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

The postsynaptic category includes all the events that follow
release of the transmitter in the vicinity of the postsynaptic receptor.
Examples include the molecular mechanisms by which receptor
occupancy alters the properties of the membrane of the postsynaptic
cell (shifts in membrane potential), as well as more enduring biochemical
actions (e.g., changes in second messenger concentrations,
protein kinase and phosphoprotein phosphatase activities, and phosphoprotein
formation). Direct postsynaptic effects of drugs generally
require relatively high affinity for the receptors or resistance to
metabolic degradation. Each of these presynaptic or postsynaptic
actions is potentially highly specific and can be envisioned as
restricted to a single, chemically defined subset of CNS cells.
Convergence, Synergism, and Antagonism Result from
Transmitter Interactions. Although the power of the reductionist
approach to clone cDNAs for receptors or receptor subunits and to
determine their properties by expression in cells that do not normally
express the receptor or subunit cannot be underestimated, the simplicity
of cell culture models may not reproduce the nuances of
receptor function in vivo and may divert attention from the complexity
of the intact CNS. A given neurotransmitter may interact simultaneously
with all of the various isoforms of its receptor on neurons
that also are under the influence of multiple other afferent pathways
and their transmitters. Thus, the use of model systems to predict the
behavioral or therapeutic consequences of drugs in humans may fail
as a consequence of the complexity of the interactions possible,
including differences between normal and diseased tissue.
CNS Drug Discovery. As is evident from the chapters to follow, a
large number of agents have been developed to treat neuropsychiatric
diseases. With few exceptions these agents offer primarily
symptomatic improvement; few are truly disease modifying. For
example, the use of L- dopa to treat Parkinson disease alleviates the
symptoms effectively but the disease continues to progress.
Similarly, although antipsychotics and antidepressants are often efficacious,
the symptoms tend to recur. Moreover, many drugs developed
to treat CNS diseases are not uniformly effective:
Approximately one- third of patients with severe depression are
“treatment-resistant.” CNS diseases are complex, with multiple
symptoms, some of which, like the negative symptoms of schizophrenia,
tend to be resistant to treatment. Furthermore, the complexity
of the brain and its neuronal pathways results in significant risk
of side effects, even when the most biochemically selective agent is
administered. Particularly disquieting side effects include tardive
dyskinesias that can result from prolonged treatment with antipsychotics
and the hypnotic effects of agents used for the treatment of
seizure disorders.
The lack of disease- modifying treatments for CNS diseases
represents a very significant unmet medical need and makes the discovery
of such agents a high priority. Drug discovery is generally a
high- risk/high- reward effort (Chapter 1) and CNS- active agents are
no exception. Overall, the probability of success in developing a drug
from the time a compound enters into clinical trials is ~10%; the
success rate for CNS drugs is somewhat lower. Myriad factors contribute
to the increased difficulty and reduced probability of success
in efforts to develop drugs to treat CNS disease. Factors that reduce
the probability of success include the complexity of neural pathways
governing behavior and its pathology, and the permeability barriers
that restrict access of drugs to CNS sites (including the blood- brain
barrier and drug export systems; see Chapters 2 and 5). For example,
a drug that affects serotinergic transmission may affect 14 5-HT
receptor subtypes that are involved in a plethora of biological systems.
Moreover, animal models of CNS diseases are often incompletely
validated and an effect in an animal model may not be
predictive of efficacy in human disease. For instance, a number of
agents reduce the size of the infarct when given to animals following
occlusion of the middle cerebral artery, yet none of these agents
has shown positive results in human clinical trials. A number of
agents that inhibit the reuptake of 5-HT and NE are effective in treating
depression. In a number of animal models of depression, these
agents produce an effect after a single dose, which corresponds
nicely with the time course for the inhibition of neurotransmitter
reuptake in experimental animals, whereas, a period of several weeks
is typically required to see a therapeutic effect in humans. Given this
discrepancy, one can understand the reluctance of pharmaceutical
companies to invest in clinical trials of new antidepressants on the
basis of effects in animal models.
Clinical trials represent another area of challenge in developing
new therapies for CNS diseases. For example, testing an agent to
treat depression likely requires a trial lasting 6 or more weeks and the
placebo response rate may exceed 50%. Such conditions necessitate
large, prolonged, and therefore expensive trials. Studies of treatments
for neurodegenerative disease are even more difficult. With current
diagnostic capabilities, it is difficult to detect a significant change in
the rate of progression of cognitive decline in patients with
Alzheimer’s disease in less than a year. One way to circumvent the
long time necessary to detect a biological meaningful result is
through the use of surrogate markers (e.g., a decrease in serum cholesterol
for improved cardiovascular morbidity and mortality).
Regrettably, there are relatively few useful surrogate markers for
CNS diseases.
Impact of Genomics on CNS Drug Discovery. The sequencing of
the human genome has the potential to significantly change drug
discovery in the CNS. Thus, genetic testing may predict the likelihood
that a given individual will develop a particular disease, will
respond to a particular therapy, or will suffer side effects from a
particular treatment paradigm. Genetic testing may be particularly
important in the case of CNS diseases, where the etiology is likely
to be multigenic. Molecular approaches will likely speed development
of more and improved animal models that better mimic
human disease.
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CHAPTER 14
NEUROTRANSMISSION AND THE CENTRAL NERVOUS SYSTEM