Introductory Pharmacology (just paraphrasing words and create fluent answer)

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Lesson B9.pdf

Lesson B.9 Dr. W.J. Racz

CANNABIS

Reference: A Primer of Drug Action, 12 th

ed.

Objectives

At the conclusion of this lesson, you should be able to: (1) describe the history of cannabis use,

(2) state the mechanism of action of the cannabinoids, (3) state the time of onset and duration of

response to smoking marijuana, (4) list the accepted medical and proposed medical uses of the

cannabinoids, (5) describe the effects of short-term, low-dose and high-dose use of cannabis, (6)

describe the effects of chronic high-dose use of cannabis, and (7) describe the degree and type of

tolerance and dependence associated with cannabis.

Introduction

The term “cannabis” refers to the drug-containing forms of the hemp plant, Cannabis sativa,

which is an herbaceous annual. There are two varieties of Cannabis sativa – resin-producing and

fibre-producing. In Cannabis sativa, there are 420 chemical compounds, many of which are

common to other plants. There are 60 compounds that are found only in Cannabis sativa, and

these compounds are referred to as cannabinoids. Of these compounds, l-trans-Δ 9 -

tetrahydrocannabinol (THC) is the most potent psychoactive agent in cannabis, and THC

accounts for most, but not all, of the psychoactive effects of cannabis. Common names for cannabis or its products include marijuana, hashish, hashish oil, charas, bhang, ganja, and dagga.

Marijuana, hashish and hashish oil are the cannabis preparations most common to North

America.

History

2700 BC – 1800’s Cannabis plant was used for manufacturing rope; marijuana was used for

its mild intoxicating effects as it was considered less harmful than alcohol.

1920’s – 1930’s Public concern was raised over the effects of marijuana on individuals and

society (“menace of marijuana”). Legislation was enacted to outlaw the

use of marijuana, which was considered to be a narcotic.

1960’s – 1970’s Increased use of cannabis, primarily in the form of marijuana. Survey in

1972: more than two million people in the U.S.A. reported daily use of

marijuana. Survey in 1977: 60% of young adults in the U.S.A. reported

some experience (?) with marijuana. A 1979 survey in Ontario revealed

that approximately 50% of students aged 16 or over reported some use of

marijuana in the preceding 12 months.

1978 U.S.A.-sponsored project using the herbicide, paraquat, was initiated in an

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attempt to destroy cannabis crops in Mexico. It failed. U.S.A. citizens

were smoking cannabis products containing paraquat, which can produce

lung toxicity.

1980’s In the early 1980’s, the use of marijuana began to stabilize. In 1982, 42%

of high school students in the U.S.A. reported use of the drug in the

previous year and 5.5% used it daily. The figures in Ontario were similar.

1990’s The decline in the use of marijuana in the 1980’s was followed by an

increase in use in the 1990’s. Marijuana is currently the third most popular

psychoactive drug, after alcohol and tobacco (fourth if one includes

caffeine).

In November 1996, voters in Arizona and California approved the legal use of marijuana for medical purposes. Other states are likely to follow the same pattern. This change in the use of

marijuana reflects the changing public (societal) attitudes towards the use of this drug. In

Canada, society must express its views through different mechanisms, e.g. lobby groups. The

changes which occurred in Arizona and California are troublesome, at least from a

pharmacological point of view. The medical use of drugs should be based on the scientific

evidence which balances benefit and risk, i.e. evidence-based medicine. Society can decide on

the societal risks that are acceptable, but not on the scientific validity of data.

In 1997, an Ontario court dismissed charges related to possession and cultivation of cannabis on the basis that the individual was using the drug to control epilepsy, which was not controlled by

conventional drug therapy.

In 1997, Canada changed the law to allow the cultivation of some varieties of cannabis that contain very small amounts of THC for use in the manufacture of rope, clothing and other hemp

products. Farmers must obtain a special license to grow hemp, as the crop is called.

In 2002 to 2005 Health Canada supported trials on the medical use of marijuana. Currently the program has been suspended.

2012 One US state votes to legalize recreational use of marijuana.

Classification of Marijuana

Legal: Marijuana is classified as a narcotic and controlled under the Narcotic Control Act.

Pharmacological: Marijuana is classified as a central nervous system depressant, euphoriant and hallucinogen, although the hallucinogenic properties only occur at high doses.

Pharmacology

The mechanism of action of marijuana is not fully understood. One of the active ingredients in

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marijuana, Δ 9 -tetrahydrocannabinol (THC), (there are other cannabinoids) binds specifically to

receptors located in the cerebral cortex, cerebellum, hippocampus, hypothalamus, and other areas

of the brain and spinal cord. These receptors have been designated CB1 or Type 1 cannabinoid

receptors. A second receptor, CB2, is found only in the periphery. CB2 receptors do not appear

to be involved in the psychotomimetic effects of THC, but may mediate some of its effects on

the immune system.

Once these receptors were identified, the search began for an endogenous ligand (an endogenous

substance which acts by binding to this receptor). Anandamide was isolated and meets the

criteria to be classified as the endogenous ligand. Anandamide may be involved in learning and

memory processes. The structures of THC and anandamide are shown in A Primer of Drug

Action, Chapter 18, page 557. The CB1 receptor, when activated by anandamide or THC,

inhibits the release of excitatory neurotransmitters. This would explain the reduction in

cognitive function seen with THC. It also explains the CNS depressant properties of the drug

(the terms “THC” and “marijuana” are used synonymously). THC produces most of its effects

by inhibiting the release of transmitters; it may well have other actions.

In the periphery, THC binds to CB2 receptors on lymphocytes (cells involved in the immune

response) and it is thought that the immunosuppressive properties of THC are mediated via this

receptor.

The absorption of THC from marijuana smoke is rapid and the onset of action is almost

immediate. The effect lasts up to three to four hours and more must be inhaled to continue the

“high”. THC is also absorbed after oral administration, but the absorption occurs slowly and is

incomplete. The onset of action will be delayed 30 to 60 minutes. The effect is less than that

from smoking the material.

THC is slowly metabolized, having a half-life of approximately 30 hours, but elimination from

adipose tissue may take longer. It is the metabolites of THC that are measured in drug tests.

Chronic users will be positive, for the metabolites, for several weeks after use has stopped. This

does not mean that they were under the influence of THC at the time of the testing.

Medical Uses of Marijuana

Cannabis extracts were once widely used, on medical prescription, as sedatives and hypnotics.

There are a number of possible uses for cannabinoids: nausea and vomiting, anorexia (loss of

appetite), epilepsy, glaucoma, spasticity, and migraine. One of the few applications that has

found some measure of medical acceptance is in the prevention of nausea and vomiting

associated with anticancer drugs. Even in this application, other anti-nausea drugs were superior

in studies. It must be recognized that, in the past fifteen years, very effective and selective drugs

have been developed to treat nausea associated with cancer chemotherapy. There are two

synthetic THC derivatives used as anti-nauseants – dronabinal and nabilone. These agents are

more selective in their actions than THC. As more information is obtained on the functions of

anandamide and its receptors, it is likely that drugs that bind to the CB1 and CB2 receptors will

be developed that are more effective and less toxic than THC.

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Recently a metered dose inhaler containing THC has been approved for the treatment of

neuropathic pain. It is hoped that this means of administration of THC will be more effective

than administering it in the form of a tablet.

Non-Medical Use of Cannabis and Cannabis Products

Cannabis products are available, on the street, in several forms. Marijuana is the dried flowering

tops and leaves of the harvested plans. Hashish consists of dried resin, usually from the flowers

and compressed flowers. Hashish oil is obtained by extracting the cannabinoids from hashish.

In most cases, the product is smoked or inhaled. Hashish may be baked into foods and eaten.

Effects of Short-Term Use – Low to Moderate Doses

CNS: ∙ Early effects will be seen as relaxation and drowsiness; there is disinhibition and

talkativeness.

∙ A feeling of well-being, exhilaration and euphoria.

∙ They experience distortions in perception of time, body image and distance. Sense of

hearing and vision are enhanced.

∙ The perception of the senses of touch, smell and taste are enhanced (this may be useful as

an appetite stimulant).

∙ There is spontaneous laughter, impairment of short-term memory and concentration, and

confusion. The attention span may be reduced.

∙ Balance and stability on standing and walking can be impaired. The user may have

decreased muscle strength.

∙ Motor coordination is impaired (driving).

∙ The occasional user may experience fearfulness, anxiety and mild paranoia. Violent

behaviour is rare.

∙ The user may experience flashbacks, especially if they abused hallucinogens.

Cardiovascular: The smoker experiences an increased heart rate and increased blood flow to the extremities. Their blood pressure may not accommodate when moving from a sitting to a

standing position (orthostatic hypotension).

Respiratory: The smoke and ingredients in the smoke irritates the mucous membranes lining the respiratory system. There is also bronchodilation.

Gastrointestinal: There is increased appetite and dryness of the mouth and throat.

Other effects: Sex drive may be reduced in males, as THC may reduce testosterone levels. In females, THC can disrupt the ovarian cycle. In utero exposure may be associated with

“behavioural problems” in children. As the drug wears off, there is an experience of a

“hangover” similar to that with alcohol.

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Effects of Short-Term Use – Higher Doses

As the dose of cannabis (THC) is increased, the effects described above for low doses will be

accentuated. In addition, the following responses may be observed.

CNS: Users may experience pseudohallucinations (hallucinations that the person knows are not real). There is a running together of senses, e.g. seeing music. Judgement will be impaired, as is

coordination; reaction time is slowed and performance in simple motor tasks is impaired. There

is often confusion of events; true hallucinations may occur as well as delusions. Mentation

becomes confused and disorganized. The user may become paranoid, agitated and panic

stricken. Occasionally, there is a toxic psychosis manifested as hallucinations, paranoid

delusions, disorientation, sever agitation, and a feeling of de-personalization (I really don’t

exist).

Cannabis and impaired driving: Tests conducted have demonstrated that THC interferes with functions required for the safe operation of a motor vehicle. These are motor coordination,

tracking, perception, and vigilance. The actual performance on the road is impaired. The degree

of disruption is dose-dependent, as little as one joint can be found to cause an impairment in

some individuals. Alcohol and THC, used simultaneously, will intensify the adverse effects of

each other on driving performance.

Effects of Long-Term Use

Psychological effects: The occasional low-dose use of cannabis does not appear to be associated with harmful psychological effects. The risk of psychological dependence is more

evident in users who have emotional problems and use cannabis to control psychological stress.

Very high doses of cannabis over a long period may be associated with significant problems in

some users. There is an “amotivational syndrome” associated with high-dose use. This is

characterized by mental slowing, loss of memory, difficulty with abstract thinking, loss of drive,

and emotional flatness. The syndrome usually disappears upon cessation of drug use, suggesting

that it represents chronic intoxication. The most common long-term effects seen are: loss of

short-term memory, lack of concentration, and loss of ability in abstract thinking. The issue of

permanent effects from long-term use has not been settled, but some data suggests that structural

changes do occur in the brain and these changes may be associated with impairment of memory

and learning.

The cardiovascular effects of cannabis are usually reversible. The changes in blood pressure do not appear to be serious. The increase in heart rate can be a potential problem for the user with

heart disease.

The respiratory system is a major target for the adverse effects of smoking marijuana. Bronchitis, asthma, sore throat and chronic irritation of and damage to membranes of the

respiratory tract are all higher in heavy users of marijuana. These adverse events are additive

with the simultaneous use of tobacco and marijuana. Marijuana smoke contains a higher amount

of tars and carcinogens (cancer-causing compounds) than tobacco smoke and is most likely to be

Lesson B.9 CANNABIS

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a cancer-causing product. Current studies suggest that cancers may occur more rapidly with

marijuana than tobacco. Cancers due to smoking tobacco have a latency period of 20-25 years.

Not only are there higher concentrations of carcinogens in marijuana smoke than in tobacco

smoke, but the method of smoking is different. The marijuana user inhales deeply and holds the

smoke in the lungs in order to maximize the absorption of THC and other cannabinoids.

Unfortunately, this process also enhances the amount of tars and carcinogens absorbed.

Other areas of concern are the long-term effects of cannabis products on human male fertility. While there is a decrease in sperm count, fertility does not appear to be affected. The other area

of concern is the effects on the developing fetus. Developmental delays have been observed, but

it is difficult to distinguish the effects of THC from those of other drugs, diet, and overall poor

prenatal care.

Tolerance and Dependence

Tolerance does occur to the cannabinoids upon long-term use. Tolerance occurs to the

psychoactive properties of THC, but also to the effects on the cardiovascular system, the

impairment of performance, and cognitive function.

Physical dependence can occur with high-dose use. Upon termination, there is a mild

withdrawal syndrome. This is characterized by sleep disturbances, irritability, loss of appetite,

nervousness, mild agitation, upset stomach, and sweating.

With regular use, psychological dependence does develop. There is often a persistent craving for

the drug and the drug is the most important component in their life.

Potential for Abuse

The dependence liability of cannabis products is low to moderate. The euphoria (high) is not as intense as some other drugs (e.g. cocaine) and the reinforcement is much less.

The inherent harmfulness of cannabis products is low, especially for low doses of the drug (infrequent use). The greatest danger may possibly be an automobile accident, which is

becoming a significant problem. The major long-term effects are the adverse effects on the

respiratory tract, although the effects of high-dose, chronic use on the CNS should not be

discounted. Recent evidence suggests that in utero exposure may lead to developmental and

cognitive deficits in future years. Deficits in cognitive function have also been linked to chronic

use.

Lesson B.9 CANNABIS

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Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following statements are correct except:

(A) The cannabis plant is used to manufacture rope and clothing.

(B) Marijuana was once widely prescribed as a sedative and hypnotic.

herbicides.

(D) Marijuana use is greater than the use of cocaine.

(E) Marijuana use was high in 1930, declined in the 1970’s, but increased again in the

1980’s.

2. Which of the following statements is correct?

(A) Marijuana is classified by law as a narcotic.

(B) Marijuana (THC) is classified as a CNS stimulant.

(D) The use of marijuana, in a number of disease states, is well established.

(E) THC found in marijuana smoke is slowly absorbed through the mucosal membranes of

the lung.

3. To which of the following receptors does THC bind?

(A) D2

(B) CB1

(D) B1

(E) Mj

4. The long-term adverse effects of cannabis use include all of the following except:

(A) Increased incidence of bronchitis.

(B) Increased incidence of lung cancer.

(D) Physical dependence.

(E) Psychological dependence.

