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

390 O
glutamate (NMDA)-mediated neurotoxicity and LTP. Neuronal NOS
(nNOS) is activated following NMDA- mediated receptor mediated
C
H
OH
N
increases in intracellular Ca 2+ . NO diffuses freely across membranes,
acting primarily to stimulate soluble guanylyl cyclase, which catalyzes
the formation of cyclic GMP. Formation of NO can also result
Anandamide
in S- nitrosylation of cysteine residues in a variety of proteins including
O
C O
CH 2 OH
CH
CH 2 OH
G proteins and ion channels. Other gases may also act as intra-
cellular messengers. One candidate is carbon monoxide (CO), which
is generated in neurons by three isoforms of hemeoxygenase (HO),
isoform 2 predominating in neurons. Like NO, CO stimulates soluble
guanylyl cyclase.
SECTION II
NEUROPHARMACOLOGY
2-Arachidonylglycerol
Cl
Cl
Rimonabant
N
N
Cl
O
C
N
H
N
Cytokines. Cytokines are a large and diverse family of polypeptide
regulators that are produced widely throughout the body by cells of
diverse embryological origin. The effects of cytokines are regulated
by the conditions imposed by other cytokines, interacting as a network
with variable effects leading to synergistic, additive, or opposing
actions. Tissue-produced peptides, termed chemokines, serve to
attract immune and inflammatory cells into interstitial spaces. These
special cytokines have received attention as potential regulators of
nervous system inflammation (as in early stages of dementia, following
infection with human immunodeficiency virus, and during
recovery from traumatic injury). Some of the more conventional neuronal-
and glial-derived growth-enhancing and growth-retarding factors
have been identified earlier. The fact that neurons and astrocytes
may be induced under some pathophysiological conditions to
express cytokines or other growth factors further blurs the dividing
line between neurons and glia (Campbell, 2004; Wang et al., 2002).
CH 3
H
OH
H
3HC O
CH
3HC
3
Δ 9 -tetrahydrocannabinol
Figure 14–17. Cannabinoid receptor ligands. Anandamide and 2-
arachidonylglycerol are endogenous agonists. Rimonabant is a
synthetic CB receptor antagonist. Δ 9 -tetrahydrocannabinol is a
CB agonist derived from marijuana.
(leading to the leukotrienes and other transient catabolites of
eicosatetraenoic acid), and CYPs (which are inducible and also
expressed at low levels in brain). Arachidonic acid metabolites have
been implicated as diffusible modulators in the CNS, possibly
involved with the formation of LTP and other forms of neuronal
plasticity.
Nitric Oxide and Carbon Monoxide. Nitric Oxide (NO), an important
regulator of vascular and inflammatory mediation, came into
focus with respect to roles in the CNS after the characterization of
brain nitric oxide synthase (NOS) activities (see Chapter 3 and
Boehning and Snyder, 2003). Both constitutive and inducible forms
of NOS are expressed in the brain. The application of inhibitors of
NOS (e.g., methylarginine and nitroarginine) and of NO donors
(such as nitroprusside) suggests the involvement of NO in a host of CNS
phenomena, including neurotransmitter release and enhancement of
ACTIONS OF DRUGS IN THE CNS
Specificity and Nonspecificity of CNS Drug Actions
The effect of a drug in the CNS is considered to be specific when it
affects an identifiable molecular mechanism unique to target cells
that bear receptors for that drug. Conversely, a drug is regarded as
being nonspecific when it produces effects at a variety of different
target cells, thus affecting a diverse set of neurobiological systems.
This distinction is often affected by the dose- response relationship of
the drug and the cell or mechanisms under scrutiny. Even a drug that
is highly specific when tested at low concentrations may exhibit nonspecific
actions at higher doses. In general, the more potent a drug
at its desired target, the lower the probability that it will have offtarget
effects. Conversely, even drugs that have a broad spectrum of
activity may not act identically at all levels of the CNS. For example,
sedatives, hypnotics, and general anesthetics would have very
limited utility if central neurons that control the respiratory and cardiovascular
systems were especially sensitive to their actions.
Although relief of pain is the goal when administering an opiate, one
must also contend with potential off- target effects including respiratory
depression and constipation.
General (Nonspecific) CNS Depressants
This category includes the anesthetic gases and vapors, the aliphatic
alcohols, and some hypnotic- sedative drugs. These agents share the
capacity to depress excitable tissue at all levels of the CNS, leading
to a decrease in the amount of transmitter released by the nerve
impulse, as well as to general depression of postsynaptic responsiveness
and ion flux. At sub- anesthetic concentrations, these agents