Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

of diazepam. On the other hand, taking the same excessive daily dose of the drug but only for its anxiolytic effect is misusing diazepam.

Dependence is a biologic phenomenon often associated with "drug abuse." Psychologic dependence is manifested by compulsive drug-seeking behavior in which the individual uses the drug repetitively for personal satisfaction, often in the face of known risks to health. Cigarette smoking is an example. Deprivation of the agent for a short period of time typically results in a strong desire or craving for it. Physiologic dependence is present when withdrawal of the drug produces symptoms and signs that are frequently the opposite of those sought by the user. It has been suggested that the body adjusts to a new level of homeostasis during the period of drug use and reacts in opposite fashion when the new equilibrium is disturbed. Alcohol withdrawal syndrome is perhaps the best-known example, but milder degrees of withdrawal may be observed in people who drink a lot of coffee every day. Psychologic dependence almost always precedes physiologic dependence but does not inevitably lead to it. Addiction is usually taken to mean a state of physiologic and psychologic dependence, but the word is too imprecise for scientific usage.

Tolerance signifies a decreased response to the effects of the drug, necessitating ever larger doses to achieve the same effect. Tolerance is closely associated with the phenomenon of physiologic dependence. It is largely due to compensatory responses that mitigate the drug's pharmacodynamic action. Metabolic tolerance due to increased disposition of the drug after chronic use is occasionally reported. Behavioral tolerance, an ability to compensate for the drug's effects, is another possible mechanism of tolerance. Functional tolerance, which may be the most common type, is due to compensatory changes in receptors, effector enzymes, or membrane actions of the drug.

A number of experimental techniques have been devised to predict the ability of a drug to produce dependence and to assess its likelihood for abuse. Most of these techniques employ selfadministration of the drug by animals. The rates of reinforcement can be altered so as to make the animal work harder for each dose of drug, providing a semiquantitative measure as well. Comparisons are made against a standard drug in the class, eg, morphine among the opioids. Withdrawal of dependent animals from drugs assesses the nature of the withdrawal syndrome and can be used to test drugs that might cross-substitute for the standard drug. Most agents with significant potential for psychologic or physiologic dependence can be readily detected by these techniques. The actual abuse liability, however, is difficult to predict, since many variables enter into the decision to abuse drugs.

Cultural Considerations

Each society accepts certain drugs as licit and condemns others as illicit. In the USA and most of Western Europe, the "national drugs" are caffeine, nicotine, and alcohol. In the Middle East, cannabis may be added to the list of licit drugs, whereas alcohol is forbidden. Among certain Native American tribes, peyote, a hallucinogen, may be used licitly for religious purposes. In the Andes of South America, cocaine is used to allay hunger and enhance the ability to perform arduous work at high altitudes. Thus, which drugs are licit or illicit or—to use other terminology—"used" or "abused" is a social judgment. A major social cost of relegating any substance to the illicit category is the criminal activity that often results, since purveyors of the substance are lured into illegal traffic by the opportunity to make large profits, while dependent users may resort to robbery, prostitution, and other types of antisocial behavior to support their habits. A major social and medical cost associated with parenteral abuse of drugs is the high incidence of transmission of HIV and hepatitis virus through the sharing of needles.

Current attitudes in the USA to drugs of this type are reflected in the Schedule of Controlled Drugs. This schedule is quite similar to those published by international control bodies. Such schedules affect principally ethical and law-abiding manufacturers and prescribers of the drugs and have little deterrent effect on illicit manufacturers or suppliers. Such schedules have been circumvented by the synthesis of "designer" drugs that make small modifications of the chemical structures of drugs with little or no change in their pharmacodynamic actions. Thus, schedules must constantly be revised to include these attempts to produce compounds not currently listed.

Because of the high social cost of drug abuse, many countries attempt to interdict their entry across borders. While surveys may indicate that the use of drugs such as cocaine and marijuana is increasing or decreasing, it is difficult to attribute such changes to law enforcement policies. Little progress has been made in decreasing the demand for illicit drugs. Some persons have argued that the only reasonable solution to the problem is legalization of the drugs. Such proposals are obviously highly controversial.

Any use of mind-altering drugs is based on a complicated interplay between three factors: the user, the setting in which the drug is taken, and the drug. Thus, the personality of the user and the setting may have a strong influence on what the user experiences. Nonetheless, it is usually possible to identify a pharmacologic "core" of drug effects that will be experienced by almost anyone under almost any circumstances if the dosage is adequate.

