Midazolam

Question 1

What class of drug is midazolam

Answer 1

Short acting benzodiazepine

Question 2

Explain the significance of the imidazole ring

Answer 2

Tautomerism
The ring opens and closes with change in pH
4 - closed -> lipid soluble
Midazolam doesn’t need a solubilising agent

Question 3

Describe the presentation

Answer 3

Clear colourless solution with pH 3.5

Contains NaCl, Disodium edetate and benzyl-alcohol as preservatives

Question 4

Mechanism of action

Answer 4

Binds to alpha subunit of GABAaR
Enhances affinity of GABA for GABAaR
Inc Cl- conductance, hyperpolarizing post-synaptic cell membrane

Question 5

By what routes can Midazolam be administered?

Answer 5

PO, IM, SC, IV, intrathecal/epidural, intranasal

Oral bioavailability = 40% (substantial 1st pass hepatic metabolism)

Question 6

What is the pKa?

What percentage is ionised at physiological pH

Answer 6

pKa 6.5 (basic)

11% ionised at pH 7.4

Question 7

Volume of distribution

Answer 7

1-1.5L/kg

Question 8

Protein binding

Answer 8

95% protein bound

Question 9

Outline the metabolism

Answer 9

2 routes of metabolism - 95% hydroxylation to 1a-hydroxyl-midazolam then conjugation to glucuronide (CYP3A4 - same path as Alfentanil)
5% to oxazepam
Metabolites are active
Excreted via urine

Question 10

Discuss the elimination

Answer 10

Duration is short due to rapid distribution
Elimination half life is 1-4 hrs
Excreted via urine as hydroxyl derivatives (impaired renal function has little effect)

Question 11

Outline CVS effects

Answer 11

Mild decrease in SBP, DBP, SVR

Mild increase HR as compensation for vasodilation

Question 12

Outline respiratory effects

Answer 12

Dec Vt with compensatory inc RR -> no change in MV
Apnoea in 10% pts
Blunts hypercarbic response

Question 13

Outline CNS effects

Answer 13

Dec CMRO2, Dec CBF
Hypnosis, anxiolysis, anterograde amnesia, sedation
Anticonvulsant
Dec MAC of volatile agents ~15%

Question 14

Clearance

Answer 14

7mLs/kg/min