3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.3. IV anaesthetic agents
                      3.1.3.3.6. Benzodiazepine
 3.1.3.3.6.1. Midazolam 

Midazolam

[SH4:p142-p147]

  • 2-3 times as potent as diazepam
  • Amnesic effect is more potent than sedative effect
  • Water soluble

Structure

  • Has an imidazole ring
    --> stability in aqueous solution and more rapid metabolism
  • Structure changes with pH
  • When pH <4
    --> Ring is open
    --> More water soluble
    --> No need to use solvent e.g. propylene glycol
  • When pH becomes >4 (e.g. at physiological pH)
    --> Ring becomes closed
    --> Highly lipid-soluble

 

Pharmacodynamics

 

Effects by system

CNS

  • Decrease in cerebral metabolic oxygen requirement and cerebral blood flow
    * Similar to propofol and barbiturates
  • Unable to produce an isoelectric EEG
    * Unlike propofol and barbiturates
    * Probably due to the ceiling effect
  • Does not increase ICP
    * But may increase ICP if administered rapidly in severe head trauma[SH4:p144]
  • Does not prevent ICP increase on direct laryngoscopy
    * Similar to thiopentone
  • No potential neuroprotective effect
  • Potent anticonvulsant
    * Useful in treatment of status epilepticus

CVS

  • At induction dose of midazolam 0.2mg/kg IV
    --> Decrease in BP and increase in HR
    * Greater than with diazepam 0.5 mg/kg IV
    * Similar to changes with thiopentone 3-4 mg/kg IV
    * Possibly due to peripheral vasodilation --> decrease in SVR
  • There is also a ceiling effect with the midazolam-induced CVS changes
  • No change in cardiac output
  • In hypovolaemia,
    --> Greater reduction in BP
  • Does not blunt CVS response to laryngoscopy

NB:

These changes are associated with induction dose, which is a lot greater than sedation doses

Respiratory

  • COPD patients experience greater midazolam-induced ventilatory depression
  • Transient apnoea occurs after large doses of midazolam (> 0.15 mg/kg IV)
    * Exaggerated
  • Benzodiazepines also depresses the swallowing reflex and decrease upper airway activity

Pharmacokinetics

Absorption

  • IV, IM, oral
  • Absorption from GIT is rapid
    * Oral bioavailability is about 50% due to substantial first-pass hepatic effect
  • IM
    * IM bioavailability is > 90% [PI]

Distribution

  • Vd = 1.0 - 1.5 L/kg
    * Small for a lipid soluble drug
    * Due to the high protein-binding
    * Similar to diazepam
  • Vd is increased in the obese and elderly
  • Protein-binding = 96-98%
    * Independent of plasma concentration of midazolam

Metabolism

  • Rapidly metabolised by hepatic and small intestine cytochrome P-450 (CYP3A4) enzyme
    --> Active and inactive metabolite
    * Redistribution also contribute to shorter duration

Metabolites

  • Metabolites
    * 1-hydroxymidazolam (principal metabolite)
    * 4-hydroxymidazolam
  • 1-hydroxymidazolam
    * Principal metabolite
    * 1/2 the activity of the parent compound
    * Rapidly glucuronidated and excreted in urine
    * Glucuronidated form still have substantial activity --> May accumulate in renal insufficiency
  • 4-hydroxymidazolam
    * Also an active metabolite
    * Not present in detectable concentration after IV

Alteration in metabolism

  • Metabolism is slowed when P450 enzyme is inhibited
    * e.g. cimetidine, erythromycin, calcium channel blockers, antifungal drugs
  • CYP3A4 enzymes are also involved in metabolism of fentanyl

NB:

  • Cimetidine binds to almost all P450 enzymes
    * [???]

Elimination

  • Renal failure does not affect elimination half-time, Vd or clearance
  • Clearance = 6-8 mL/kg/min
  • Elimination half-time = 1-4 hours
  • Elimination half-time is prolonged in elderly due to:
    * Decrease in hepatic blood flow
    * Possibly decreased enzyme activity
  • Emergence time from midazolam is increased by
    * Advanced age
    * Obesity
    * Severe liver disease
    * [???]
  • Less than 0.03% of midazolam is excreted unchanged in urine

Action profile

  • Readily crosses blood-brain barrier
    * Effect-site equilibration time = 0.9 to 5.6 min
    * Slow compared to propofol and thiopentone
  • Short duration of action is due to:
    * Rapid clearance
    * Redistribution from brain

When used IV

  • Onset = 30-60 seconds
  • Time to peak effect = 3-5 min
  • Duration of sedation = 15-80 min

When used IM [PI]

  • Onset = 15 min
  • Time to peak effect = 30-60 min
  • Maximum plasma concentration = 45 min
  • Peak concentration is about 1/2 that achieved by IV route

Physicochemical properties

[SH4:p143]

  • Midazolam pK = 6.15
  • Midazolam parenteral solution is buffered to pH 3.5

Pharmaceutics

Presentation

  • 0.1% = 5 mg / 5 mL
  • 0.5% = 5 mg / 1 mL, 15 mg/ 3 mL, 50mg / 10 mL

Composition

[PI on MIMs]

  • Active = Midazolam
  • Inactive
    * NaCl
    * HCl
    * NaOH
  • pH = 2.9 - 3.7

 

Clinical

Administration and Usage

  • Preoperative medication
    * Useful in children
    * 0.25mg/kg PO (at least 20min before surgery)
    * Minimal effect on ventilation and oxygen saturation even with 1mg/kg PO (max 20mg)
  • Intravenous sedation during regional anaesthesia
    * 1-2.5mg IV
  • Induction of anaesthesia
    * 0.1 to 0.2mg/kg IV
    * 0.15 to 0.2 mg/kg IV [PI]
  • Maintenance of anaesthesia
    * Decreases requirement for volatile AA
    * Rarely associated with N&V or emergence excitement
  • Postoperative sedation
    * 1-7 mg/hr IV for intubated patient
  • Paradoxical vocal cord motion
    * 0.5-1 mg IV

NB:

  • Elderly requires less midazolam for IV induction
    * May be due to increased sensitivity of CNS to midazolam

Midazolam vs diazepam for IV sedation

Midazolam has:

  • More rapid onset
  • Less post-operative sedation
  • Greater amnesia
  • Time to complete recovery is NOT shorter
    * [SH4:p146]
  • Greater ventilatory depressant effect than lorazepam and diazepam