Medical Pharmacology Chapter 12:  Anxiolytics and Sedative-Hypnotics

 

• ³Midazolam (Versed) and diazepam (Valium) comparisons:

  • Pharmacokinetic issues:

    • Midazolam (Versed): short half-life (1-4 hours); diazepam (Valium), including active metabolites: long half-life 20-100 hours

    • In elderly patients, diazepam (Valium) half-life may be extended to several days (midazolam (Versed) half-life may be extended by eight hours)

  •  Diazepam (Valium) metabolites: oxazepam which is Serax and desmethyldiazepam are active

  •  Weak midazolam (Versed) metabolites suggest that in the outpatient setting, midazolam (Versed) would be preferred. 

    • Quicker recovery and  greater amnesia have been found with midazolam (Versed).

  •  Midazolam (Versed) in combination with opioids: cautious use in view of possible respiratory depression leading to inadequate oxygenation. 

    • Nalbuphine (0.2 mg/kg) and midazolam (Versed) (0.09 mg/kg) may be the most appropriate combination in order to minimize respiratory complications at least in patients undergoing minor oral surgery

•   Pediatric uses of  Midazolam (Versed)³:

  • Oral midazolam (Versed) (0.5 mg/kg) is useful in preventing "facemask phobia"

  • Following oral administration (midazolam (Versed), 0.5 mg/kg) the child is typically easily separated from parents and willing to accept monitoring and facemask

  • At a midazolam (Versed) dosage of 0.75 mg/kg, most pediatric patients {90%} undergo induction without crying or combative behavior

  • At these dosages, midazolam (Versed) effects last <  1 hour and do not appear to prolong recovery

  • Midazolam (Versed) administration (occasionally in combination with atropine, e.g.) can be facilitated by mixing with cherry syrup or with a melted popsicle.

  •  Special circumstances:

    •  In pediatric patients with congenital heart disease, midazolam (Versed) may improve oxyhemoglobin saturation in most cases; however in some children with cyanotic heart disease (3 of 17 tested) desaturation may occur with a reduction of greater than 10%

      • Accordingly,  pulse oximetry monitoring is essential.

  • Children with a compromised airway: midazolam (Versed) premedication would not be advised because apnea following midazolam (Versed) administration may be associated with an inability to mask ventilate.

    • Crying itself (which may be made less likely by midazolam (Versed) administration) can worsen airway obstruction in the presence of, for example, epiglottitis or laryngeal papillomatosis, a condition of multiple papilloma grows on the larynx caused by a viral infection-this condition occurs with approximately equal frequency and children and adults.  

• Intranasal midazolam (Versed) administration (0.2 mg/kg)

  • Less patient cooperation required (appropriate for combative children)

  • Quicker onset compared to oral Route of Administration

  • Occasionally (rare), midazolam (Versed) made evoked a hyperexcitability reaction-some anesthesia providers may wish to employ midazolam (Versed) only with relatively uncooperative patients

• ³Lorazepam (Ativan)

  • Overview

    • No active metabolites; short half-life (approximately 15 hours)

    • Half-life not influenced by patient age

  • Pharmacokinetic/metabolism characteristics

    • Reduced, compared to diazepam (Valium), rate of CNS access secondary to relatively less lipophilicity

    • Onset of action for both diazepam (Valium) and lorazepam (Ativan) is similar, about 30-60 minutes

    • CNS effects e.g. psychomotor impairment, may be observed for 12 hours following the single lorazepam (Ativan) dose

    • Metabolism:

      • Glucuronidation (conjugation) followed by renal excretion

      • Glucuronidation reactions tend to be less susceptible to effects of aging or hepatic disease, i.e. typically no significant change in half-life as a function of age or liver dysfunction

  • Comparing lorazepam (Ativan) and diazepam (Valium):

    • Dosage:  2 mg orally of lorazepam (Ativan) is about equal to 10 mg oral diazepam (Valium)

    • Sedation following a single 2 mg dose less about five hours

    • At higher dosages, such as 5 mg, anterograde amnestic effects may last up to about eight hours

    • Disorientation following the 5 mg dose may last as long as 17 hours; this finding suggests that the upper dosage limit for lorazepam (Ativan) perhaps should be 4 mg

    • Diazepam (Valium)

      • At the 10 mg level: typically no amnesia

      • At the 20 mg level, about 30% of patients exhibit amnesia {4 mg of lorazepam (Ativan) (oral) results in an amnesia frequency of > 70%}

  • Lorazepam (Ativan) uses:

    • Appropriate for patients undergoing major surgical procedures which will be followed by intensive care unit monitoring

    • Advantage for seriously ill (critically ill) patients include:

      • Absence of myocardial depression or vascular smooth muscle relaxation even at doses above 9 mg 

    • Concerning typical premedication in patients with heart disease, sedative and anxiolytic action of flurazepam (Dalmane) (orally administered; 0.06 mg/kg, administered 90 minutes prior surgery) was comparably effective to a more traditional premedication regimen consisting of intramuscular morphine (0.1 mg/kg) combined with scopolamine.

References

• ¹Preoperative Medication in Basis of Anesthesia, 4th Edition, Stoelting, R.K. and Miller, R., p 119- 130, 2000) 

• Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives; Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc., 1996, pp. 364-367.

• ³Sno E. White The Preoperative Visit and Premedication in Clinical Anesthesia Practice pp.  576-583 (Robert Kirby and Nikolaus Gravenstein, eds) W.B.  Saunders Co., Philadelphia, 1994

• ⁴John R. Moyers and Carla M. Vincent Preoperative Medication in Clinical Anethesia, 4th edition (Paul G. Barash, Bruce. F. Cullen, Robert K. Stoelting, eds) Lippincott Williams and Wilkins, Philadelphia, PA, 2001

• ⁵Kathleen R. Rosen and David A. Rosen, "Preoperative Medication" pp. 61-70 in  Principles and Procedures in Anesthesiology (Philip L. Liu, ed) J. B. Lipincott Company, Philadelphia, 1992 

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