Schedule of Controlled Drugs1

SCHEDULE I

(All nonresearch use illegal under federal law.)

Flunitrazepam (Rohypnol)

Narcotics: Heroin and many nonmarketed synthetic narcotics

Hallucinogens:

LSD

MDA, STP, DMT, DET, mescaline, peyote, bufotenine, ibogaine, psilocybin, hencyclidine (PCP; veterinary drug only)

Marijuana Methaqualone

SCHEDULE II

(No telephone prescriptions, no refills.)2

Opioids:

Opium

Opium alkaloids and derived phenanthrene alkaloids: morphine, hydromorphone (Dilaudid), oxymorphone (Numorphan), oxycodone (dihydroxycodeinone, a component of Percodan, Percocet, Roxicodone, Tylox)

Designated synthetic drugs: levomethadyl (Orlaam), meperidine (Demerol), methadone, levorphanol (Levo-Dromoran), fentanyl (Sublimaze, Duragesic, Actiq), alphaprodine, alfentanil (Alfenta), sufentanil (Sufenta), remifentanil (Ultiva)

Stimulants:

Coca leaves and cocaine Amphetamine

Amphetamine complex (Biphetamine) Amphetamine salts (Adderall) Dextroamphetamine (Dexedrine) Methamphetamine (Desoxyn) Phenmetrazine (Preludin)

Methylphenidate (Ritalin)

Above in mixtures with other controlled or uncontrolled drugs

Depressants:

Amobarbital (Amytal)

Pentobarbital (Nembutal)

Secobarbital (Seconal) Mixtures of above (eg, Tuinal)

SCHEDULE III

(Prescription must be rewritten after 6 months or five refills.)

Opioids:

Buprenorphine (Buprenex, Subutex, Suboxone)

The following opioids in combination with one or more active nonopioid ingredients, provided the amount does not exceed that shown:

Codeine and dihydrocodeine: not to exceed 1800 mg/dL or 90 mg/tablet or other dosage unit

Dihydrocodeinone (hydrocodone in Hycodan, Vicodin, and Lortab): not to exceed 300 mg/dL or 15 mg/tablet

Opium: 500 mg/dL or 25 mg/5 mL or other dosage unit (paregoric)

Stimulants:

Benzphetamine (Didrex)

Phendimetrazine (Plegine)

Depressants:

Schedule II barbiturates in mixtures with noncontrolled drugs or in suppository dosage form

Butabarbital (Butisol)

Ketamine (Kentalar)

Thiopental (Pentothal)

Cannabinoids:

Dronabinol (Marinol)

Anabolic Steroids:

Fluoxymesterone (Halotestin) Methyltestosterone (Android, Testred) Nandrolone decanoate (Dec-Durabolin) Nandrolone phenpropionate (Durabolin) Oxandrolone (Oxandrin) Oxymetholone (Androl-50)

Stanozolol (Winstrol)

Testolactone (Teslac) Testosterone and its esters

SCHEDULE IV

(Prescription must be rewritten after 6 months or five refills; differs from Schedule III in penalties for illegal possession.)

Opioids:

Butorphanol (Stadol)

Difenoxin (Motofen)

Pentazocine (Talwin)

Propoxyphene (Darvon)

Stimulants:

Diethylpropion (Tenuate) Mazindol (Sanorex) Modafinil (Provigil)

Phentermine (Ionamin) Pemoline (Cylert) Sibutramine (Merida)

Depressants:

Benzodiazepines Alprazolam (Xanax) Chlordiazepoxide (Librium) Clonazepam (Klonopin) Clorazepate (Tranxene) Diazepam (Valium) Estazolam (ProSom) Flurazepam (Dalmane) Halazepam (Paxipam) Lorazepam (Ativan) Midazolam (Versed) Oxazepam (Serax) Prazepam (Centrax) Quazepam (Doral) Temazepam (Restoril) Triazolam (Halcion)

Chloral hydrate Ethchlorvynol (Placidyl)

Meprobamate (Equanil, Miltown, etc) Mephobarbital (Mebaral) Methohexital (Brevital)

Paraldehyde

Phenobarbital Zaleplon (Sonata) Zolpidem (Ambien)

SCHEDULE V

(As any other nonopioid prescription drug; may also be dispensed without prescription unless additional state regulations apply.)

