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

550 few side effects. However, succinylcholine has multiple
serious side effects (bradycardia, hyperkalemia, and
severe myalgia) including induction of malignant
hyperthermia in susceptible individuals.
SECTION II
NEUROPHARMACOLOGY
ANESTHETIC CYTOPROTECTION
AND TOXICITY
The conventional view of general anesthesia is that
anesthetics produce a reversible loss of consciousness
and that CNS function returns to basal levels upon termination
of anesthesia and recovery of consciousness.
Recent data, however, have cast doubt upon this notion.
Exposure of rodents to anesthetic agents during the
period of synaptogenesis (within the first 10 days post
birth) results in widespread neurodegeneration in the
developing brain (Jevtovic-Todorovic et al., 2003). This
neuronal injury, which is apoptotic in nature, results in
disturbed electrophysiologic function and cognitive
dysfunction in adolescent and adult rodents that were
exposed to anesthetics during the neonatal period. A
variety of agents, including isoflurane, propofol, midazolam,
nitrous oxide, and thiopental, manifest this toxicity
(Patel and Sun, 2009).
Although the etiology is not clear, GABA A
agonism
and NMDA receptor antagonism play a role. In
particular, the combination of a GABA A
agonist and
NMDA receptor antagonist produce the greatest toxicity.
Until the occurrence of this neurotoxicity during
brain development has been established in pre-clinical
studies, its relevance to the use of anesthetics in humans
will not be clear. To date, there are no data to suggest
that the provision of anesthesia to neonates and infants
undergoing surgery produces any neurotoxicity.
Ongoing clinical trials in humans should clarify this
within the next few years.
By contrast, anesthetics reduce ischemic injury to a variety of
tissues, including the brain and heart. This protective effect is robust
and results in better functional outcomes in comparison to ischemic
injury that occurs in unanesthetized awake subjects. With respect to
ischemic injury of the brain, anesthetics (inhalational agents, propofol,
barbiturates, ketamine, lidocaine, midazolam) suppress excitotoxic
injury produced by excessive glutamate release, reduce
inflammation, and promote pro-survival signaling (Head et al.,
2007). In addition, exposure to anesthesia results in the activation
of plasmalemmal and mitochondrial ATP-dependent K + channels, activation
of signal transduction pathways (NO synthase, MAP kinases),
and protein synthesis that render the brain less vulnerable to subsequent
ischemic injury. In a similar fashion, volatile anesthetics and,
under some conditions, propofol and barbiturates, reduce myocardial
ischemia-reperfusion injury (Frassdorf et al., 2009). The molecular
mechanisms leading to cardiac protection by volatile anesthetics
involve activation of “classical” preconditioning signaling pathways
(e.g., GPCRs, endothelial NO synthase, survival protein kinases,
PKC, reactive oxygen species, ATP-dependent K + channels, and the
mitochondrial permeability transition pore) (Hausenloy and
Scorrano, 2007). Propofol and barbiturates may induce specific components
of the “classical” pathways involved in cardiac protection;
however, there is debate as to whether these agents are truly protective
or injurious to the ischemic myocardium (Frassdorf et al., 2009).
OXYGEN
Therapeutic Gases
Oxygen (O 2
) is essential to life. Hypoxia is a lifethreatening
condition in which oxygen delivery is inadequate
to meet the metabolic demands of the tissues.
Since oxygen delivery is the product of blood flow and
oxygen content, hypoxia may result from alterations in
tissue perfusion, decreased oxygen tension in the blood,
or decreased oxygen-carrying capacity. In addition,
hypoxia may result from restricted oxygen transport
from the microvasculature to cells or impaired utilization
within the cell. An inadequate supply of oxygen
ultimately results in the cessation of aerobic metabolism
and oxidative phosphorylation, depletion of highenergy
compounds, cellular dysfunction, and death.
Normal Oxygenation
Oxygen makes up 21% of air, which at sea level represents
a partial pressure of 21 kPa (158 mm Hg). While
the fraction (percentage) of O 2
remains constant regardless
of atmospheric pressure, the partial pressure of O 2
(PO 2
) decreases with lower atmospheric pressure. Since
the partial pressure drives the diffusion of O 2
, ascent to
elevated altitude reduces the uptake and delivery of
oxygen to the tissues. Conversely, increases in atmospheric
pressure (e.g., hyperbaric therapy or breathing
at depth) raise the PO 2
in inspired air and increase gas
uptake. As the air is delivered to the distal airways and
alveoli, the PO 2
decreases by dilution with CO 2
and
water vapor and by uptake into the blood.
Under ideal conditions, when ventilation and
perfusion are well matched, the alveolar PO 2
will be
~14.6 kPa (110 mm Hg). The corresponding alveolar
partial pressures of water and CO 2
are 6.2 kPa (47
mm Hg) and 5.3 kPa (40 mm Hg), respectively. Under
normal conditions, there is complete equilibration of
alveolar gas and capillary blood, and the PO 2
in endcapillary
blood is typically within a fraction of a kPa of
that in the alveoli. In some diseases, the diffusion barrier