Pharmacology of Alcohol Use Disorder

Alcohol use disorder definition

Medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences

Alcohol binge drinking definition

Pattern of drinking alcohol that brings blood concentration (BAC) to 0.08 percent or HIGHER

• 5 or more drinks (male) in 2 hours

• 4 or more drinks (female) in 2 hours

AUD etiology

• > 178,000 deaths per year in the US

AUD subjects are more prone to

• Bacterial pneumonia

• Seizures

• Peripheral neuropathy

• Liver disease

• Septicemia

• TB

• HEP C

• HIV

What components of Ethanol make it so potent???

It is an Ampiphile

• hydrophobic and hydrophilic

• Readily passes through biological membranes

• Tissue content is proportional to water content

• NO ethanol-protein binding in plasma

• Tissue levels rapidly equilibrate with serum levels

Chemical reactions

• Binding sites on A LOT of proteins —- it is promiscuous !!

• Hydrogen binding at OH group

• Very weak hydrophobic interactions

• Limits to low affinity interactions

Determinants of BAC?

• Type of drink and rate of consumption

• Absorption — impaired by food

• Body weight

• Gender - body fat and metabolism - men have lower BAC

• Liver disease

Alcohol metabolism

• 90% metabolized by alcohol dehydrogenase

• Follows zero-order kinetics

• Differences in metabolism by men and women

Steps:

1. Alcohol

2. converted to Acetaldehyde by ADH

3. Converted to Acetyl CoA by ALDH

4. Puts it into the Krebs cycle

ALDH2 polymorphisms do what?

They decrease metabolism of acetaldehyde == alcohol flush reaction!!! - Nausea, vomiting, etc…. (moreso in certain asian populations)

Disulfiram (ANTABUSE) works similarly!!!!

Blood alcohol Concentration/Blood Alcohol Level correlation to motor impairment symptoms

2-20 etOH(<0.08%) = Impaired coordination, Euphoria

21-40 blood etOH = Ataxia, decreased mentation, judgment, labile mood

41-60 = marked Ataxia, slurred speech, N/V

61-85 = Stage 1 Anesthesia, memory lapse

86-100 (~0.4%) = Brainstem/Respiratory Failure, Coma, Death

Alcohol withdrawal symptoms

• Anxiety/Dysphoria

• Sympathetic hyperactivity

• Muscle cramping

• Hyperreflexia

• Seizures

• Tremor, hallucinations, psychosis (48-72 hrs after stopping intake)

• Circulatory collapse and death (50% risk and lethal!!!!! — due to High BP)

Some suggested causes for eTOH toxicity

• Redox state changes

• Acetaldehyde formation

• Mitochondrial damage?

• Cytokine formation

• Kupffer cell activation

• increased gut permeability

• Immune response

• Oxidative stress

• Excitotoxicity

• Vitamin deficiency

Fetal Alcohol Spectrum Disorders points

• Growth deficiency

• FAS facial features

  • short palpebral fissures

  • Smooth philtrum

  • Thin upper lip

• Learning disability (CNS damage)

  • most common worldwide preventable cause of cognitive impairment in children

Are Serious liver disease cases seen in all AUD subjects?

NO!!!! - not in habitual drinkers

Stages of Alcohol related liver disease (ARLD)

• Alcohol related fatty liver

• Alcohol-related hepatitis

• Alcohol-related cirrhosis

  • 50%mortality in 5 years without stopping alcohol

What is the “Multiple HIT” hypothesis?

Taking EtOH is okay for the gut - can cause some inflammatory

bodily TNFalpha on its own - can also cause liver inflammatory

BUT

• EtOH + TNFalpha == LIVER DISEASE!!!!!!!

• So interplay between alcohol effects and direct toxicity causes TNF alpha to be released and damage the LIVER!!!

Targets of Acute EtOH that we need to know in regard to intoxication

GABAa receptors AND NMDA receptors (glutamate)

Ethanol is also a ____ like BZDs and Barbituates

Positive Allosteric Modulator (PAM)!!!

Ethanol binding on GABA _____

essentially locks the GABA receptor into place - they bind at the “water-filled” sites

Ethanol at the NMDA receptor

Inhibitory functions!!!

How does addiction play into affect with regard to alcohol and the brain?

DOPAMINE RELEASE in the Nucleus Accumbens!!

• EtOH allosterically inhibits GABA — actually INCREASES activity of those neurons, so DOPAMINE is released more

• THINK — the more that the receptor is inhibited, the body INCREASES dopamine release —- leads to addiction

Chronic EtOH use leads to ______

Chronic DOWNREGULATION of D2 receptors

Alcohol and Geneticism

there is a 4x fold risk in primary relatives —- 50% genetic — NOT DETERMINANT THOUGH

• Similar risk also seen in

  • Monozygotic twins

  • Adopted children

What are the treatments for Alcoholism?

• Disulfiram (Antabuse), alcohol flush reaction (ALDH2)

• Naltrexone, IM long-acting naltrexone

• Acamprosate

• Psychosocial intervention

• GLP-RA and others in progress

Bold ones are the only FDA approved

How does Naltrexone work in treating alcoholism?

Blocks MU opioid receptors —- increased GABA activity —- less dopamine released — less rewarding feeling with alcohol use

Acamprosate treatment points for Alcoholism

Not too sure how it wrks

• reduces intensity of post-cessation alcohol craving on exposure to high-risk drinking situations