Kinetics of drug action in disease states. XXXVII. Effects of acute fluid overload and water deprivation on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline in rats.

Fluid overload and dehydration are potentially serious physiologic perturbations. Their effects on the pharmacodynamics of drugs are essentially unknown. This investigation was designed to determine the effects of acute fluid overload or water deprivation on the hypnotic activity of phenobarbital and on the neurotoxicity of theophylline in male Lewis rats. In the first experiment, 5% dextrose in water (D5W) was infused i.v. in an amount equal to 5 or 10% of body weight and phenobarbital was infused immediately thereafter until the onset of loss of righting reflex (LRR). The total infused dose and the serum and cerebrospinal fluid (CSF) concentrations of phenobarbital at that time were significantly lower than in control animals. When phenobarbital was infused about 2.5 hr after D5W, the infused dose and the serum and CSF concentrations of phenobarbital at LRR were normal. When the rats received D5W and an injection of vasopressin, 25 I.U./kg, or vasopressin only, the infused dose and the serum and CSF concentrations of phenobarbital at LRR were significantly lower than in controls despite the 2.5-hr interval between the respective pretreatments and the phenobarbital infusion. Water deprivation for 24 or 48 hr had no significant effect on phenobarbital dose and concentrations at LRR. Intravenous infusion of D5W to 10% of body weight immediately or 2.5 hr before theophylline infusion had no significant effect on the total infused dose and the serum and CSF concentrations of theophylline at onset of maximal seizures. This lack of effect occurred despite appreciable hyponatremia and hypomagnesemia immediately after D5W infusion.(ABSTRACT TRUNCATED AT 250 WORDS)