Opioids:

Diphenoxylate (not more than 2.5 mg and not less than 0.025 mg of atropine per dosage unit, as in Lomotil)

The following drugs in combination with other active nonopioid ingredients and provided the amount per 100 mL or 100 g does not exceed that shown:

Codeine: 200 mg Dihydrocodeine: 100 mg

1See http://www.dea.gov/pubs/scheduling.html for additional details.

2Emergency prescriptions may be telephoned if followed within 7 days by a valid written prescription annotated to indicate it was previously placed by telephone.

Neurobiology of Abused Drugs

During the last 20 years, substantial progress has been made in elucidating the neurobiology of abused drugs and their effects not only on neurotransmitter receptors and reuptake carriers but also on the cascade of second, third, and fourth intracellular messenger systems (Nestler, 2001). Many abused drugs act through G protein-linked receptors such as the opioid, cannabinoid, and dopamine

receptors. These G proteins frequently are coupled to the cyclic adenosine monophosphate (cAMP) second messenger system, and through phosphorylation of various intracellular proteins a cascade of changes occurs in the cytoplasm and nucleus. Immediate early genes such as c-fos and c-jun are activated followed by regulation of other genes with more sustained effects on protein transcription that may lead to the observed down-regulation of receptor numbers and up-regulation of second messenger systems. These effects on DNA are also reflective of genetic risk factors for drug dependence; it is estimated that up to 50% of the risk for dependence is due to polygenic inheritance. Extensive studies are underway for alcohol, opioids, and stimulants including nicotine in order to identify specific genes associated with this risk.

For each of the classes of abused drugs a complex molecular biology has been described, including specific neuroanatomic substrates linked to different neurotransmitters during acute intoxication and during withdrawal after dependence is established. Acute reinforcing effects of abused drugs are clearly a function of specific receptor binding but are also related to the rate of change in synaptic levels of dopamine, a key neurotransmitter involved in reinforcement in the nucleus accumbens. The chronic effects of abused drugs include tolerance and sensitization as well as the neurobiologic substrates for withdrawal symptoms. Much has been learned about these neurobiologic substrates for withdrawal in opioid dependence, including the activation of adrenergic brain systems such as the locus ceruleus during withdrawal. The latter findings have important treatment implications, such as the use of clonidine for opioid withdrawal.

Other drug classes, such as the benzodiazepines, have specific receptors on chloride channels associated with the neurotransmitter -aminobutyric acid (GABA), while other abused drugs, such as phencyclidine, bind to sites on excitatory amino acid receptor-channel complexes. The functions of other receptors that bind abused drugs such as opioid and cannabinoid receptors also have been clarified with the identification of endogenous ligands for these receptors, such as -endorphin for the opioid receptor and anandamide for the cannabinoid receptor. These binding sites appear to be critical for the acute effects of these abused drugs, and substantial progress has been made in understanding the neurotransmitter basis for reinforcement of most abused drugs including recent work with the inhalant toluene (Riegel and French, 2002). The dopamine neurons connecting the ventral tegmental area to the nucleus accumbens have been considered the major reinforcement pathway for a wide range of abused drugs, but their role in reinforcement has been most clearly established for cocaine and amphetamine and less clearly for other drugs, particularly inhalants and several hallucinogens.

The neurobiologic findings in animal models have been increasingly confirmed in human studies. These human studies include pharmacologic challenges with neuroendocrine and behavioral outcomes, assessments of endogenous ligands in cerebrospinal fluid from drug-dependent patients, and neuroimaging studies, particularly neuroreceptor imaging. Available radioligands have permitted examination in humans of dopamine receptors and transporters, opioid receptors, and functional brain activity based on blood flow or glucose utilization. These receptor-neuroimaging studies have demonstrated that chronic abuse of drugs which can produce tolerance, dependence, and sensitization may have associated effects on receptor numbers (eg, dopamine D2 receptors decrease in cocaine abusers) and on transporter numbers (eg, dopamine transporters increase in cocaine abusers). Blood flow and glucose utilization studies have shown that acute drug use is associated with substantial reductions in cerebral metabolic activity and that the rate of change is a correlate of the reinforcing effects of abused drugs.

In the following sections, we review current knowledge about the molecular neurobiology of each class of abused drugs and their clinical pharmacology.

Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 32. Drugs of Abuse >

Opioids

History

The nepenthe (Gk "free from sorrow") mentioned in the Odyssey probably contained opium. Opium smoking was widely practiced in China and the Near East until recently. Isolation of active opium alkaloids and the introduction of the hypodermic needle, allowing parenteral use of morphine, increased opioid use in the West. The first of several "epidemics" of opioid use in the USA followed the Civil War. About 4% of adults in the USA used opiates regularly during the postbellum period. By the 1900s, the number had dropped to about 1 in 400 people in the USA, but the problem was still considered serious enough to justify passage of the Harrison Narcotic Act just before World War I. A new epidemic of opioid use started around 1964 and has continued unabated ever since. While fear of AIDS has reduced intravenous use of heroin, recent increases in its purity have led to markedly increased intranasal use. Present estimates are that the number of opioiddependent people in the USA has stabilized at around 750,000.

Chemistry & Pharmacology

The most commonly abused drugs in this group are heroin, morphine, oxycodone, and—among health professionals—meperidine. The chemistry and general pharmacology of these agents are presented in Chapter 31: Opioid Analgesics & Antagonists.

Tolerance to the mental effects of opioids develops with long-term use. The need for everincreasing amounts of drugs to sustain the desired euphoriant effects—as well as to avoid the discomfort of withdrawal—has the expected consequence of strongly reinforcing dependence once it has started. The role of endogenous opioid peptides in opioid dependence is uncertain.

Clinical Aspects

Intravenous administration is routine not only because it is the most efficient route but also because it produces a bolus of high concentration of drug that reaches the brain to produce a "rush," followed by euphoria, a feeling of tranquility, and sleepiness ("the nod"). Heroin produces effects that last 3–5 hours, and several doses a day are required to forestall manifestations of withdrawal in dependent persons. Symptoms of opioid withdrawal begin 8–10 hours after the last dose. Many of these symptoms resemble those of increased activity of the autonomic nervous system. Lacrimation, rhinorrhea, yawning, and sweating appear first. Restless sleep followed by weakness, chills, gooseflesh ("cold turkey"), nausea and vomiting, muscle aches, and involuntary movements ("kicking the habit"), hyperpnea, hyperthermia, and hypertension occur in later stages of the withdrawal syndrome. The acute course of withdrawal may last 7–10 days. A secondary phase of protracted abstinence lasts for 26–30 weeks and is characterized by hypotension, bradycardia, hypothermia, mydriasis, and decreased responsiveness of the respiratory center to carbon dioxide.

Heroin users in particular tend to be polydrug users, also using alcohol, sedatives, cannabinoids, and stimulants. None of these other drugs serve as substitutes for opioids, but they have desired additive effects. One needs to be sure that the person undergoing a withdrawal reaction is not also withdrawing from alcohol or other sedatives, which might be more dangerous and more difficult to manage.

Besides the ever-present risk of fatal overdose, hepatitis B and AIDS are among the many potential complications of sharing contaminated hypodermic syringes. Bacterial infections lead to septic complications such as meningitis, osteomyelitis, and abscesses in various organs. Attempts to illicitly manufacture meperidine have resulted in the highly specific neurotoxin 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonism in users (see Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders).

Treatment

Treatment of acute overdoses of opioids can be lifesaving and is described in Chapters 31 and 59. In long-term treatment of opioid-dependent persons, pharmacologic and psychosocial approaches are often combined. Chronic users tend to prefer pharmacologic approaches; those with shorter histories of drug abuse are more amenable to detoxification and psychosocial interventions.

Pharmacologic treatment is most often used for detoxification. The principles of detoxification are the same for all drugs: to substitute a longer-acting, orally active, pharmacologically equivalent drug for the abused drug, stabilize the patient on that drug, and then gradually withdraw the substituted drug. Methadone is admirably suited for such use in opioid-dependent persons. Clonidine, a centrally acting sympatholytic agent, has also been used for detoxification. By reducing central sympathetic outflow, clonidine mitigates many of the signs of sympathetic overactivity. Clonidine has no narcotic action and is not addictive. Lofexidine, a clonidine analog with less hypotensive effect, is being developed for use.

