Abstract

The order of appearance of a number of clinical signs was examined after the intravenous administration of large doses of pentobarbital, thiopental, paraldehyde, trichlorethanol and ethanol to dogs. The data suggested that the depression caused by these substances could be conveniently and reliably divided into 5 levels of intensity which extend from the counterpart of deep anesthesia to freedom from ataxia.

During recovery from large doses of pentobarbital or trichlorethanol dogs spend roughly the same percentage of the total time in each of the defined levels of depression. In contrast after large doses of thiopental, paraldehyde or ethanol the animals pass rapidly through the deeper levels of depression but lose their ataxia slowly. Evidence is presented that thiopental, paraldehyde and ethanol do not possess any special ability to depress the neurological mechanisms involved in normal gait. The fact that ethanol and paraldehyde resemble thiopental very closely but have little affinity for fat raises a serious doubt that localization in fat is of major importance in the "ultrashort" action of thiopental. It appears possible to interpret the patterns of recovery from the 5 drugs on the basis of differences in the rate of entry into the nervous system compared with entry into the other tissues of the body.

The intensity of depression produced by any multiple of the median ataxic dose is practically the same for all of the drugs studied. However, this remarkable similarity does not appear to extend to lethal doses.

The total duration of action of pentobarbital and trichlorethanol is practically a linear function of the dose. In contrast the duration of depression following thiopental, paraldehyde and ethanol increases slowly up to 4 or 5 median ataxic doses and more rapidly after higher doses. The configurations of the various curves are consistent with an extensive redistribution of drug from the nervous system to the other tissues after thiopental, paraldehyde and ethanol but not after trichlorethanol or pentobarbital.

A method was devised for separating the effects of distribution from metabolism and excretion in determining duration of action. This was used to predict the relative rates of metabolism of the various drugs.