Lesson B.9
CANNABIS
Reference
Objectives
Introduction
History
Classification of Marijuana

Legal
Pharmacological

Pharmacology
Medical Uses of Marijuana
Non-Medical Use of Cannabis and Cannabis Products
Effects of Short-Term Use – Low to Moderate Doses

CNS
Cardiovascular
Respiratory
Gastrointestinal
Other effects

Effects of Short-Term Use – Higher Doses

CNS
Cannabis and impaired driving

Effects of Long-Term Use

Psychological effects
cardiovascular effects
respiratory system
Other areas of concern

Tolerance and Dependence
Potential for Abuse
Questions

Lesson B8.pdf

Lesson B.8 Dr. W.J. Racz ALCOHOL (ETHANOL) Reference: A Primer of Drug Action, 12th ed. Objectives At the conclusion of this lesson, you should be able to: (1) state the properties of ethanol in terms of absorption, distribution and biotransformation; (2) state the effect of various blood alcohol concentrations on central nervous system function; (3) state the proposed mechanism of neuronal inhibition of ethanol; (4) state the effects of ethanol on the central nervous system, cardiovascular system, gastrointestinal tract, and liver in terms of short-term and chronic use; (5) list the effects of ethanol on the developing fetus; and (6) list the effects of ethanol on driving. Introduction Ethanol (ethyl alcohol) is one of the three most used non-medical drugs in Canada, the other two being caffeine and tobacco. While alcohol consumption has decreased in the past decade, the health care and social costs remain enormous as alcohol produces more health problems and deaths than all illicit drugs combined. The major reason for the extensive use and abuse of alcohol is its ready availability and the permissive attitudes of society, although societal attitudes to abuse of alcohol, at least to drinking and driving, has undergone substantive changes since 1970. Historically, alcohol is an old drug. It was the first sedative-hypnotic drug to be used by ancient physicians. The use of fermented beverages can be traced back to 8000 B.C., when mead was prepared from honey. Traditionally, alcohol has been used for three major purposes. ∙ In medicine as a sedative and hypnotic. ∙ For religious and other occasions, e.g. sacramental use by Christians and Jews. ∙ Recreational purposes. The terms “alcohol” and “ethanol” are used interchangeably. Ethanol Content of Alcoholic Beverages The following is a comparison of the alcohol content of different forms of alcoholic drinks. 1 drink = 341 ml (12 oz.) beer (5% v/v) = 43 ml (1.5 oz.) (40% v/v) = 170 ml (6 oz.) wine (10% v/v) = 17 ml absolute ethanol = 13 g absolute ethanol Ten to 13 ml of absolute alcohol is the amount metabolized by the liver each hour.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

Absorption of Ethanol Ethanol is absorbed rapidly from the stomach and the upper small intestine (the major site of absorption). The overall absorption rate for a given dose of ethanol is affected by: (a) Stomach-emptying time, or the time required for the alcohol to reach the small intestine. (b) Ethanol concentration in the G.I. tract. The time from the last drink and the maximal blood alcohol concentration ranges from 30 to 90 minutes. Distribution of Ethanol Ethanol distributes throughout the total body water and readily distributes across the blood-brain barrier. In pregnant women who drink alcoholic beverages, ethanol is readily transferred across the placenta and distributes throughout the total body water of the fetus. Metabolism and Excretion Over 95% of ethanol in the body is eliminated by biotransformation, primarily in the liver. The remaining 5% is excreted in the breath, urine and sweat. Aldehyde dehydrogenase (ADH) converts alcohol to acetaldehyde, and in turn aldehyde dehydrogenase converts acetaldehyde (ALDH) to acetic acid. Acetic acid is then further metabolized by a number of tissues. Disulfiram and calcium carbimide (drugs used to treat alcohol abuse) inhibit aldehyde dehydrogenase, and as a result, acetaldehyde accumulates and the individual will feel ill and presumably stop abusing alcohol to stop the adverse effects of acetaldehyde.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

The metabolism of alcohol is unusual as it occurs at a constant rate, irrespective of the blood alcohol concentration. A constant amount of alcohol is metabolized each hour. This is because ADH becomes rate-limiting or saturated at 20 mg of alcohol per 100 ml of blood (saturation is a term used when a process is running at full capacity). Normally, the body rate of ethanol metabolism is about 120 mg ethanol/kg body weight/hour; for a 70 kg person, the rate is 8.4 g ethanol/hour or 10.6 ml ethanol/hour. Normally, with this rate of ethanol metabolism, the blood ethanol concentration decreases at the rate of 15 mg ethanol/100 ml blood/hour. Pharmacology and Toxicology of Alcohol Ethanol is classified as a general central nervous system (CNS) depressant. Acute use of ethanol more obviously affects the CNS, whereas chronic, high-dose use affects many organ systems of the body including the CNS, cardiovascular system, gastrointestinal tract and liver. Chronic, maternal use of high-dose ethanol can adversely affect the fetus, including teratogenesis, which can manifest as the fetal alcohol syndrome or fetal alcohol effects. Medical Uses of Ethyl Alcohol (Ethanol) There are very few medical uses for ethanol. Some of the current uses are: as alcohol sponges applied topically to treat fever; as skin disinfectant; a low dose is occasionally used as an aperitif to improve appetite and digestion; and it is an antidote in the treatment of methanol (wood alcohol) poisoning. A major use since the SARS episode is as a hand sanitiser. Central Nervous System Ethanol produces dose-dependent depression of CNS function: disinhibition → sedation → hypnosis → general anesthesia → coma. Low dose: Disinhibition (inhibition of an inhibitory pathway in the CNS).

This is usually manifested by increased social interaction, e.g. talkativeness.

High dose: Sedation → hypnosis → general anesthesia → coma → death (respiratory

depression). The CNS effects are proportional to the blood ethanol concentration. This is shown in the following table.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

RELATIONSHIP BETWEEN BLOOD ETHANOL CONCENTRATION AND PHARMACOLOGIC EFFECT*

Blood [Ethanol] (mM) (mg/100 ml)

Effect

11 50 (≈ 2 drinks) 13 60 17 80 22-33 100-150 44-65 200-300 65-76 300-350 76-130 350-600

Euphoria and minor motor disturbances (increased reaction time, diminished fine motor control, impaired critical faculty). Nystagmus, more errors on mathematical tests, increased motor incoordination. Impaired driving ability, changes in electroencephalographic patterns. Gross motor incoordination. Amnesia for the drinking experience. Coma. May cause or contribute to death.

*There is appreciable interindividual variability in this relationship. A change in sleep pattern often occurs. The changes are an increase in slow-wave sleep and a decrease in rapid-eye-movement sleep. A reduction in rapid-eye-movement sleep is associated with a feeling of having “slept poorly”. Mechanism of Neuronal Action of Alcohol The mechanism of action of alcohol is not understood. At high concentrations of alcohol, it was believed that the drug acted as a general anesthetic,that is, depressing all excitable cells in a non- selective manner. This may occur at high alcohol concentrations. At lower alcohol concentrations, alcohol binds to the GABA receptor and augments GABA-mediated neuronal transmission. The reader is reminded that GABA-mediated events are inhibitory and that the barbiturates and the benzodiazepines have selective binding sites on the GABA receptor (see previous lessons). The interaction of alcohol with the GABA receptor may explain the reinforcing effects of the drug.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

Effects of Short-Term Use – Low Dose Alcohol is a CNS depressant, but at low dose the response observed is one of disinhibition. Drinkers feel gregarious, jovial, relaxed and more self-confident. A few individuals will feel irritable, depressed or sleepy. A number of perceptual and motor functions are impaired with low to moderate doses of alcohol. The user thinks they can function better, i.e. drive better. They are more willing to take risks, even though reflexes and motor skills are impaired. Effects of Short-Term Use – Higher Doses As the dose increases, the individual may demonstrate exaggerated emotional responses, e.g. very effusive or aggressive. Thinking, memory, judgement, perception and motor skills are severely impaired. If the dose is sufficient, stupor, followed by coma and death can occur. Adverse Effects of Short-Term Use Blackouts: This is the phenomenon where the drinker does not remember events while under the influence of alcohol. They are conscious, but can act in a dangerous manner. Crimes may be committed. These blackouts can be very frightening to many drinkers and may result in them seeking help. Psychiatric effects: Low doses of alcohol (one to three drinks) causes relaxation, while heavy drinking (five drinks or more) often leads to depression, irritability and over-sedation. The negative mood states, in concert with impaired judgement and impulsiveness, may lead to suicide and acts of violence. Drinking and driving: Alcohol is one of the major causes of automobile accidents. In Canada, results of a recent survey observed that 43 percent of fatally-injured drivers had consumed alcohol and 35 percent were over 0.08%. The same survey found that 20% of drivers reported driving after drinking. The age group at highest risk of drinking and driving is 25 to 45 years. Impairment of driving increases exponentially as the blood alcohol increases. To put this in perspective, a person who has a blood alcohol level of 50 mg/100 ml is twice as likely to have an accident as a person who has not taken a drink (0 mg/100 ml blood alcohol level). If a person has a blood alcohol level of 80 mg/100 ml (0.08%), the chances of having an accident are eight times that of the non-drinker. Violence: Individuals who drink heavily are more prone to violence than non-drinkers. Men who are heavy drinkers are six times more likely to assault their wives/significant others than non-drinkers. This observation is most likely due, at least in part, to the impairment of judgement. The other risks associated with excessive use of alcohol is associated with respiratory depression, coma and death. In addition, a number of comatose drinkers die each year after aspirating their vomit. Contrary to popular belief, alcohol (at all doses) does not enhance sexual performance in men; the exact opposite is true. It has been said that alcohol increases the desire, but reduces the performance.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

Adverse Effects of Long-Term Use Central nervous system: There are a number of neurological and mental disorders associated with chronic alcohol abuse. Alcohol damages the axons of the brain, resulting in fewer connections between neurons. This causes alcoholic dementia. Dementia can be defined as a global decrease in cognitive functioning, affecting memory, judgement, and thinking. Alcohol increases the metabolism of vitamin B1 (thiamine), resulting in thiamine deficiency. There are two conditions which result from alcohol-induced thiamine deficiency – Werniche’s encephalopathy in which the patient becomes drowsy, confused and cannot walk properly, and Korsakoff’s psychosis, a severe form of dementia. The peripheral nervous system is also subject to alcohol damage. Alcohol damages the axons in the peripheral nervous system, resulting in a peripheral neuropathy that is manifested by loss of feeling in the feet and is often accompanied by burning pain and difficulty in walking. Ethanol Dependence Chronic use of ethanol, especially in high doses, can lead to a state of drug dependence, often referred to as alcoholism. Ethanol drinking is a serious problem when it interferes with home life, job or scholastic performance, finances or personal mental/physical health. Tolerance to, and Dependence on, Ethanol Tolerance is defined as a state in which repeated administration of the same dose of drug (ethanol) has progressively less effect, or a state in which the dose of drug needs to be increased to obtain the same quantity of effect as was produced by the original dose. During chronic use of ethanol, there is a decreased intensity of ethanol action or a shortened duration of action. A larger dose of ethanol is needed to produce the original pharmacologic effect. Recently, it has been reported that individuals can develop tolerance more rapidly to the ethanol-induced impairment of performance of a task when they perform that task repeatedly under the influence of ethanol. Mechanism: 1. Metabolic (dispositional, pharmacokinetic) tolerance due to increased ethanol metabolic

rate. During chronic consumption of ethanol, the same dose produces a lower blood ethanol concentration or maintains the blood ethanol concentration above a certain level for a shorter time.

2. Cellular (functional, pharmacodynamic) tolerance. The CNS adapts to the effects of

ethanol. The consensus is that cellular tolerance plays a greater role in the overall development of tolerance. The extent or rate of development of tolerance depends on the individual, dose of

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

ethanol, and frequency of ethanol administration. It is important to note that, normally, minimal tolerance develops to the lethal dose of

ethanol. Cross-tolerance: 1. Occurs between ethanol and sedative-hypnotics such that a higher dose of a sedative-

hypnotic drug is required for the desired therapeutic effect. 2. Occurs between ethanol and general anesthetics such that a higher dose of anesthetic agent

is required for surgical anesthesia. Physical dependence is defined as an abnormal physiologic state brought about by repeated administration of a drug that leads to the appearance of a characteristic and specific group of symptoms when drug administration is stopped or decreased (withdrawal syndrome). The intensity of physical dependence is judged by the severity of the withdrawal syndrome. The basis of physical dependence on ethanol primarily involves the CNS. Withdrawal from ethanol (CNS depressant) produces excitability of the CNS (arousal, stimulation). Hyperexcitability leads to tremors, irritability, restlessness, anxiety, sweating, sleeplessness, agitation, nausea, muscular tension, hyperthermia, and increased heart rate. A severe ethanol withdrawal syndrome may involve convulsions, coma and possibly death. In severe cases of ethanol withdrawal, delirium tremens (DTs) may occur. Delirium tremens is characterized by tremulousness, auditory, visual and tactile hallucinations, confusion, psychomotor agitation, disorientation, and sleep disorders. The ethanol withdrawal syndrome can be treated effectively by oral administration of diazepam, a benzodiazepine-type sedative-hypnotic drug. The pharmacological basis for this therapy involves the principle of cross-dependence, in which the withdrawal syndrome following cessation of use of a particular drug is suppressed by administration of a second drug of the same or similar pharmacological classification. Following successful withdrawal of the patient from ethanol, the dose of diazepam is decreased gradually over the course of several days. Psychological dependence is defined as a compulsion that requires periodic or continuous administration of a drug to produce pleasure or to avoid discomfort. There is a compulsive desire to seek, obtain and drink ethanol. The drug-induced effects of relief from anxiety, disinhibition and euphoria are perceived as pleasurable and reinforce the use of ethanol. The development of physical dependence helps to reinforce continuous drug administration in order to avoid the withdrawal syndrome. Psychological dependence could be the most powerful factor in chronic use of ethanol, leading to alcohol-problem-drinking. Recently, naltrexone has been demonstrated to be effective in the treatment of the psychological dependence on ethanol. Naltrexone diminishes the craving for ethanol and assists in the

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

maintenance of abstinence. Potential for Abuse Ethanol can produce pleasurable intoxication and is very effective in reducing tension; thus, it has significant reinforcing properties. The dependence liability is moderate. The ease of availability and social and legal acceptance contributes to ethanol’s abuse potential. Effects on the Cardiovascular System Acute use: Low doses of acute use lead to vasodilation (flushing) of the vessels to the skin, resulting in a feeling of warmth. High doses of alcohol can depress the cardiovascular system and lead to alterations in the normal rhythm of the heart. Chronic use: Low chronic doses of alcohol can reduce the risk of coronary heart disease and stroke. High chronic doses can lead to alcoholic cardiomyopathy (destruction of or poor heart muscle). In addition, there is an increased incidence of hypertension and stroke. Effects on the Gastrointestinal Tract Low doses of alcohol will stimulate gastric secretion, and hence the use of a small dose of alcohol before a meal to stimulate digestion and enhance appetite. Higher doses of alcohol will irritate the lining of the stomach, causing inflammation and erosion (known as gastritis). This condition causes vomiting and abdominal pain. Ulcers may be aggravated, often leading to a serious gastrointestinal bleed. Effects on the Liver Low doses of alcohol on occasional use does not appear to have significant adverse effects on the liver. Acute high doses of alcohol (alcohol binge) will inhibit glucose production, and in association with fasting, can lead to hypoglycemia (low blood sugar). Chronic high doses of alcohol leads to alcoholic liver disease, a major cause of hospitalization and deaths in North America. There are three stages to alcoholic liver disease. In stage 1, the liver cells accumulate fat, causing the liver to enlarge (fatty liver). This stage is usually asymptomatic and is reversible if the alcohol is stopped. Stage 2 is alcoholic hepatitis. The liver cells are damaged and inflamed. The stage of alcoholic hepatitis can be asymptomatic or there can be severe liver function impairment. With abstinence, hepatitis is usually reversible. The liver is one of the few organs which can regenerate. The final stage is cirrhosis. This stage is not reversible as the damaged cells have been replaced by scar tissue. The scar tissue in the liver can modify the blood flow from the portal vein (drains the blood from the intestine) and the blood backs up into other veins causing distention, and occasionally these veins rupture and bleed. Effects on the Embryo/Fetus Epidemiologic and laboratory animal studies have demonstrated that ethanol is a teratogen.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

Chronic, maternal use of high-dose ethanol throughout pregnancy can produce teratogenic effects in the embryo/fetus, which can manifest postnatally as the Fetal Alcohol Syndrome. Principal features: CNS dysfunction. Pre-natal and post-natal growth deficiency. Cluster of facial abnormalities. Associated features: Variable major and minor malformations of other organ systems (e.g.

heart, joints). The effects of chronic or occasional maternal ingestion of one drink of alcoholic beverage per day on the embryo/fetus are not clearly understood. While the above describes fetal alcohol syndrome (FAS), there is also a condition known as fetal alcohol effects (FAE), where the neonate has some but not all of the features of fetal alcohol syndrome. FAE is five times more common than FAS. The safe dose of alcohol has not been determined and abstinence is recommended. Drugs Used in the Treatment of Alcoholism: Disulfiram and Calcium Carbimide (Calcium Cyanamide) These drugs are used as pharmacological adjuncts to psychotherapy or group therapy, and are referred to as alcohol-deterrent or alcohol-sensitizing drugs. These drugs inhibit hepatic aldehyde dehydrogenase and result in increased acetaldehyde concentration if the patient drinks ethanol, thereby producing cardiovascular/respiratory changes that are perceived as aversive. Alcohol and Drug Interactions 1. Acute ethanol use during drug therapy (body contains ethanol). (a) Ingestion of ethanol and other CNS depressants leads to an additive effect or

synergism of CNS depression. (b) Ethanol inhibits biotransformation (metabolism) of certain drugs (e.g. sedative-

hypnotics, phenytoin). 2. Chronic ethanol use followed by drug therapy (no ethanol in body). Ethanol causes proliferation (increase in growth) of the smooth endoplasmic reticulum of the liver cell, leading to increased activity of the liver drug-metabolizing enzyme system. There will be increased biotransformation of certain drugs (e.g. sedative-hypnotics, phenytoin), if there is no co-existing ethanol-induced liver injury.

