Modification of drug action by hyperammonemia.

Pretreatment with ammonium acetate (NH4Ac) (6 mmol/kg s.c.) approximately doubled the time morphine-treated mice remained on a hot surface and similarly increased muscular incoordination by diazepam, but NH4Ac treatment alone had no effect. Thus, hyperammonemia is capable of altering drug action and must be considered along with impaired drug metabolism in enhanced drug responses associated with liver disease. Experiments in vitro showed that acetylcholine-induced catecholamine release from bovine adrenal medulla is depressed as much as 50% by 0.3 mM NH4Ac and KCl-induced contractions of guinea-pig ileum were inhibited 20% by 5 mM NH4Ac. Addition of excess calcium reversed the depression in both tissues, but calcium-independent catecholamine release by acetaldehyde was not blocked by NH4Ac. These results suggested that ammonia blocks calcium channels. Parallels in the actions of NH4Ac and the calcium channel blocker verapamil support this concept. Both verapamil (10 mg/kg i.p.) and NH4Ac pretreatment enhanced morphine analgesia- and diazepam-induced muscular incoordination and antagonized amphetamine-induced motor activity, and neither verapamil nor NH4Ac affected the convulsant action of metrazol. The data suggest that hyperammonemia exerts a calcium channel blocking action which enhances the effects of central nervous system depressants and certain opioid analgesics.