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

S
S
N
N
H 3 C H 3 C O
H 3 C H 3 C
H
O H
THIOPENTAL
THIAMYLAL
H 3 C
H 2 C
H 3 C
METHOHEXITAL
O
O
O
H 3 C O
NH
CH 3
N
KETAMINE
H
N
N
CI
CH 3
H
H 3 C
H 2 C
H 3 C
ETOMIDATE
Figure 19–1. Structures of some parenteral anesthetics.
O
time. Subsequently blood levels fall rapidly, resulting
in drug redistribution out of the CNS back into the
blood. The anesthetic then diffuses into less perfused
tissues such as muscle and viscera, and at a slower rate
into the poorly perfused but very hydrophobic adipose
tissue. Termination of anesthesia after single boluses of
parenteral anesthetics primarily reflects redistribution
out of the CNS rather than metabolism (Figure 19–2).
After redistribution, anesthetic blood levels fall according
to a complex interaction between the metabolic rate
and the amount and lipophilicity of the drug stored in
the peripheral compartments. Thus, parenteral anesthetic
half-life are “context-sensitive,” and the degree
to which a t 1/2
is contextual varies greatly from drug to
drug, as might be predicted based on their differing
hydrophobicities and metabolic clearances (Table 19–2 and
Figure 19–3). For example, after a single bolus of thiopental,
patients usually emerge from anesthesia within 10
minutes; however, a patient may require more than a day
to awaken from a prolonged thiopental infusion.
Most individual variability in sensitivity to parenteral
anesthetics can be accounted for by pharmacokinetic
factors. For example, in patients with lower
cardiac output, the relative perfusion of the brain and
the fraction of anesthetic dose delivered to the brain are
higher; thus, patients in septic shock or with cardiomyopathy
usually require lower doses of anesthetic. The
elderly also typically require a smaller anesthetic
dose, primarily because of a smaller initial volume of
O
O
O
N
H
N
N
Serum thiopental (μg/mL)
100
10
1.0
0.1
0
t 1
2 = 6.8 + – 2.8
min
1
2
g/mL
μ
200
100
4 8 12 16 20 24
Hours
distribution. As described later in the chapter, similar
principles govern the pharmacokinetics of the
hydrophobic inhalational anesthetics, with the added
complexity of drug uptake by inhalation.
SPECIFIC PARENTERAL AGENTS
Barbiturates
Chemistry and Formulations. Barbiturates are derivatives
of barbituric acid (2,4,6-trioxohexahydropyrimidine),
with either an oxygen or a sulfur at the 2-position
(Figure 19–1). The three barbiturates most commonly
used in clinical anesthesia are sodium thiopental, thiamylal,
and methohexital. Sodium thiopental (PEN-
TOTHAL, others) has been used most frequently for
inducing anesthesia. Thiamylal (SURITAL) is licensed in
the U.S. only for veterinary use. Barbiturates are supplied
as racemic mixtures despite enantioselectivity in
their anesthetic potency. Barbiturates are formulated
as the sodium salts with 6% sodium carbonate and
10
t = 719 + – 329 min
1 5 10 15
Minutes
Figure 19–2. Thiopental serum levels after a single intravenous
induction dose. Thiopental serum levels after a bolus can be
described by two time constants, t 1/2
α and t 1/2
β.The initial fall is
rapid (t 1/2α
<10 min) and is due to redistribution of drug from the
plasma and the highly perfused brain and spinal cord into less
well-perfused tissues such as muscle and fat. During this redistribution
phase, serum thiopental concentration falls to levels at
which patients awaken (AL, awakening level; see inset—the
average thiopental serum concentration in 12 patients after a
6-mg/kg intravenous bolus of thiopental). Subsequent metabolism
and elimination is much slower and is characterized by a
half-life (t 1/2
β) of more than 10 hours. (Adapted with permission
from Burch PG, and Stanski DR, The role of metabolism
and protein binding in thiopental anesthesia. Anesthesiology,
1983, 58:146–152. Copyright Lippincott Williams & Wilkins.
http://lww.com.)
AL
533
CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES