Medical Pharmacology Chapter 12:  Anxiolytics and Sedative-Hypnotics

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Preoperative Medication: Sedative Hypnotics and Other Agents and Issues

Benzodiazepines

  • Overview:

    • Most commonly used sedative/anxiolytic

    • Anxiolytic effectiveness is observed at dosages which do not result in cardiopulmonary depression or excessive sedation

    • Certain benzodiazepines also exhibit significant anterograde amnesia (amnesia subsequent to drug administration).  

      •  Examples of these benzodiazepines include midazolam (Versed) and lorazepam (Ativan).

      •  These agents may also cause, on predictably, some degree of retrograde amnesia as well.

    • Benzodiazepines may also be used the night before schedule surgery in management of pre-surgical insomnia-- examples include lorazepam (Ativan), temazepam (Restoril), and triazolam (Halcion)

    • Sometimes benzodiazepines used pre-surgically can result in prolonged and excessive sedation. 

      • Patients receiving lorazepam (Ativan) at high dosages (total dose > 4 mg orally at 5 ug/kg) may be most susceptible to this excessive sedation.  

      • A benzodiazepine antagonist, flumazenil (Romazicon) may be used to reverse benzodiazepine effects.

    • Intramuscular injection of diazepam (Valium) may be painful because diazepam (Valium) is dissolved in the irritating solvent propylene glycol; intramuscular injections of midazolam (Versed) does not cause local irritation since the chemical characteristics of midazolam (Versed) do not require the use of propylene glycol as a solvent (an aqueous solvent is used).

  • Adverse Effects: benzodiazepines

    • Major adverse effects

      • Respiratory depression

      • Reduction in cognitive and motor function

    •  Inpatient considerations:

      • If cognitive function need not be immediately returned to normal following procedure, lorazepam (Ativan) (oral) may be appropriate the morning of surgery

    •  Outpatient considerations:

      • Diazepam (Valium) (oral)

      • Midazolam (Versed) (IV), particularly appropriate

    • Factors/conditions which increase likelihood of preoperative excessive sedation associated with the use of benzodiazepines and other sedative hypnotics:

      • Infancy, advanced age (elderly patients), chronic debilitating disease or malnutrition, pregnancy, renal dysfunction, hepatic dysfunction, pulmonary dysfunction, adrenal insufficiency, myasthenia gravis, myotonia, sickle cell disease, acute drug/ethanol intoxication5.

 

3Comparisons: midazolam (Versed), diazepam (Valium), and lorazepam (Ativan)
 

Midazolam (Versed)

Diazepam (Valium)

 Lorazepam (Ativan)

Dosage (oral)

0.3-0.5 mg/kg

0.15-0.2 mg/kg

0.015-0.03 mg/kg

Time to peak effect

30 minutes-60 minutes

1-1.5 hours

2-4 hours

Duration

1-2 hours

2-2.5 hours

4-6 hours

Elimination halftime (time to reduce drug concentration by 50%)

1-4 hours

20-100 hours (includes active metabolites)

8-24 hours

Apparent volume of distribution (Vd)

1.1-1.7 L/kg

0.7-1.7 L/kg

0.8-1.3 L/kg

Presence of active metabolites

Yes, but relatively weak in effect

Prominent

None

Metabolic mechanism

Hydroxylation and conjugation

Hydroxylation and conjugation

Conjugation; conjugation reactions are less likely to be affected by age or the presence of hepatic disease

Clearance

6-11 ml/kg per minute

0.2-0.5 ml/kg per minute

0.7-1 ml/kg per minute

Lipid solubility

High

High

Intermediate

Effect of age

In the elderly, midazolam (Versed) half-life may be increased by as much as eight hours

In the elderly the half-life of diazepam (Valium) may be increased by several days

 
Laryngeal papillomatosis, Epiglottitis

  • "The arrows point to multiple papilloma growths on the larynx caused by a viral infection. Permission to reproduce photo courtesy of the University of Pittsburgh Voice Center.

  • (Ed. note: This is a photograph that shows how laryngeal papillomatosis--RRP of the larynx--does not invariably present with a traditional cauliflower-appearance.)"

 

Papillomatosis

Epiglottis (with Abscess)

  • From On-Line Airway Atlas 2000, John Sherry, II, M.D 1999, 2000

 
Benzodiazepine pharmacology

Diazepam (Valium)

Midazolam (Versed)

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