While it is easy to detoxify patients, the recidivism rate (return to abuse of the agent) is high. Methadone maintenance therapy, which substitutes a long-acting orally active opioid for heroin, has been effective in some settings. A single dose can be given each day. Methadone saturates the opioid receptors and prevents the desired sudden onset of central nervous system effects normally produced by intravenous administration of additional opiates. An even longer-acting methadone analog, L-acetylmethadol, allows three times a week rather than daily dosing and reduced abuse potential, but its association with sudden cardiac death due to prolonged QT arrhythmias has made its use uncommon. Another candidate drug for use in this setting is buprenorphine, a partial opioid agonist, that can be given once daily or even less often at sublingual doses of 4–32 mg daily depending on the patient. The lower doses are useful for detoxification from heroin, while the higher doses are for longer maintenance treatment. Treatment in an office-based primary care setting is a potential advantage of this agent over methadone (Kosten, 2002).

Use of a narcotic antagonist is a rational alternative to the above agonist-based therapies because blocking the action of self-administered opioids should eventually extinguish the habit, but this therapy is poorly accepted by patients. Naltrexone, a long-acting orally active pure opioid antagonist, can be given three times a week at doses of 100–150 mg and a depot form for monthly administration is being developed. Because it is an antagonist, the patient must first be detoxified from opioid dependence before starting naltrexone.

Psychosocial approaches include drug-free residential communities, which use peer group pressures, emphasizing confrontation and discussion.

Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 32. Drugs of Abuse >

Barbiturates, Other Sedative-Hypnotics, & Ghb

History

Ethanol is the sedative-hypnotic with the longest history of both use and abuse; it is discussed in Chapter 23: The Alcohols. Barbiturates were introduced in 1903; they have been largely replaced in medical practice by newer agents, especially benzodiazepines in the 1960s (see Chapter 22: Sedative-Hypnotic Drugs). Short-acting members of the sedative-hypnotic group are widely abused and the most recent addition to this abused group is gamma-hydroxybutyric acid (GHB).

Chemistry & Pharmacology

The chemical relationships among this class of drugs are reviewed in Chapter 22: SedativeHypnotic Drugs. Depending on the dose, these drugs produce sedation, hypnosis, anesthesia, coma, and death. Both barbiturates and benzodiazepines can be classified pharmacokinetically into shortand long-acting compounds; GHB is relatively short-acting. Most abuse involves short-acting drugs, eg, secobarbital or pentobarbital sodium, and not long-acting ones, eg, phenobarbital. Drugs with half-lives in the range of 8–24 hours produce a rapidly evolving, severe withdrawal syndrome; those with longer half-lives, eg, 48–96 hours, produce a withdrawal syndrome that is slower in onset and less severe but longer in duration. Drugs with half-lives longer than 96 hours usually have a built-in tapering-off action that reduces the possibility of withdrawal reactions.

Clinical Aspects

Although statistics on alcoholism are extensive, no one knows how many persons are dependent on prescription sedatives. However, physiologic dependence has been relatively rare and usually occurs following long-term treatment with doses of 40 mg/d or more of diazepam or its equivalent. These abusers often are codependent on other drugs such as opioids, alcohol, or stimulants. "Therapeutic dose dependence" at doses of 15–30 mg/d of diazepam may be characterized by weight loss, changes in perception, paresthesias, and headache.

Finally, very rapid onset benzodiazepines have been widely reported as a means of "date rape," by using a small tasteless dose of the drug to make the victim incapable of protecting herself (or himself). This produces intoxication but not dependence. The drug most commonly used in this situation has been flunitrazepam (Rohypnol, "roofies," not available in the USA) and more recently GHB. The amnesia-producing effects of the benzodiazepines (see Chapter 22: SedativeHypnotic Drugs) make the victim unable to describe the events after she or he has recovered.

As these drugs are usually taken orally and the tablets or capsules are consistent in drug content, inadvertent fatal overdoses of single agents are rare. Tolerance may develop to the sedative effect but not to the respiratory depressant effect. Thus, if these drugs are used with other respiratory depressants, eg, large amounts of alcohol or opioids, fatalities can occur.

The withdrawal syndrome from sedatives is almost identical to that from alcohol and includes anxiety, tremors, twitches, and nausea and vomiting. In the case of long-acting drugs, symptoms may not appear for 2–3 days, and initial symptoms may suggest a recrudescence of those originally treated (nervousness, anxiety). Only by the fourth or fifth day can one be sure that a withdrawal reaction is under way. Convulsions are a late manifestation when they do occur—often not until the eighth or ninth day. Following this, the syndrome subsides. Severe cases are associated with delirium, hallucinations, and other psychosis-like manifestations.

