2018B11 Describe the pharmacology of midazolam.

 

List:

·     PC

·     PK

·     PD

 

Physicochemical:

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

 

Pharmacokinetic:

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%

·  VDSS 1.5L/kg

·  Highly lipid soluble

·  t1/2ke0 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

·  t1/2β 2 hours

Excretion

·  <1% midazolam -> urine

·  Glucuronidated metabolites -> urine

 

Pharmacodynamic:

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