KINETICS OF DRUG-ACTION IN DISEASE STATES .5. ACUTE EFFECT OF UREA INFUSION ON PHENOBARBITAL CONCENTRATIONS IN RATS AT ONSET OF LOSS OF RIGHTING REFLEX

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (2) , 430-434
Abstract
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. The thopental 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 C SF 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 were repeated in normal rats made azotemic (.apprx. 170 mg of urea N2/100 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, 2 barbiturates that (unlike thiopental) are not racemic mixtures and are therefore more suitable for this investigation. Urea infusion had no apparent effect on the concentrations of PB and heptabarbital in serum, brain and COF 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.