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midazolam (Versed, Buccolam)
Tradename: Versed. DEA-controlled substance: class 4.
Indications:
- used in anesthesia for sedation
- conscious sedation
- management of sedation/agitation (< 24 h) in an ICU setting
- NOT recommended for sedation > 24 h due to active metabolite accumulation, especially in elderly & patients with renal impairment
- status epilepticus
- when IV access not available (buccal) 56% effective
- anxiety [7]
- amnesia [7]
Contraindications:
1) uncontrolled pain
2) pre-existing CNS depression
3) shock
4) narrow angle glaucoma
Caution:
1) increased potential for toxicity in elderly
2) congestive heart failure
3) renal impairment
4) pulmonary disease
5) hepatic dysfunction
Dosage:
1) 5 mg or 0.07 mg/kg IM [1].
2) 0.08 mg/kg IM [2].
3) conscious sedation:
a) 1 mg IV slowly every 2-3 min up to 5 mg [1]
b) 0.035-0.100 mg/kg [2]
4) 2-4 mg IV every 3-4 hours (1-2 mg if > 60 years of age)
5) infusion 2-8 mg/hr (1-4 mg/hr > 60 yr), titrate to effect
6) 2.5-10 mg (buccal)
1 mg lorazepam = 4 mg midazolam
Injection: 1 mg/mL (2 mL, 5 mL, 10 mL) 5 mg/mL (1 mL, 2 mL, 5 mL, 10 mL)
Pharmacokinetics:
1) well absorbed with IM administration
2) rapid onset of action
3) duration of action 60-90 minutes
4) poor systemic absorption after oral administration
5) highly lipophilic
6) metabolized in the liver by cyt P450 3A4 to active metabolites (hydroxylation)
-> principal metabolite is alpha-hydroxymidazolam
7) excreted in the urine
8) active metabolites accumulate with renal dysfunction
9) 1/2life 1.5-3 hours
10) metabolite 1/2life 24-36 hours
Adverse effects:
1) common (> 10%)
- decreased respiratory rate, apnea, hypotension, hiccups, pain at site of injection
2) less common (1-10%)
- cardiac arrest, bradycardia, drowsiness, ataxia, amnesia, dizziness, paradoxical excitement, sedation, headache, nausea/vomiting, blurred vision, diplopia, laryngospasm, bronchospasm
3) uncommon (< 1%)
- wheezing, tachycardia, rash, delirium
4) other [3]
- withdrawal
- agitation
- anterograde amnesia
- phlebitis
- cardio-respiratory depression
- hallucinations
- relaxation of lower esophageal sphincter (GERD)
- over sedation, especially with renal insufficiency
- tachyphylaxis
- physical & psychologic dependence with prolonged use
Drug interactions:
1) disulfiram, nefazodone, fluoxetine, fluvoxamine, cimetidine, ranitidine, erythromycin & grapefruit juice decrease metabolism of benzodiazepines
2) CNS depressants in combination increase CNS depression
3) anticonvulsants, rifampin increase metabolism of benzodiazepines
4) flumazenil antagonizes effects of benzodiazepines
5) any drug that inhibits cyt P450 3A4 may increase levels of midazolam
6) any drug that induces cyt P450 3A4 may diminish levels of midazolam
Laboratory:
2) Loincs:
- midazolam in hair
- midazolam in tissue
- midazolam in body fluid
- midazolam in meconium
- midazolam in blood
- midazolam in serum/plasma
- midazolam in stool
- midazolam in urine
- midazolam in vitreous fluid
2) methods: GLC, HPLC
Mechanism of action:
- potentiates inhibitory effects of GABA by inhibiting neuronal membrane permeability to Cl-
Interactions
drug interactions
drug adverse effects (more general classes)
Related
cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
General
benzodiazepine
Properties
MISC-INFO: elimination route LIVER
1/2life 1-4 HOURS
protein-binding 94-97%
pregnancy-category D
safety in lactation -
Database Correlations
PUBCHEM correlations
References
- The Pharmacological Basis of Therapeutics, 9th ed.
Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- Manual of Medical Therapeutics, 28th ed, Ewald &
McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 7
- Drug Information & Medication Formulary, Veterans Affairs,
Central California Health Care System, 1st ed., Ravnan et al
eds, 1998
- Kaiser Permanente Northern California Regional Drug
Formulary, 1998
- Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed,
WB Saunders, Philadelpha 1995
- McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP,
Phillips B, Martland T, Berry K, Collier J, Smith S, Choonara I.
Safety and efficacy of buccal midazolam versus rectal diazepam f
or emergency treatment of seizures in children: a randomised
controlled trial.
Lancet. 2005 Jul 16-22;366(9481):205-10.
PMID: 16023510
- Deprecated Reference