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

More recent research has added details to
Shakespeare’s enumeration—see the bracketed additions
to the Porter’s words in the preceding paragraph
and the section on organ systems later in the chapter—
but the most noticeable consequences of the recreational
use of ethanol still are well summarized by the
gregarious and garrulous Porter, whose delighted and
devilish demeanor demonstrates a frequently observed
influence of modest concentrations of ethanol on the
CNS. The sections that follow detail ethanol’s effects
on physiological systems.
Central Nervous System
Although the public often views alcoholic drinks as
stimulating, ethanol primarily is a CNS depressant.
Ingestion of moderate amounts of ethanol, like that of
other depressants such as barbiturates and benzodiazepines,
can have anti-anxiety actions and produce
behavioral disinhibition at a wide range of dosages.
Individual signs of intoxication vary from expansive
and vivacious affect to uncontrolled mood swings and
emotional outbursts that may have violent components.
With more severe intoxication, CNS function generally
is impaired, and a condition of general anesthesia ultimately
prevails. However, there is little margin between
the anesthetic actions and lethal effects (usually owing
to respiratory depression).
About 10% of alcohol drinkers progress to levels of consumption
that are physically and socially detrimental. Chronic
abuse is accompanied by tolerance, dependence, and craving for the
drug (see Tolerance, Dependence, and Chronic Ethanol Use, and
Chapter 24). Alcoholism is characterized by compulsive use despite
clearly deleterious social and medical consequences. Alcoholism is
a progressive illness, and brain damage from chronic alcohol abuse
contributes to the deficits in cognitive functioning and judgment
seen in alcoholics. Alcoholism is a leading cause of dementia in the
U.S. (Oslin et al., 1998). Chronic alcohol abuse results in shrinkage
of the brain owing to loss of both white and gray matter (Kril and
Halliday, 1999). The frontal lobes are particularly sensitive to damage
by alcohol, and the extent of damage is determined by the
amount and duration of alcohol consumption, with older alcoholics
being more vulnerable than younger ones (Pfefferbaum et al.,
1998). It is important to note that ethanol itself is neurotoxic, and
although malnutrition or vitamin deficiencies probably play roles
in complications of alcoholism such as Wernicke’s encephalopathy
and Korsakoff’s psychosis, most of the alcohol-induced brain damage
in Western countries is due to alcohol itself. In addition to loss
of brain tissue, alcohol abuse also reduces brain metabolism (as
determined by positron-emission tomography), and this hypometabolic
state rebounds to a level of increased metabolism during
detoxification. The magnitude of decrease in metabolic state is
determined by the number of years of alcohol use and the age of
the patients (Volkow et al., 1994).
Table 23–1
Impact of Ethanol on Key Neurochemical Systems
NEUROTRANSMITTER
SYSTEM
GABA A
NMDA
DA
ACTH
Opioid
5-HT
Cannabinoid
EFFECTS
GABA release, ↑ receptor density
Inhibition of postsynaptic NMDA
receptors; with chronic use,
up-regulation
↑ Synaptic DA, ↑ effects on
ventral tegmentum/nucleus
accumbens reward
↑ CNS and blood levels of ACTH
Release of endorphins, activation
of μ receptors
↑ in 5-HT synaptic space
↑ CB1 activity → changes in DA,
GABA, glutamate activity
Actions of Ethanol on Neurochemical Pathways and Signaling.
Ethanol affects almost all brain systems. The changes across neurochemical
pathways occur simultaneously and the alterations often
interact. An additional complication in describing CNS effects is the
rapid adaptation to ethanol observed in the brain, with the result that
the acute effects of the first dose of ethanol are often the opposite of
the neurochemical consequences from repeated administration and
those observed during falling blood ethanol levels and withdrawal
syndromes (Schuckit, 2006b).
Alcohol perturbs the balance between excitatory
and inhibitory influences in the brain, resulting in anxiolysis,
ataxia, and sedation. This is accomplished by either
enhancing inhibitory or antagonizing excitatory neurotransmission.
Ethanol likely produces its effects by simultaneously
altering the functioning of a number of proteins
that can affect neuronal excitability (Table 23–1). A key
issue has been to identify proteins that determine neuronal
excitability and are sensitive to ethanol at the concentrations
(5-20 mM) that produce behavioral effects. Many
of the prominent effects are on ligand-gated and voltagegated
ion channels and GPCR systems.
Ion Channels. The primary mediators of inhibitory neurotransmission
in the brain are the ligand-gated -aminobutyric acid A
(GABA A
) receptors, whose function is markedly enhanced by a
number of classes of sedative, hypnotic, and anesthetic agents,
including barbiturates, benzodiazepines, and volatile anesthetics
(Chapter 14). Substantial data implicate the GABA A
receptor as an
important target for the in vivo actions of ethanol. Stimulation of this
multi-subunit, ligand-gated Cl − channel system contributes to feelings
of sleepiness, muscle relaxation, and the acute anticonvulsant
properties associated with all GABA-boosting drugs (Krystal et al.,
633
CHAPTER 23
ETHANOL AND METHANOL