Toxicology and Poisoning

Question 1

Every student should be able to:
1. List the pharmacokinetic (decreased absorption or enhanced elimination) interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each.

Answer 1

Not sure (maybe see below?), but you need good supportive care!

Question 2

2. Compare and contrast the concepts of toxicokinetics and toxicodynamics and the important differences seen with toxic amounts of drugs relative to therapeutic doses and therapeutic plasma levels to “normal” pharmacokinetics and pharmacodynamics.

Answer 2

Toxic doses can yield abnormal pharmacokinetics.
-with absorption, you’ll see a delayed peak effect.
-Vd tells us which drugs can be removed by dialysis/transfusion
-clearance metabolism helps plan the treatment strategy
-half-lives may be prolonged in toxic overdoses.
-Want to decrease rate in and increase rate out.
-Prevent absorption with emesis (helped by ipecac, gastric lavage and washing stomach with saline, activated charcoal to bind drug in gut, and osmotic cathartics that decrease the time of toxin the GI tract [polyethylene glycol]).
Inhibit toxication (especially by methanol and ethylene glycol) by administering ethanol to occupy the alcohol dehydrogenase (which would produce toxic metabolites if reacted with methanol).
-Can also remove toxins with hemodialysis, and correct metabolic acidosis with sodium bicarbonate.
-Enhance elimination with hemodialysis, or hemoperfusion, or enhanced renal excretion (via forced diuresis and blocking reabsorption by trapping acids and bases in the urine by changing urine pH).
-Can also chelate heavy metals.

Question 3

3. Describe the mechanism of acetaminophen overdose toxicity and its treatment with N-acetylcysteine (role of hepatic bioactivation to toxic metabolite and depleted hepatic glutathione in hepatocellular injury).

Answer 3

• Most acetaminophen conjugated with glucuronic acid or sulfate and is detoxed by GSH-transferase to be excreted.
• Hepatocellular injury happens when the phase II enzymes (sulfate and glucuronidate enzymes) get saturated by the toxic dose –> excessive formation of reactive Ac* which depletes the GSH-transferase –> buildup of this reactive metabolite.
• Increased CYP2E1 can make you more prone.
• Treat with activated charcoal, gastric lavage, and n-acetylcysteine.

Question 4

4. Describe the basic pharmacokinetics and pharmacodynamic actions of methanol and ethylene glycol that underlie their toxicities: rapid oral absorption, metabolism by common hepatic enzyme systems.

Answer 4

• Methanol and ethylene glycol cause severe metabolic acidosis.
• Methanol poisoning = visual disturbances, and EG poisoning = deposition of calcium oxalate crystals –> renal failure.
• Work because they’re well absorbed orally and get metabolized into formic acid and oxalic acid.
• These metabolites come about when reacted with alcohol dehydrogenase (from liver?) and can damage tissues/organs, which is why you give EtOH to occupy the enzyme.