PHARMACODYNAMICS OF TOLERANCE DEVELOPMENT TO THE ANESTHETIC AND ANTICONVULSANT EFFECTS OF PHENOBARBITAL IN RATS

In this study, the potential development of tolerance towards the anesthetic and anticonvulsant effects of phenobarbital after chronic administration to rats was investigated, differentiating between dispositional and functional tolerance. Chronic exposure to phenobarbital by daily ip injections of 20 or 100 mg/kg for 14 days caused a 30% increase in clearance within 1 week. No changes occurred in the total amounts of phenobarbital and para‐hydroxyphenobarbital excreted into urine and feces. Pharmacodynamic effects were quantitated after 2 weeks of treatment. The anesthetic effect was measured by slow iv infusion of phenobarbital until onset of loss of righting reflex (LRR), followed by measurement of drug concentrations in serum (both total and free), brain, and cerebrospinal fluid (CSF). With a phenobarbital dose of 100 mg/kg daily, CSF concentrations at the onset of LRR significantly increased from 136 ± 12 to 176 ± 21 mg/L (p < 0.001), indicating that functional tolerance developed for the anesthetic effect. Protection of phenobarbital against convulsions induced by pentylenetetrazol (PTZ), as measured by the elevation of the PTZ plasma threshold concentration necessary to elicit seizures at the EC50 of phenobarbital, was not altered. The discrepancy observed in the development of functional adaptation of the CNS demonstrates that different mechanisms of action are reflected in the different measures of the anesthetic and anticonvulsant effects of phenobarbital that were utilized. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company