Toxicology & Metabolic Disease

Alcohol

• Alcohol’s mechanism of action is not entirely understood, but it acts as an agonist of gamma-aminobutyric acid (GABA, the primary inhibitory neurotransmitter in the CNS) .
• Acute intoxication:
  • Presents with slurred speech, incoordination, unsteady gait, and nystagmus.
• Chronic EtOH:
  • Can cause vitamin deficiencies such as B12 deficiency and B1 deficiency-related Wernicke’s encephalopathy and Wernicke-Korsakoff disease. See below regarding vitamin deficiencies.
  • Subcortical alcohol-related dementia.
  • Cerebellar atrophy

• Marchiafava-Bignami disease
  • Corpus callosum damage.
  • Presents with a sudden onset of stupor, coma, and seizures. Can also present with dementia, gait problems, psychiatric disturbances, incontinence, hemiparesis, aphasia, and apraxia of the left hand (due to callosal disconnection).

Methanol

• Ingested as an alcohol substitute and in suicide attempts.
• Methanol → formaldehyde → formic acid.
• Presents with a headache, confusion, hyperventilation and anion gap metabolic acidosis, and visual deficit.
• Pathology: Necrosis and hemorrhage of the putamen and toxic optic neuropathy.
• Treatment: bicarbonate and fomepizole are first-line. Ethanol works similarly to fomepizole. Dialysis may also be needed.

Ethylene Glycol

• Presents with edema and petechial hemorrhages secondary to calcium oxalate deposits within vessels.

PCP

• Presents with nystagmus, hypertension, tachycardia, muscle rigidity, dysarthria, decreased response to pain, and seizures.

Bath salts/methylenedioxypyrovalerone (MDPV)

• Presents with hypertension, tachycardia, delusions, hallucinations, and violent behavior.

Opioids 

• Acute overdose will present with miosis (constricted pupils), hypotension, bradycardia, and decreased respirations.
  • Can be treated with naloxone.
• Constipation can occur with chronic use.
• Long-term treatment for opioid dependence includes naltrexone (long-acting opioid antagonist), methadone, or buprenorphine.
• Withdrawal symptoms include lacrimation, rhinorrhea, diaphoresis, mydriasis, and yawning.
  • Clonidine (alpha 2-receptor agonist) can blunt the sympathetic symptoms associated with opioid withdrawal.
• Meperidine is metabolized into a neurotoxic metabolite that can provoke myoclonus, tremors, and seizures.

Benzodiazepines

• Mechanism: Increases frequency of GABA_A channel opening.
  • Barbiturates, on the other hand, increase the duration of GABA_A opening.
• Most benzodiazepines are metabolized by the cytochrome p450 system.
  • Lorazepam, oxazepam, and temazepam, however, undergo direct glucuronidation without cytochrome p450 metabolism and therefore can be used in patients with renal or hepatic dysfunction with only minor effects on pharmacokinetics.

Cocaine

• Works by inhibiting dopamine reuptake and increasing dopamine concentrations in the nucleus accumbens. Also inhibits the reuptake of serotonin and norepinephrine.
• Acute intoxication presents with mydriasis, euphoria, and tachycardia.

Amphetamines

• Amphetamine intoxication presents similarly to cocaine, except the mechanism of action is through both the direct release of dopamine and norepinephrine and the inhibiting of reuptake.

Nitrous Oxide (inhaled)

• Exam: progressive paresthesias secondary to myelopathy of the posterior and lateral columns, mimicking B12 deficiency. Additional symptoms include ataxia, weakness, and positive Lhermitte’s sign.
• Pathophysiology: Irreversible oxidization of methylcobalamin which interferes with the vitamin B12-dependent conversion of homocysteine to methionine as well as methyl-malonyl CoA into succinyl CoA. Homocysteine levels will be elevated. Treat with methionine supplementation.

Glue (Toluene)

• Inhalation of toluene causes myelin damage and diffuse leukoencephalopathy.

“Chasing the Dragon”

• Inhalation of heated heroin or morphine fumes. Can produce a toxic leukoencephalopathy.