Drugs of Abuse

Drugs of Abuse


This chapter addresses the grave medical, legal, and social problems of drug abuse, also called substance abuse. It begins with a review of general concepts and mechanisms of drug abuse, moves on to specific classes and agents that are likely to be abused, and follows with an update on prescription drug, steroid, and inhalant abuse. The chapter ends with a discussion of pharmacologic agents used to treat drug dependence and the agents’ mechanisms of action.

Drug Abuse

It is human nature that some individuals will experiment with occasional use of or become dependent on mind-altering substances. Nearly every society in recorded history has sanctioned the use of certain drugs while banning the use of others. In many Western countries, for example, products containing ethanol, nicotine, or caffeine are socially acceptable or at least tolerated by the majority of the population, whereas the use of cocaine, marijuana, hallucinogens, and other psychoactive drugs is illegal. In other countries, use of alcohol is discouraged, but the use of other psychoactive drugs, such as marijuana, is socially acceptable. Hence, what constitutes drug abuse from a social or political perspective is highly dependent on cultural attitudes and legal restrictions.

From a medical and psychological perspective, drug abuse can be defined as the use of a drug in a manner that is detrimental to the health or well-being of the drug user, other individuals, or society as a whole. Drug abuse is not restricted to the use of illegal drugs, as the cumulative health and social effects caused by the use of alcoholic beverages and tobacco products in the United States far outweigh the negative effects of all illicit drug use.

Drug Dependence

Drug dependence is a condition in which an individual feels compelled to repeatedly administer a psychoactive drug. When this is done to avoid physical discomfort or withdrawal, it is known as physical dependence; when it has a psychological aspect (the need for stimulation or pleasure, or to escape reality), then it is known as psychological dependence. Repeated drug use is a learned behavior that is reinforced, both by the pleasurable effects of the drug and by the negative effects of drug abstinence (withdrawal). These effects are the basis of drug craving in drug-dependent individuals. Psychological dependence is caused by the positive reinforcement of drug use that results from the activation of neurons located in the nucleus accumbens. Physical dependence is a state in which continued drug use is required to prevent an unpleasant withdrawal syndrome. Hence, physical dependence leads to negative reinforcement of drug use. Both psychological and physical dependence appear to result from neuronal adaptation to the presence of the drug, albeit in different areas of the brain.

Psychological Dependence

The craving for alcohol, barbiturates, caffeine, cocaine, opioids, and tobacco is remarkably similar, despite the varied behavioral and physiologic effects that these drugs produce. This similarity supports the hypothesis that psychological dependence is mediated by a common neuronal pathway that leads to behavioral reinforcement of drug use. Psychoactive drugs that evoke behavioral reinforcement of their use appear to sensitize dopaminergic neurons that project from the ventral tegmental area to the nucleus accumbens. Other psychoactive drugs that are used for their mind-altering effects, including lysergic acid diethylamide (LSD), have a much smaller effect on the dopamine pathway and cause little reinforcement, resulting in less compulsive use of LSD and other such agents.

Much evidence indicates that dopamine mediates drug reinforcement by binding to dopamine D1 receptors in the nucleus accumbens. This signal transduction pathway activates adenylyl cyclase, increasing cyclic adenosine monophosphate (cAMP) levels and activating cAMP-dependent kinases. The kinases, in turn, activate other proteins in the signal transduction pathway, including transcription factors. In the accumbens, the transcription factor, cAMP-response element binding protein, increases the synthesis of G proteins, cAMP-dependent protein kinases, and other cell transduction molecules that amplify responses to dopamine. Dopamine release onto accumbens neurons also increases the expression of glutamate receptors, which strengthens synaptic pathways for dopamine neurotransmission in a manner much like the molecular mechanisms of learning discovered in the hippocampus. These mechanisms lead to sensitization to dopamine, which underlies the behavioral reinforcement of drug use.

The peak of dopamine release in the nucleus accumbens occurs at the time of the drug’s peak effect on the central nervous system (CNS). The degree of short-term reinforcement of drug use is linked to the rate of increase of dopamine levels in the nucleus accumbens. This relationship appears to account for the propensity of some drugs to produce drug dependence. It also appears to explain the difference in reinforcement effects produced by different routes of administration of a particular drug. For example, the oral administration of an opioid or cocaine causes less reinforcement and psychological dependence than does the intravenous administration or inhalation of an equivalent dose of the same drug. The differences in effect are determined by the rate at which the drug is distributed to the brain and the rate at which dopamine levels in the nucleus accumbens are increased. Figure 25-1 illustrates the neuroanatomy and mechanisms of reinforcement for drugs of abuse.

Physical Dependence

Physical dependence, also called neuroadaptation, results from the adaptations of specific neurons or areas of the brain to the continued presence of a drug. Physical dependence is observed outwardly only by the development of a drug-specific withdrawal syndrome if the drug is discontinued or blocked, as during drug abstinence. For this reason, physical dependence contributes to the continued use of a drug to avoid unwanted symptoms. The negative effects of nicotine withdrawal, for example, are responsible for the high relapse rate in persons trying to stop smoking cigarettes. The withdrawal symptoms are often opposite to the drug’s acute effect, unmasking the neuroadaptation that acted to balance the effects of chronic drug administration. For example, opioids inhibit neurons regulating the peristaltic tone of the gastrointestinal tract and cause constipation; diarrhea is a classic sign of opioid withdrawal.

