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

392 (e.g., ethanol) can exert relatively specific effects on certain groups
of neurons, which may account for differences in their behavioral
effects, especially the propensity to produce dependence.
SECTION II
NEUROPHARMACOLOGY
General (Nonspecific) CNS Stimulants
The drugs in this category include pentylenetetrazol and related
agents that are capable of powerful excitation of the CNS, and the
methylxanthines, which have a much weaker stimulant action.
Stimulation may be accomplished by one of two general mechanisms:
(1) blockade of inhibition or (2) direct neuronal excitation
that may involve increased transmitter release or more prolonged
transmitter action, as occurs when the reuptake of a released transmitter
is inhibited.
Drugs That Selectively Modify CNS Function
The agents in this group may cause either depression or excitation.
In some instances, a drug may produce both effects simultaneously
on different systems. Some agents in this category have little effect
on the level of excitability in doses that are used therapeutically. The
principal classes of these CNS drugs are anticonvulsants, drugs used
in treating Parkinson disease, opioid and non- opioid analgesics,
appetite suppressants, anti- emetics, analgesic- antipyretics, certain
stimulants, antidepressants, anti- manic and anti- psychotic agents,
tranquilizers, sedatives and hypnotics, and medications employed in
the treatment of Alzheimer’s disease (cholinesterase inhibitors and
anti- glutamate neuroprotectants). Although selectivity of action may
be remarkable, a drug usually affects several CNS functions to varying
degrees. When only one constellation of effects is wanted in a
therapeutic situation, the remaining effects of the drug are regarded
as limitations in selectivity (i.e., unwanted side effects or off- target
effects). The specificity of a drug’s action is frequently overestimated.
This is partly due to the fact that drugs are often identified
with the effect that is implied by the class name.
General Characteristics of CNS Drugs
Combinations of centrally acting drugs frequently are administered to
therapeutic advantage (e.g., an anticholinergic drug and levodopa for
Parkinson disease). However, other combinations of drugs may be
detrimental because of potentially dangerous additive or mutually
antagonistic effects. The effects of a CNS drug may be additive with
the physiological state and the effects of other depressant and stimulant
drugs. For example, anesthetics are less effective in a hyperexcitable
subject than in a normal patient; the converse is true for
stimulants. In general, the depressant effects of drugs from different
categories are additive (e.g., the potentially fatal combination of
barbiturates or benzodiazepines with ethanol), as are the effects of
stimulants. Therefore, respiration depressed by morphine is further
impaired by depressant drugs, while stimulant drugs can augment the
excitatory effects of morphine to produce vomiting and convulsions.
Antagonism between depressants and stimulants is variable.
Some instances of true pharmacological antagonism among CNS
drugs are known; for example, opioid antagonists can selectively
antagonize the effects of opioid analgesics. However, the antagonism
exhibited between two CNS drugs is most often physiological
in nature. For example, an individual whose CNS is depressed by an
opiate cannot be returned entirely to normal by stimulation with
caffeine.
The selective effects of drugs on specific neurotransmitter systems
may be additive or competitive. The potential for drug interactions
must be considered whenever such drugs are concurrently
administered. To minimize such interactions, a drug- free period may be
required when modifying therapy; in fact, development of desensitized
and supersensitive states with prolonged therapy may limit the speed
with which one drug may be halted and another started. An excitatory
effect is commonly observed with low concentrations of certain depressant
drugs due either to depression of inhibitory systems or to a transient
increase in the release of excitatory transmitters. Examples include
the stage of excitement seen during induction of general anesthesia.
The excitatory phase typically occurs with low concentrations of the
depressant; uniform depression ensues with increasing drug concentration.
The excitatory effects can be minimized, when appropriate, by
pretreatment with a depressant drug that is devoid of such effects (e.g.,
benzodiazepines in preanesthetic medication). Acute, excessive stimulation
of the cerebrospinal axis normally is followed by depression,
which is in part a consequence of neuronal fatigue and exhaustion of
stores of transmitters. Postictal depression is additive with the effects
of depressant drugs. Acute, drug- induced depression generally is not
followed by stimulation. However, chronic drug- induced sedation or
depression may be followed by prolonged hyperexcitability upon
abrupt withdrawal of the medication (barbiturates or alcohol). This type
of hyperexcitability can be controlled effectively by the same or another
depressant drug (Chapters 17, 23, and 24).
Organization of CNS-Drug Interactions. The structural and functional
properties of neurons provide a means to specify the possible
sites at which drugs could interact, specifically or generally, in the
CNS. In this scheme, drugs that affect neuronal energy metabolism,
membrane integrity, or transmembrane ionic equilibria would be
generally acting compounds. Similarly general in action would be
drugs that affect molecular motors and thereby affect the transport of
materials from cell bodies to nerve terminals and back. These general
effects may exhibit different dose- response or time- response
relationships based, e.g., on neuronal properties such as rate of firing,
dependence of discharge on external stimuli or internal pacemakers,
resting ionic fluxes, or axon length. In contrast, when the
actions of a drug can be related to specific aspects of the metabolism,
release, or function of a neurotransmitter, then the site, specificity,
and mechanism of action of the drug can be defined by systematic
studies of dose- response and time- response relationships.
Transmitter- dependent actions of drugs can be grouped into
presynaptic and postsynaptic categories. The presynaptic category
includes the events in the perikaryon and nerve terminal that regulate
transmitter synthesis (including the acquisition of adequate substrates
and co- factors), storage, release, and metabolism. Transmitter
concentrations can be lowered by blockade of synthesis, inhibition
of storage, or both. The amount of transmitter released per impulse
generally is stable but may be subject to regulation. The effective
concentration of transmitter may be increased by inhibition of
metabolic enzymes or by blockade of re- uptake transporters. The
transmitter that is released at a synapse also can exert actions on the
terminal from which it was released by interacting with receptors at
these sites (autoreceptors). Activation of presynaptic autoreceptors
can inhibit or stimulate the rate of release of transmitter and thereby
provide a feedback mechanism that controls the concentration of
transmitter in the synaptic cleft.