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

Pharmacokinetics and Metabolism. The pharmacokinetics of
propofol are governed by the same principles that apply to barbiturates.
Onset and duration of anesthesia after a single bolus are similar
to thiopental. Recovery after multiple doses or continuous
infusion has been shown to be much faster after propofol than after
thiopental or even methohexital. Propofol has a context-sensitive t 1/2
of ~10 min with an infusion lasting 3 hours and ~40 minutes for
infusions lasting up to 8 hours (Figure 19–3). Propofol’s shorter
duration of action after infusion can be explained by its very high
clearance, coupled with the slow diffusion of drug from the peripheral
to the central compartment (Figure 19–3). The rapid clearance
of propofol explains the more rapid emergence from anesthesia in
comparison to barbiturates; this facilitates a more rapid discharge
from the recovery room.
Propofol is metabolized in the liver by conjugation to sulfate
and glucunoride to less active metabolites that are renally excreted;
however, its clearance exceeds hepatic blood flow, and anhepatic
metabolism, particularly in the lungs and kidneys, has been demonstrated
(Veroli et al., 1992). In patients with moderate cirrhosis, the
volume of distribution of propofol is increased significantly.
However, terminal elimination t 1/2
and emergence from propofol
anesthesia is not substantially different from healthy patients (Servin
et al., 1990). Propofol is highly protein bound, and its pharmacokinetics,
like those of the barbiturates, may be affected by conditions
that alter serum protein levels.
Clearance of propofol is reduced in the elderly; given that the
central volume of distribution of propofol is also reduced, the
required dose of propofol for both induction and maintenance of
anesthesia may be decreased. In neonates, propofol clearance is also
reduced (Allegaert et al., 2007). Infusion of propofol in neonates
therefore has the potential for substantial accumulation and a consequent
delay in emergence from anesthesia or sedation. By contrast,
in young children, a more rapid clearance in combination with a
larger central volume may necessitate larger doses of propofol for
induction and maintenance of anesthesia (Kataria et al., 1994).
The t 1/2
for hydrolysis of fospropofol is 8 min. Fospropofol
has a small volume of distribution and a terminal t 1/2
~46 min. The
currently published pharmacokinetic data on fospropofol were
derived using an analytical method that has now been shown to be
inaccurate; correct pharmacokinetic data are not yet available
(Fechner et al., 2008).
Pharmacology and Side Effects
Nervous System. The sedation and hypnotic actions of propofol are
mediated by its action on GABA A
receptors; agonism at these receptors
results in an increased chloride conduction and hyperpolarization
of neurons. Propofol suppresses the EEG, and in sufficient
doses, can produce burst suppression of the EEG. Propofol decreases
CMRO 2
, cerebral blood flow, and intracranial and intraocular pressures
by about the same amount as thiopental. Like thiopental,
propofol has been used in patients at risk for cerebral ischemia; however,
no human outcome studies have been performed to determine
its efficacy as a neuroprotectant. Excitatory phenomena, such as
choreiform movements and opisthotonus, have been observed after
propofol injection with the same frequency as that seen with thiopental
but less than with methohexital. These movements, which are
transient, are not associated with seizure activity. Results from studies
on the anticonvulsant effects of propofol have been mixed; some
data even suggest it has proconvulsant activity when combined with
other drugs. However, propofol has been shown to suppress seizure
activity in experimental models and has been used for the treatment
of status epilepticus in humans (Parviainen et al., 2007).
Cardiovascular System. Propofol produces a dose-dependent decrease
in blood pressure that is significantly greater than that produced by
thiopental. The fall in blood pressure can be explained by both
vasodilation and possibly mild depression of myocardial contractility.
Propofol appears to blunt the baroreceptor reflex and reduce
sympathetic nerve activity (Ebert and Muzi, 1994). As with thiopental,
propofol should be used with caution in patients at risk for or
intolerant of decreases in blood pressure; these include patients with
significant blood loss and hypovolemia.
Respiratory System. At equipotent doses, propofol produces a
slightly greater degree of respiratory depression than thiopental
(Blouin et al., 1991). Patients given propofol should be monitored to
ensure adequate oxygenation and ventilation. Propofol appears to
be less likely than barbiturates to provoke bronchospasm and may be
the induction agent of choice in asthmatics (Pizov et al., 1995). The
bronchodilator properties of propofol may be attenuated by the
metabisulfite preservative in some propofol formulations (Brown
et al., 2001).
Other Side Effects. Propofol has no clinically significant effects
on hepatic, renal, or endocrine organ systems. Unlike thiopental,
propofol does not have an anti-analgesic effect. It has a significant
anti-emetic action. Propofol elicits pain on injection that can be
reduced with lidocaine and the use of larger arm and antecubital
veins. Propofol provokes anaphylactoid reactions at about the same
low frequency as thiopental; the histamine release (in the absence
of anaphylactic or anaphylactoid reactions) that occurs with thiopental
administration is greater than that with propofol. Although propofol
does cross placental membranes, it is considered safe for use in
pregnant women; like thiopental, propofol only transiently depresses
activity in the newborn (Abboud et al., 1995). Propofol does not trigger
malignant hyperthermia.
A rare but potentially fatal complication, termed propofol
infusion syndrome (PRIS), has been described primarily in prolonged,
higher-dose infusions of propofol in young or head-injured
patients. The syndrome is characterized by metabolic acidosis,
hyperlipidemia, rhabdomyolysis, and an enlarged liver. While the
precise mechanisms by which PRIS occurs are not clear, alterations
in mitochondrial metabolism and electron transport chain function
have been described (Kam and Cardone, 2007).
The side-effect profile of fospropofol is similar to that of
propofol. Fospropofol’s slower onset of sedation (due to the need
for hydrolysis of the prodrug) results in a lower incidence of
hypotension, respiratory depression, apnea, and loss of airway
patency. Nonetheless, unintended deep levels of sedation can occur
with fospropofol, and the drug should therefore be used only by individuals
who can maintain an adequate airway and support cardiorespiratory
function.
Whether fospropofol can also cause PRIS is not currently
known (Fechner et al., 2008). A metabolic byproduct of fospropofol is
formic acid. This is degraded to CO 2
and water by tetrahydrofolate
dehydrogenase, an enzyme that requires folate as a co-factor. In patients
who have a folate deficiency, there is a theoretical risk of formic acid
accumulation; to date, such an adverse event has not been reported.
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES