DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

agents are considerably more effective in acid-peptic disorders
(Chapter 45).
Absorption, Fate, and Excretion. The physicochemical
and pharmacokinetic properties of the benzodiazepines
greatly affect their clinical utility. They all have high
lipid–water distribution coefficients in the non-ionized
form; nevertheless, lipophilicity varies >50-fold according
to the polarity and electronegativity of various substituents.
All the benzodiazepines are absorbed completely,
with the exception of clorazepate; this drug is decarboxylated
rapidly in gastric juice to N-desmethyldiazepam
(nordazepam), which subsequently is absorbed completely.
Drugs active at the benzodiazepine receptor
may be divided into four categories based on their
elimination t 1/2
:
• Ultra-short-acting benzodiazepines
• Short-acting agents (t 1/2
<6 hours), including triazolam,
the non-benzodiazepine zolpidem (t 1/2
~2 hours),
and eszopiclone (t 1/2
5-6 hours)
• Intermediate-acting agents (t 1/2
6-24 hours), including
estazolam and temazepam
• Long-acting agents (t 1/2
>24 hours), including flurazepam,
diazepam, and quazepam
Flurazepam itself has a short t 1/2
(~2.3 hours), but a major
active metabolite, N-des-alkyl-flurazepam, is long-lived (t 1/2
47-100 hours), which complicates the classification of individual
benzodiazepines.
The benzodiazepines and their active metabolites bind to
plasma proteins. The extent of binding correlates strongly with lipid
solubility and ranges from ~70% for alprazolam to nearly 99% for
diazepam. The concentration in the cerebrospinal fluid is approximately
equal to the concentration of free drug in plasma. While competition
with other protein-bound drugs may occur, no clinically
significant examples have been reported.
The plasma concentrations of most benzodiazepines exhibit
patterns that are consistent with two-compartment models (Chapter 2),
but three-compartment models appear to be more appropriate for the
compounds with the highest lipid solubility. Accordingly, there is
rapid uptake of benzodiazepines into the brain and other highly perfused
organs after intravenous administration (or oral administration
of a rapidly absorbed compound); rapid uptake is followed by a
phase of redistribution into tissues that are less well perfused, especially
muscle and fat. Redistribution is most rapid for drugs with the
highest lipid solubility. In the regimens used for nighttime sedation,
the rate of redistribution sometimes can have a greater influence than
the rate of biotransformation on the duration of CNS effects (Dettli,
in Symposium, 1986a). The kinetics of redistribution of diazepam
and other lipophilic benzodiazepines are complicated by enterohepatic
circulation. The volumes of distribution of the benzodiazepines
are large and in many cases are increased in elderly patients. These
drugs cross the placental barrier and are secreted into breast milk.
The benzodiazepines are metabolized extensively by hepatic
CYPs, particularly CYPs 3A4 and 2C19. Some benzodiazepines,
such as oxazepam, are conjugated directly and are not metabolized
by these enzymes (Tanaka, 1999). Erythromycin, clarithromycin,
ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit
juice are inhibitors of CYP3A4 (Chapter 6) and can affect the metabolism
of benzodiazepines (Dresser et al., 2000). Because active
metabolites of some benzodiazepines are biotransformed more
slowly than are the parent compounds, the duration of action of many
benzodiazepines bears little relationship to the t 1/2
of elimination of
the parent drug that was administered, as noted above for flurazepam.
Conversely, the rate of biotransformation of agents that are
inactivated by the initial reaction is an important determinant of their
duration of action; these agents include oxazepam, lorazepam,
temazepam, triazolam, and midazolam.
Metabolism of the benzodiazepines occurs in
three major stages. These and the relationships between
the drugs and their metabolites are shown in Table 17–2.
For benzodiazepines that bear a substituent at position 1
(or 2) of the diazepine ring, the initial and most rapid phase of
metabolism involves modification and/or removal of the substituent.
With the exception of triazolam, alprazolam, estazolam, and midazolam,
which contain either a fused triazolo or a imidazolo ring, the
eventual products are N-desalkylated compounds that are biologically
active. One such compound, nordazepam, is a major metabolite
common to the biotransformation of diazepam, clorazepate, and
prazepam; it also is formed from demoxepam, an important metabolite
of chlordiazepoxide.
The second phase of metabolism involves hydroxylation at
position 3 and also usually yields an active derivative (e.g.,
oxazepam from nordazepam). The rates of these reactions are usually
very much slower than the first stage (t 1/2
>40-50 hours) such
that appreciable accumulation of hydroxylated products with intact
substituents at position 1 does not occur. There are two significant
exceptions to this rule: (1) small amounts of temazepine accumulate
during the chronic administration of diazepam and (2) following
the replacement of S with O in quazepam, most of the
resulting 2-oxoquazepam is hydroxylated slowly at position 3 without
removal of the N-alkyl group. However, only small amounts of
the 3-hydroxyl derivative accumulate during chronic administration
of quazepam because this compound is conjugated at an unusually
rapid rate. In contrast, the N-desalkylflurazepam that is formed by
the “minor” metabolic pathway does accumulate during quazepam
administration, and it contributes significantly to the overall clinical
effect.
The third major phase of metabolism is the conjugation of
the 3-hydroxyl compounds, principally with glucuronic acid; the t 1/2
of these reactions usually are ~6-12 hours, and the products invariably
are inactive. Conjugation is the only major route of metabolism
for oxazepam and lorazepam and is the preferred pathway for
temazepam because of the slower conversion of this compound to
oxazepam. Triazolam and alprazolam are metabolized principally
by initial hydroxylation of the methyl group on the fused triazolo
ring; the absence of a chlorine residue in ring C of alprazolam slows
this reaction significantly. The products, sometimes referred to as
α-hydroxylated compounds, are quite active but are metabolized very
463
CHAPTER 17
HYPNOTICS AND SEDATIVES