2018B11 Describe the pharmacology of midazolam.

Presentation

·   5mg in 5mL ampoule, aqueous solution

Also as tablets

Structure

·   Heterocyclic benzodiazepine

·   Imidazole moiety

Tautomerism

·   In ampoule: pH 3.5, diaz ring open, water soluble (protonation of imidazole nitrogen)

·   In blood: pH 7.4 diaz ring closed, lipid soluble, can cross blood-brain barrier

·   Transformation at pH 4

Ionisation

·   pKa 6.5, weak base. 90% unionized at pH 7.4

Routes

·   IV, IM, SC, PO, IN, PR

Dosing

·   IV induction: 0.3mg/kg

·   IV pre-induction adjuvant: 0.025mg/kg

·   PO pre-med: 0.5mg/kg

Time course

(short acting)

·   Onset IV 2 mins

·   Peak IV 10 mins

·   Duration IV 1-6 hours (prolonged if elderly, liver disease, acute illness)

Absorption

·   Oral bioav 50%

Distribution

·   Plasma protein binding 98%

·   V_DSS 1.5L/kg

·   Highly lipid soluble

·   t_1/2ke0 4 minutes

Metabolism

·   Hepatic

·   Phase 1 (3A4) then phase 2

·   Cl 5-10mL/kg/min

·   Active metabolites: α-OH-midaz (50% as active) and oxazepam (active)

o These undergo glucuronidation

·   t_1/2β 2 hours

Excretion

·   <1% midazolam -> urine

·   Glucuronidated metabolites -> urine

Mechanism of action

·   Positive allosteric modulator at BDZ site on GABA-A receptor, at A-G interface

·   ↑probability of active conformation

·   ↑Cl^- conductance, prevention of depolarisation to action potential

·   (Not hyperpolarization, since RMP -70mV and Cl- Nernst potential -65mV)

GABA-A subtypes

·   α₁: sedation, amnesia, anticonvulsant

·   α₂, α₃: muscle relaxation, anxiolysis

Drug interactions

·   Synergistic with propofol, volatile anaesthetics at GABA-A

·   Synergistic with opioids in causing respiratory depression

·   Antagonised by flumazenil (competitive antagonist)

Specific use

·   Premedication for children

·   Sedation for procedures or in ICU

·   Adjuvant at induction

·   Induction agent if high cardiovascular risk (e.g. CABG with fentanyl)

CNS effects

Dose-dependent in this order:

·   Anxiolysis

·   Antegrade amnesia

·   Sedation

·   Anticonvulsant

·   Muscle relaxation

·   Hypnosis (here?)

Also:

·   ↓MAC

·   ↓CMRO₂

·   ↓Side effects of ketamine

·   10% risk paradoxical reaction in children; agitation, violence etc.

Respiratory

·   ↓TV more than ↓RR; mild ↑PaCO₂

o Synergistic depression with opioids

o Can be dangerous if sleep-disordered breathing

·   ↓Airway reflexes

Cardiovascular

·   ↓SNS output: -> mild ↓cardiac output, ↓SVR, ↓mAP

Special

·   Paradoxical reaction 1 in 10 children; agitation, rage

·   Much slower offset if elderly, unwell, liver failure (? slower metabolite elimination)

·   Risk delirium in elderly, ? risk of prolonged cognitive impairment