506 10. EFFECTS OF MORE THAN ONE INHIBITOR 



Two Inhibitors Acting on the Metabolism of a Pharmacologically Active 



Compound 



Many active substances (agonists) are formed continuously or intermit- 

 tently in the tissues and efficient inactivation of these substances is gen- 

 erally necessary for the proper control of function (page 466). Thus each 

 agonist is formed and destroyed enzymically: 



El Ej 

 Y-> A->X 



where E^ and E2 can represent either single enzymes or sequences. As in 

 any linear system, the agonist concentration will depend on the relative 

 rates of formation and destruction, amongst other things such as diffusion 

 from the region. An inhibitor will alter (A) as described previously (page 468). 

 Two inhibitors, one acting on the formation and the other on the inac- 

 tivation, will usually counteract each other with respect to the effect on (A), 

 whereas two inhibitors acting together on either the formation or destruc- 

 tion may augment each other. If the effects of monoamine oxidase inhi- 

 bitors, such as iproniazid, are primarily due to the rise in certain amine 

 concentrations in the tissues, this action could be increased by the simul- 

 taneous use of another inhibitor that blocked the 0-methylation of some 

 of these amines (since this is another pathway available for inactivation) 

 or decreased by the use of an inhibitor blocking in some manner the syn- 

 thesis of these amines. In the future it may be possible to potentiate the 

 clinical actions of these monoamine oxidase inhibitors, or to i^rovoke a more 

 specific rise in certain amines, by the administration of a second inhibitor. 

 The possibilities for the useful control of agonist levels are many but at 

 the present time are limited by the ignorance of some of the metabolic 

 pathways involved and the lack of specific inhibitors for pinpoint blocking. 



One Inhibitor Prevents the Adaptation of the Cells to Another Inhibitor 



Cells may develop resistance to an inhibitor by several different mech- 

 anisms. Most of these mechanisms seem to involve the formation of a 

 new enzyme (either to destroy the inhibitor or to establish an alternate 

 pathway around the block) and thus the ability to adapt is dependent 

 on the whole complex of reactions, exergonic and endergonic, required 

 for protein synthesis. It is not surprising that enzyme adaptation has 

 been found to be susceptible to a variety of inhibitors. Consequently it 

 would appear that in long-term experiments where the development of 

 resistance is an important factor, another inhibitor would commonly de- 

 press this, not so much by the block of an alternate pathway as by the pre- 

 vention of the appearance of the alternate pathway. Such phenomena have 

 been taken advantage of in the treatment of tuberculosis where the use of 



