 2-compartment kinetic model. Pyridostigmine kinetics following renal transplantation (n = 5) were not different from those in patients with normal renal function. Renal function (n = 5) elimination half-life increased from 112 +/- 12 min (mean +/- SD) to 379 +/- 162 min, and serum clearance decreased from 9 +/- 2 ml/kg/min to 2 +/- 0.6 ml/kg/min in anephric patients (n = 4). We conclude that renal function accounts for 75% of pyridostigmine clearance.

Adult↗