Kinetics of drug action in disease states. V. Acute effect of urea infusion on phenobarbital concentrations in rats at onset of loss of righting reflex.

It has been reported that patients suffering from azotemia attributable to urinary obstruction required significantly less thiopental for induction and maintenance of general anesthesia than did a comparable group of patients with normal blood urea concentrations. Moreover, the thiopental requirements of normal subjects could be reduced by urea administration. In rats, experimental renal dysfunction was associated with reduced concentrations of phenobarbital (PB) in serum, serum water, brain and cerebro-spinal fluid at onset of a defined hypnotic effect (loss of righting reflex) produced by a slow i.v. infusion of PB. To determine the mechanism of this effect, these studies have now been repeated in normal rats made azotemic (approximately 170 mg of urea nitrogen/100 ml of serum) by intra-arterial infusion of urea and in control animals infused with saline solution. The total dose of thiopental required to produce loss of righting reflex was significantly reduced in the rats infused with urea. confirming the clinical observations. Similar results were obtained with PB and heptabarbital, two barbiturates that (unlike thiopental) are not racemic mixtures and are therefore more suitable for this investigation. On the other hand, urea infusion had no apparent effect on the concentrations of PB and heptabarbital in serum, brain and cerebrospinal fluid at onset of loss of righting reflex. Urea apparently affects the distribution kinetics of barbiturates and this, rather than increased receptor sensitivity, appears to be responsible for the decreased barbiturate dose requirements in acute experimental azotemia produced by urea infusion.