Page 599 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 32 Drugs of Abuse 585

the equilibrative nucleoside transporter, ENT1), glycine recep- experiences have been reported. Although ketamine and phency-
tor, NMDA receptor, and 5-HT receptor. They are all, with the clidine do not cause dependence and addiction (relative risk = 1),
3
exception of ENT1, either ionotropic receptors or ion channels. It chronic exposure, particularly to PCP, may lead to long-lasting
is not clear which of these targets is responsible for the increase of psychosis closely resembling schizophrenia, which may persist
dopamine release from the mesolimbic reward system. The inhibi- beyond drug exposure. Surprisingly, intravenous administration
tion of ENT1 is probably not responsible for the rewarding effects of ketamine can eliminate episodes of depression within hours
(ENT1 knockout mice drink more than controls) but seems to (see Chapter 30), which is in strong contrast to selective serotonin
be involved in alcohol dependence through an accumulation of reuptake inhibitors and other antidepressants, which usually take
adenosine, stimulation of adenosine A receptors, and ensuing weeks to act. The antidepressive mechanism is believed to involve
2
enhanced CREB signaling. the antagonism of NMDA receptors, thus favoring the mTOR
Dependence becomes apparent 6–12 hours after cessation pathway downstream of other glutamate receptors. Recent evi-
of heavy drinking as a withdrawal syndrome that may include dence suggests an alternate explanation. Hydroxynorketamine, a
tremor (mainly of the hands), nausea and vomiting, exces- metabolite of ketamine, may actually target AMPA receptors to
sive sweating, agitation, and anxiety. In some individuals, exert the antidepressant effect. Regardless, a limitation is the tran-
this is followed by visual, tactile, and auditory hallucinations sient nature of the effect, which wears off within days even with
12–24 hours after cessation. Generalized seizures may manifest repetitive administration.
after 24–48 hours. Finally, 48–72 hours after cessation, an
alcohol withdrawal delirium (delirium tremens) may become INHALANTS
apparent in which the person hallucinates, is disoriented, and
shows evidence of autonomic instability. Delirium tremens is Inhalant abuse is defined as recreational exposure to chemical
associated with 5–15% mortality.
vapors, such as nitrites, ketones, and aliphatic and aromatic
hydrocarbons. These substances are present in a variety of
Treatment household and industrial products that are inhaled by “sniffing,”
Treatment of ethanol withdrawal is supportive and relies on “huffing,” or “bagging.” Sniffing refers to inhalation from an open
benzodiazepines, taking care to use compounds such as oxazepam container, huffing to the soaking of a cloth in the volatile sub-
and lorazepam, which are not as dependent on oxidative hepatic stance before inhalation, and bagging to breathing in and out of a
metabolism as most other benzodiazepines. In patients in whom paper or plastic bag filled with fumes. It is common for novices to
monitoring is not reliable and liver function is adequate, a longer- start with sniffing and progress to huffing and bagging as addic-
acting benzodiazepine such as chlordiazepoxide is preferred. tion develops. Inhalant abuse is particularly prevalent in children
As in the treatment of all chronic drug abuse problems, heavy and young adults.
reliance is placed on psychosocial approaches to alcohol addiction. The exact mechanism of action of most volatile substances
This is perhaps even more important for the alcoholic patient remains unknown. Altered function of ionotropic receptors and
because of the ubiquitous presence of alcohol in many social ion channels throughout the central nervous system has been
contexts. demonstrated for a few. Nitrous oxide, for example, binds to
The pharmacologic treatment of alcohol addiction is limited, NMDA receptors, and fuel additives enhance GABA receptor
A
although several compounds, with different goals, have been used. function. Most inhalants produce euphoria; increased excitability
Therapy is discussed in Chapter 23. of the VTA has been documented for toluene and may underlie its
addiction risk. Other substances, such as amyl nitrite (“poppers”),
primarily produce smooth muscle relaxation and enhance erec-
KETAMINE & PHENCYCLIDINE (PCP) tion but are not addictive. With chronic exposure to the aromatic
hydrocarbons (eg, benzene, toluene), toxic effects can be observed
Ketamine and PCP were developed as general anesthetics (see in many organs, including white matter lesions in the central ner-
Chapter 25), but only ketamine is still used for this applica- vous system. Management of overdose remains supportive.
tion. Both drugs, along with others, are now classified as “club
drugs” and sold under names such as “angel dust,” “Hog,” and
“Special K.” They owe their effects to their use-dependent, non- DRUGS THAT BIND TO
competitive antagonism of the NMDA receptor. The effects of TRANSPORTERS OF BIOGENIC
these substances became apparent when patients undergoing
surgery reported unpleasant vivid dreams and hallucinations after AMINES
anesthesia. Ketamine and PCP are white crystalline powders in Cocaine
their pure forms, but on the street they are also sold as liquids,
capsules, or pills, which can be snorted, ingested, injected, or The prevalence of cocaine abuse has increased greatly over the last
smoked. Psychedelic effects last for about 1 hour and also include decade and now represents a major public health problem world-
increased blood pressure, impaired memory function, and visual wide. Cocaine is highly addictive (relative risk = 5), and its use is
alterations. At high doses, unpleasant out-of-body and near-death associated with a number of complications.