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

666 demonstrated in humans, the cerebrospinal fluid of chronic MDMA
users has low levels of serotonin metabolites (Ricaurte et al., 2000).
Thus, there is possible neurotoxicity with no evidence that the
claimed benefits of MDMA actually occur.
SECTION II
NEUROPHARMACOLOGY
Phencyclidine (PCP). PCP deserves special mention because of its
widespread availability and because its pharmacological effects are
different from those of the psychedelics such as LSD. PCP was
developed originally as an anesthetic in the 1950s and later was
abandoned because of a high frequency of postoperative delirium
with hallucinations. It was classified as a dissociative anesthetic
because, in the anesthetized state, the patient remains conscious with
staring gaze, flat facies, and rigid muscles. PCP became a drug of
abuse in the 1970s, first in an oral form and then in a smoked version
enabling a better regulation of the dose. The effects of PCP have
been observed in normal volunteers under controlled conditions. As
little as 50 μg/kg produces emotional withdrawal, concrete thinking,
and bizarre responses to projective testing. Catatonic posturing also
is produced and resembles that of schizophrenia. Abusers taking
higher doses may appear to be reacting to hallucinations and may
exhibit hostile or assaultive behavior. Anesthetic effects increase with
dosage; stupor or coma may occur with muscular rigidity, rhabdomyolysis,
and hyperthermia. Intoxicated patients in the emergency room
may progress from aggressive behavior to coma, with elevated blood
pressure and enlarged nonreactive pupils.
PCP binds with high affinity to sites located in the cortex and
limbic structures, resulting in blocking of N-methyl-D-aspartate
(NMDA)–type glutamate receptors (Chapter 14). LSD and other
psychedelics do not bind to NMDA receptors. There is evidence that
NMDA receptors are involved in ischemic neuronal death caused by
high levels of excitatory amino acids; as a result, there is interest in
PCP analogs that block NMDA receptors but with fewer psychoactive
effects. Both PCP and ketamine (“Special K”), another “club
drug,” produce similar effects by altering the distribution of the neurotransmitter
glutamate.
Tolerance, Dependence, and Withdrawal. PCP is reinforcing in monkeys,
as evidenced by self-administration patterns that produce continuous
intoxication. Humans tend to use PCP intermittently, but a
small fraction may use it daily. Tolerance to the behavioral effects of
PCP develops in animals, but this has not been studied systematically
in humans. Signs of a PCP withdrawal syndrome have been
observed in monkeys after interruption of daily access to the drug,
and include somnolence, tremor, seizures, diarrhea, piloerection,
bruxism, and vocalizations.
Pharmacological Intervention. Overdose must be treated by life support
because there is no antagonist of PCP effects and no proven way
to enhance excretion, although acidification of the urine has been proposed.
PCP coma may last 7-10 days. The agitated or psychotic state
produced by PCP can be treated with diazepam. Prolonged psychotic
behavior requires antipsychotic medication. Because of the anticholinergic
activity of PCP, antipsychotic agents with significant
anticholinergic effects such as chlorpromazine should be avoided.
Inhalants
Abused inhalants consist of many different categories of
chemicals that are volatile at room temperature and
produce abrupt changes in mental state when inhaled.
Examples include toluene (from model airplane glue),
kerosene, gasoline, carbon tetrachloride, amyl nitrite, and
nitrous oxide. There are characteristic patterns of response
for each substance. Solvents such as toluene typically are
used by children. The material usually is placed in a plastic
bag and the vapors inhaled. After several minutes of
inhalation, dizziness and intoxication occur. Aerosol
sprays containing fluorocarbon propellants are another
source of solvent intoxication. Prolonged exposure or
daily use may result in damage to several organ systems.
Clinical problems include cardiac arrhythmias, bone marrow
depression, cerebral degeneration, and damage to
liver, kidney, and peripheral nerves. Death occasionally
has been attributed to inhalant abuse, probably from cardiac
arrhythmias, especially accompanying exercise or
upper airway obstruction.
Amyl nitrite produces dilation of smooth muscle, has been
used in the past for the treatment of angina, and continues to be available
by prescription as a component of cyanide antidote kits and for
certain diagnostic procedures. It is a yellow, volatile, flammable liquid
with a fruity odor. In recent years, amyl nitrite and butyl nitrite
have been used to relax smooth muscle and enhance orgasm, particularly
by male homosexuals. These agents are commercially available
as room deodorizers and can produce a feeling of “rush,”
flushing, and dizziness. Adverse effects include palpitations, postural
hypotension, and headache progressing to loss of consciousness.
Anesthetic gases such as nitrous oxide and halothane sometimes
are used as intoxicants by medical personnel. Nitrous oxide
also is abused by food-service employees because it is supplied for
use as a propellant in disposable aluminum mini tanks for whipping
cream canisters. Nitrous oxide produces euphoria and analgesia
and then loss of consciousness. Compulsive use and chronic
toxicity are reported rarely, but there are obvious risks of overdose
(coma) and chronic use (neuropathy) associated with the abuse of
this anesthetic.
CLINICAL SUMMARY
The management of drug abuse and addiction must be
individualized according to the drugs involved and the
associated psychosocial problems of the individual
patient. An understanding of the pharmacology of the
drug or combination of drugs ingested by the patient is
essential to rational and effective treatment. This may
be a matter of urgency for the treatment of overdose or
for the detoxification of a patient who is experiencing
withdrawal symptoms. It must be recognized, however,
that the treatment of the underlying addictive disorder
requires months or years of rehabilitation. The behavior
patterns encoded in memory during thousands of prior
drug ingestions do not disappear with detoxification
from the drug, even after a typical 28-day inpatient
rehabilitation program. Long periods of outpatient