ISOBOLS OF DOSE-EFFECT RELATIONS IN THE COMBINATION OF PENTYLENETETRAZOLE AND PHENOBARBITAL

¹ Department of Pharmacology, University of Utah College of Medicine, Salt Lake City, Utah

The combined action of Metrazol and phenobarbital was studied by determining, for seven endpoints, the combined doses required for equieffectiveness and by establishing the course of the isobols of these endpoint effects. The endpoints, determined in terms of median effective doses, were: threshold seizure, generalized clonic seizure, tonic extensor seizure, ejaculation, prehypnotic excitation, hypnotic effect, and death.

The field of combined doses studied extended to 1.2 lethal doses of the phenobarbital component and to 4 lethal doses of the Metrazol component. In this large combined-dose field, each effect of each drug was found to be modified by the other drug in an individually characteristic and different manner; none of the isobols follows a rectilinear course and no two isobols, not even those of merely gradually different endpoints of the same effect, run consistently parallel.

The tonic extensor effect of Metrazol was counteracted with preferential selectivity by phenobarbital. Phenobarbital was less selective in its action against ejaculation and still less so against clonic seizures. The prehypnotic excitatory effect of phenobarbital was facilitated and its hypnotic effect counteracted by Metrazol. The lethal effect of phenobarbital was only moderately counteracted by Metrazol, whereas Metrazol markedly protected against the lethal effect of phenobarbital. Convulsive threshold to Metrazol was raised by low phenobarbital doses, was decreased in the range of prehypnotic excitatory doses of phenobarbital and was again elevated in the range of hypnotic doses of phenobarbital.

The significance of mutual and varying interference between different effects of the components of a drug combination as a factor imparting individual characteristics to each of the effects of the combination is discussed.