Uses
Sedative
Anxiolytic
Anticonvulsant
Mechanism of action
Bind to the α subunit of the GABAa rec which enhances the action of GABA on the rec to ↑ the frequency of Cl channel opening
GABAa
Ligand gated Cl channel (2α, β, d, g)
Mostly postsynaptic
GABAb
G protein (metabotropic)
K conductance → hyperpolarisation
Pre and post synaptic
2 BDZ rec subtypes on α subunit
BZ1 – SC and cerebellum – anxiolysis
BZ2 – SC, cortex, hippocampus – sedative and anticonvulsant
Midazolam
Presentation
Clear solution pH 3.5
Chemical
Imidazole
Base
pKa 6.2
99% unionized at pH 7.4
Structure dependent on surrounding pH
At pH 3.5 ring structure is open so ionized and water soluble; at pH >4 ring closes so unionized and lipid soluble
Routes
40% bioavailability PO
IV, IM, intranasal
Effects
CNS
Sedative, amnesia, anxiolysis, anticonvulsant
RS and CVS depression
Kinetics
Distribution
Vd 100L
95% protein bound
Short duration of action due to redistribution
Fast onset as v. lipid soluble
Metabolism
Phase 1 hydroxylation then phase 2 congugation with glucuronic acid prior to renal excretion
Mostly inactive metabolites (<5% to oxazepam)
Excretion
Clearance 500mls/min
T1/2 2h
Metab by same enzyme as alfentanil so prolong each others effects
T1/2
Midazolam 2
Lorazepam 12 inactive metabolites
Diazepam 36 active metabolites
Flumazenil
Competitive BDZ antagonist
Inverse agonist
IV injection in 100mcg increments
Works in 2 mins
T1/2 1h
