Pharmacology Case Study: Valproic Acid

Protein Binding

• Binding capacity becomes saturated, leading to an increase in the free/bound ratio
• An increase in free concentration can result in effects
• Example: 32-year-old with valproic acid overdose, medical student looks up information, and poison center specialist suggests dialysis despite manufacturer's info saying it's not dialyzable

Phenytoin

• 17-year-old with phenytoin toxicity, ataxic and bumping into things
• Level is 26 mcg/ml, higher than usual due to significant weight loss (anorexia) and low albumin level (2.5 mg/dl)
• Free phenytoin level is very high, corrected level of 43 mcg/ml compared to 28 mcg/ml with normal albumin level

Metabolism

• Liver is the major organ involved in metabolism
• Oxidation, reduction, hydrolysis, and conjugation occur through the P-450 enzyme system
• Metabolism can result in:
  • Active medication to inactive metabolites
  • Active drug to active metabolites + inactive metabolites
  • Inactive medication to active medication
• Examples of active drug to active/toxic metabolites:
  • Citalopram/Escitalopram, where desmethylcitalopram metabolite is responsible for qt prolongation
  • Methanol and Ethylene glycol, where metabolism can be blocked using Fomepizole (4mp) or Ethanol

Elimination

• Irreversible loss of substance from the site of measurement
• Total clearance is the sum of renal clearance, metabolic clearance, and other clearance mechanisms
• Renal elimination involves glomerular filtration, secretion, and reabsorption
• Example: ASA (weak acid), where using NaBicarb can increase elimination by ion trapping and raising plasma and urine pH

Half-life

• Time for the medication concentration to decrease by ½
• Half-life is substance-specific, patient-specific, and influenced by organ function, age, disease states, and other medications
• Half-life relates to the duration of toxicity

Pharmacodynamics vs Toxicodynamics

• Insulin, BB, water, opioid, benzodiazepines, and almost every medication can have different effects at toxic levels

Idiosyncratic Side Effects

• Rare after an overdose
• Risk of idiosyncratic effects is not more common after an overdose compared to a therapeutic dose

Antidotes

• Examples of antidotes carried by EMS/Paramedics:
  • Naloxone
  • Glucose
  • Oxygen
  • Atropine
  • Physostigmine
  • Pralidoxime (2-Pam)
• Examples of antidotes carried by hospitals:
  • Cyanide antidote kits
  • Snake antivenin (some hospitals)
  • Succimer
  • Calcium Disodium Versonate
  • Antibiotics (for anthrax)
• Specialized resources:
  • Snake antivenin (some hospitals)
  • HBO
  • Botulism immune globulin
  • Strategic National Stockpile

Pharmacokinetics vs Toxicokinetics

• Pharmacokinetics: the study of ADME at therapeutic doses
• Toxicokinetics: the study of ADME at doses above the therapeutic dose, which can result in altered absorption, distribution, metabolism, and elimination rates
• Therapeutic dose vs excessive dose: absorption, distribution, metabolism, and elimination can be altered at excessive doses

A case study on valproic acid poisoning, involving a 32-year-old patient with a high serum level. The scenario requires knowledge of protein binding and dialysis.