Jay Ham

Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d‐tubocurarine

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time‐independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non‐equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first‐order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least‐squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d‐tubocurarine (dTC). In 7 normal subjects, the (mean ± SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 ± 0.04 min−1 and the (mean ± SD) steady‐state Cp required to produce 50% paralysis is 0.37 ± 0.05 µg/ml.

Pharmacology of ketamine isomers in surgical patients.

To assess the intraoperative and postoperative effects of the optical isomers of ketamine. compared with the racemic mixture as sole anesthetics, equianesthetic doses of racemic ketamine (RK), 2 mg/kg, (+)ketamine (PK), 1 mg/kg, and (−)ketamine (MK), 3 mg/kg, were administered intravenously in a randomized, double-blind fashion to 60 healthy patients undergoing elective outpatient operations. Intraoperative effects, adequacy of anesthesia, and need for adjunctive agents were assessed by the same two anesthesiologists. Psychologic assessment was achieved utilizing a trait anxiety scale, a profile of mood states questionnaire, an open-ended sentence-completion form, and a postoperative check list, as well as observations made by a psychologist in the recovery room. Samples of plasma and urine were obtained for gas chromatographic analysis of ketamine and its major metabolites. The durations of anesthesia (35 ± 4 min) were the same in all three groups; however, the amounts of drug needed ranged from 2.4 mg/kg in the PK group to 8.5 mg/kg in the MK group. At the termination of anesthesia, mean plasma levels of the parent compounds were 0.9 (RK), 0.5 (PK), and 1.7 pg/ml (MK), consistent with a PK:MK potency ratio of 3.4:1. The slopes of the plasma decay curves were not significantly different among the three groups. PK was judged to produce more effective anesthesia than RK or MK (95 vs. 75 vs. 68 per cent). Verbal responses in the postanesthetic period suggested significantly more psychic emergence reactions after MK than after RK or PK (37 vs. 15 vs. 5 per cent). Furthermore, MK produced more agitated behavior than did RK or PK (26 vs. 10 vs. 0 per cent). Postoperative pain occurred more commonly in the RK (10 per cent) and MK (16 per cent) groups than in the PK group (0 per cent). The incidences of dreaming (84 per cent) were the same in all three groups. Relative to preoperatively, fear was decreased to a greater extent postoperatively in the PK group than in the RK and MK groups (43 vs. 13 vs. 30 per cent). Finally, patients found PK more acceptable than either RK or MK (85 vs. 65 vs. 63 per cent). The study disclosed differences in anesthetic potencies, intraoperative effects, analgesia, physical side effects, incidences and types of postanesthetic emergence phenomena, and anesthetic preferences among the optical isomers of ketamine. Parallelism of the plasma decay curves and similarities in the patterns of appearance and excretion of the ketamine metabolites for the three groups suggest that the differences were due to pharmacodynamic factors.

Pharmacokinetics and pharmacodynamics of d-tubocurarine during nitrous oxide-narcotic and halothane anesthesia in man.

The relative contributions of changes in pharmacokinetics and pharmacodynamics to the potentiation of d-tubocurarine (dTc)-induced paralysis by halothane in comparison with nitrous oxide (N2O)–narotic anesthesia were studied in three groups of patients. Fourteen patients received N2O-narcotic mainte

Pharmacokinetics and Pharmacodynamics of d -Tubocurarine during Hypothermia in the Cat

To determine the effects of hypothermia on the pharmacokinetics and pharmacodynamics of d-tubocurarine (dTc), serum, biliary, and urinary concentrations were determined and twitch tension monitored following intravenous administration of dTc, 0.7 mg/kg, at 39 (n = 5), 34 (n = 5), and 28 C (n = 6) in cats anesthetized with chloralose and urethane. Time from injection of dTc to maximum neuromuscular blockade was prolonged by hypethermia (28 C). Similarly, moderate (28 C) but not mild (34 C) hypothermia delayed recovery from paralysis. The serum half-life was prolonged 76 per cent and the serum clearance rate decreased 60 per cent by hypothermia (28 C). The combined biliary and urinary elimination of dTc was decreased 47 per cent at 28 C compared with 34 and 39 C. The serum concentration of dTc necessary for neuromuscular blockade was less at 39 C (ED50 0.87 μg/ml) than at 34 or 28 C (ED50 1.13 μg/ml). It is concluded that, in vivo, hypothermia antagonizes a dTc-induced neuromuscular blockade but decreases the elimination of dTc. At 28 C the net effect is a prolongation of neuromuscular blockade.

