Pharmacology Case Study: Valproic Acid

Study Notes

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

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

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

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

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

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

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

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: 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