Pharmacokinetics
The three benzodiazepines used in anesthesia are classified as
short (midazolam), intermediate (lorazepam), and
Figure 10-11
Simulated time course of plasma levels of midazolam after
an induction dose of 0.2 mg/kg. Plasma levels required for hypnosis and amnesia
during surgery are 100 to 200 ng/mL, with awakening usually occurring at levels lower
than 50 ng/mL.
long lasting (diazepam), according to their metabolism and plasma clearance (see
Table 10-1
).[21]
[37]
The plasma disappearance curves of all the
benzodiazepines can be fitted to a two- or three-compartment model. Protein binding
and volumes of distribution are not importantly different among these three benzodiazepines,
but their clearance is significantly different. The clearance rate of midazolam
ranges from 6 to 11 mL/kg/min, whereas clearance of lorazepam is 0.8 to 1.8 mL/kg/min
and that of diazepam is 0.2 to 0.5 mL/kg/min.[21]
Because of these differences in clearance, the drugs have predictably different
plasma disappearance curves ( Fig.
10-11
Fig. 10-12
Fig. 10-13
). They also
have different context-sensitive half-times (see Fig.
10-3
). Although the termination of action of these drugs is primarily
a result of redistribution of the drug from the CNS to other tissues after use in
anesthesia, after daily (long-term) repeated administration or after prolonged continuous
infusion, midazolam blood levels will decrease more rapidly than blood levels of
the other drugs because of its greater hepatic clearance. Thus, patients given continuous
infusions of midazolam or repeated boluses over days should awaken faster than those
given diazepam or lorazepam.
Factors known to influence the pharmacokinetics of benzodiazepines
are age, gender, race, enzyme induction, and hepatic and renal disease. Diazepam
is sensitive to
Figure 10-12
Simulated time course of plasma levels of diazepam after
an induction dose of 0.5 mg/kg. Plasma levels required for hypnosis and amnesia
during surgery are 0.6 to 1.0 µg/mL, with awakening usually occurring at levels
lower than 0.5 µg/mL.
Figure 10-13
Simulated time course of plasma levels of lorazepam after
an induction dose of 0.1 mg/kg. Plasma levels required for hypnosis and amnesia
during surgery are between 50 and 150 ng/mL, with awakening usually occurring at
levels lower than 50 ng/mL.
some of these factors, particularly age. Increasing age tends to reduce the clearance
of diazepam[38]
significantly and the clearance
of midazolam to a lesser degree.[39]
Lorazepam
is resistant to the effects of age, gender, and renal disease on pharmacokinetics.
These drugs are all affected by obesity. The volume of distribution is increased
as drug goes from plasma into adipose tissue. Although clearance is not altered,
elimination half-lives are prolonged because of delayed return of the drug to plasma
in obese persons.[39]
In general, sensitivity to
benzodiazepines in some groups, such as the elderly, is greater despite relatively
modest pharmacokinetic effects; thus, factors other than pharmacokinetics must be
considered when these drugs are used.