Time-dependent increase in sensitivity to d-tubocurarine during enflurane anesthesia in man.

The pharmacokinetics of d-tubocurarine (dTc) during enflurane and during halothane anesthesia were compared in man. Seven patients received enflurane (1.3–1.4 per cent end-tidal) with nitrous oxide (70 per cent), while seven patients received an equipotent anesthetic concentration of halothane (0.5–0.7 per cent end-tidal) with nitrous oxide (70 per cent). Force of thumb adduction was used to assess paralysis. Using a rapid followed by a slower infusion of dTc, relatively constant plasma concentrations were obtained within an hour and were maintained for one to two hours. To determine the effect of enflurane with nitrous oxide on force of thumb adduction, a control group of four patients did not receive dTc while thumb adduction was monitored for two to three hours. In the halothane-treated group, a constant plasma concentration of dTc resulted in a constant degree of paralysis. With enflurane, however, a constant plasma concentration resulted in a time-dependent increase of paralysis, indicating an increased sensitivity of the neuromuscular junction to dTc. In the control group, enflurane alone did not decrease the force of thumb adduction.The increase in paralysis in the enflurane-treated group was linear over a one to two hour period, with a mean increase of 9.0 per cent per hour. Evaluating only the first hour of enflurane anesthesia, the steady-state plasma concentration that caused 50 per cent paralysis (Cpss(50) was .52 ± .13 μg/ml (mean ± SD), while the Cpss(50) for halothane was significantly lower, .36 ± .04 μg/ml. Thus, during the first hour of enfluranne anesthesia, larger amounts of dTc will be needed to initiate paralysis in comparison with halothane anesthesia. As the duration of enfluranne anesthesia increases, sensitivity to dTc will progressively increase, and subsequent maintenance doses of dTc needed will be smaller, relative to equipotent halothane anesthesia.

Pharmacokinetics and Dynamics of d-Tubocurarine during Hypothermia in Humans

&NA; To determine the influence of hypothermia on the pharmacokinetics and dynamics of d‐tubocurarine (dTc), 17 patients were studied during halothane 0.5‐0.7 per cent end‐tidal and 60 per cent nitrous oxide anesthesia with controlled hyperventilation (PaCO2 ˜ 25 torr) during craniotomy. Ten patients were deliberately cooled to an esophageal temperature of 31.9 ± 0.3° C (mean ± SE) and a hypothenar muscle temperature of 31.8 ± 0.3° C while seven patients had an esophageal temperature maintained at 35.8 ± 0.1° C and a hypothenar muscle temperature of 36.7 ± 0.2° C. Hypothermia did not affect the pharmacokinetics of dTc. Using 75 per cent to 25 per cent recovery times, dTc neuromuscular blockade was prolonged in the hypothermic patients by 82 per cent, compared with the normothermic patients, as measured by twitch tension of the thumb adductors, but was unchanged as measured by the compound electromyogram (EMG). The steady state serum concentration necessary to produce 50 per cent paralysis (Cpss(50)), was not significantly different during hypothermia (0.46 ± 0.07 μg/ml) relative to normothermia (0.57 ± 0.07 μg/ml). The half‐time for equilibrium between serum dTc concentration and paralysis (t1/2 Keo) approached (P = 0.06) but was not significantly different during hypothermia (9.2 ± 1.2 min) versus normothermia (5.4 ± 0.7 min). However four of the nine patients in the hypothermic group had a marked prolongation (>10 min) of this value. This suggests that hypothermia reduces blood flow to the neuromuscular junction, delaying onset of paralysis after administration of dTc. Other than a delayed half‐time for equilibrium and differential effect on EMG vs. twitch tension, we conclude that a decrease in body temperature to 31.9° C does not significantly alter the pharmacokinetics and pharmacodynamics of d‐tubocurarine.

