2002A16 Briefly outline the pharmacology of flumazenil.

Presentation

·  0.5mg in 5mL clear solution in ampoule

(note 1mL NEAT flumazenil for 1mL NEAT midazolam)

Structure

·  Two benzene rings

·  One diazepine ring

Administration

·  IV route only

·  0.1mg q1 min

·  Max 2mg

Time course

·  Onset IV 2 mins

·  Peak IV 10 mins

·  Duration IV 1 hour

·  Note risk of resedation due to longer t_1/2β of most BDZ

·  e.g. diazepam metabolite desmethyldiazepam t_1/2β 100 hours

Absorption

·  Oral bioav <25%

Distribution

·  Plasma protein binding 50%

·  Moderately lipid soluble

·  V_DSS 1L/kg

Metabolism

·  >99% metabolized

·  Liver

·  CYP3A4

·  Inactive carboxylic acid and glucuronide metabolites

·  t_1/2β 1 hour

Excretion

·  Metabolites -> urine

·  0.1% of parent -> urine

Mechanism of action

·  Competitive antagonist (or inverse agonist) at BDZ receptor on GABA-A.

·  ↓Cl^- conductance -> allow depolarisation to action potential

Use

·  Benzodiazepine toxicity e.g. midazolam

Side effects

·  Anxiety

·  Nausea, vomiting

·  Withdrawal symptoms if BDZ dependent

·  Seizures