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