Classification of Drugs of Abuse

The psychoactive drugs that are used by some individuals for nonmedicinal purposes can be classified as CNS depressants, CNS stimulants, and miscellaneous agents, with the latter group including marijuana, hallucinogens, and phencyclidine (PCP). In many cases, individuals with a substance-abuse disorder are using legal or illegal substances as self-medication for comorbid disorders such as anxiety or depression. After describing the pharmacologic effects of these drugs and any clinical use that they may have, this chapter discusses the treatment of substance abuse. Tables 25-1, 25-2, and 25-3 provide information about the manifestations and treatment of drug intoxication and withdrawal.

TABLE 25-1

Common Signs and Symptoms of Drug Intoxication

Alcohol Ataxia, incoordination, loquacity, and slurred speech Euphoria, impaired attention, irritability, mood changes, and sedation Flushed face Nystagmus
Amphetamines Agitation and loquacity Decreased fatigue, euphoria, grandiosity, hypervigilance, and paranoia Hypertension or hypotension and tachycardia Chills, mydriasis, nausea, nystagmus, sweating, and vomiting
Barbiturates Same as alcohol Same as alcohol Hypotension Nystagmus
Benzodiazepines Same as alcohol Same as alcohol Hypotension Nystagmus
Cocaine Same as amphetamines Altered tactile sensation (“cocaine bugs”), decreased fatigue, euphoria, grandiosity, hypervigilance, and paranoia Same as amphetamines Same as amphetamines
Hallucinogens Dizziness, incoordination, tremor, and weakness Depersonalization, derealization, hallucinations, illusions, and synesthesia Tachycardia Blurred vision, mydriasis, and sweating
Marijuana Loquacity and rapid speech Euphoria, hallucinations (with high doses), jocularity, and sensory intensification Hypertension and tachycardia Conjunctivitis, dry mouth, increased appetite, and tightness in chest
Opioids Motor slowness and slurred speech Apathy, euphoria or dysphoria, impaired attention, and sedation None Miosis
Phencyclidine Agitation, ataxia, muscle rigidity, and slurred speech Anxiety, delusions, emotional lability, euphoria, and hallucinations Hypertension and tachycardia Hostility, miosis, nystagmus, and violent behavior


Central Nervous System Depressants

Alcohols and Glycols

In North America, about 12 million individuals have one or more symptoms of alcoholism, making alcohol abuse the number one substance abuse problem. In the United States alone, the cost of health care, lost work hours, criminal activity, and other problems related to alcohol use is roughly $90 billion each year.

The alcohols and glycols most commonly ingested are ethanol, methanol, and ethylene glycol. Whereas ethanol selectively produces CNS depression at normal doses, even relatively small doses of methanol and ethylene glycol affect multiple organ systems and can produce severe or life-threatening toxicity, even when ingested in relatively small doses.


Ethanol, or ethyl alcohol, is classified as a CNS depressant and has pharmacologic effects similar to those of the barbiturates and benzodiazepines.


Ethanol has sufficient lipid solubility to enable rapid and almost complete absorption from the gut. It is more rapidly absorbed from the duodenum than from the stomach, and food slows its absorption by slowing the rate of gastric emptying. Ethanol is widely distributed throughout the body and has a volume of distribution that is roughly equivalent to the total body water, or about 38 L/70 kg of body weight.

As shown in Figure 25-2, ethanol is primarily oxidized by alcohol dehydrogenase to form acetaldehyde and is then oxidized by acetaldehyde dehydrogenase to form acetate. The acetate derived from ethanol enters the citric acid cycle for further oxidation to carbon dioxide and water. The oxidation of ethanol uses significant quantities of nicotinamide adenine dinucleotide (NAD), and the depletion of NAD is responsible for some of the metabolic effects of ethanol that are described later. Ethanol at higher or chronic doses also undergoes oxidation by cytochrome P450 enzymes, namely the CYP2E1 isozyme. Unlike alcohol dehydrogenase metabolism, CYP2E1 metabolism is induced by long-term alcohol use, contributing to alcohol tolerance in heavy drinkers.

About 2% of ethanol is excreted unchanged by the kidneys and lungs. The concentration of ethanol in alveolar air is about 0.05% of that in the blood, and this relationship is used to estimate the blood alcohol concentration (BAC) in exhaled air when the breathalyzer test is administered. Because ethanol can markedly impair the psychomotor skills required to safely drive a vehicle, nearly all nations prohibit the operation of motor vehicles while under the influence of alcohol. As of July 2004, the legal limit of blood alcohol is a BAC less than 0.08% (80 mg/dL) in all states and federal territories of the United States.

The capacity of alcohol dehydrogenase to metabolize ethanol is limited because the enzyme is saturated at relatively low ethanol concentrations. Hence, ethanol metabolism exhibits zero-order kinetics, except when serum concentrations of ethanol are very low. For this reason, the BAC is largely determined by the rate of ethanol ingestion. An adult weighing 70 kg usually metabolizes only about 10 mL of absolute ethanol per hour, which is roughly equivalent to the amount of ethanol contained in one alcoholic drink. A BAC of 0.08% to 0.10% in most cases is reached after consuming two to four standard drinks in an hour. A standard drink is a 12-ounce serving of beer, a 5-ounce glass of wine, or 1.5-ounces (shot) of 80 proof distilled spirits.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Drugs of Abuse

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