8: Alcohols (Ocular Toxicology)

What is proof?

2x percent alcohol content

(40% AbV = 400 mL/L = 80 proof)

What are the units for blood alcohol concentration (BAC)?

g ethanol in 100 mL blood

0.08% = 0.8 mg/mL = 0.8 g/L

What are the dangerous acute effects of ethanol?

• Vasodilation

• Respiratory depression

• Loss of protective airway reflexes

• Hypothermia

• Incontinence

• Hypotension

• Cardiovascular collapse

• Death

Describe the ADME of ethanol

• Passive diffusion across GI lining

  • 90% small intestine

• Highly water soluble

  • More body fat = less places alc to go = plasma [EtOH] increases

• Hepatic metabolism

Describe ethanol mechanisms of action

• Multiple mechanisms

• Some CNS effects:

  • Nonspecific effects on cell membranes and membrane proteins

  • Specific effects on GABA, dopamine, and endogenous opioid signaling

    • Acts at NT binding site

    • Modifies gating mechanism inside channel

    • Stimulates G_s which is linked to adenylyl cyclase

Describe hepatic biotransformation of ethanol

Ethanol → alcohol dehydrogenase (ADH) converts to acetaldehyde → acetaldehyde dehydrogenase (ALDH) converts to acetate

What ethanol metabolite is responsible for the dangerous effects of EtOH?

Ethanol

What ethanol metabolite makes people feel sick?

Acetaldehyde

What is a small sex difference in ethanol metabolism

Females have lower gastric ADH activity → females break down ethanol slower

Describe the genes regulating ADH

• ADH1B*2 = faster

• ADH1B*1 = slower

Describe the genes regulating ALDH

ALDH2*2 = slower than ALDH2*1

Explain the genetic difference for ethanol metabolism in Asian populations

Higher percentage of ADHB*2 and ALDH2*2 → produce acetaldehyde faster, produce acetate slower → experience quicker and possibly longer periods of negative effects

What are the effects of methanol in humans?

• Lower doses

  • Drunkenness

  • Nausea

  • Headache

• Moderate doses

  • Tachycardia

  • Drowsiness

• Higher doses

  • Acidosis

  • Convulsions

  • Respiratory depression

  • Coma

  • Blindness

  • Infarcts of basal ganglia or striatum in brain

Describe the ADME of methanol

• Absorption and distribution similar to ethanol

• Humans and non-human primates have limited conversion of formate to CO₂ → formate accumulates

What do humans and primates lack that causes an accumulating of formate?

H₄ folate

What are methanol-related effects?

Similar to ethanol tox:

• Ataxia

• CNS depression

• Hypotension

• Acidosis

What are formate effects?

Self-perpetuating cycle of acidosis & lack of O₂ in tissues → blindness and brain infarcts

Severe lactic acidosis → decrease cardiac contractility → decrease responsiveness of vasculature to vasopressors (EPI, NE)

Describe the ocular effects of methanol in humans

• Initial optic neuritis

  • Swollen optic discs visible from inflammation of optic nerves

• Optic nerve atrophy

  • Demyelination of optic nerve fibers contributes

What are the treatments of methanol toxicosis

• All: treat signs as ethanol toxicosis

• Primates

  • Inhibit ADH with fomepizole or ethanol

  • Provide folinic acid

• Hemodialysis recommended

Describe the metabolism of methanol

methanol → formaldehyde → formate → CO₂

Why is fomepizole or ethanol used to treat methanol toxicosis?

Inhibiting ADH inhibits the transformation of methanol into dangerous metabolites → prevents formation of formate

Alcohol dehydrogenase (ADH) is important for what 3 related toxicoses?

• Methanol → formaldehyde (eventually folic acid)

• Ethanol → acetaldehyde (eventually CO₂ and H₂O)

• Ethylene glycol → glycol aldehyde (eventually organic acids)