Pharmacodynamics of the hypnotic effect of salicylamide in rats

Salicylamide (SAM) can produce sedation and sleep in humans and animals. To explore the potential utility of the drug as a research tool for assessing disease effects on the response of the central nervous system to depressant drugs, and to obtain a better understanding of the clinically evident sedative action of SAM, studies were performed to characterize the relationship between the concentrations and hypnotic effect of this drug in rats. Female Lewis rats weighing 170–200 g received SAM by intravenous infusion at a rate of 0.49, 1.22, or 2.47 mg/min until the onset of loss of the righting reflex. This well‐defined pharmacological endpoint occurred from 16.7 ± 2.3 min (fastest infusion rate) to 110 ± 27 min (slowest infusion rate) after the start of the infusion. SAM concentrations at that time in serum, serum water, brain, and cerebrospinal fluid (CSF) were similar in animals that had received the 1.22‐ or 2.47‐mg/min infusion and lower in animals that were infused at a rate of 0.49 mg/min. The slowest infusion rate group also exhibited increased serum protein binding of the drug. The SAM concentration ratio, CSF–serum water, was essentially unity in all three groups, indicative of rapid equilibration of the drug across the blood–CSF barrier. Gentisamide, the hydroxylated metabolite of SAM, was found in serum, CSF, and brain, but in low concentrations at which this metabolite alone had no hypnotic effect. When SAM was infused for some time beyond the onset of loss of the righting reflex, concentrations of the drug in serum, CSF, and the brain at recovery of the righting reflex were somewhat higher than at onset of loss of the righting reflex. The results of this investigation suggest that SAM exerts a direct effect on the central nervous sytem and that its hypnotic activity may be subject to development of acute tolerance.