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

662 high school students has declined, the number of frequent
users (at least weekly) has remained steady since
1991 at ~600,000. Not all users become addicts, and
the variables that influence this risk are discussed at the
beginning of this chapter. A key factor is the widespread
availability of relatively inexpensive cocaine in the
alkaloidal form (free base, “crack”) suitable for smoking
and in the hydrochloride powder form suitable for
nasal or intravenous use. Drug abuse in men occurs
about twice as frequently as in women. However, free
basing is particularly common in young women of
child-bearing age, who may use cocaine in this manner
as commonly as do men.
SECTION II
NEUROPHARMACOLOGY
The reinforcing effects of cocaine and cocaine analogs correlate
best with their effectiveness in blocking the transporter that recovers
DA from the synapse. This leads to increased DA concentrations
at critical brain sites (Ritz et al., 1987). However, cocaine also blocks
both NE and 5-HT reuptake, and chronic use of cocaine leads to reductions
in the neurotransmitter metabolites 3-methoxy-4 hydroxyphenethyleneglycol
(MOPEG or MHPG) and 5-hydroxyindoleacetic
acid (5-HIAA).
The general pharmacology and medicinal use of cocaine as a
local anesthetic are discussed in Chapter 20. Cocaine produces a dosedependent
increase in heart rate and blood pressure accompanied by
increased arousal, improved performance on tasks of vigilance and
alertness, and a sense of self-confidence and well-being. Higher doses
produce euphoria, which has a brief duration and often is followed by
a desire for more drug. Repeated doses may lead to involuntary motor
activity, stereotyped behavior, and paranoia. Irritability and increased
risk of violence are found among heavy chronic users. The t 1/2
of
cocaine in plasma is ~50 minutes, but inhalant (crack) users typically
desire more cocaine after 10-30 minutes. Intranasal and intravenous
uses also result in a high of shorter duration than would be predicted
by plasma cocaine levels, suggesting that a declining plasma concentration
is associated with termination of the high and resumption of
cocaine seeking. This theory is supported by positron-emission tomographic
imaging studies using 11 C-labeled cocaine, which show that
the time course of subjective euphoria parallels the accumulation and
decline of the drug in the corpus striatum (Volkow et al., 2003).
The major route for cocaine metabolism involves hydrolysis
of each of its two ester groups. Benzoylecgonine, produced on loss of
the methyl group, represents the major urinary metabolite and can be
found in the urine for 2-5 days after a binge. As a result, the benzoylecgonine
test is a valid method for detecting cocaine use; the metabolite
remains detectable in the urine of heavy users for up to 10 days.
Cocaine frequently is used in combination with other drugs, as discussed
previously. Ethanol is frequently abused with cocaine, as it
reduces the irritability induced by cocaine. Dual addiction to alcohol
and cocaine is common. When cocaine and alcohol are taken concurrently,
cocaine may be transesterified to cocaethylene, which is
equipotent to cocaine in blocking DA reuptake (Hearn et al., 1991).
Addiction is the most common complication of cocaine abuse.
Intranasal users can continue intermittent use for years. Others become
compulsive users despite elaborate methods to maintain control. In
general, stimulants tend to be abused much more irregularly than
opioids, nicotine, and alcohol. Binge use is very common, and a binge
may last hours to days, terminating only when supplies of the drug
are exhausted.
Toxicity. Other risks of cocaine, beyond the potential for addiction,
include cardiac arrhythmias, myocardial ischemia, myocarditis, aortic
dissection, cerebral vasoconstriction, and seizures. Death from
trauma also is associated with cocaine use. Cocaine may induce premature
labor and abruptio placentae (Chasnoff et al., 1989). The
developmental abnormalities reported in infants born to cocaine
users may be the result of cocaine effects as well as multiple other
factors (the infant’s prematurity, multiple-drug and alcohol exposure,
and inadequate pre- and postnatal care).
Cocaine has been reported to produce a prolonged and intense
orgasm if taken prior to intercourse, and users often indulge in compulsive
and promiscuous sexual activity. However, chronic cocaine
use reduces sexual drive. Chronic use is also associated with psychiatric
disorders, including anxiety, depression, and psychosis, and
while some of these disorders undoubtedly existed prior to addiction,
many are likely attributable to the drug (McLellan et al., 1979).
Tolerance, Dependence, and Withdrawal. Sensitization, a consistent
finding in animal studies of cocaine and other stimulants, is produced
by intermittent use and typically is manifested as behavioral
hyperactivity. In human cocaine users, the euphoric effect typically
is not subject to sensitization. On the contrary, most experienced
users become desensitized and, over time, require more cocaine to
obtain euphoria, i.e., tolerance develops. In the laboratory, tolerance
is rapidly induced by repeated administration of the same dose in
one session (tachyphylaxis). Sensitization may involve conditioning
(Figure 24–2). Cocaine users often report a strong response on seeing
cocaine before it is administered, consisting of physiological
arousal and increased drug craving with concomitant activation of
brain limbic structures (Childress et al., 1999). Sensitization in
humans has been linked to paranoid, psychotic manifestations of
cocaine use (Satel et al., 1991). Since cocaine typically is used intermittently,
even heavy users go through frequent periods of withdrawal
or “crash.” The symptoms of withdrawal seen in users
admitted to hospitals are listed in Table 24–8. Careful studies of
cocaine users during withdrawal show gradual diminution of these
symptoms over 1-3 weeks (Weddington et al., 1990). Residual
depression, often seen after cocaine withdrawal, should be treated
with antidepressant agents if it persists (Chapter 15).
Pharmacological Interventions. Since cocaine withdrawal is generally
mild, treatment of withdrawal symptoms usually is not required. The
major problem in treatment is not detoxification but helping the patient
to resist the urge to resume compulsive cocaine use. Rehabilitation
programs involving individual and group psychotherapy based on the
principles of Alcoholics Anonymous, and behavioral treatments based
Table 24–8
Cocaine Withdrawal Symptoms and Signs
Dysphoria, depression
Sleepiness, fatigue
Cocaine craving
Bradycardia