Alcohol Pharmacokinetics and Pharmacodynamics

Alcohol Pharmacokinetics

• Alcohol readily diffuses across membranes, rapidly entering the bloodstream from the GI tract.
• It easily crosses the blood-brain barrier.
• Approximately 15% is metabolized by gastric alcohol dehydrogenase (primarily in the liver).
• Women tend to have lower levels of this enzyme than men.
• The average person metabolizes about 10 mL of 100 proof alcohol per hour—a zero-order metabolism.
• Alcohol is broken down into acetaldehyde via alcohol dehydrogenase. Acetaldehyde is then broken into acetic acid. This process causes that "icky" feeling after drinking.
• About 5% of alcohol is exhaled through the lungs.

Alcohol Pharmacodynamics

• Alcohol suppresses NMDA receptor function, reducing glutamate release. Chronic alcohol use increases the number of NMDA receptors.
• Alcohol acts as a GABA agonist, increasing chloride ion influx. Chronic alcohol use decreases chloride ion influx.
• Alcohol induces opioid release, triggering dopamine release, leading to pain relief, sleepiness, and increased intestinal motility.
• Alcohol stimulates the production of anandamide, an endogenous cannabinoid, leading to its "dirty drug" label.

Alcohol Tolerance

• Acute tolerance: Occurs with a single exposure.
• Metabolic tolerance: Alcohol dehydrogenase increases in the liver.
• Pharmacodynamic tolerance: NMDA receptors increase [glutamate], and chloride influx decreases [GABA].
• Behavioral tolerance: Related to learned coping mechanisms.

Alcohol Use Disorder (AUD) Pharmacotherapy

• Prevent/treat withdrawal seizures: Long-acting benzodiazepines (e.g., diazepam) and anticonvulsants (e.g., lamotrigine, topiramate) are used.
• Prevent relapse: Disulfiram (Antabuse) & calcium carbimide (Temposil) inhibit aldehyde dehydrogenase, prolonging the unpleasant effects of acetaldehyde build-up— low patient compliance. Naltrexone (ReVia, Trexan), a mu opioid antagonist, is an alternative with better efficacy than placebo and may be more effective via injection.
• Treat comorbid conditions: Alcohol-related disorders often coexist with conditions like major depressive disorder (MDD) and post-traumatic stress disorder (PTSD)—difficult to treat.

Binge Drinking

• NIAAA defines binge drinking as consuming enough alcohol to reach a blood alcohol content (BAC) of 0.08 or higher within two hours.
• Binge drinking has negative effects such as increased inflammation, oxidative stress, and excitotoxicity, resulting in downregulated trophic support, neurogenesis, and smaller white matter tracks.
• Even occasional binge drinking has long-term neurological effects, particularly frequent binge drinking during college years.