-hydroxybutyrate (GHB; sodium oxybate) also render the victim incapable of resisting rape. The latter compound, a minor metabolites of GABA, binds to GABAB receptors in the CNS. When used as a “club drug” GHB causes euphoria, enhanced sensory perception, and amnesia.

Withdrawal

Physiologic dependence occurs with continued use of sedative-hypnotics; the signs and symptoms of the withdrawal (abstinence) syndrome are most pronounced with drugs that have a half-life of less than 24 h (eg, ethanol, secobarbital, methaqualone). However, physiologic dependence may occur with any sedative-hypnotic, including the longer acting benzodiazepines. The most important signs of withdrawal derive from excessive CNS stimulation and include anxiety, tremor, nausea and vomiting, delirium, and hallucinations (Table 32-2). Seizures are not uncommon and may be life-threatening.

Treatment of sedative-hypnotic withdrawal involves administration of a long acting sedative-hypnotic (eg, chlordiazepoxide or diazepam) to suppress the acute withdrawal syndrome, followed by gradual dose reduction. Clonidine or propranolol may also be of value to suppress sympathetic overactivity. The opioid receptor antagonist naltrexone, and acamprosate , an antagonist at N-methyl-D-aspartate (NMDA) glutamate receptors, are both used in the treatment of alcoholism (see Chapter 23).

A syndrome of therapeutic withdrawal has occurred on discontinuance of sedative-hypnotics after long-term therapeutic administration. In addition to the symptoms of classic withdrawal presented in Table 32-2, this syndrome includes weight loss, paresthesias, and headache. (See Chapters 22 and 23 for additional details.)

Opioid Analgesics

Effects

As described in Chapter 31, the primary targets underlying the actions of the opioid analgesics are the , , and receptors. However, the opioids have other actions including disinhibition in dopaminergic pathways in the CNS. The most commonly abused drugs in this group are heroin, morphine, codeine, oxycodone, and, among health professionals, meperidine and fentanyl. The effects of intravenous heroin are described by abusers as a “rush” or orgasmic feeling followed by euphoria and then sedation. Intravenous administration of opioids is associated with rapid development of tolerance and psychological and physiologic dependence. Oral administration or smoking of opioids causes milder effects, with a slower onset of tolerance and dependence. Overdose of opioids leads to respiratory depression progressing to coma and death (Table 32-2). Overdose is managed with intravenous naloxone or nalmefene and ventilatory support.

Withdrawal

Deprivation of opioids in physiologically dependent individuals leads to an abstinence syndrome that includes lacrimation, rhinorrhea, yawning, sweating, weakness, gooseflesh (“cold turkey”), nausea and vomiting, tremor, muscle jerks (“kicking the habit”), and hyperpnea (Table 32-2). Although extremely unpleasant, withdrawal from opioids is rarely fatal (unlike withdrawal from sedative-hypnotics). Treatment involves replacement of the illicit drug with a pharmacologically equivalent agent (eg, methadone ), followed by slow dose reduction. Buprenorphine , a partial agonist at opioid receptors and a longer acting opioid (half-life >40 h), is also used to suppress withdrawal symptoms and as substitution therapy for opioid addicts. The administration of naloxone to a person who is using strong opioids (but not overdosing) may cause more rapid and more intense symptoms of withdrawal (precipitated withdrawal). Neonates born to mothers physiologically dependent on opioids require special management of withdrawal symptoms.

Stimulants

Caffeine and Nicotine

Effects

Caffeine (in beverages) and nicotine (in tobacco products) are legal in most Western cultures even though they have adverse medical effects. In the United States, cigarette smoking is a major preventable cause of death; tobacco use is associated with a high incidence of cardiovascular, respiratory, and neoplastic disease. Addiction (psychological dependence) to caffeine and nicotine has been recognized for some time. More recently, demonstration of abstinence signs and symptoms has provided evidence of dependence.

Withdrawal

Withdrawal from caffeine is accompanied by lethargy, irritability, and headache. The anxiety and mental discomfort experienced from discontinuing nicotine are major impediments to quitting the habit. Varenicline , a partial agonist at the ACh-N(22) subtype nicotinic receptors which occludes the rewarding effects of nicotine, is used for smoking cessation. Rimonabant, an agonist at cannabinoid receptors, approved for use in obesity, is also used off-label in smoking cessation.

Toxicity

Acute toxicity from overdosage of caffeine or nicotine includes excessive CNS stimulation with tremor, insomnia, and nervousness; cardiac stimulation and arrhythmias; and, in the case of nicotine, respiratory paralysis (Chapters 6 and 7). Severe toxicity has been reported in small children who ingest discarded nicotine gum or nicotine patches, which are used as substitutes for tobacco products.

Amphetamines

Effects

Amphetamines inhibit transporters of CNS amines including dopamine, norepinephrine, and serotonin, thus enhancing their actions. They cause a feeling of euphoria and self-confidence that contributes to the rapid development of addiction. Drugs in this class include dextroamphetamine and methamphetamine

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