PT  - JOURNAL ARTICLE
AU  - E. W. Maynert
AU  - Gerda I. Klingman
TI  - ACUTE TOLERANCE TO INTRAVENOUS ANESTHETICS IN DOGS
DP  - 1960 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 192--200
VI  - 128
IP  - 2
4099  - http://jpet.aspetjournals.org/content/128/2/192.short
4100  - http://jpet.aspetjournals.org/content/128/2/192.full
SO  - J Pharmacol Exp Ther1960 Feb 01; 128
AB  - Drugs of the anesthetic-hypnotic type were compared with respect to the development of acute tolerance in dogs by determining the plasma concentrations of drug at the time of disappearance of ataxia after intravenous doses ranging from those causing only a short-lived ataxia to those producing the counterpart of deep anesthesia. Alcohol, paraldehyde, thiopental, pentobarbital and trichlorethanol were found to resemble one another fairly closely in that the administration of a dose equivalent to 5 median ataxic doses appeared to cause the maximum amount of tolerance which could be acquired acutely. The largest amount of tolerance which occurred with any of these drugs was reflected by an increase of about 100% in the plasma concentration of drug. Somewhat less tolerance developed to pentobarbital and paraldehyde than to the other drugs. The amount of tolerance which could be acquired acutely was dependent upon the level of neurological derangement under scrutiny. When ability to walk was the criterion the maximal tolerance developed to alcohol was only a 30% increase in the plasma concentration of drug compared with a 100% increase when disappearance of ataxia was the neurological end-point. The development of acute tolerance occurred quickly. With some of the drugs a significant amount of tolerance was observed after an increase in dose which increased the duration of ataxia by only 5 or 10 minutes. A series of experiments on trichlorethanol revealed that the maximum amount of tolerance which can be developed acutely to this drug was developed within the 40 minutes which are necessary for recovery from a dose equivalent to 5 At-D50's. The acute tolerance appeared to disappear completely during one week of abstinence. The acute tolerance observed in these experiments appears to be causally related to either the peak concentration of drug attained in the central nervous system or the maximal intensity of depression caused by the drug. The possible connection between acute tolerance and the tolerance developed in connection with the chronic administration of hypnotic drugs is discussed.