Pharmacodynamic DDIs: Ach, GABA, and Others

Dr. Preskorn is Professor, Chair, Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, CEO, Clinical Research Institute

Dr. Flockhart is Professor of Medicine, Genetics, and Pharmacology; Chief, Division of Clinical Pharmacology, Indiana University School of Medicine

Among notable DDIs involving acetylcholine, ethanol, GABA, histamine, ion channel inhibition, and opiate receptor agonism are the following:

Acetylcholine

Muscarinic Acetylcholine Receptor Antagonism

• Mitigates and can even fully reverse the EPS caused by excessive

D₂ Blockade

• Can block the memory-enhancing effects of cholinesterase inhibitors in dementing illnesses, such as Alzheimer’s disease
• Decreases gastric empyting, thus decreasing the absorption of acetaminophen
• Cholinesterase Inhibition: Opposite consequences to muscarinic acetylcholine receptor antagonism. See above

Ethanol

The CNS impairment caused by ethanol can be enhanced by a number of different mechanistic class of drugs including:

• Drugs which promote GABA in the brain
• Drugs which block central H₁ receptors
• Opiates

GABA Barbiturates

The CNS impairment caused by ethanol can be enhanced by a number of different mechanistic classes of drugs including:

Other drugs which promote GABA in the brain:

• Drugs which block central H₁ receptors (Opiates, ethanol)
• Barbiturate-like drugs (See barbiturates above)
• Benzodiazepine binding site agonism (See barbiturates above)
• Benzodiazepine-like drugs (See barbiturates above)
• GABA transaminase inhibition and stimulation of glutaminic acid decarboxylase (See barbiturates above)
• Promotion of nonvesicular release of GABA (See barbiturates above)

Histamine

Central Active H₁ Antagonism

The sedation caused by central H₁ antagonism can be amplified by:

• Drugs which promote GABA in the brain
• Ethanol, opiates

Ion Channel Inhibition

There is a concern that the effects of drugs which inhibit channel function may have additive or synergistic effects in terms of prolonging intracardiac conduction and/or causing seizures. These theoretical effects have not been formally tested due to the potential risk involved, but have led in some instances to class labeling warning against such combined use.

Opiate Receptor Agonism

The decreased CNS arousal particularly respiratory depression caused by opiates can be amplified by:

• Drugs which promote GABA in the brain
• Drugs which block central H₁ receptors
• Ethanol

Disclosure: Dr. Preskorn is a consultant to Bristol-Myers Squibb, Cyberonics, Eli Lilly, Johnson & Johnson, Memory, Otsuka, Pfizer, Shire, Somerset, and Wyeth; is on the speaker’s bureaus of Bristol-Myers Squibb, Cyberonics, Forest, Otsuka, and Pfizer; and receives grant support from Brtistol-Myers Squibb, Cyberonics, Johnson & Johnson, Memory, Merck, The National Institute of Mental Health, Novartis, Organon, Otsuka, Pfizer, Predix, Sepracor, and Somerset.

Disclosure: Dr. Flockhart is a consultant to Hoffman-La-Roche.