Ethanol

Fomepizole – Mechanism & Clinical Use

• MOA: inhibits alcohol dehydrogenase (ADH)
• Used for: methanol poisoning
• Ethanol is used only when fomepizole is unavailable or cannot be obtained quickly
• Chronic ethanol users metabolize methanol faster → become toxic faster → fomepizole is preferred

Enzymes That Metabolize Ethanol

• ADH and ALDH account for >90% of ethanol metabolism

• CYP enzymes account for ~10% (microsomal ethanol-oxidizing system)

• CYP2E1 is the primary CYP enzyme

Major Toxic Metabolite

• Acetaldehyde
 – Responsible for acute withdrawal symptoms
 – Responsible for hangover effects
 – Blocking ALDH with disulfiram → ↑ acetaldehyde → toxic reaction if ethanol is ingested

Ethanol Elimination Kinetics

• First-order elimination at very low BACs
• Zero-order elimination at BACs >0.010
• Average ↓ in BAC = 0.017% per hour
• Attempts to accelerate ethanol metabolism fail because:
 – ADH is saturated
 – Zero-order = fixed amount per hour → cannot be increased

NMDA receptor

1. Ethanol interacts with the glutamate NMDA receptor

2. NMDA receptor normally allows Ca²⁺ influx

3. Ethanol blocks glutamate from opening the channel → reduced glutamatergic/excitatory activity

GABA-A receptor

1. Ethanol interacts with the GABA-A receptor

2. GABA-A receptor permits Cl⁻ influx

3. Ethanol increases GABAergic activity by increasing frequency & duration of channel opening

Ethanol absorption occurs primarily in the:

Duodenum

The major mechanism of action of fomepizole is inhibition of:

ADH

Fomepizole is primarily used for treatment of:

Methanol poisoning

Ethanol is used instead of fomepizole only when:

Fomepizole is unavailable

Why does a chronic ethanol user require fomepizole when ingesting methanol?

They metabolize methanol faster and become toxic faster

Which enzymes account for >90% of ethanol metabolism?

ADH + ALDH

Which enzyme is responsible for approximately 10% of ethanol metabolism?

CYP2E1

The major toxic metabolite of ethanol is:

Acetaldehyde

Blocking ALDH with disulfiram results in ______ acetaldehyde accumulation.

Increased

Ethanol follows zero-order elimination when BAC is:

> 0.010

Average ethanol metabolism decreases BAC by approximately:

0.017% per hour

Ethanol metabolism cannot be accelerated because:

ADH is saturated

NMDA receptors normally permit influx of:

Calcium

Ethanol blocks glutamate from opening the NMDA channel, leading to:

Reduced glutamatergic activity

GABA-A receptor activation normally allows influx of:

Cl⁻

Ethanol increases GABAergic activity by increasing:

Channel opening frequency & duration

How ethanol produces rewarding effects (opioid, GABA, dopamine circuits)

1. Ethanol ingestion → release of endogenous opioids

2. Endogenous opioids bind μ-opioid receptors, which inhibit GABA release in the ventral tegmental area (VTA)

3. Reduced GABA release → reduced inhibition of dopaminergic neurons → increased dopamine in the nucleus accumbens (reward pathway)

Importance of knowing if a patient drinks occasionally vs. chronically

• Always assume ethanol interacts with medications unless proven otherwise

• Knowing chronic vs. occasional use is critical

• Chronic ethanol use induces CYP2E1, the enzyme responsible for metabolism of many drugs

• This induction changes drug levels and increases risk of drug-drug interactions

Therapeutic goal in alcohol withdrawal

Goal: Prevent uncontrolled excitation

Strategies:

• Reduce glutamate activity

• Increase GABA activity

FDA-approved medications for Alcohol Use Disorder (AUD)

Disulfiram

• MOA: Inhibits ALDH → ↑ acetaldehyde after drinking

• Effect: Causes unpleasant reaction; discourages drinking

Naltrexone

• MOA: μ-opioid receptor antagonist

• Effect: ↓ rewarding effects of alcohol, reduces cravings

Acamprosate

• MOA: Weak NMDA receptor antagonist + GABA receptor activator

• Effect: May decrease mild withdrawal symptoms and reduce craving

Ethanol’s rewarding effects are primarily due to increased dopamine release in which brain region?

Nucleus accumbens

Endogenous opioids released after ethanol ingestion bind to which receptor type?

μ-opioid receptors

Inhibition of GABA release in the VTA causes dopamine neurons to become:

More active

Chronic ethanol use induces which enzyme important for drug-drug interactions?

CYP2E1

The therapeutic goal in alcohol withdrawal is to:

Prevent uncontrolled excitation

Which combination helps prevent uncontrolled excitation during alcohol withdrawal?

Decrease glutamate and increase GABA

Which FDA-approved AUD medication inhibits ALDH, increasing acetaldehyde levels after alcohol intake?

Disulfiram

Naltrexone works in AUD treatment by acting as a:

μ-opioid receptor antagonist

A medication that decreases the rewarding effects of alcohol by blocking μ-opioid receptors is:

Naltrexone

Which AUD medication produces aversive effects if alcohol is consumed?

Disulfiram

Which FDA-approved AUD medication weakly antagonizes NMDA receptors and activates GABA receptors?

Acamprosate

Reduction of mild withdrawal symptoms and decreased urges to drink are therapeutic effects of:

Acamprosate