Intravenous Benzodiazepines as Anaesthetic Agents: Pharmacokinetics and Clinical Consequences

Kanto, J.; Klotz, Ulrich

doi:10.1111/j.1399-6576.1982.tb01817.x

Cited by 43 publications

(17 citation statements)

References 163 publications

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“…Total distribution volume and clearance values of midazolam agreed with previous data (Smith et a1 1981). As anticipated, apparent elimination half-life values of midazolam were slightly longer than those reported during single dose studies (Kanto & Klotz 1982;Smith et a1 1981). There was no difference in the pharmacokinetic parameters calculated using the serum levels determined by RRA or GLC (Aaltonen et a1 1985).…”

Section: Pharmacokinetic Parameterssupporting

confidence: 54%

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Plasma concentrations and pharmacokinetics of midazolam during anaesthesia

Crevat-Pisano

Dragna

Granthil

et al. 1986

Journal of Pharmacy and Pharmacology

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Midazolam and 1-hydroxymidazolam plasma concentrations have been monitored and pharmacokinetic parameters of midazolam estimated during anaesthesia induced and maintained by its repeated injection according to two protocols (3 X 0.3 mg kg-1 at 45 min intervals or an induction dose of 0.3 mg kg-1 with maintenance doses of 0.15 mg kg-1 at 30 min intervals). Minimum plasma concentrations of midazolam measured just before each injection were 258.8 +/- 108.4 ng ml-1 for the first protocol and 353.1 +/- 55.2 ng ml-1 for the second protocol; maximum midazolam concentrations, measured 5 min after the last administration, were 1103.1 +/- 237.9 ng ml-1 and 743.0 +/- 103.2 ng ml-1, respectively, suggesting that a continuous infusion of midazolam after a loading dose should be better than repeated injections at keeping the concentration close to the sedative level of 400 ng ml-1. The estimated pharmacokinetic parameters were similar to those already published, except for the beta elimination half-life of midazolam (3.24 +/- 0.90 h for protocol 1 and 3.34 +/- 1.47 h for protocol 2) which was slightly longer than that reported for single dose studies. The comparison of plasma determinations, obtained either by gas-liquid chromatography or by a radioreceptor assay technique, clearly showed that 1-hydroxymidazolam, even after repeated midazolam administration, was not present at a concentration sufficient to affect the overall pharmacological activity of the parent drug.

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Section: Pharmacokinetic Parameterssupporting

confidence: 54%

“…It has the characteristic properties of benzodiazepines, i.e. sleep inducing, sedative, anxiolytic, anticonvulsant and muscle relaxant effects coupled with a short elimination half-life of about 2 h (Kanto & Klotz 1982;Smith et a1 1981) and the watersolubility of its salts (maleinate).…”

mentioning

confidence: 99%

Plasma concentrations and pharmacokinetics of midazolam during anaesthesia

Crevat-Pisano

Dragna

Granthil

et al. 1986

Journal of Pharmacy and Pharmacology

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“…The individual response varied severalfold. This clinical problem has also been observed with other benzodiazepines and might complicate their use in anaesthesiology (for review see Kanto and Klotz, 1982). Since plasma concentrations and free fractions of midazolam were very similar in our subjects, the different response might be due to variability in penetration into cerebrospinal fluid (CSF) and/or to the number/affinity of the benzodiazepine receptors in the brain.…”

Section: Discussionmentioning

confidence: 80%

Chronopharmacokinetic Study with Prolonged Infusion of Midazolam

Klotz

Reimann

1984

Clinical Pharmacokinetics

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Physiological and temporal variation in the disposition of midazolam has been reported. In order to delineate the underlying mechanisms of these alterations, we infused in 5 healthy male volunteers for 26 hours midazolam at a rate of 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg. Thus, steady-state conditions were rapidly achieved. Plasma levels of midazolam were monitored on a 2-hourly basis during this period. In addition, the pharmacodynamic response to the new sedative/hypnotic benzodiazepine was characterised by a pencil tracking test, sedation index formed from visual analogue scales, and choice reaction time. In all subjects, small (4 to 16%) but clinically irrelevant fluctuations of steady-state plasma concentrations around 45 ng/ml were observed. During the night-time (11pm to 7am) plasma concentrations were slightly (p = 0.074) higher than during the daytime. Total plasma clearance varied from 563 to 823 ml/min. Plasma protein binding of midazolam was time independent. Since in only 1 of 5 subjects was a circadian rhythm observed, fluctuations in plasma midazolam concentrations under controlled and constant conditions are probably not of clinical significance.

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“…The amnesic effect of preanesthetic medication may not be desirable in every patient because it is often associated with loss of self-control that may be alarming (22).…”

Section: Discussionmentioning

confidence: 99%

Midazolam as an Intravenous Induction Agent in the Elderly

Kanto

Aaltonen

Himberg

et al. 1986

Anesthesia & Analgesia

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HOVI-WANDER M. Midazolam as an intravenous induction agent in the elderly: a clinical and pharmacokinetic study. Anesth Analg 1986;65:15-20.Midazolam, the first benzodiazepine derivative with watersoluble salts, was studied as an induction agent in general anesthesia for the elderly. In group 1 (n = 14), 5 or 10 mg oral diazepam was used as premedication, but in group 2 f n = 9), both oral (10 mgdixyrazin asa night-timesedative) and intramuscular (0.01 mglkg atropine + 1 mglkg meperidine) premedicants were used. Serum concentrations of benzodiazepines were determined using both gas-liquid chromatographic (unchanged rnidazolam) and radioreceptor assays (binding equivalents of benzodiazepines plus their active metabolites). In general, midazolam, 0.15 mglkg, intravenously resulted in smooth induction of anesthesia, although the time required for induction was rather long and a sudden but transient decrease in blood pressure was found in a significant number of patients. The course of anesthesia was otherwise satisfactory. A marked amnesic effect was observed, especially when diazepam was used as premedication. The pharmacokinetic parameters based on gas-liquid chromatographic measurements were quite comparable with those in young, healthy persons published earlier. In both groups, the binding equivalents measured with radioreceptor assay (reflecting total benzodiazepine activity) were higher than the levels of unchanged midazolani determined with gas-liquid chromatography. The relatively low dose of 0.15 mglkg of midazolam needed for anesthetic iizduction in the elderly indicates not pharmacokinetic, but pharrnacodynamic, alterations in older patients. We conclude that midazolam is a new intravenous induction agent for use in the elderly, but careful titration of the dosage according to the response of the patient is required. Diazepam premedication prior to midazolain causes a marked anterograde amnesic effect.

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Intravenous Benzodiazepines as Anaesthetic Agents: Pharmacokinetics and Clinical Consequences

Cited by 43 publications

References 163 publications

Plasma concentrations and pharmacokinetics of midazolam during anaesthesia

Plasma concentrations and pharmacokinetics of midazolam during anaesthesia

Chronopharmacokinetic Study with Prolonged Infusion of Midazolam

Midazolam as an Intravenous Induction Agent in the Elderly

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