Treatment

If short-acting drugs have been abused, chlordiazepoxide or phenobarbital is substituted as the pharmacologically equivalent agent. If long-acting drugs have been used, the same drug may be continued. The patient is stabilized on whatever dose is required to cause signs and symptoms to abate, and the drug is then gradually withdrawn. The rate of decrement may be 15–25% of the daily dose early in treatment, with later decrements of 5–10%. Complete detoxification can usually be achieved in less than 2 weeks.

No specific treatment programs have been developed for prescription sedative abusers. The problem is so often complicated by abuse of other drugs that it may be more expeditious to enroll the patient in a program designed for alcoholics or opiate-dependent persons. Patients with psychiatric disorders that can be defined, especially those with depression, may be treated with drug therapy specific for the underlying disorder.

Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 32. Drugs of Abuse >

Stimulants

History

In this section, caffeine is discussed only briefly and the focus is on other stimulants that produce psychiatric disorders. Caffeine can lead to a withdrawal syndrome characterized by lethargy, irritability, and headache, but withdrawal appears to occur in less than 3% of regular coffee drinkers. Moreover, the morbidity associated with caffeine overdose, which can include disturbing effects on sleep and heart rhythm, is much less than the morbidity associated with other stimulants.

Nicotine is one of the most widely used licit drugs because it is heavily promoted and produces powerful psychologic and physical dependence. About 28% of adults in the USA still smoke cigarettes because they have become dependent on nicotine. The use of smokeless tobacco products (eg, snuff, chewing tobacco) has increased in adolescents. Deaths directly attributable to smoking account for 20% of all deaths and 30% of cancer deaths in the USA. It is estimated that about 90% of cases of chronic obstructive pulmonary disease in the USA are due to smoking. Cocaine is a plant product that has been used for at least 1200 years in the custom of chewing coca leaves by natives of the South American Andes. In contrast, amphetamine was synthesized in the late 1920s and has a large number of analogs including methylphenidate (Ritalin) and methylenedioxymethamphetamine (MDMA, "ecstasy"). A closely related natural alkaloid, cathinone, is found in khat, a plant that produces effects indistinguishable from those of the amphetamines.

Chemistry & Pharmacology

Despite their similar behavioral effects, caffeine, nicotine, cocaine, and amphetamine have very different structures and sites of action in the brain. Caffeine, a methylxanthine compound, appears to exert its central actions (and perhaps some of its peripheral ones as well) by blocking adenosine receptors. Because caffeine does not act on the dopaminergic brain structures related to reward and addiction, its abuse and dependence potential are quite small. As noted in the above section Neurobiology of Abused Drugs, dopamine is very important in the reward system of the brain; its increase probably accounts for the high dependence potential of cocaine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting reuptake of dopamine as well as norepinephrine. Amphetamines probably act mainly by increasing release of catecholaminergic neurotransmitters, including dopamine, by reversal of the vesicular transporter.

A useful model of the action of these two drugs in the reward centers of the CNS is shown in Figure 32–1. Cocaine reduces reuptake of dopamine into the neuron by inhibiting the dopamine reuptake transporter. Amphetamine causes the intracellular release of dopamine within the terminal and reverses the transporter direction so that dopamine is released into the synapse by reverse transport rather than ordinary exocytosis. In addition, amphetamine inhibits intracellular MAO metabolism of dopamine. Note that both drugs result in an increase in the concentration of dopamine in the synapse.

Figure 32–1.

A model for the action of cocaine and amphetamine at a dopaminergic synapse in the central nervous system. Cocaine (right side) blocks the dopamine reuptake transporter (DAT). Amphetamine (left side) has several effects. It enters the nerve ending via reverse transport by the DAT and displaces dopamine (DA) from vesicles by altering their pH. It also inhibits dopamine metabolism by MAO in the nerve ending. The increased intraneuronal dopamine causes reversal of the DAT and dopamine floods into the synapse.

Clinical Aspects

One common pattern of amphetamine or cocaine abuse is called a "run." Repeated smoked or intravenous injections are self-administered to obtain a "rush"—an orgasm-like reaction—followed by a feeling of mental alertness and marked euphoria. When free base cocaine is smoked, entry through the lungs is almost as fast as by intravenous injection, so that effects are more accentuated