24B20: Exam Report

Explain the mechanism of action by which the following drugs exert their clinical and pharmacological effect when used to treat drug toxicity or overdose, including the time taken to exert this clinical effect:

  1. N-acetylcysteine (25% of marks).
  2. Digoxin FAb (25% of marks).
  3. Naloxone (25% of marks).
  4. Lipid emulsion (i.e. Intralipid) (25% of marks).

65% of candidates passed this question.

This question was best answered by using each drug as the heading with their subsequent mechanism of action and time of onset of their clinical effect.

Brief discussion of what drug toxicity or overdose these agents offset and how is implied in the mechanism of action and was included in our marking rubric.

N-Acetyl-Cysteine, Digoxin FAb, Naloxone, Lipid emulsion

N-Acetyl-Cysteine

Drug toxicity used against

  • Treatment of acute Acetaminophen toxicity
  • Prevention of CIN (contrast induced nephrotoxicity)

Mechanism of action

  • Acetaminophen metabolism
    • ~5% oxidized by CYP450
  • Produces toxic metabolite  N-acetyl-p-benzoquinone imine (NAPQI)
    • Precursor to cellular injury
    • Normally detoxified by liver glutathione
  • Overdose
    • Depletes the glutathione reserves
  • NAC
    • Glutathione inducer – providing cysteine, an essential precursor in glutathione production
    • Directly conjugate NAPQI
    • Antioxidant-  binds to toxic metabolites and scavenges free radicals
    • Also increases oxygen delivery to tissues, increases ATP production, and alters the microvascular tone to increase blood flow and oxygen delivery to the liver and other vital organs

Effects offset

  • Liver-Prevent  cellular necrosis
  • Kidneys-reduces oxidative stress
    • Improves blood flow 

Time to clinical effect

  • Nebuliser: 1-2 hours
  • Oral: 2 hours
  • IV: No data available

Digoxin FAb

Drug toxicity used against

  • Acute
  • Chronic Digoxin toxicity

Mechanism of action

  • Immunoglobulin – Antibody binding (Fab)fragment which binds digoxin molecule
    • Makes it unavailable for binding at the site of action on cells
    • Fab fragment-digoxin complex is excreted by the kidney

Effects offset

  • Prevents the toxic effects of digoxin eg:
    • Bradycardia
    • VF
    • VT,
    • Asystole,
    • Heart blocks

Time to clinical effect

  • 30 – 45 minutes

Naloxone

Drug toxicity used against

  • Opioid toxicity

Mechanism of action

  • Competitive inhibitor of the µ-opioid receptor
    • Block or reverse the effects of opioids

Effects offset

  • Abates the effects like respiratory depression
  • Reduced heart rate
  • Slurred speech,
  • Drowsiness
  • Constricted pupils

Time to clinical effect

  • IV / Nasal spray
  • 2-5 minutes

Lipid emulsion (i.e. Intralipid)

Drug toxicity used against

  • Local anaesthetic systemic toxicity (LAST)
  • Including cardiac arrest Eg
    • Bupivacaine
    • Cocaine
  • Class I antiarrhythmic cardiotoxicity
  • Studied in other Lipophilic drugs Eg
    • Bupropion
    • Lamotrigine

Mechanism of action

  • Precise mechanism unclear
  • Several theories exist
  • Weinberg’s “lipid sink” theory
    • A lipid compartment is created in the blood into which the lipophilic drugs may dissolve and remove them from the aqueous plasma circulation
  • Dynamic “lipid shuttle” or “lipid subway”
    • Lipid compartment scavenges local anesthetic from high blood flow sensitive organs (ie, heart and brain), then redistributes to muscles for storage and the liver for detoxification
  • Cardiotonic and postconditioning effects
    • Directly increases cardiac contractility
  • Cardioprotective effects through multiple biochemical pathways

Effects offset

  • Reverses both neurologic and cardiac toxicity

Time to clinical effect

  • ? Minutes

Author: Nazma Navilehal Rajasab