Simultaneous Modeling of Pharmacokinetics and Pharmacodynamics: Application to D-Tubocurarine

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.

Dosage-Schedule Independence of d-Tubocurarine Pharmacokinetics and Pharmacodynamics, and Recovery of Neuromuscular Function

To study the relationship of d-tubocurarine (dTc) dosage schedule to its pharmacokinetics and pharmacodynamics, and recovery of neuromuscular function, 30 patients were given markedly different doses of dTc to produce 90 per cent or greater depression of twitch tension for two hours during stable halothane anesthesia. Ten patients each were given dTc in one of three dosage schedules: 20 mg/m2 as a single large bolus; repeated smaller doses of 5 mg/m2; or a continuous infusion. After two hours of neuromuscular blockade, all patients experienced spontaneous recovery to 10 per cent of control twitch tension. Thereafter, five patients in each group continued with spontaneous recovery and five had antagonism of paralysis by neostigmine, 0.25 mg, and atropine, 0.1 mg, every 5 min. Serum dTc concentrations were determined by radioimmunoassay every 30 min and during recovery. There was no difference among the three dosage protocols in any of the following variables: total dose of dTc (mg/m2/hr) needed for two hours of paralysis and spontaneous recovery to 10 per cent of control twitch tension; time for recovery of twitch tension occurring spontaneously or during antagonism by neostigmine; or total dose of neostigmine needed during antagonism of paralysis. There was a relationship between serum dTc concentration and neuromuscular blockade, which was the same among the three dosage protocols. There was no clinically significant difference in pharmacokinetics among the groups. The authors conclude that there is a relationship between serum dTc concentration and neuromuscular blockade, and that it is independent of dTc dosage administered. Duration of neuromuscular blockade following dTc administration was related to serum dTc concentration and not to initial dTc dosage.

Pharmacokinetics and Pharmacodynamics of d-Tubocurarine during Nitrous Oxide-Narcotic and Halothane Anesthesia in Man

The relative contributions of changes in pharmacokinetics and pharmacodynamics to the potentiation of d-tubocurarine (dTc)-induced paralysis by halothane in comparison with nitrous oxide (N2O)–narotic anesthesia were studied in three groups of patients. Fourteen patients received N2O-narcotic maintenance anesthesia, while seven patients received halothane, 0.5–0.7 per cent, end-tidal, with N2O, 70 per cent, and seven patients received halothane, 1.0–1.2 per cent, end-tidal, with N2O, 70 per cent. The steady-state plasma concentration necessary to cause 50 per cent paralysis (Cpss(50)) was highest in the N2O–narcotic group at 0.6 μg/ml; it was 0.36 μg/ml with halothane, 0.5–0.7 per cent, and 0.22 μg/ml with halothane, 1.0–1.2 per cent. Greater absolute and relative variability of the Cpss(50) was present in the N2O–narcotic group when compared with halothane, 0.5–0.7 per cent. The equilibration half-times t1/2Keu between plasma concentration and pharmacologic effect (paralysis) were 4.7 min for the N2O–narcotic group, 6.9 min for the halothane, 0.5–0.7 per cent, group and 7.9 min for the halothane, 1.0–1.2 per cent, group. The greater t1/2Keu with halothane anesthesia is interpreted as decreased muscle perfusion. Halothane did not alter the pharmacokinetics of dTc in comparison with N2O-narcotic anesthesia. It affected the pharmacodynamics by prolonging the equilibration between plasma concentration and pharmacologic effect and increasing the sensitivity of the neuromuscular junction to dTc.