2018B Question 11
Describe the pharmacology of midazolam.
Examiner Report
27% of candidates achieved a pass in this question.
Midazolam is widely-used in anaesthesia and critical care, so a detailed knowledge of its pharmacology is expected for specialist practice.
To pass, candidates were expected to provide a minimum number of facts in each of the key areas: general, pharmaceutics, pharmacokinetics and pharmacodynamics. Candidates who provided accurate factual information coupled with an understanding of the significance of some of the pharmacological properties of midazolam typically performed well.
Specific information relevant to midazolam is available in all the pharmacology texts recommended in the reading list and it was clear that for those candidates familiar with the information, passing this question was relatively straightforward.
Model Answer
Structure:
- PC
- PK
- PD
Physicochemical
| Factor | Detail |
|---|---|
| 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
| Factor | Detail |
|---|---|
| Routes | - IV, IM, SC, PO, IN, PR |
| Dosing | - IV induction: 0.3mg.kg-1 - IV pre-induction adjuvant: 0.025mg.kg-1 - PO pre-med: 0.5mg.kg-1 |
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 bioavailability 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-1.min-1 - Active metabolites: Α-OH-midaz (50% as active) and oxazepam (active) - These undergo glucuronidation - t1/2β 2 hours |
| Excretion | - ≤1% midazolam → Urine - Glucuronidated metabolites → Urine |
Pharmacodynamic
| Factor | Detail |
|---|---|
| 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 - Synergistic depression with opioids - Can be dangerous if sleep-disordered breathing - ↓ Airway reflexes |
| Cardiovascular | |
| 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 |