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Modification of drug action by hyperammonemia.

C C Kuta, R P Maickel, J L Borowitz

The Journal of Pharmacology and Experimental Therapeutics

|April 1, 1984

Summary

Hyperammonemia, a condition of excess ammonia in the blood, can alter drug responses. This study suggests ammonia acts as a calcium channel blocker, enhancing the effects of certain central nervous system depressants.

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Area of Science:

Pharmacology
Neuroscience
Biochemistry

Background:

Liver disease can lead to hyperammonemia, potentially altering drug responses.
Enhanced drug effects in liver disease are often attributed to impaired drug metabolism.
The direct impact of hyperammonemia on drug action requires further investigation.

Purpose of the Study:

To investigate the direct effects of hyperammonemia on drug action.
To determine if ammonia interferes with neurotransmitter release or cellular signaling pathways.
To explore the potential role of calcium channels in ammonia's effects on drug responses.

Main Methods:

In vivo studies: Mice pretreated with ammonium acetate (NH4Ac) were tested for responses to morphine and diazepam.
In vitro studies: Ammonium acetate's effect on acetylcholine-induced catecholamine release from bovine adrenal medulla and KCl-induced guinea-pig ileum contractions were measured.
Comparison with verapamil: The effects of NH4Ac and the calcium channel blocker verapamil on various drug-induced responses were compared.

Main Results:

Ammonium acetate pretreatment significantly enhanced morphine analgesia and diazepam-induced muscular incoordination in mice.
In vitro, NH4Ac inhibited catecholamine release and ileum contractions, effects reversed by calcium.
NH4Ac and verapamil exhibited similar effects on drug responses, suggesting a calcium channel blocking mechanism.

Conclusions:

Hyperammonemia can directly alter drug action, independent of impaired drug metabolism.
Ammonia appears to exert its effects by blocking calcium channels.
This calcium channel blockade enhances the effects of central nervous system depressants and certain opioid analgesics.

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