MetroHealthAnesthesiaIV Anesthesia - Benzodiazepines

Historical Points

Chlordiazepoxide (Librium) was synthesized in 1955 by Sternbach. In 1957 it was discovered to have hypnotic properties. Amnesic effects were noted sometime after its release for oral use in 1960.
Sternbach synthesized diazepam (Valium) in 1959. In 1966 diazepam became the first benzodiazepine to be used to produce anesthesia.
Oxazepam (Serax) was synthesized by Bell in 1961.
Lorazepam (Ativan), 2'-chloro substituted oxazepam, was synthesized in 1971.
In 1976 Fryer and Walker synthesized the first clinically used water-soluble benzodiazepine, midazolam (Versed).
The benzodiazepine receptor was characterized in the 1970's.

Physicochemical Properties

The three benzodiazepines in common anesthetic use today are diazepam, lorazepam and, especially, midazolam. Midazolam is the most lipid soluble of the three in vivo, but is water-soluble at pH < 4. At pH > 4, midazolam becomes lipid soluble. Midazolam's imidazole ring helps provide stability in solution as well as allow for rapid metabolism.

Metabolism

Benzodiazepines are metabolized in the liver by hepatic microsomal oxidation and glucuronide conjugation. Hepatic microsomal oxidation (N-dealkylation or aliphatic hydroxylation) is impaired by age, hepatic cirrhosis and by the coadministration of certain drugs (e.g.: cimetidine). Habitual alcohol consumption leads to increased clearance of midazolam. Diazepam is metabolized to two active metabolites that help prolong the benzodiazepine effect. Midazolam, on the other hand, is metabolized to hydroxymidazolam which has very little activity.

Pharmacokinetics

The three benzodiazepines may be grouped according to elimination clearance:
Clearance in ml/kg/min
short midazolam 6-11
intermediate lorazepam 0.8-1.8
long diazepam 0.2-0.5
It should be noted that termination of anesthetic effect is due primarily to redistribution (not elimination clearance).

Pharmacology

Properties:
  • hypnotic, sedative
  • anxiolytic
  • amnestic
  • anticonvulsant
  • centrally acting muscle relaxant
Mechanism of action: GABAA receptor binding
GABAA receptor affinity:
lorazepam > midazolam > diazepam
Binding is stereospecific and saturable.
GABAA receptor occupancy and clinical effect:
  • >20%: anxiolysis
  • >30-50%: sedation
  • >50%: unconsciousness
GABAA receptor complex is reported to be a pentameric complex consisting of 2 alpha1, 2 beta1, and one gamma2 components surrounding and controlling a central chloride ion channel. The specific benzodiazepine receptor is part of the gamma2 component. GABA, the physiologic inhibitory transmitter, triggers gating ('opening') of the chloride channel which leads to hyperpolarization (hence inhibition) of the postsynaptic neuron. Another mechanism, alteration in calcium ion flux, may play a role in the benzodiazepine hypnotic effect.

Uses

IV sedation

Midazolam, 0.5-1 mg IV prn, produces its peak effect in 2-3 minutes. Midazolam may be administered IM: 0.07 mg IM. A continous IV infusion of midazolam 0.5-1 mcg/kg/min provides reliable amnesia.
Lorazepam, 0.25 mg IV prn provides sedation and an unpredictable duration of amnesia.

Induction and maintenance of anesthesia

Midazolam 0.1 - 0.2 mg/kg IV induces general anesthesia in about 30 seconds. It is slower than thiopental, but produces more reliable anmesia. The dose should be reduced for patients > 55 years old, ASA III and IV patients, and when used with other drugs (coinduction). Emergence is slower than after thiopental or propofol for short operations. Maintenance may be provided with midazolam 0.25-1 mcg/kg/min to maintain a plasma level of 50 ng/ml. It may be used concomittantly with fentanyl and perhaps an inhalational agent.

Side Effects and Reversal

Benzodiazepines are relatively free of allergenic side effects. Midazolam may cause respiratory depression when used for sedation. Lorazepam and diazepam may cause venous irritation and thrombophlebitis. Benzodiazepines may produce a prolonged period of sedation and amnesia.
Benzodiazepines are reversible with flumazenil (Anexate, Romazicon) 0.1-0.2 mg IV prn to 1 mg, and then 0.5 - 1 mcg/kg/min.




Send Comments to Greg Gordon MD, gjg@po.cwru.edu
Department of Anesthesiology
The MetroHealth System
2500 MetroHealth Drive
Cleveland, Ohio 44109-1998
Phone: (216) 778-4801
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