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Nalbuphine hydrochloride (Nubain) is a relatively new agonist-antagonist analgesic, chemically related to both oxymorphone and naloxone, which can be used as a systemic obstetric analgesic. After intravenous administration to six patients in labor at term, serial maternal serum specimens were obtained and assayed for their nalbuphine concentration. The maternal disposition of nalbuphine followed a two-compartment pharmacokinetic model, with an initial distribution phase of 4 to 20 minutes and a terminal elimination half-life of 2.4 +/- 0.4 hours. Measurement of umbilical cord blood nalbuphine concentrations demonstrated that nalbuphine crossed the placenta and entered the fetal circulation. Newborn concentrations varied substantially, ranging from one third to six times the simultaneous maternal concentration.

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Naloxone hydrochloride is extremely valuable for diagnosing and managing the opioid overdose. Due to naloxone's short half life and a long duration of action of most opioids, repeated naloxone dosing often is required to prevent the recurrence of respiratory depression. An alternative to repeated bolus administration is a continuous IV infusion. We conducted a two-phase study to determine the pharmacokinetics of naloxone and to develop a continuous dosing nomogram. In the first phase seven patients were given an IV bolus dose alone and serial plasma naloxone levels were determined. Naloxone elimination was found to be biexponential with the mean beta half life equal to 0.023 +/- 0.002 reciprocal minutes in two patients and 0.015 +/- 0.02 reciprocal minutes in five patients. In the second phase ten volunteers were given either a 2-mg or a 4-mg bolus dose followed by a 1.5-mg/hr or a 3-mg/hr continuous infusion. The mean volume of distribution of the central compartment was found to be 0.806 +/- 0.408 L/kg. The mean beta rate constant of elimination was found to be 0.036 +/- 0.027 reciprocal minutes. A computer simulation of the pharmacokinetic parameters determined in our study found that a continuous infusion of two-thirds of the bolus dose that resulted in reversal each hour will maintain the plasma naloxone levels equal to or greater than the naloxone levels that would have existed 30 minutes following the bolus dose.

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Nalbuphine is an agonist/antagonist analgesic. After parenteral administration of 'usual' doses it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies in patients with moderate to severe pain, usually following surgery, the characteristics of analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anaesthesia when used as a component of a 'balanced' anaesthesia technique, although a relatively low 'ceiling' effect for reduction of anaesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other agonist/antagonist analgesics, a 'ceiling' effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important haemodynamic changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist/antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. Thus, nalbuphine appears to offer a useful alternative to morphine in patients with moderate to severe pain.

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Caffeine citrate in doses of 6.96 mg/kg (equivalent to 3.50 mg/kg of caffeine) of combined maternal and fetal weight and 69.6 mg/kg (35.0 mg/kg of caffeine) was administered in 1-dl solutions intravenously over ten minutes to chronically prepared pregnant sheep. The ewes and their fetuses were monitored for cardiovascular and acid-base status. The mean maternal and fetal caffeine concentrations were simultaneously evaluated with a two-compartment pharmacokinetic model. Fetal concentrations in excess of 80% of maternal concentrations were rapidly achieved and maintained. Caffeine was undetectable in all the maternal and fetal samples obtained 48 hours after the infusion. Both doses caused similar but slight reductions in uterine blood flow without adversely affecting fetal and maternal acid-base status. Only the higher concentration of the drug produced a significant maternal and fetal tachycardia. The high fetal concentrations of caffeine were believed to be responsible for the persistent fetal tachycardia.

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An analog-computer method is described that provides estimates of steady-state plasma theophylline concentration nd total body clearance well before steady-state is achieved. An analog computer was programmed to simulate single compartment disposition of plasma theophylline for a constant rate infusion and an initial bolus. The two simulations were algebraically summed and the curve displayed on an oscilloscope. A series of 20 simulations was performed to define the rate of theophylline administration as applied to the analog-computer rate constant. The method was then tested using patient data previously reported in the literature. Presteady-state plasma concentration-time data points (n = 72) for the 20 simulations were compared; r2 for the analog-computer fit with calculated values as 0.99995. Using data for four patients, the estimates of total body clearance compared favorably with values generated by nonlinear least-squares regression analysis. An r2 of 0.86 was obtained for the analog-computer fit to 16 presteady-state patient data points. Use of the analog-computer method may enable clinicians to adjust aminophylline doses early in therapy to achieve optimal plasma theophylline concentrations.

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