ETHANOL and ALCOHOL (METHANOL/ETHYLENE GLYCOL) TOXICITY

1. In CNS, ethanol affects many different receptors
   • Increased GABA activity at the GABA-A receptor
   • Decreased glutamate activity at the NMDA receptor
   • Also affects the Na/K ATPase, phospholipase C and other ion channels.
2. Organ system effects (acute)
   • CNS
     • Disinhibition, sedation, anxiolysis
     • At higher doses – coma, respiratory depression and death
   • CVS
     • Decreased myocardial contractility
   • Smooth muscle
     • Vasodilation, probably due to acetaldehyde
3. Organ system effects (chronic)
   • GIT and liver
     • Fatty liver disease à alcoholic hepatitis à cirrhosis/liver failure
     • Chronic pancreatitis
     • Gastritis
     • Multiple vitamin deficiencies (especially water soluble ones)
   • Nervous system
     • Tolerance and both physical and psychological dependence.
     • Withdrawal syndrome/delirium tremens if acute cessation. DTs are characterized by excitability/agitation and may cause seizures.
     • Neurotoxicity – peripheral neuropathy, ataxia, Wernicke-Korsakoff encephalopathy and optic neuropathy
   • CVS
     • Dilated cardiomyopathy with ventricular hypertrophy and fibrosis
     • Arrhythmias, probably due to chronic electrolyte abnormalities
     • HTN
     • Vascular disease – stroke/MI/PVD
   • Haematological
     • Iron deficiency anaemia secondary to gastritis
     • Folate deficiency – megaloblastic anaemia

1. PO

1. Well absorbed from GIT. Peak blood levels in 30 minutes.
2. Vd is ~0.7L/kg (total body water)
3. Ethanol easily passes BBB, and therefore readily enters the CNS.

1. Metabolism follows zero order kinetics
2. ~7-10mg/hour typically metabolized by average adult.
3. Ethanol is metabolized to acetaldehyde via two major pathways:
   • Alcohol dehydrogenase pathway
     • Alcohol dehydrogenase found mainly in liver, but small amounts can be found in the brain and stomach.
     • Alcohol is converted by alcohol dehydrogenase to acetaldehyde. NAD+ acts as a co-factor, and is converted to NADH.
     • Note that in acute toxicity, NADH will accumulate and cause lactic acidosis and hypoglycaemia.
   • Microsomal ethanol oxidizing system (MEOS)
     • MEOS uses CYP450 enzymes and NADPH as a co-factor.
     • It is inducible (and therefore ethanol may induce the metabolism of other drugs)
4. The acetaldehyde is then converted to acetate, which is broken down to CO2 and H2O. The enzyme metabolizing this reaction is aldehyde dehydrogenase.
   • Note that aldehyde dehydrogenase (and not alcohol dehydrogenase) is inhibited by disulfiram and other drugs (e.g. metronidazole and trimethoprim)

1. Urine
2. Small amount in lungs (forms the basis for ethanol breathalyzer tests)

1. Be prepared to treat respiratory and CNS complications in acute intoxication
   • Respiratory: be prepared for respiratory depression, vomiting and aspiration
   • CNS: remember to give thiamine.
2. Also give glucose (monitor for hypoglycaemia)

1. Enzyme induction leads to increased metabolism of drugs metabolized by the CYP450 system. Especially important in concurrent paracetamol overdose – increased metabolism of paracetamol to its toxic byproducts may increase hepatotoxicity.
2. Additive effects with other CNS depressants.

1. As mentioned above

1. Found in “canned heat” and windshield washing products
2. The toxicity of methanol is due to the metabolic byproducts of formaldehyde and formic acid

1. Symptoms (note that because symptoms are due to metabolic byproducts, they are only seen ~6-30 hours post ingestion)
   • Non-specific early signs (intoxication, gastritis, high osmolar gap)
   • Characteristic visual disturbance – “like being in a snowstorm”
   • May progress to bradycardia, coma and seizures.
   • Death is due to respiratory arrest
2. Treatment
   • Good supportive care
   • Suppression of metabolism – fomepizole and IV ethanol are temporizing measures
   • Removal of toxin – haemodialysis
   • Alkalinisation in order to counteract metabolic acidosis (Na bicarbonate)
   • Folic acid and folinic acid may be useful adjuncts (but does not directly improve patient’s clinical state)

Ethylene glycol

1. Found in antifreeze/industrial solvent
2. Toxicity comes from its toxic byproducts (aldehydes and oxalate crystals)
3. Symptoms occur in three stages:
   • First few hours: CNS excitation, then CNS depression
   • Severe metabolic acidosis
   • Renal failure, due to oxalate crystals.
   • Features suggestive of ethylene glycol toxicity are HAGMA, high osmolar gap and oxalate crystals in urine. There is no visual disturbance.
4. Treatment
   • As with methanol toxicity: good supportive care, fomepizole, IV ethanol and haemodialysis.