Lesson B.8 ALCOHOL (ETHANOL) ______________________________________________________________________________

Questions The following are typical questions you would be expected to answer after reviewing this lesson. Instructions Each of the questions or incomplete statements below is followed by several suggested answers or completions. Select the one that is best in each case. 1. The CNS depressant effects of ethanol are additive with all of the following except: (A) Antihistamines. (B) Benzodiazepine. (C) General anesthetics (D) Caffeine. (E) Barbiturates. 2. Which of the following statements is correct? (A) Twelve ounces of beer, six ounces of wine and one and one-half ounces of whiskey all

contain the same amount of ethanol. (B) The dose of ethanol required to produce the same level of intoxication is greater in

women than men, on average. (C) Ethanol is transferred across the placenta with some difficulty.

(A) The maximum blood alcohol level is usually reached within 15 minutes of the last drink.

(E) Chronic ethanol use can lead to hypotension. 3. All of the following statements are correct except: (A) Low doses of ethanol cause relaxation. (B) Acute high doses of ethanol can lead to blackouts. (C) Low doses of ethanol often give a feeling of confidence. (D) High doses of ethanol may initiate aggressive behaviour. (E) Moderate doses of ethanol cause relaxation and hence an improvement in sexual

performance. 4. Which of the following statements is correct? (A) Chronic ethanol abuse can result in cirrhosis of the liver, an irreversible condition. (B) One or two drinks is usually sufficient to lead to depression and irritability. (C) Low dose of ethanol is defined as five drinks. (D) Alcohol blocks the metabolism of thiamine (vitamin B1). (E) Tolerance develops rapidly to the lethal effects of ethanol.

Lesson B.8
ALCOHOL (ETHANOL)
Reference
Objectives
Introduction
Ethanol Content of Alcoholic Beverages
Absorption of Ethanol
Distribution of Ethanol
Metabolism and Excretion
Pharmacology and Toxicology of Alcohol
Medical Uses of Ethyl Alcohol (Ethanol)
Central Nervous System
RELATIONSHIP BETWEEN BLOOD ETHANOL CONCENTRATIONAND PHARMACOLOGIC EFFECT*
Mechanism of Neuronal Action of Alcohol
Effects of Short-Term Use – Low Dose
Effects of Short-Term Use – Higher Doses
Adverse Effects of Short-Term Use

Blackouts
Psychiatric effects
Drinking and driving
Violence
other risks

Adverse Effects of Long-Term Use

Central nervous system
The peripheral nervous system

Ethanol Dependence
Tolerance to, and Dependence on, Ethanol

Mechanism
Cross-tolerance
Physical dependence
Withdrawal from ethanol
Psychological dependence

Potential for Abuse
Effects on the Cardiovascular System
Effects on the Gastrointestinal Tract
Effects on the Liver
Effects on the Embryo/Fetus

Principal features
Associated features

Drugs Used in the Treatment of Alcoholism: Disulfiram and Calcium Carbimide (Calcium Cyanamide)
Alcohol and Drug Interactions
Questions

Lesson B6.pdf

Lesson B.6 Dr. G.S. Marks

CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

References: A Primer of Drug Action, 12 th

ed.

Objectives

At the conclusion of this lesson, you should be able to: (1) differentiate between psychoses,

affective disorders and neuroses; (2) describe the evidence that excessive dopaminergic activity

underlies schizophrenia; (3) describe the mechanism of action of antipsychotic agents; (4)

describe the adverse effects of phenothiazines and mechanisms responsible for these adverse

effects; (5) differentiate between the adverse effect of phenothiazines, butyrophenones and

clozapine; (6) describe the mechanism of action of lithium as a therapeutic agent in manic-

depressive illness; (7) list the adverse effects of lithium and one means of trying to minimize the

adverse effects; (8) classify the various types of depression; (9) describe the amine hypothesis of

depression; (10) describe the types of depressants and their mechanism of action; and (11)

describe the adverse effects of different types of antidepressants.

Psychoses

The psychoses are among the most severe psychiatric disorders. People with this disorder suffer

from a marked impairment of behaviour. They have a serious inability to think coherently, to

comprehend reality, or to gain insight into these abnormalities. They may suffer from delusions

and hallucinations.

There are at least two subdivisions: (a) organic, and (b) functional (of unknown cause).

Organic psychoses are associated with causes that are understood and definable e.g. toxic, metabolic or neuropathological changes. They are characterized by confusion, disorientation,

memory disturbances and behavioural disorganization.

Functional (of unknown cause) psychoses are characterized by retention of orientation and memory in the presence of severely disordered thought or reasoning, emotion and behaviour.

The functional psychoses include schizophrenia. Schizophrenia is characterized by chronically

disordered thinking and emotional withdrawal and is often associated with paranoid delusions

and auditory hallucinations. Schizophrenia has a genetic component.

Affective (Mood) Disorders

Affective disorders are characterized primarily by a change in emotion or mood. Thus, an individual may exhibit depression, a feeling of unpleasantness or discomfort (dysphoria),

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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irritability, lability of emotion, elation or mania. Affective disorders consist mainly of a single

disorder of mood - either mania or severe depression. Mania is characterized by elation, hyperactivity, and uncontrollable thought and speech. An individual suffering from depression has feelings of intense sadness and self-disapproval, and physical and mental slowing.

An individual suffering from manic-depressive disorder exhibits alternating periods of mania and depression.

Neuroses

In contrast to the psychoses, individuals suffering from neuroses retain the ability to comprehend

reality. However, suffering and disability may be severe. The symptoms may involve mood changes such as anxiety, panic or restlessness, and a feeling of being ill at ease. Individuals may exhibit limited abnormalities of thought such as obsessions or irrational fears or of behaviour such as rituals or compulsions.

Antipsychotic Drugs

Approximately one in 100 people develop schizophrenia in their lifetime. Symptoms of

schizophrenia are classified as positive and negative. The positive symptoms include delusions and hallucinations, bizarre behaviour, lack of logic and incoherence while apathy, social

withdrawal and loss of motivation are among the symptoms referred to as negative symptoms.

The theory of schizophrenia – the dopamine hypothesis is the most fully developed theory of schizophrenia, but recent evidence indicates that other neurotransmitters such as serotonin,

gamma-aminobutyric acid, and glutamic acid may be involved in schizophrenia. The following

lines of circumstantial evidence suggest that excessive dopaminergic activity explains, at least in part, this disorder.

Two other transmitters have also been postulated to play a role in schizophrenia, serotonin and

glutamate. The newer atypical antipschotics such as clopzapine and quetiapine are 5-HT

antagonists and some glutamate agonists exacerbate the symptoms of schizophrenia.

1. Most of the “typical” antipsychotic drugs are potent blockers of postsynaptic dopamine receptors in the CNS. The binding affinity of antipsychotic drugs is highly correlated with their clinical antipsychotic potency.

2. Drugs that increase dopaminergic activity such as levodopa (a precursor of dopamine), amphetamines (releasers of dopamine), or apomorphine (a direct dopamine receptor

agonist) either aggravate schizophrenia or induce it in some individuals.

3. Dopamine receptor density has been found, in postmortem studies, to be increased in the brains of schizophrenics who had not been treated with antipsychotic drugs. It is of interest

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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that key studies of this type were carried out by pharmacologists at the University of

Toronto.

4. Using a technique known as positron emission tomography (PET), dopamine receptor density has been shown to be higher in schizophrenic than in non-schizophrenic persons.

Mechanism of Action of Antipsychotic Drugs

In the late 1950’s, the antipsychotic phenothiazines were introduced into therapy. In 1959, dopamine was recognized as a neurotransmitter in the CNS. In the 1960’s, it was shown that the effects of dopamine on electrical activity in synapses of the CNS and on production of the second messenger, cyclic AMP, could be blocked by the phenothiazine antipsychotic drugs. It was therefore concluded that the phenothiazine antipsychotics are antagonists at dopamine

receptors. Moreover, both the therapeutic and adverse effects of these drugs could be explained

by antagonism of dopamine receptors in different regions of the CNS, as outlined below.

Antipsychotic action can be explained by antagonism of dopamine receptors in the mesolimbic and mesofrontal systems of the brain (meso = middle). The limbic system controls emotion and

behaviour.

Extrapyramidal movement disorders: Antagonism of dopamine receptors in the nigrostriatal system. Parkinsonism-like symptoms are observed – tremor, rigidity of limbs, slowing of

movement, and a reduction in spontaneous activity. Also observed are dystonia (involuntary

muscle spasms) and akathesia (anxiety, restlessness and repetitive purposeless action). Tardive

dyskinesia is a serious movement disorder that can occur; it is characterized by involuntary

movements of the face, tongue, trunk and limbs and can be severely disabling.

Endocrine effects: Dopamine in the hypothalamus exerts a tonic inhibitory effect on prolactin release from the pituitary gland. By antagonizing dopamine receptors, excess prolactin will be

released (hyperprolactinemia). This will result in women in the flow of milk from the breast,

menstrual changes, and in men will cause sexual dysfunction.

Other Receptors Blocked by Phenothiazine Antipsychotics

Cholinergic (muscarinic) receptors: Therapeutic effects: Reduction of extrapyramidal adverse effects.

Adverse effects: Blurred vision, dry mouth, constipation, difficulty urinating.

Blockade of serotonin receptors: Therapeutic effects: Reduction of extrapyramidal adverse effects.

Reduction in the negative symptoms of psychosis.

Adverse effects: Unknown.

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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Blockade of histamine receptors: Adverse effects: Sedation, drowsiness, and weight gain.

Blockade of α-adrenoceptors: Adverse effects: Postural hypotension (hypotension when assuming an erect position),

dizziness, reflex tachycardia

Other Antipsychotic Drugs

Haloperidol has a chemical structure which is very different to that of chlorpromazine (a prototype phenothiazine) and other phenothiazines. Like chlorpromazine, it competitively

blocks dopamine receptors and has very similar pharmacological effects. Its sedative and

hypotensive action is less than that observed with chlorpromazine (and other phenothiazines),

but it has a high propensity for producing extrapyramidal movement disorders. It is considered a

useful alternative for patients who do not respond to or cannot tolerate phenothiazines.

Second-Generation Antipsychotics (Also called atypical antipsychotics)

Since 1990, a series of new antipsychotic agents have been introduced into therapy. While the

phenothiazines and haloperidol provided relief primarily for the positive symptoms of

schizophrenia, the second-generation of antipsychotic agents are claimed to relieve both positive

and negative symptoms, while at the same time having a lower propensity to produce

extrapyramidal side effects. It is thought that these second-generation antipsychotics have a dual

action by producing receptor blockade of dopamine and serotonin receptors. Some of these

second-generation agents are clozapine, risperidone and olanzapine.

Clozapine

Clozapine is a very useful addition to our therapeutic armamentarium of antipsychotic drugs

because it relieves both the positive and negative symptoms of schizophrenia. Since patients

have fewer extrapyramidal side effects when taking clozapine, compliance is better with

clozapine than with older antipsychotics. Clozapine can cause granulocytopenia (a decrease in

the number of white blood cells) in 1-2% of patients and this adverse effect can result in very

serious problems. For this reason, patients receiving this drug are required to have blood counts

at frequent intervals. Other atypical antipsychotics are resperidone and olanzapine.

Lithium Carbonate

Lithium carbonate is a mood-stabilizing agent which is used to prevent mood swings in patients

with manic-depressive disorder. It is also used to treat mania.

The mechanism of action of lithium has not been resolved. Three possibilities are under investigation:

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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1. Effect on electrolytes and ion transport. 2. Effects on neurotransmitters and the release of neurotransmitters. 3. Effect on second messengers that mediate transmitter action.

We shall consider only the third possibility for which the evidence appears to be the strongest.

Phosphatidylinositol-4,5-biphosphate (P1P2) is the cell membrane precursor of inositol-1,4,5-

triphosphate (IP3) and diacylglycerol (DAG). This enzymic reaction is catalyzed by the enzyme

phospholipase C (PLC). IP3 and DAG are important second messengers for alpha-adrenergic

(and muscarinic) transmission as shown in the diagram below. After P1P2 is converted to the

second messengers, IP3 + DAG, it must be reconstituted from IP3 via IP2, IP, and inositol (I).

Lithium blocks two steps in the reconstitution process, namely IP2 → IP, and IP1 → I, thus

leading to depletion of P1P2. The effects of the transmitter on the receptor (R) and consequently

on the cell will diminish. G denotes the G-protein involved in coupling the effects of drug

combination with the receptor to the enzyme PLC.

OUTSIDE CELL

PIP2

Inositol PLC G

INSIDE

CELL

Lithium DAG

IP1 IP3

IP2

Lithium

EFFECTS

Clinical Pharmacology of Lithium

Lithium is the drug of choice for long-term maintenance to prevent both manic and depressive

episodes in patients with manic-depressive disorder. A period of 2-4 weeks of lithium

administration may be required for lithium to have a full therapeutic effect; acutely manic

patients often require temporary treatment with an antipsychotic drug such as haloperidol or a

benzodiazepine such as lorazepam. During depressive episodes, an antidepressant is often

needed temporarily in addition to lithium, but it may precipitate mania.

Monitoring of Serum Concentration of Lithium

The safety and efficacy of lithium is enhanced by monitoring serum lithium concentration.

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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Measurements should be made approximately 12 hours after the last dose. For many individuals,

serum concentrations of 0.6 to 0.7 mEqu/L are effective and well tolerated.

Adverse Effects of Lithium

Nausea and fatigue may occur in the first weeks of treatment. Tremor, thirst, excessive

urination, edema and weight gain may persist for the duration of treatment. Confusion and loss

of muscle coordination may occur. Toxic kidney effects are observed in individuals treated

chronically with lithium but are uncommon. Mild hypothyroidism is fairly common. Can cause

acne and skin reactions. When taken during pregnancy, can, as a rare event, cause cardiac

malformations in the fetus.

For patients who cannot tolerate lithium, the anticonvulsants valproic acid, carbamazepine and

clonazepam have been found to be useful agents. These agents have a more rapid onset of action

than lithium and are often preferred. Patients suffering from bipolar disorder are often given an

antidepressant as well as the antipsychotics.

Antidepressant Agents

Depression affects five to six percent of the population at any given time. There are several

types of depression and depressions are classified as follows:

1. Reactive (secondary) depression. This is the most common type and accounts for over 60% of all depressions. It occurs in response to real stimuli such as grief and illness.

Reactive depression may resolve spontaneously or may respond to a variety of treatments.

2. Major depression (endogenous). In major depression there are characteristic disturbances of major body rhythms of sleep, hunger and appetite. A loss of pleasure and interest in

most usual activities is experienced. There is a decrease in sexual drive and mental slowing

and loss of concentration is experienced. According to current evidence it is a genetically

determined biochemical disorder which causes an inability to cope with ordinary stress.

Major depression accounts for approximately 25% of all depressions and tends to recur

throughout life. It usually responds to antidepressant therapy.

3. Depression associated with manic-depressive disorder. This type of depression accounts for approximately 10-15% of all depressions. Lithium is used to stabilize mood in this

disorder and depression is managed with antidepressants.

Theory of the Causes of Major Depression

The major theory which has been proposed to explain major depression is known as the amine hypothesis. This hypothesis arose in the following manner. It will be recalled from an earlier section on the History of Drug Use and Development that reserpine was introduced in the 1950’s

for the treatment of psychosis and hypertension. A serious adverse effect of reserpine was the

induction of depression. Animal studies showed that reserpine inhibited reuptake and storage of

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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serotonin and norepinephrine in the vesicles of presynaptic nerve endings. As a result, there was

a depletion of amine stores in these vesicles and amine-dependent neurotransmission would be

diminished. Since reserpine induced depression and depleted stores of amine neurotransmitters,

it was reasoned that depression might be associated with decreased functional amine dependent

neurotransmission.

Consistent with the amino hypothesis is the fact that all antidepressant drugs have their primary

actions on the storage, metabolism, or re-uptake of serotonin or norepinephrine (and in some

cases of dopamine).

The amine hypothesis does not explain all the effects of antidepressants in depression. The

neurotrophic hypothesis suggests that depression is associated with reduced neurotrophic

(growth and inter-connectivity of neurons) support and that antidepressants stimulate

neurogenesis and synaptic connectivity in cortical areas.

Types of Antidepressants

Tricyclic antidepressants: Imipramine is a member of this class of antidepressants which share a three-ring nucleus. Imipramine was introduced into therapeutics forty years ago.

Second-generation (atypical) antidepressants: Bupropion and amoxapine, introduced after 1980, are structurally unrelated to the tricyclic antidepressants and were introduced in an attempt

to have available antidepressants with less adverse effects.

Selective serotonin reuptake inhibitors (SSRI’s): This class of antidepressants was introduced from the late 1980’s to the mid-1990’s. The first of these agents, fluoxetine (Prozac), has

received a great deal of publicity. The tricyclic antidepressants have anticholinergic

(muscarinic), antiadrenergic (alpha), and antihistaminic actions which do not contribute to their

efficacy but do contribute to their toxicity. The SSRI’s, in contrast, have much less effect on the

autonomic nervous system and therefore have less toxicity.

Drugs that block Serotonin and norepinephrine uptake: Drugs such as venlafaxine block transporters for both serotonin and norepinephrine and have an advantage over the tricyclic

antidepressants due to their better safety profiles. (Less adverse effects).

Monoamine oxide (MAO) inhibitors: There are two monoamine oxidase (MAO) enzymes, designated MAO-A and MAO-B. MAO-A is the enzyme primarily responsible for metabolism

of norepinephrine, serotonin and tyramine. MAO-B is more selective for dopamine metabolism.

Selective blockade of MAO-A is therefore considered more selective for therapy of depression.

Phenelzine and tranylcypromine are non-selective inhibitors of MAO-A and MAO-B. They combine irreversibly with the enzymes and therefore have a prolonged duration of action. When

these inhibitors are used, the inhibition of the MAO enzymes persist even after the inhibitors are

no longer detectable in the serum. The inhibitory effect of tranylcypromine persists for seven

days after the drug is administered, while the inhibitory effect of phenelzine persists for two to

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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three weeks after the drug is administered. This persistence of inhibition has important

therapeutic consequences and must be borne in mind to avoid drug and/or food interactions.

In recent years, a selective MAO-A inhibitor has been introduced into therapy. Moclobemide is a new short-acting reversible inhibitor of MAO-A and 90% of the drug appears in urine within

12 hours of administration.

Action of Antidepressants on Biogenic Amine Neurotransmitters

The amine hypothesis of depression has been strengthened by studies on the mechanism of

action of the different types of antidepressant drugs. Thus, tricyclic antidepressants block the amine (norepinephrine and serotonin) presynaptic transporter proteins which are the “off

switches” of amine neurotransmission. Such an action permits a longer sojourn of the

neurotransmitters at the receptor sites and greater stimulation of the postsynaptic neuron.

The MAO inhibitors block a major degradative pathway for the amine neurotransmitters, thus permitting more amines to accumulate in presynaptic stores and more to be released when the

nerve impulse reaches the presynaptic neuron.

The SSRI’s are relatively selective for blockade of the serotonin transporter protein in the presynaptic terminal. Their effect on the norepinephrine transporter protein is less than that on

the serotonin transporter protein.

Thus, the bottom line is that antidepressant drugs appear to remedy a deficiency in amine neurotransmission through different mechanisms.

Choice of Antidepressants

In the past, a tricyclic antidepressant such as imipramine has been considered as the drug of first

choice for treatment of depression. In recent years, an SSRI such as fluoxetine (Prozac) is often

used instead, especially for patients with major depressive disorder anxiety disorder. MAO

inhibitors such as phenelzine are effective antidepressants that can be helpful (used with

appropriate precautions) for some patients who cannot tolerate or fail to respond to a tricyclic

antidepressant or a SSRI. TCAs and MAOi are considered second line drugs.

Adverse Effects

Tricyclic antidepressants: The most common adverse effects that limit therapeutic usefulness are anticholinergic effects (dry mouth, urinary retention, constipation, and blurred vision),

sedation, weight gain, sexual dysfunction, and hypotension with assuming an erect position

(orthostatic hypotension). A particularly serious adverse effect is the propensity of this class of

drugs to disturb the electrical rhythm of the heart. For a patient with a heart problem, it is

preferable to use a different class of antidepressant. Over-dosage can be lethal and severe

reactions are characterized by serious disturbances of the electrical rhythm of the heart,

hypotension, convulsions and coma.

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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SSRI’s: The SSRI’s cause nausea, headache, nervousness, and insomnia more commonly than the tricyclic antidepressants. There is a high incidence of sexual dysfunction with these drugs.

Generally, the SSRI’s do not cause weight gain, are less likely to cause anticholinergic effects or

orthostatic hypotension. An important advantage of the SSRI’s is that they are much safer than

the tricyclic antidepressants in over-dosage.

MAO inhibitors: If MAO inhibitors are prescribed, patients must be warned that they interact with dangerous consequences with many other drugs, both prescription and over-the-counter,

and with tyramine-containing foods. The use of a tricyclic antidepressant, SSRI or meperidine,

or dextromethorphan in a patient taking a MAO inhibitor could cause delirium, high fever,

convulsions, coma and death. One must wait for a considerable time for the effects of an MAO

inhibitor to wear off, usually several weeks, before relaxing caution.

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following drugs are correctly matched with an appropriate therapeutic use except:

(A) Haloperidol – schizophrenia.

(B) Chlorpromazine – schizophrenia.

(D) Fluoxetine - depression.

(E) Clozapine – depression.

2. Which of the following mechanisms lead to the therapeutic action of chlorpromazine in

schizophrenia?

(A) Blockade of dopamine receptors.

(B) Blockade of serotonin receptors.

(D) Blockade of acetylcholine receptors.

(E) Blockade of enkephalin receptors.

3. Which of the following mechanisms lead to the therapeutic action of the new

antidepressant, moclobemide?

(A) Blockade of monoamine oxidase A.

(B) Blockade of monoamine oxidase B.

(D) Blockade of monoamine oxidases A and B.

(E) Blockade of monoamine oxidases A and C.

Lesson B.6 CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS

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4. The antidepressant, phenelzine, has been administered to a patient daily for two weeks. For

how long would monoamine oxidase inhibition persist after cessation of drug

administration?

(A) 4 hours.

(B) 12 hours.

(D) 2 days.

(E) 2 weeks.

Lesson B.6
CLASSIFICATION OF MENTAL DISORDERS ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS
References
Objectives
Psychoses

Organic
Functional

Affective (Mood) Disorders
Neuroses
Antipsychotic Drugs
Mechanism of Action of Antipsychotic Drugs

Antipsychotic action
Extrapyramidal movement disorders
Endocrine effects

Other Receptors Blocked by Phenothiazine Antipsychotics

Cholinergic (muscarinic) receptors
Blockade of serotonin receptors
Blockade of histamine receptors
Blockade of α-adrenoceptors

Other Antipsychotic Drugs
Second-Generation Antipsychotics
Clozapine
Lithium Carbonate
Clinical Pharmacology of Lithium
Monitoring of Serum Concentration of Lithium
Adverse Effects of Lithium
Antidepressant Agents

Reactive (secondary) depression
Major depression (endogenous)
Depression associated with manic-depressive disorder

Theory of the Causes of Major Depression
Types of Antidepressants

Tricyclic antidepressants
Second-generation (atypical) antidepressants
Selective serotonin reuptake inhibitors (SSRI’s)
Drugs that block Serotonin and norepinephrine uptake
Monoamine oxide (MAO) inhibitors
Phenelzine and tranylcypromine

Action of Antidepressants on Biogenic Amine Neurotransmitters
Choice of Antidepressants
Adverse Effects

Tricyclic antidepressants
SSRI’s
MAO inhibitors

Questions

Lesson B7.pdf

Lesson B.7 Dr. W.J. Racz

STIMULANT DRUGS

Reference: A Primer of Drug Action, 12 th

Objectives

At the conclusion of this lesson, you should be able to: (1) describe the mechanism of action of

cocaine, the amphetamines and caffeine; (2) describe the response to various doses of cocaine,

amphetamines and caffeine; (3) describe the methods used to administer illicit cocaine and

amphetamines; (4) describe the dependence liability of cocaine, amphetamines and caffeine; and

(5) state the differences in response to cocaine and amphetamines.

Amphetamines

The amphetamines are a class of central nervous system (CNS) stimulant drugs that enhance the

activity of the brain. The amphetamines include dextroamphetamine, methamphetamine, and a

host of designer drugs such as methylenedioxyamphetamine (MDA). There are other drugs that

are CNS stimulants and function in an analogous manner to the amphetamines, e.g.

methylphenidate (Ritalin).

History

The following list of dates demonstrates that amphetamine was once considered a panacea for a

number of disorders (34 at one time), but is now a drug of widespread abuse.

1887 First synthesis of amphetamine.

1933 Discovery of CNS stimulant action of amphetamine.

1939-1945 Use of amphetamines during World War II as anti-fatigue agents.

1945 First marketing of amphetamine as an appetite suppressant in U.S.A. This led to

a large number of patients dependent on the drugs.

1945-1958 Epidemic of abuse of amphetamines in Japan that was eventually eliminated.

1960’s Outbreaks of abuse of amphetamines in Sweden, U.S.A. and Canada.

Amphetamine became a drug of “choice”.

1973 Classification of amphetamines as controlled drugs in Canada and restriction of

legal use to certain medical problems (epilepsy, narcolepsy – sudden

uncontrollable attacks of sleep, parkinsonism, mental retardation, hyperkinetic

Lesson B.7 STIMULANT DRUGS

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disorders and hypotension during anesthesia). The reader will note that suppression of

appetite is not allowed.

Chemistry

The amphetamines are synthetic organic compounds that are structurally similar to

norepinephrine, epinephrine and dopamine found in the body. Three common amphetamine

compounds are amphetamine, dextroamphetamine, and methamphetamine.

The amphetamines can be synthesized readily, and this has resulted in the illicit manufacturing

of these substances, especially methamphetamine, in underground laboratories. However, the

purity of illicit methamphetamine (Meth, Crystal, Speed) is variable, and may contain side-

products of the chemical reaction, unreacted chemicals and “cutting” agents (e.g. starch, baking

soda).

Pharmacology

The amphetamines stimulate both the CNS and the sympathetic nervous system (e.g. increased

blood pressure, dilation of pupils). Methamphetamine seems to produce more central stimulation

and less sympathetic stimulation compared to amphetamine. In the CNS, the amphetamines

act primarily by releasing the neurotransmitters, norepinephrine and dopamine, from

nerve terminals. The neurotransmitters then act on postsynaptic receptors giving a response.

The effects produced by amphetamines depend on the drug dose and the route of administration.

The dopamine released is responsible for the “reward” or pleasurable responses produced by

amphetamine.

CVS (Cardiovascular System) effects of amphetamine are due to drug-induced displacement

of norepinephrine from adrenergic nerve terminals, which then acts on postsynaptic α

(vasculature) and β1 (heart) receptors. The effects include:

1. Fight-flight response.

2. Increased blood pressure.

3. Increased heart rate.

CNS effects of amphetamine are mediated by the actions of catecholamines in the CNS,

whereby amphetamine primarily increases release (by displacement) and also inhibits active

reuptake of dopamine and norepinephrine in several brain regions. Dopamine appears to be

involved primarily in many of the CNS effects. The CNS stimulation is dose-dependent, with

low doses primarily affecting the cerebral cortex and high doses affecting the entire

cerebrospinal axis, and can manifest as:

1. Behavioural and psychomotor stimulation (alertness, hyperactivity, insomnia).

2. Anorexia (reduction in appetite).

Lesson B.7 STIMULANT DRUGS

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3. Hyperthermia (increase in body temperature).

4. Respiratory centre stimulation.

5. Neurotransmission in spinal cord.

6. Convulsions, with high doses.

The amphetamines act on the following brain areas:

1. Reticular activating system (RAS). The amphetamines decrease the threshold for

transmitting sensory (peripheral) input to the cerebral cortex.

2. The medial forebrain bundle (MFB) is stimulated. This area is involved in mediating

reward.

3. Hypothalamus. The temperature-regulating and feeding centres are modified.

4. Limbic system. This system is involved in emotion. Amphetamine may lead to aggressive

behaviour and mood swings.

The common amphetamines vary in the magnitude of their CNS effects.

Dextroamphetamine > amphetamine.

Methamphetamine > dextroamphetamine

Therapeutic uses of amphetamine-like drugs:

1. Narcolepsy. Both amphetamine and methylphenidate are effective; however,

methylphenidate is the drug of choice because of the reported lower incidence of

cardiovascular effects. No tolerance develops to the therapeutic effect during chronic use.

2. Attention-deficit hyperactivity disorder (hyperactive child syndrome). This disorder,

usually first evident in childhood, consists of disruptive behaviour, decreased

attention/concentration spans and poor scholastic achievement. Both D-amphetamine and

methylphenidate have been used to treat this disorder. However, methylphenidate is the

drug of choice because of the lower incidence of cardiovascular and anorectic effects.

Drug therapy increases classroom attention/concentration and can improve scholastic

performance. During chronic therapy, no tolerance develops to the therapeutic effect. It

must be emphasized, however, that the treatment approach should consist of

behavioural therapy, special educational curriculum and family counseling in

combination with drug therapy.

3. Parkinson’s disease. Some Parkinsonian patients benefit from amphetamines. This may be

related to the enhanced dopamine levels in the brain.

Lesson B.7 STIMULANT DRUGS

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Amphetamine Abuse

The amphetamines produce euphoria and are effective CNS stimulants; for these reasons, they

are widely abused. The source of street amphetamines is usually illicit laboratories. Street

names for amphetamines are: Bennies, black beauties, copilots, eye-openers, uppers, etc.

Dextroamphetamine is called dexies and methamphetamine is referred to as speed, crystal meth

or crack. A smokeable form of methamphetamine is called, ice, Hawaiian salt or rock candy.

Most common amphetamines are taken orally, injected or smoked. Occasionally it is sniffed or

snorted.

Effects of Short-Term Use – Low Dose

CNS: overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria (fearful reactions),

mild confusion, tremor, and in rare instances, panic and psychosis; reduced appetite, increased

talkativeness, alertness and energy, reduction of fatigue and drowsiness, general increase in

activity, and a feeling of well-being, enhanced performance.

Cardiovascular: irregular heartbeat, headache, increased blood pressure.

Respiratory: increased respiratory rate.

Other: increase or decrease in libido, possible temporary impotence.

Effects of Short-Term Use – Higher Doses

Increase in the exhilaration and euphoria. Ideas flow rapidly, feeling of increased strength. The

individual becomes talkative and may demonstrate excitation, agitation and irritability.

Stimulant psychosis may occur, which consists of paranoid thinking, confusion, and distortion of

events with hallucinations. The amphetamine rush might be accompanied with violent

behaviour. The user may suffer a seizure, high fever and stroke.

Cardiovascular: The user may suffer a heart attack, angina pain, dysrhythmias (irregular heart

rhythm), changes in blood pressure and fainting. Finally cardiovascular collapse can occur.

Effects of Long-Term Use

Long-term use leads to chronic sleeping problem (insomnia, awakening at night, and poor

quality sleep). The subject is anxious and tense. They have a poor appetite. The blood pressure

may be elevated and the cardiac rhythm abnormal. They are suspicious and paranoid and exhibit

repetitive behaviour.

In addition, a number of health risks are associated with contaminated needles, poor nutrition and

the lifestyle of the addict (AIDS, hepatitis, collapsed vessels, etc.).

The Amphetamine Run

Lesson B.7 STIMULANT DRUGS

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In an attempt to maintain the initial effects of exhilaration and enhanced awareness and self

confidence induced by the drugs, abusers will repeatedly administer the drug to maintain the rush

or high. This may continue for several days. The terms “speeders” or “speed freaks” have been

used to refer to these abusers. The run stops when the drug supply or the abuser is exhausted.

Tolerance

Tolerance develops to some, but not all of the effects of the amphetamines. Tolerance develops

rapidly to the euphoria and mood elevating effects. Tolerance also occurs to the anorectic effects

of the drug, but not the drug-induced psychosis. Tolerance also develops to the lethal effects of

the drugs. Tolerance has also been reported to the cardiovascular and respiratory stimulatory

effects of the amphetamines.

Physical Dependence

Cessation of administration of the amphetamines results in mood depression that may be

profound, prolonged sleep, huge appetite, lassitude and fatigue. The mood depression may be

long-lasting and could be the main symptom of the withdrawal syndrome and hence, physical

dependence on the amphetamines.

Psychological (Psychic) Dependence

Amphetamines usually are self-administered to produce pleasurable effects, including euphoria

and an abrupt awakening sensation (“rush”). These effects act as rewards and users will crave

the drug’s effects so intensely that if it is not available they will experience panic.

Other drugs may be sought concurrently with the amphetamines (e.g. benzodiazepines,

barbiturates, opioids) in an attempt to antagonize various toxic effects of the amphetamines.

Potential for Abuse

The abuse liability of the amphetamines is considered to be extremely high. Both amphetamine

and methamphetamine produce powerful euphoria. These drugs are water soluble in their salt

forms and large doses can be readily injected.

Inherent harmfulness of the amphetamine reside in the long-term toxicities (cardiovascular

effects and drug-induced psychoses). In addition, there is a substantial health risk with the user

life style, i.e. contaminated needles and poor nutrition. The inherent harmfulness of the drug

does not appear to be a deterrent to abusers.

Cocaine

Cocaine is a naturally-occurring alkaloid found in the leaves of the cocoa bush that is indigenous

to Bolivia, Columbia and Peru. The local people in these areas have chewed cocoa leaves for

centuries. Cocaine is classified pharmacologically as a local anesthetic and as a CNS stimulant.

In terms of law, cocaine is classified as a narcotic according to the Narcotic Control Act of

Lesson B.7 STIMULANT DRUGS

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Canada.

History

1884 Sigmund Freud studied the CNS effects of cocaine and used it clinically to withdraw a

colleague from morphine, which then led to dependence on cocaine. Freud then spoke

out against cocaine, calling it the “third scourge” of humanity.

1884 Karl Koller introduced cocaine into medicine as a local anesthetic.

1970’s Dramatic increase in non-medical use of cocaine in North America.

to Cocaine replaced amphetamines as a major stimulant drug, subject to abuse.

1990s’s

Currently cocaine is one of the most popular recreational drugs, next to alcohol,

nicotine, caffeine and marijuana.

Pharmacology

CNS effects are due to generalized CNS stimulation produced by cocaine and are dose-

dependent. In general, the behavioural effects of cocaine are very similar to those produced by

the amphetamines. However, the duration of these effects is relatively brief, usually less than an

hour, compared with the duration of amphetamine-induced effects.

Cocaine inhibits the active re-uptake of released dopamine and norepinephrine into the

presynaptic nerve terminal. This increases the concentration of these transmitters in the synaptic

cleft and in turn an increase in the activation of the postsynaptic receptors. In the CNS, the

stimulatory effect appears to be mediated mainly via dopamine and in the periphery, changes in

blood pressure which is mediated by norepinephrine.

The local anesthetic effect of cocaine is due to its blockade of nerve impulse in sensory nerve

fibres. Note that cocaine can interfere with the function of all organs in which conduction or

transmission of impulses occurs (e.g. heart). The probability of such action is proportional to the

cocaine concentration in the systemic circulation.

Cocaine is almost indistinguishable from amphetamine in its acute effects and its pattern of

toxicity. The main differences are:

∙ Shorter duration of action for cocaine.

∙ Lower incidence of complications associated with intravenous use as cocaine is usually

sniffed or smoked.

∙ Tolerance does not develop as readily to the hallucinatory and behavioural effects of

cocaine as compared to the amphetamines.

Therapeutic Uses of Cocaine

The only legitimate use of cocaine is as a local anesthetic for the mouth and throat. It is rarely

Lesson B.7 STIMULANT DRUGS

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used. Also used in the eye.

Metabolism

Cocaine is metabolized to an inactive metabolite benzoylecgonine which is excreted in the urine.

This metabolite can be detected up to 48 hours after a single dose and up to two weeks in a

chronic user.

Cocaine Abuse

Cocaine is a very powerful CNS stimulant that increases alertness, reduces the need for sleep,

and produces an intense feeling of euphoria. The drug is widely abused. Street names for

cocaine hydrochloride (salt) are: C., coke, flake, snow and stardust. The names for the freebase

of cocaine are: crack, rock and freebase. Cocaine is also used in combination with other drugs,

e.g. heroin. Cocaine hydrochloride is usually “snorted” into the nose. It can also be injected.

The freebase of cocaine is not water-soluble, but is volatile when heated and is usually smoked

or inhaled.

Effects of Short-Term – Low Doses

CNS: dilation of the pupils; exaggerated reflexes; euphoria and a sense of well-being;

postponement of physical and mental fatigue; reduced appetite and need for sleep; increased

talkativeness or quiet contemplation; increased self-confidence and feelings of superiority;

increased speed of performance on fairly simple physical and intellectual tasks. The euphoric

phase may be followed by a period of dysphoria characterized by agitation and anxiety.

Cardiovascular: vasoconstriction, increase in heart rate after initial slowing, and increased

blood pressure.

Respiratory: increased respiratory rate.

Effects of Short-Term – Higher Doses

Intensification of cocaine’s low-dose effects may occur at higher doses, in addition to the

following.

Behavioural: intense euphoria followed by a state of severe agitation. Users may

experience anxiety, rapid flight of ideas, feelings of grandiosity, paranoid thinking, and

often bouts of repeated, seemingly meaningless behaviour (stereotypy). With repeated use,

the cocaine user may suffer from a paranoid psychosis.

Neurological: tremor and muscle twitches, seizures, headache, hemorrhagic stroke and

cerebral infarction.

Cardiovascular: high blood pressure, headache, pallor, rapid weak pulse and heart attack.

Lesson B.7 STIMULANT DRUGS

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Gastrointestinal: nausea and vomiting.

Respiratory: Hazerdous dose levels may cause rapid, irregular and shallow breathing;

pulmonary edema (fluid accumulation in the lungs) and other lung damage including

hemorrhage (coughing up blood), lung tissue diseases and hypersensitivity lung reactions.

Lung trauma may also result from the high pressures sometimes used to force cocaine into

the lungs rapidly or from the cocaine-anesthetized airways allowing inhalation of foreign

objects and very hot vapours.

Renal: acute renal failure, secondary to the deterioration of muscle tissue.

Other: elevated body temperature and cold sweat.

Effects of Long-Term Use

The heavy user is nervous, agitated and excitable with mood swings. Users often experience a

toxic psychosis including paranoia. They often experience hallucinations or sensations of insects

crawling under the skin. Sleep disorders are common as are eating disorders. Sexual function is

impaired. There may be permanent damage to the brain and impairment of neuronal function.

They may exhibit high blood pressure and an irregular heart rhythm. As the drug is “snorted”

changes occur to the nasal mucosa. The cocaine user also experiences social problems. They are

obsessed with obtaining the drug and abandon their friends and family. The drug-induced

irritability also contributes to the social problems.

The Cocaine Binge

Heavy cocaine users may take the drug repeatedly over several hours to days. The attempt is to

maintain the euphoric experience. The binge is followed by a crash, manifested as depression,

lethargy and hunger.

Cocaine Dependence

Tolerance develops to some, but not all, of the effects of cocaine. Tolerance to the mood-

elevating effect of cocaine occurs, but tolerance does not develop to the drug-induced psychotic

effect.

Physical dependence on cocaine has been demonstrated by the appearance of a withdrawal

syndrome following the cessation of drug use. The withdrawal symptoms are very similar to

those associated with physical dependence on the amphetamines.

Psychological dependence on cocaine can occur. The pharmacodynamic characteristics of

smoking “crack” (rapid onset and short duration of behavioural effects) are almost “ideal” for the

development of compulsive drug use. The behavioural effects of cocaine usually are perceived

as pleasurable and rewarding, and reinforce repeated drug use. Other types of psychoactive

drugs often are used concurrently with cocaine (e.g. opioids, ethanol, sedative-hypnotic drugs).

Lesson B.7 STIMULANT DRUGS

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Potential for Abuse

The abuse liability of cocaine is one of the highest among all drugs of abuse. This is due to the

powerful euphoria, which can be reached rapidly by injecting the drug or smoking the freebase.

The inherent harmfulness of the drug is also among the highest among drugs of abuse. Users

will experience physical and psychological deficits. These include respiratory arrest, psychosis

and seizures. In addition, cardiovascular damage can result. These events do not appear to deter

the abuser.

Caffeine

Caffeine is the most widely and regularly used drug in the world. It is found in significant

concentrations in tea, coffee, chocolate and cola drinks. Caffeine affects the CNS and the

cardiovascular system.

Pharmacology

The CNS effects of caffeine involve several areas of the brain. In the cerebral cortex, caffeine

increases mental performance and decreases drowsiness and fatigue. It also enhances motor

activity. These effects are observed with 100 to 250 mg of caffeine (one to two cups of strong

coffee). In the medulla, the respiratory and vasomotor centres are stimulated, leading to

increased respiration and heart rate.

In the cardiovascular system (CVS), low doses may lead to an increase in heart rate and blood

pressure. High doses may lead to a disturbance in the normal rhythm of the heart.

The actions of caffeine are exerted by competitively blocking adenosine receptors in the brain.

Adenosine exerts an inhibitory effect on a number of neurons and transmitter systems. When

caffeine blocks these adenosine receptors, the neurons are released from the adenosine inhibition

and the neuronal activity is increased (stimulation).

Effects of Short-Term Use – Low Dose

CNS: Caffeine can produce mild mood elevation and reduce fatigue. There probably is a small

increase in performance, but this has not been conclusively demonstrated. Flow of thought may

be clearer and more rapid. When taken by abstainers, caffeine, produces nervousness and the

jitters. It can also interfere with sleep.

Cardiovascular: Caffeine produces constriction of cerebral blood vessels (useful in a

headache), peripheral blood flow is increased and cardiac muscle is stimulated.

Respiration: There is mild stimulation of the respiratory rate and a relaxation of bronchial

smooth muscle.

Lesson B.7 STIMULANT DRUGS

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Effects of Short-Term Use – High Dose

CNS: irritability, restlessness, nervousness, insomnia, rambling flow of thoughts and

speech, and psychomotor agitation (agitated movement of voluntary muscles).

Cardiovascular: rapid and irregular heartbeat.

Other: increased capacity for muscular work.

Effect of Long-Term Use

Excess use of caffeine over a long period will lead to restlessness, nervousness, insomnia,

increased urinary output, gastric upset, and rambling speech and thought. There is no definite

link between caffeine consumption and disease states, although not all experts agree on this

view.

Tolerance and Dependence

There is some evidence that tolerance does develop to caffeine, at least in some individuals. The

same “pick me up” can occur with a cup of decaffeinated coffee as regular coffee suggesting that

the act of drinking coffee is very important.

Dependence on caffeine does develop. Abrupt cessation of caffeine intake will result in

headache, fatigue and drowsiness. These symptoms can be alleviated with caffeine, the

headache is amenable to treatment with analgesic, e.g. acetaminophen. Psychological

dependence does occur.

Potential for Abuse

The abuse liability of caffeine is low. Caffeine does act as a reinforcer, but the activity is low.

The “high” experienced is mild in intensity and thus the abuse liability is low.

The inherent harmfulness of caffeine is very low. Low to moderate intake of caffeine (three cups

of coffee) each day does not appear to be associated with adverse events. Larger doses will

result in irritability, nervousness, insomnia, and irregular rhythm of the heart.

Lesson B.7 STIMULANT DRUGS

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Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following statements are correct except:

(A) Amphetamines are synthetic compounds.

(B) Cocaine is extracted from the leaves of the cocoa plant.

(D) Abuse of amphetamines and cocaine often results in a life style change for the user.

(E) The amphetamines stimulate both the central and the sympathetic nervous system.

2. All of the following are responses observed with the administration of amphetamines

except:

(A) Increased state of alertness.

(B) Hypothermia.

(D) Increased respiration.

(E) Increased activity and enhanced performance.

3. Which of the following statements is incorrect?

(A) Cocaine is classified as a narcotic, by the Narcotic Control Act.

(B) Cocaine is obtained from the leaves of the cocoa plant which is indigenous to Africa.

(D) Cocaine has local anesthetic properties.

(E) Cocaine and amphetamine produce similar effects.

4. Which of the following pairs is correctly matched?

(A) Methamphetamine – releases transmitters from nerve ending.

(B) Caffeine – inhibits uptake of dopamine.

(D) Methylphenidate – used to prevent seizures.

(E) Amphetamine – widely prescribed for appetite control.

Lesson B.7
STIMULANT DRUGS
Reference
Objectives
Amphetamines

History
Chemistry
Pharmacology
Amphetamine Abuse
Effects of Short-Term Use – Low Dose
Effects of Short-Term Use – Higher Doses
Effects of Long-Term Use
The Amphetamine Run
Tolerance
Physical Dependence
Psychological (Psychic) Dependence
Potential for Abuse

Cocaine

History
Pharmacology
Therapeutic Uses of Cocaine
Metabolism
Cocaine Abuse
Effects of Short-Term – Low Doses
Effects of Short-Term – Higher Doses
Effects of Long-Term Use
The Cocaine Binge
Cocaine Dependence
Potential for Abuse

Caffeine

Pharmacology
Effects of Short-Term Use – Low Dose
Effects of Short-Term Use – High Dose
Effect of Long-Term Use
Tolerance and Dependence
Potential for Abuse

Questions

Lesson B5.pdf

Lesson B.5 Dr. G.S. Marks

CLASSIFICATION OF THE MAJOR PSYCHOACTIVE DRUGS

Reference: A Primer of Drug Action, 12 th

ed.

Objectives

At the conclusion of this lesson, you should be able to: (1) describe the mechanism of action of

the psychomotor stimulants, cocaine, amphetamine, caffeine and nicotine; (2) list the six

categories of CNS depressant drugs; (3) describe how increasing doses of CNS depressant drugs

effect an individual; and (4) explain the terms “cross tolerance” and “cross dependence”.

Definition

Psychoactive drugs are agents that can act on the central nervous system and alter sensation,

perception, mood, behaviour or consciousness.

Possible Classification of Psychoactive Drugs

1. Mechanism of action: At the present time there is insufficient information available to

make a classification on this basis, but as research progresses such a classification may

become possible.

2. Chemical structure: Classification based on chemical structure does not work since some

drugs with similar chemical structures have different pharmacological activities, while

other drugs with dissimilar structures have closely similar pharmacological activities.

3. Major behavioural effect or major clinical or non-medical use: Classification of agents

based on either of these is the most practical method.

Psychoactive drugs do not create new behavioural or physiological responses, but act by

modifying ongoing physiological and biochemical responses. This appreciation of the

limitations of psychoactive drugs has been appropriately summarised as described below by the

well known author, Koestler, in 1967.

“. . . It is fundamentally wrong, and naive, to expect that drugs can present the mind

with gratis gifts – put into it something which is not already there. Neither mystic

insights, nor philosophic wisdom, nor creative power can be provided by the pill or

injection. The psychopharmacologist cannot add to the faculties of the brain – but he

can, at best, eliminate obstructions and blockages which impede their proper use. He

cannot aggrandise us – but he can, within limits, normalize us: he cannot put

additional circuits into the brain, but he can, again within limits, improve the

coordination between existing ones, alternate conflicts, prevent blowing of the fuses,

and ensure a steady power supply. That is all the help we can ask for -- but if we were

Lesson B.5 CLASSIFICATION OF THE MAJOR PSYCHOACTIVE DRUGS

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able to obtain it, the benefits to mankind would be incalculable . . .”

According to current views the behavioural effects of psychoactive drugs are secondary to their

effects on physiological and biochemical processes, particularly those processes involved in

synaptic transmission in the brain.

Psychoactive drugs can either stimulate or depress the central nervous system.

The following are examples of drugs that are psychomotor stimulants and their mechanism of

action which involve actions on neurotransmission.

(a) Cocaine: Acts by blocking dopamine reuptake into presynaptic nerve terminals.

(b) Amphetamine and derivatives: Act by releasing dopamine from presynaptic nerve

terminals.

located on cell membranes in the central and peripheral nervous system. Its action as a

psychostimulant results from antagonism of adenosine-induced neuronal inhibition.

(d) Nicotine: Stimulates a selective subgroup of acetylcholine receptors in the central nervous

system known as nicotinic receptors.

The following are examples of general CNS depressants. There are at least six categories,

namely, barbiturates, non-barbiturate hypnotics, general anesthetics, ethyl alcohol,

benzodiazepines, and inhalants of abuse. The effects of CNS depressants are dependent on

dose. A small dose of barbiturate will cause relief of anxiety. As the dose increases, depression

of inhibitory neuronal pathways will result in disinhibition. Further increases in dosage will

result in sedation followed by hypnosis (sleep). A further increase in dosage will result in

general anesthesia, followed by coma, and if the dosage is large enough, to death. Thus,

barbiturates, commonly prescribed as hypnotics (sleeping tablets) before the advent of the

benzodiazepines, were commonly used in suicide attempts. CNS depressants are marketed by

the pharmaceutical industry as sedatives, anti-anxiety (Anxiolytic) agents, hypnotics, minor

tranquillizers, and major tranquillizers. It should be appreciated that the medical use of a CNS

depressant drug is usually a function of dose and that the above terms are convenient means for

marketing of drugs. Thus, a drug marketed as an anti-anxiety agent will in higher doses induce

hypnosis, and in still higher doses will induce further degrees of CNS depression. One of the

reasons that the barbiturates, once widely used as sedative-hypnotics, have been replaced in large

part by the benzodiazepines is that barbiturates have a lower therapeutic index than the

benzodiazepines.

An interesting exercise for you is to read the following section from Romeo and Juliet, Act IV,

Scene I, and try to deduce which drug available at the present time might be appropriate for the

purpose. You might also consider what the elimination half-time (t1/2) of the drug should be.

Remember that a drug would be eliminated completely after a period of 5 × t1/2.

Lesson B.5 CLASSIFICATION OF THE MAJOR PSYCHOACTIVE DRUGS

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Friar Lawrence to Juliet:

“. . . Take thou this vial, being then in bed,

And this distilled liquor drink thou off:

When presently, through all thy veins shall run

A cold and drowsy humour; for no pulse

Shall keep his native progress, but surcease:

No warmth, no breath, shall testify thy liv’st;

The roses in the lips and cheeks shall fade

To paly ashes; thy eyes’ windows fall,

Like death, when he shuts up the day of life;

Each part depriv’d of supple government,

Shall, stiff and stark and cold appear like death:

And in this borrow’d likeness of shrunk death

Thou shalt continue two-and forty-hours

And then awake as from a pleasant sleep . . .”

Four Principles of CNS Depressant Use

1. The effect of CNS depressants are additive, and sometimes supra-additive, with one

another. A particular hazard is that which occurs when an individual has ingested a CNS

depressant such as a benzodiazepine, an antihistamine, or a narcotic analgesic and then

attends a cocktail party and has several alcoholic drinks. Not surprisingly, the additive

effect can cause the individual to have severe CNS depression. The combined CNS

depressant effect can be even more severe in an individual who is physically tired or

depressed.

2. Use of a behavioural stimulant such as caffeine in a patient severely depressed by a CNS

depressant drug may, through non-specific antagonism, cause a temporary arousal of the

depressed individual. However, when the stimulant effect of the caffeine terminates the

individual may be left in an even more depressed state.

3. An individual consuming large doses of a CNS depressant for a prolonged period will

usually become physiologically dependent (addiction) upon the drug. When physical

dependence to the drug occurs, rebound excitability is observed upon withdrawal from the

drug.

4. The use of any CNS depressant drug is associated with the risk of inducing psychological

dependence and tolerance. Cross tolerance may be observed. In cross tolerance,

individuals tolerant to one CNS depressant drug may show a diminished response to a

second CNS depressant drug. In cross dependence, one drug (e.g. a benzodiazepine) may

ameliorate the symptoms which develop upon withdrawal from a second drug (e.g. ethanol)

in a physiologically-dependent individual.

Lesson B.5 CLASSIFICATION OF THE MAJOR PSYCHOACTIVE DRUGS

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Classification of Drugs that Alter Mood or Behaviour or that are Used to Treat CNS Disorders

1. CNS depressants (e.g. barbiturates, ethyl alcohol).

2. CNS stimulants (e.g. cocaine and amphetamine).

3. Antidepressants (e.g. tricyclic antidepressants) and mood stabilizers (e.g. lithium).

4. Antipsychotic drugs (e.g. phenothiazines, atypical antipsychotics.)

5. Narcotic analgesics (e.g. morphine).

6. Psychedelics and hallucinogens (e.g. lysergic acid diethylamide, LSD).

7. Cannabis.

8. Neurological drugs (e.g. antiepileptic drugs such as phenytoin).

Medical and Non-Medical Use

Some drugs have medical uses and are used to treat individuals who are sick (medical use).

Some drugs are used to alter the mental state of a normal person (non-medical use).

Immediate and Slowly Evolving Pharmacological Effects

Some drug effects can be immediate, e.g. amphetamines which can rapidly alter behaviour.

Some drug effects can evolve slowly, e.g. antidepressant action can take weeks to develop fully.

Lesson B.5 CLASSIFICATION OF THE MAJOR PSYCHOACTIVE DRUGS

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Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following drugs are correctly matched with their mechanism of action except:

(A) Cocaine – blocks dopamine reuptake.

(B) Amphetamine – releases dopamine.

(D) Nicotine – blocks epinephrine receptors.

2. All of the following drugs are correctly matched with an appropriate therapeutic use except:

(A) Phenytoin – epilepsy.

(B) Phenothiazines – psychosis.

(D) Tricyclics – depression.

(E) Lithium – hypnotic-sedative.

3. The half-life of an appropriate modern drug or an herbal preparation prescribed by Friar

Lawrence for Juliet would have been:

(A) 10 minutes.

(B) 1.5 hours.

(D) 8.4 hours.

(E) 10.4 days.

Lesson B.5
CLASSIFICATION OF THE MAJOR PSYCHOACTIVE DRUGS
Reference
Objectives
Definition
Possible Classification of Psychoactive Drugs

Mechanism of action
Chemical structure
Major behavioural effect or major clinical or non-medical use
psychomotor stimulants
general CNS depressants

Four Principles of CNS Depressant Use
Classification of Drugs that Alter Mood or Behaviour or that are Used to Treat CNS Disorders
Medical and Non-Medical Use
Immediate and Slowly Evolving Pharmacological Effects
Questions

Lesson B4.pdf

Lesson B.4 Dr. W.J. Racz

NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

Reference: A Primer of Drug Action, 12 th

ed.

Objectives

At the conclusion of this lesson, you should be able to: (1) define the terms opioid “endorphins”

and “opiate”, (2) state the role of opioid receptors in mediating opioid-induced analgesia, (3) list

the classification of the opiates and give an example of each class, (4) state the therapeutic uses

for opioid drugs, (5) state the pharmacological effects of the opioids, (6) describe dependence to

morphine and heroin, (7) describe opioid abuse, and (8) state the accepted treatment for opioid

abuse.

Introduction

Opium, the crude resinous exudate of the cut capsule of the opium poppy, Papaver somniferum,

was used for thousands of years (3000 B.C. to 1800 A.D.) for social and medicinal purposes to

produce euphoria, analgesia, sleep, and relief from diarrhea. Opium contains at least 20 different

chemical compounds, two of which, morphine and codeine, are analgesic (pain-relieving)

drugs. Morphine and codeine comprise about 10% and 0.5%, respectively, of the crude exudate.

In the early 1800’s, morphine was isolated as the major analgesic agent from opium. The

purification of morphine revolutionized the use of opiates. Since then, morphine has been used

worldwide for the treatment of pain and diarrhea.

Terminology

The term “opioid” refers to any natural or synthetic substance which exerts actions on the body

that are similar to those induced by morphine and that are antagonized (blocked) by the drug

naloxone.

Opioids include:

1. Opiate narcotics (analgesic agents obtained from the opium poppy).

2. Substances structurally related to morphine.

3. Synthetic drugs with structures different from that of morphine.

4. Endogenous brain peptides that exert analgesic actions (opioid peptides: enkephalins and

endorphins).

Concept of Opioid Receptors

In the 1970’s, specific receptor sites for opioid molecules were found in the brains of

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

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experimental animals and humans. The questions were: Why did these receptors exist and was

there an endogenous substance that interacted with these receptors? In 1975, endogenous

substances were isolated that interacted with these receptors. These substances, which were

peptides, are known collectively as endorphins. There are now at least three known families of

endorphins; these are: enkephalins, dynorphins and β-endorphins. The endorphins are able to

act as neurotransmitters and neuromodulators. They affect the perception of pain and emotional

response to pain. They may influence mood and are associated with the reward pathways in the

brain.

There are several types of opioid receptors; three will be discussed briefly.

Mu (µ) receptors are present in all structures in the brain and spinal cord. They mediate

analgesia. They also mediate morphine mediated depression of respiration in the brain stem.

Thus, analgesia and depression of respiration are linked. If they are mediated by the same

receptor subtype, it is difficult to obtain drugs where there is separation in the two responses.

These receptors are also involved in the compulsive abuse behaviour demonstrated by opiate

users.

Kappa (k) receptors are involved in analgesia, dysphoria and miosis (pin-point pupils). The

mixed agonist/antagonists, e.g. pentazocine, act predominantly on these receptors. The

endogenous ligand are the dynorphins, although the endorphins have some activity at these

receptors.

Delta (δ) receptors have as their endogenous ligand, the enkephalins. These receptors are

involved in analgesia at the level of the spinal cord and brain. They may also modulate the

emotional response to opioids.

Opioid receptors are located in the peripheral as well as the central nervous system. These are

located in the gastrointestinal tract and are responsible for the constipation caused by opiates.

Classification of Opiates/Opioids

Agonists: Illicit a full response.

Natural – morphine and codeine

Semi-synthetic – heroin

Synthetic – meperidine and methadone

Mixed Agonists/Antagonists: Pentazocine is the best example of this group. This group can

illicit a response when given alone, but can block part of the

response to morphine, when given together with morphine.

Antagonists: These agents block the response to morphine, heroin and other

opiates at the respective receptor. Administration of an

antagonist to an addict will precipitate “withdrawal”. The

prototype antagonist is naloxone. It has no analgesic activity

and is used in:

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

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(a) Reversal of opioids overdose.

(b) Treatment of opioid dependence.

(d) Naltrexone – an opioid antagonist is used to treat alcohol dependence.

Therapeutic Uses of Opioid Drugs

The therapeutic uses listed below apply to morphine and most of the other opiates:

 Relief of severe pain (e.g. post-surgical pain and pain experienced by some terminally ill patients). Analgesia is the major use for the opiates.

 Treatment of diarrhea. Opioid receptors in the neural plexus of the gastrointestinal tract mediate opiate-induced inhibition of gastrointestinal motility. Thus, opiates are used to

treat diarrhea, but constipation is a problem when the drugs are used as analgesics.

Diphenoxylate (Lomotil) is an opiate which is not an analgesic, does not produce

dependence, but is useful in controlling diarrhea. It is sold as an over-the-counter drug.

Pharmacological Effects of Opioid Agonists

1. Analgesia. Morphine is the most effective analgesic available. There is no ceiling to the

intensity of pain which can be relieved. Respiratory depression is the limiting factor.

2. Euphoria (feeling of wellbeing, energetic). In some individuals, dysphoria (fear, anxiety,

lethargy, apathy) may occur.

3. Sedation. All opiates/opioids produce sedation, at least those that are analgesics.

4. Hypnosis/sleep (narcotic effect). Morphine produces sedation and hypnosis, but not as

intense as that produced by the CNS depressants. The patient is usually arousable. There is

reduced mentation and lack of concentration and apathy.

5. Relief or prevention of cough.

6. Respiratory depression (basis of toxicity) → respiratory arrest.

7. Decreased gastrointestinal motility (constipation).

8. Constriction of the pupils of the eyes (miosis). All opiates/opioids which gain access to the

central nervous system will cause pin-point pupils. A sign of the user.

9. Nausea, vomiting. Morphine stimulates the vomiting centre (chemotrigger zone) in the

medulla. Vomiting is an unpleasant but not life-threatening side effect.

10. Drug dependence. Develops to all opiate analgesics.

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

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Note: Depending on the circumstances, all of these responses can be considered as adverse

effects, except analgesia and cough suppression, and of course the effect on the

gastrointestinal tract in severe diarrhea.

Mechanism of Action

Morphine and related opioids act on specific receptors on neurons – the opioid receptors.

Responses are elicited when these receptors are activated. Naloxone does not activate these

receptors. However, it occupies and blocks the opioid receptors (an antagonist).

The following diagram depicts the action of the opiates:

Narcotic (Opioid) Drug Dependence

1. Tolerance: Loss of effectiveness with repeated administration. Tolerance to most, but not

all, pharmacological effects occurs; the exceptions are constriction of the pupils and the

constipating effect.

Cross-tolerance between all narcotic (opioid) analgesics occurs providing they act on the

same receptor. Tolerance is reversible in a few days after the opioid is discontinued.

2. Physical dependence: Develops after repeated administration. A pronounced withdrawal

syndrome can occur and is an indicator of physical dependence. It is not life threatening.

A withdrawal syndrome can occur after discontinuing the drug or after administration of

Naloxone. The withdrawal syndrome is manifested as:

(a) Restlessness, anxiety, insomnia.

(b) Sweating, fever, chills

(d) Retching and vomiting

(e) Cramping

(f) Explosive diarrhea

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

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The kinds of symptoms, as well as their severity and duration, are determined by the

particular drug, the chronicity and pattern of use, the typical daily dose, concurrent use of

other drugs, the route of administration, and the health of the user.

3. Psychological dependence: (addiction) Pronounced craving and compulsion for narcotic

(opioid) analgesics can develop. Use of narcotic analgesics with other psychoactive drugs

(e.g. cocaine) can occur. The basis for the psychic dependence is the euphoric action of the

opioids which serves as a very powerful reinforcing factor in the drug-seeking behaviour.

Neonatal Drug Dependence

A mother physically dependent on opioid analgesics during pregnancy faces an increased risk of

premature delivery and a low birth weight infant. At birth, the infant undergoes an abrupt

termination of drug supply resulting in a withdrawal reaction (irritability, sleep disturbances,

poor feeding and occasionally seizures). The withdrawal may last weeks to months.

Opioid Overdose

Opioid overdose is a medical emergency. Overdose of all opioid drugs can produce profound

respiratory depression which is the cause of death. Treatment consists of opioid antagonists such

as naloxone and support of respiration and other vital functions.

Opioid Abuse

The euphoria produced by opioid analgesics is the primary reason for their abuse. Factors which

determine abuse of opioids are:

 Inherent properties of the compound. How much euphoria and reinforcement does it produce?

 The size of the dose. The greater the dose the greater the euphoria.

 The route of administration. The euphoria is rapid in onset and intense following intravenous administration as compared to oral doses.

 The use of opioids in combination with other drugs. The euphoria of two drugs is usually greater than one drug, e.g. heroin and cocaine or methamphetamine (the

mixture is called a “speed ball”).

Effects of opioid abuse:

 A large number of intravenous drug users suffer deleterious effects of chronic needle use.

 Abscesses and infections at the site of administration. The major concern is the spread of disease through contaminated needles (hepatitis and AIDS).

 Lifestyle of the user is often aberrant. They may need to resort to crime or prostitution to obtain money for drugs. They spend all their money on drugs and leave very little

for nutrition, etc. They do not seek medical help when ill as their use of drugs will be

detected and thus they are often in poor health. They may abandon friends and

family.

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

______________________________________________________________________________

Treatment of Opioid Dependence

Some European countries allow a physician to provide morphine, and in some cases heroin, to

individuals dependent on these drugs. Canada does not. In Canada, methadone is the drug used

to treat opioid dependence. It is used in two different modalities:

1. Cessation of drug use. Oral methadone replaces the drug of dependence and the dose of

methadone is slowly reduced over time. Other pharmacological agents may be added to the

program and should be accompanied by counselling and rehabilitation.

2. Methadone maintenance. This is a method where methadone replaces the drug of

dependence but the dose is not reduced. The individual substitutes methadone dependence

for street heroin or other drug dependence. The advantages are that methadone is available

and is effective orally, and the addict has a ready supply of drug and does not need to resort

to crime to fulfill their need. The substitution of a long acting oral drug in place of an

intravenous drug also removes the person from the circumstances of administering the drug.

The health risks to the addict are less. In short, this is a risk-reduction method.

It is useful to consider two of the opiates in terms of abuse potential.

Morphine

The street names for morphine are “M”, Morph or Miss Emma. Morphine is usually used alone,

but may be found in combination with cocaine and methamphetamine. Morphine may be taken

orally in tablet form, smoked, sniffed and injected.

Effects of Short-Term Use – Low Doses

CNS: Effects or morphine use include suppression of the sensation of pain and emotional

response to it, euphoria, drowsiness, lethargy, relaxation, difficulty in concentrating, decreased

physical activity in some users, and increased physical activity in others, mild anxiety or fear,

pupillary constriction, blurred vision, impaired night vision, and suppression of cough reflex.

Respiratory: slightly reduced respiratory rate.

Gastrointestinal: nausea and vomiting, constipation, loss of appetite, decreased gastric

motility.

Effects of Short-Term Use – Higher Doses

Intensification of morphine’s low-dose effects may occur with administration of higher doses.

Duration of effects also increases with increased dosage. As the dose increases, sensitivity and

emotional response to painful stimuli decrease, probability of sleep increases, ability to

concentrate is increasingly impaired, breathing becomes progressively slower and more shallow,

heart rate gradually slows and blood pressure decreases. The rush also increases in intensity. In

very high doses, the CNS depression can be profound resulting in coma. The heart rate is

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

______________________________________________________________________________

irregular and respiration is shallow. The body temperature is low. The skin is cold and clammy,

and the pupils are constricted.

Effects of Long-Term Use

There does not appear to be marked physiological deterioration or psychological impairment on

long-term use. Adverse effects of long-term use include mood instability, pupillary constriction

(impairs night vision), constipation, reduced libido, menstrual irregularity, and respiratory

impairment.

Potential for Abuse

The dependence liability of morphine exceeds that of all other opioids in common use except

heroin. This reflects its powerful euphoric and analgesic properties.

The inherent harmfulness of morphine is not high with low to moderate doses. Nausea and

vomiting are common. Lethality with high doses can occur.

Morphine is available by prescription and its importation and sale are controlled by the Narcotic

Control Act. The strict control on the prescribing of morphine reduces its potential for abuse. It

is available as a street drug.

Heroin

Heroin is diacetylmorphine. It is produced synthetically from morphine. Heroin was used in the

early 1900’s for medical purposes as an analgesic. The high dependence liability led to the

abandonment of the drug and a change in laws to prohibit its importation, manufacture and sale.

In the mid 1980’s, Canadian physicians and the public lobbied to have the drug available for

medical purposes and the laws were changed to allow the drug to be imported from the United

Kingdom. The legitimate medical uses are extremely low. Heroin is more potent than morphine,

but between the two drugs, it is not more efficacious. Double-blind studies do not detect any

differences in analgesic efficacy. It should be noted that heroin is rapidly converted to morphine

in the body.

The street names for heroin are Dust, “H”, Horse, Junk, Smack, Scag and Black Tar. Heroin is

sometimes encountered on the illicit market in combination with amphetamines (bombitas) or

with cocaine (dynamite, speed ball, whiz bang). The concentration of heroin in a street sample

can vary from 3% to 20% and in rare cases 90%. The heroin powder and the cutting or diluting

material, are usually dissolved in water and injected either subcutaneously (skin popping),

intramuscularly or intravenously (mainlining). The latter is the preferred route by most addicts.

Occasionally, heroin can be sniffed (snorted) or smoked (chasing the dragon). Smoking of

heroin was evidently very popular among military personnel during the Vietnam war. The drug

was readily available and cheap, at least by western standards.

Effects of Short-Term Use – Low Dose

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

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CNS: Effects of heroin use include suppression of the sensation of pain, euphoria, mental

clouding, heightened feelings of well-being, relaxation and drowsiness in some, and in others

talkativeness and activity. After dosing, users experience a drowsy, dreamy, mild dozing state

referred to as a “nod” (owing to the characteristic lolling of the head). Users may experience

decreased physical activity, inability to concentrate, apathy, pupillary constriction, droopy

eyelids, and impaired night vision. Novice users may react with giddiness and dizziness or

fearfulness and anxiety.

Respiratory: Decreased respiratory rate; at high doses this is the major cause of death.

Gastrointestinal: Nausea and vomiting are common among new users; reduced appetite,

decreased gastric motility, and constipation.

Effects of Short-Term Use – Higher doses

As the dose is increased, the magnitude and duration of the response also increase. The response

to painful stimuli is blunted further. The individual becomes less able to concentrate, and wishes

to sleep. Respiration may be depressed, heart rate slows, and blood pressure decreases.

In very high doses, heroin will induce deep sleep, low blood pressure, slow and irregular heart

rate, with shallow and depressed respiration. The body temperature is lowered and the skin is

cold and clammy.

Effects of Long-Term Use

As with morphine, heroin, when administered under medical supervision, does not result in

marked physiological or psychological impairment. Use of street heroin is associated with that

lifestyle and the use of contaminated needles and impure drugs. Long-term use of heroin can

lead to mood swings, reduced libido, menstrual irregularities, and certain types of respiratory

impairment.

Heroin and Pregnancy

Pregnant heroin-dependent women have a high neonatal mortality rate. The infant is often born

premature and of low birth weight. This effect is due to heroin, but also to lack of proper

nutrition.

Tolerance and Dependence

Tolerance develops to heroin with chronic use as it does to all other opiates. Powerful physical

and psychological dependence develops rapidly upon regular high dose use. These phenomena

are described above.

Potential for Abuse

The dependence liability of heroin is the greatest of the opioids in common use, including

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

______________________________________________________________________________

morphine. This is due to its extremely powerful euphoric and analgesic effects and its solubility.

The drug enters the brain quickly after intravenous administration and there is immediate and

intense gratification.

The inherent harmfulness in low to moderate doses is low. Nausea and vomiting are unpleasant

adverse effects. However, higher doses of heroin, especially those greater than those to which

the user is tolerant, can be life-threatening. Users of street heroin are at risk as they are not sure

of the dose and they can easily administer a lethal dose. Street users know the risks, but accept

them as the pleasure of the drug is intense.

The availability of heroin is controlled by law. There has been an international effort to curtail

trafficking in heroin and all other illicit drugs. Despite all these efforts, the drug is widely

available on the streets of most major cities.

Other Drugs:

A number of narcotic analgesics have become problematic in terms of producing drug

dependence when used clinically, probably more correct to state over-used. Thus oxycodone,

and hydrocodone have become drugs which are sought after by those dependent on narcotic

analgesics. The source for the illicit market is diversion from legal sources. Recently oxycodone

was marketed in a tamper resistant tablet. A gel is formed when mixed with water and the

resulting mixture cannot be drawn into a syringe for injection.

Lesson B.4 NARCOTIC ANALGESICS (OPIATES, OPIOIDS)

______________________________________________________________________________

Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following statements are correct except:

(A) Morphine acts on specific opioid receptors.

(B) Heroin is a more efficacious analgesic than morphine.

(D) Antagonist refers to a drug which can block the response of another drug.

(E) An agonist is a drug or substance which activates a response through a receptor.

2. Which of the following pairs are incorrectly matched?

(A) Morphine – miosis (constriction of pupil).

(B) Morphine – analgesic.

(D) Morphine – respiratory depression.

(E) Morphine – physical dependence.

3. The pharmacological effects of opioid agonists include all of the following except:

(A) Euphoria.

(B) Severe diarrhea.

(D) Analgesia.

(E) Sedation.

4. All of the following statements are correct except:

(A) Opioid overdose can result in death due to respiratory depression.

(B) A major problem associated with abuse of street heroin is change in lifestyle often

leading to criminal activities.

(D) Methadone maintenance is a process where the addict substitutes methadone for

heroin.

(E) Long-term use of morphine does not result in marked physiological or psychological

deterioration.

Lesson B.4
NARCOTIC ANALGESICS (OPIATES, OPIOIDS)
Reference
Objectives
Introduction
Terminology
Concept of Opioid Receptors

Mu (μ) receptors
Kappa (k) receptors
Delta (δ) receptors

Classification of Opiates/Opioids

Agonists
Mixed Agonists/Antagonists
Antagonists

Therapeutic Uses of Opioid Drugs

Relief of severe pain
Treatment of diarrhea

Pharmacological Effects of Opioid Agonists

Analgesia
Euphoria
Sedation
Hypnosis/sleep
Relief or prevention of cough
Respiratory depression
Decreased gastrointestinal motility
Constriction of the pupils of the eyes
Nausea, vomiting
Drug dependence

Mechanism of Action
Narcotic (Opioid) Drug Dependence

Tolerance
Physical dependence
Psychological dependence

Neonatal Drug Dependence
Opioid Overdose
Opioid Abuse

Effects of opioid abuse
Treatment of Opioid Dependence

Cessation of drug use
Methadone maintenance

Morphine

Effects of Short-Term Use – Low Doses
Effects of Short-Term Use – Higher Doses
Effects of Long-Term Use
Potential for Abuse

Heroin

Effects of Short-Term Use – Low Dose
Effects of Short-Term Use – Higher doses
Effects of Long-Term Use
Heroin and Pregnancy
Tolerance and Dependence
Potential for Abuse

Other Drugs
Questions

Lesson B3.pdf

Lesson B.3 Dr. W.J. Racz

SEDATIVE-HYPNOTICS AND ANXIOLYTICS

Reference: A Primer of Drug Action, 12 th

ed.

Objectives

At the conclusion of this lesson, you should be able to: (1) state the mechanism of action of

benzodiazepines and barbiturates; (2) list the therapeutic uses and the rationale for the clinical

use of benzodiazepines and barbiturates; (3) describe the response to barbiturates and

benzodiazepines at various doses and duration of use; (4) describe the dependence liability for

benzodiazepines and barbiturates; and (5) describe the withdrawal syndrome associated with

barbiturate dependence.

Introduction

The sedative-hypnotic agents are central nervous system (CNS) depressants. These drugs

produce dose-dependent CNS depression ranging from: antianxiety effect → sedation →

hypnosis (sleep) → general anesthesia. The magnitude of CNS depression produced by a drug

at a particular dose determines whether the agent is considered as an antianxiety agent, a

sedative, or a hypnotic at that dose.

Interactions of sedative-hypnotic agents with other CNS depressants (e.g. alcohol, some

antihistamines) are clinically important and can be dangerous.

History of Use

The first agents to be introduced into clinical medicine as sedatives and hypnotics were the

bromides in the mid 19th century. Prior to that, ethyl alcohol and herbal preparations were the

only drugs available. Unfortunately, bromides are eliminated at a slow rate from the body and

the drug accumulated. This produced a condition known as bromism, characterized by mental

and neurological aberrations, skin rash and gastrointestinal disturbances. Chloral hydrate and

paraldehyde were introduced shortly after bromide and were found to be safer drugs. In 1912,

the introduction of phenobarbital heralded the age of the barbiturates. In the 1950's,

meprobamate and glutethimide were introduced and enjoyed considerable success. In 1961,

chlordiazepoxide was introduced and ushered in the era of the benzodiazepines. These drugs are

widely used today and indeed much overused.

Therapeutic Uses

(a) Antianxiety relief: The benzodiazepines are the drugs of choice.

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS

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(b) Sedative (reduce sensory-motor function, reduce tension): The wide margin of safety of

the benzodiazepines allows these drugs to be used in clinical situations where sedation is

required.

hypnotics.

(d) Anticonvulsant agent for certain types of epilepsy: Phenobarbital has been used to control

generalized tonic-clonic and partial seizures. Some of the benzodiazepines are useful in

absence seizures and status epilepticus.

(e) Treatment of skeletal muscle spasm: Benzodiazepines reduce elevated skeletal muscle

tone and are useful in neuromuscular disorders, e.g. cerebral palsy.

(f) Treatment of alcohol withdrawal syndrome: Most of the benzodiazepines are useful in the

treatment of alcohol withdrawal. There is cross-dependence on the two agents, diazepam

substituting for alcohol. Diazepam is the drug of choice.

Classification

 Benzodiazepines (e.g. diazepine, flurazepam).

 Barbiturates (e.g. phenobarbital).

 Other agents (e.g. chloral hydrate).

Benzodiazepines (Drugs of First Choice)

Mechanism of CNS Action

In 1977, specific receptors for the benzodiazepines were discovered in the nervous system.

These receptors are highest in density in the cerebral cortex, cerebellum and limbic system.

These drugs:

(a) Increase synaptic inhibition and thus dampen neuronal responses.

(b) By activating the benzodiazepine receptor, they enhance the action of gamma-

aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. The sites of

action include the cerebellum, cerebral cortex, limbic system, reticular activating system,

and the spinal cord. They act on the same structure as GABA, but not on the GABA

receptor.

Pharmacological Properties

1. They possess a very high therapeutic index.

2. They produce relief from anxiety.

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS _____________________________________________________________________________________

3. They can decrease aggression.

4. They produce sedation and amnesia.

5. Some members of this group are effective hypnotics (drowsiness, facilitates onset and

maintenance of sleep).

6. They produce minimal suppression of rapid-eye-movement (REM)-type sleep with

hypnotic benzodiazepines (e.g. flurazepam) at normal doses.

7. They produce skeletal muscle relaxation (e.g. diazepam).

8. They have anticonvulsant action (e.g. diazepam for status epilepticus), i.e. an acute

episode of seizures.

Pharmacokinetics: This is the pharmacological property for which there are appreciable

differences among the various benzodiazepines. They have different durations of action, which

is determined by rate of liver metabolism and formation or lack of pharmacologically active

metabolites. The individual benzodiazepines have similar pharmacological profiles, but are used

for different purposes. Diazepam is used as an anxiolytic and anticonvulsant. Flurazepam is

used as a hypnotic. Alprazolam is the drug of choice for panic disorders.

Routes of administration: Benzodiazepines are usually taken as a capsule or tablet, but some

are available for intravenous use.

Effects of short-term use – low to moderate doses: CNS; the desirable effects are the relief

from anxiety and tension, relaxation and calmness. Other effects may include mild to moderate

impairment of motor coordination, drowsiness, lethargy, fatigue, and impairment of thinking and

memory. Respiratory depression has been observed following rapid intravenous

administration. Gastrointestinal symptoms are nausea, constipation, dry mouth and abdominal

discomfort. Moderate doses of all benzodiazepines can impair motor coordination and impair

driving. There is conflicting evidence as to the extent of the effect moderate doses of

benzodiazepines have on automobile accidents, but as the effect on any one individual is not

known, it is suggested that patients taking these drugs during the day refrain from diving or

operating dangerous machinery.

Effects of short-term use – higher doses: The major effects of higher doses are drowsiness,

over-sedation and sleep. Prior to sleep, the clinical picture may resemble an intoxicated state.

The subject would have blurred vision, incoordination, slow reflexes, and impaired thought.

These symptoms become more intense as the dose is increased. At very high doses, sleep may

proceed to coma. Coma can result from lower doses if the benzodiazepines are taken with other

CNS depressants (e.g. alcohol).

Effects of long-term use: The effects of long-term use varies between individuals. Some

individuals can take large amounts for long periods of time without any major evidence of

intoxication, while others will demonstrate the symptoms of chronic sedative-hypnotic

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS _____________________________________________________________________________________

intoxication. These are: impaired thinking, poor memory and judgement, disorientation, slurred

speech, incoordination, and weak muscles.

Lethality: The benzodiazepines are among the drugs most commonly involved in overdose.

Fortunately, the wide margin of safety for these drugs means that deaths from overdoses are very

rare. Death has occurred following ingestion of enormous doses, rapid intravenous injection of a

large dose, or when a large dose was taken in combination with other drugs for example alcohol.

Tolerance develops to the sedative and impairment of coordination effects of the

benzodiazepines. Tolerance to the anxiolytic effect is less common. Tolerance does not appear

to be a problem for the clinical use of these drugs, but tolerance may develop to the desired

effects (euphoria) when the drugs are used for non-therapeutic purposes. A high degree of cross

tolerance occurs among the benzodiazepines and other sedative-hypnotic drugs such as

barbiturates and alcohol.

Physical dependence/withdrawal: It is generally acknowledged that, for the millions of

patients who take benzodiazepines for short periods (up to a few months), the risk of physical

dependence is low. If use is chronic, one year or more, sudden discontinuation of the drug may

lead to withdrawal symptoms. The severity of the withdrawal is determined by the individual

benzodiazepine used, the dose and duration of use, as well as the abruptness of stopping the

drug. The symptoms would include agitation, paranoia, seizures and delirium. These extreme

symptoms occur much less frequently than with the barbiturates. There has been a lot of debate

whether or not withdrawal symptoms occur after stopping therapeutic doses of the

benzodiazepines. There is evidence that a mild but distinct withdrawal occurs, exhibiting

anxiety, headache, insomnia, tension, difficulty concentrating, and fatigue.

Psychological dependence (addiction) may develop in some users, but by no means all. There

is a persistent craving for the drug, even when it no longer produces an effect.

Patterns of use: The benzodiazepines are among the most widely prescribed drugs in the world.

Ten percent of Canadians use a benzodiazepine at least once a year for medical reasons. Abuse

and dependence on the benzodiazepines for recreational purposes does occur. Diazepam and

lorazepam are the preferred drugs and are often used in combination with alcohol to enhance the

effect of alcohol. Interestingly, 30-76% of alcohol abusers use benzodiazepines.

Potential for abuse: Benzodiazepines have a low abuse liability. They have weaker

reinforcing properties than barbiturates, alcohol, opioids and stimulants. The inherent

harmfulness is also low. The margin of safety is high; they may make one uncoordinated, but

they do not depress respiration at these doses and do not often lead to death.

Barbiturates

The barbiturates are potent CNS depressants. At low doses, they induce a state of relaxation and

tranquillity and will mildly impair cognitive (thinking) and motor function. At moderate doses,

they can induce sleep, but prior to inducing sleep, they can impair motor and cognitive functions.

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS _____________________________________________________________________________________

This moderately impaired state can be pleasurable. At higher doses still, they induce anesthesia,

i.e. a state of unconsciousness where powerful or painful stimuli are not experienced. As the

dose increases, they cause greater and greater depression of the respiratory centre in the brain.

Death results from respiratory failure.

The clinical uses for the barbiturates are limited. The short-acting ones are used to induce

anesthesia, and phenobarbital (a long-acting agent) is used as an antiepileptic. They have been

replaced for the most part by newer and safer drugs.

Common street names are barbs, downers and goofballs. Other street names are based on the

colour of the capsule, e.g. red devils for Seconal.

Mechanism of Action

The action of the barbiturates is less selective than that of the benzodiazepines on the CNS.

They potentiate the effect of GABA at its receptor, enhancing the inhibitory effect of GABA, but

they do not bind to the benzodiazepine receptor but have their own binding sites. Through this

mechanism they modulate the chloride channel.

Pharmacological Properties

The pharmacological properties/effects of the barbiturates are:

1. They possess a low therapeutic index. The dose required to produce a beneficial effect is

close to the dose that will produce a toxicity.

2. The barbiturates demonstrate a full spectrum of dose-dependent CNS depression.

Antianxiety → sedation → hypnosis → general anesthesia → death.

3. When used as a hypnotic (e.g. secobarbital), they suppress REM-type sleep. REM sleep is

essential so that we do not wake up feeling "not having slept".

4. Some of the long-acting barbiturates are effective in suppressing epileptic seizures.

5. Thiopental, an ultrashort-acting drug, is used to induce general anesthesia. It also

suppresses respiration, but the patient is artificially ventilated.

6. Respiratory depression is a major problem and is dose-dependent.

7. The cardiovascular system is depressed by high doses. The response usually seen is a

slowing of the heart and lowering of blood pressure.

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS _____________________________________________________________________________________

Barbiturates are classified according to their duration of action:

Long-acting (1-2 days), e.g. phenobarbital.

Short-acting (3-8 hours), e.g. secobarbital (seconal).

Ultrashort-acting (20 minutes), e.g. thiopental.

Routes of administration: For medical use in epilepsy, the usual route is oral. To induce

anesthesia, the route is intravenous. The recreational use of barbiturates is usually oral. Some

users (e.g. heroin addicts) will inject barbiturates in order to obtain the "rush effect", despite the

inherent dangers.

Effects of short-term use – low doses: Low doses usually result in tranquillity, relaxation, mild

euphoria, and reduced interest in one's surroundings. There may also be dizziness and mild

impairment of motor coordination. Movements or activities requiring fine motor dexterity are

especially affected.

Effects of short-term use – moderate doses: Moderate doses induce sleep. Prior to sleep, there

is a period of increased activity (the drug inhibits an inhibitory pathway), a pleasurable state of

intoxication, and euphoria. Some individuals will become hostile and aggressive. Other effects

are similar to those with lower doses, but of greater magnitude. There may be a small decrease

in blood pressure and respiration.

Effect of short-term use – high doses: Sleep is highly probable and the subject may lose

consciousness. All other responses are as described above, but become progressively greater in

magnitude as the dose is increased. At very high doses, death results from respiratory

depression.

Effects of long-term use: Chronic inebriation is the term which best describes long-term use.

Memory, judgement and thinking are impaired. The person exhibits hostility and mood swings,

including depression.

Lethality with barbiturates is common, especially when combined with alcohol. There are no

specific antidotes for barbiturate poisoning as there is with the opioids. A number of deaths also

result during barbiturate withdrawal.

Tolerance can develop very rapidly to sleep induction and the mood effects of the barbiturates,

often within a few weeks of nightly administration. Tolerance develops more slowly to the

impaired motor coordination and slowed reaction time. Tolerance to the anticonvulsant actions

develops much more slowly and does not appear to be a major problem clinically. There is a

high degree of cross tolerance between barbiturates, and other sedatives.

Psychological dependence (addiction) on barbiturates can result from regular use, irrespective

of the dose. Users crave the psychological effects of the drug, even though they may not use it

every day. There may be a feeling of panic if they cannot get an adequate supply. The craving

often persists long after use has stopped.

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS _____________________________________________________________________________________

Physical dependence/withdrawal usually follows abrupt discontinuance of the barbiturates.

The syndrome following withdrawal after low doses presents as sleep disturbances. A more

severe withdrawal syndrome occurs if cessation follows chronic use. Symptoms occur in 12 to

24 hours and initially appear as tremors, anxiety, weakness and insomnia, as well as rapid drop

in blood pressure when the person goes from sitting to standing. There is also severe weakness,

a hyperactive blink and other reflexes. The symptoms peak between 24 and 72 hours after the

last administration and may eventually include seizures, delirium, visual hallucinations, and a

high body temperature. The person may not survive the seizures and fever. If the person

survives, the symptoms will decline after several days. The barbiturates must be withdrawn

slowly under medical supervision to prevent the withdrawal syndrome.

Patterns of use: Barbiturates are prescribed much less in 2010 than 40 years ago. Illicit use

continues to be a problem. Barbiturates are sometimes combined with heroin and the mixture

given intravenously to obtain a pleasurable "high". Similarly, barbiturates are combined with

methamphetamine and the claim is that the euphoria with the combination is greater than either

drug alone.

Potential for abuse: The abuse liability of the barbiturates is equal to or greater than alcohol.

The pleasurable effects of some of the barbiturates give a significant degree of reinforcement.

The inherent harmfulness of the barbiturates is very high. The risk of death from respiratory

depression or from withdrawal is high. These drugs should be avoided.

Other Agents

Flumazenil is a GABAA receptor antagonist and blocks the effect of the benzodiazepines. It can

be used as an antidote for benzodiazepine poisoning.

Zolpidem is a new GABA receptor agonist and may have advantages over the benzodiazepines

as a hypnotic as it does not disturb sleep patterns (REM sleep) to the same extent as the

benzodiazepines.

Buspirone does not act on the GABA receptor, but rather at the 5-HT receptor. It is used in

generalized anxiety states and may have an advantage over other sedatives in that it does not

appear to have an additive effect with other sedative-hypnotic drugs.

Chloral hydrate is an old drug that was once widely used as a hypnotic. It is used occasionally

in the geriatric patient. It causes epigastric distress (heartburn) and an unusual taste in the

mouth. There is limited rationale for its use.

Lesson B.3 SEDATIVE-HYPNOTICS AND ANXIOLYTICS _____________________________________________________________________________________

Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following statements are correct except:

(A) Bromides were widely used as sedatives and hypnotics.

(B) Chloral hydrate is the drug of choice as a hypnotic in a 30-year-old male.

(D) The benzodiazepines are the drugs of choice for treating anxiety states.

(E) The CNS depressant effect of the benzodiazepines can be enhanced by alcohol.

2. All of the following statements correctly apply to the benzodiazepines except:

(A) The benzodiazepines, when taken in large doses, often cause lethality.

(B) The benzodiazepines exhibit a high degree of cross tolerance with the barbiturates.

(D) Psychological dependence does not develop as rapidly with the benzodiazepines as

with the barbiturates.

(E) The benzodiazepines have weak reinforcing properties compared to the barbiturates.

3. All of the following statements are correct except:

(A) Flumazenil is a GABA receptor antagonist.

(B) Zolpidem is a new GABA receptor agonist which has minimal effects on sleep

patterns.

(D) The barbiturates are rarely, if ever, associated with lethality.

(E) Phenobarbital is useful as an antiepileptic (anticonvulsant).

4. Which of the following pairs is incorrectly matched?

(A) Diazepam – a benzodiazepine.

(B) Phenobarbital – a long-acting barbiturate.

(D) Flumazenil – a barbiturate antagonist.

(E) Flurazepam – a benzodiazepine used as a hypnotic.

Lesson B.3
SEDATIVE-HYPNOTICS AND ANXIOLYTICS
Reference
Objectives
Introduction
History of Use
Therapeutic Uses

Antianxiety relief
Sedative (reduce sensory-motor function, reduce tension)
Hypnotic (sleep)
Anticonvulsant agent for certain types of epilepsy
Treatment of skeletal muscle spasm
Treatment of alcohol withdrawal syndrome

Classification
Benzodiazepines (Drugs of First Choice)

Mechanism of CNS Action
Pharmacological Properties

Pharmacokinetics
Routes of administration
Effects of short-term use – low to moderate doses
Effects of short-term use – higher doses
Effects of long-term use
Lethality
Tolerance
Physical dependence/withdrawal
Psychological dependence
Patterns of use
Potential for abuse

Barbiturates

Mechanism of Action
Pharmacological Properties
Routes of administration
Effects of short-term use – low doses
Effects of short-term use – moderate doses
Effect of short-term use – high doses
Effects of long-term use
Lethality
Tolerance
Psychological dependence
Physical dependence/withdrawal
Patterns of use
Potential for abuse

Other Agents

Flumazenil
Zolpidem
Buspirone
Chloral hydrate

Questions

Lesson B2.pdf

Lesson B.2 Dr. W.J. Racz

DRUG DEPENDENCE AND DRUG ABUSE

Objectives

At the conclusion of this lesson, you should be able to: (1) state the definition for tolerance,

psychic dependence, and physical dependence; (2) state or list the clinical features of substance

dependence; (3) state the difference between the medical perspectives and social aspects of drugs

abuse; (4) state the contributing factors and their role in determining the abuse potential of a

substance; and (5) state the influence of societal values on determining what constitutes drug

abuse.

Introduction

Why do people use drugs? Because they gain something from their use. The gain may be the

altered feeling, benefits from social interaction, and the thrill of experiencing something new and

perhaps risky. Some users enjoy the different feeling they get from drug use. For example,

morphine may be used to relieve pain, alcohol to relax or escape problems, amphetamines to

obtain a sense of high energy and achievement, and hallucinogens to experience a unique

relationship with one's surroundings. The greater the "good feeling" obtained from a drug, the

more likely the use of the drug will be repeated. This phenomenon is known as reinforcement.

Some users rarely use psychoactive substances when alone, but use the drug to reduce social

inhibitions (e.g. alcohol). One school of thought suggests that drugs which cause dependence

increase dopamine levels in the mesolimbic system and this increase in dopamine levels leads to

maladaptive behaviour. It should be recognized that not all the evidence supports the dopamine

hypothesis of dependence.

It should be noted that society often has complex rules for acceptable use of substances. The use

of morphine or other opioids to relieve pain is accepted, but not the use for the pleasure

associated with euphoria. Alcohol use is accepted at social gatherings, but drinking and driving

have restrictions. It must be recognized that North American society does not approve of the use

of hallucinogens, but some societies have used these agents in ceremonies, religious as well as

others, for centuries.

There are many definitions of the phenomenon of drug dependence, including the terms drug

addiction and drug habituation. The term "drug addiction" has often been used to describe an

intense pattern of drug use that is detrimental to the individual and society. The term "drug

habituation" has been used to refer to a less intense form of drug use that produces detrimental

effects on the individual only. It is obvious that the difference between these two terms is quite

arbitrary since value judgements are involved. Currently the term dependence is used to denote

“physical dependence” and addiction is used to denote “psychological dependence”.

Lesson B.2 DRUG DEPENDENCE AND DRUG ABUSE

_____________________________________________________________________________________

Drug dependence is a state of periodic or chronic intoxication produced by repeated

consumption of a drug (natural or synthetic). Its characteristics include:

1. An overpowering desire or need (compulsion) to continue taking the drug and to obtain it

by any means.

2. A tendency to increase the dose.

3. A psychic (psychological) “addiction” and sometimes a physical dependence

“dependence” on the effects of the drug.

The term drug dependence includes all degrees of intensity of desire for the drug, all degrees of

damage to both the individual and society, and all degrees of both physical and psychological

and need to continue using the drug.

From a pharmacological viewpoint, there are three important aspects of drug dependence: (a)

drug tolerance, (b) physical dependence, (c) psychic (psychological) dependence.

(a) Drug tolerance is defined as a state in which repeated administration of a given dose or a

drug has progressively less pharmacological effect or a state in which the dose of a drug

must be increased to obtain the same magnitude of pharmacological effect as was

produced by the original drug dose.

(b) Physical dependence (dependence) is defined as an abnormal physiological state

produced by repeated administration of a drug that leads to the appearance of a

characteristic and specific group of symptoms (withdrawal syndrome) when drug

administration is discontinued or decreased. The intensity of physical dependence is

gauged by the severity of the withdrawal syndrome.

the dose of a given drug produces non-physical symptoms. Psychological dependence is

characterized by emotional and mental preoccupation with the drug's effects and by a

persistent craving for the drug. Craving is believed to be a major factor governing the

continued self-administration of psychoactive drugs. It was only believed that the sleep

disturbances and irritability that occur when heavy users stop their drug use were of

psychological origin, but these symptoms are now widely believed to be subtle withdrawal

effects associated with physical dependence.

The clinical feature of substance dependence is a cluster of cognitive, behavioural and

physiological symptoms indicating that the individual continues to use the substance despite

significant substance-related problems, i.e. a pattern of repeated self-administration that usually

results in tolerance, withdrawal, and compulsive drug-taking behaviour.

Lesson B.2 DRUG DEPENDENCE AND DRUG ABUSE

_____________________________________________________________________________________

What is compulsive use? The individual takes the substance in larger doses and for a longer

period of time than intended, e.g. a patient who takes morphine for pain may continue taking the

drug longer than intended. The individual may express a desire to stop taking the drug, but are

often unsuccessful. The person spends a predominant amount of their time obtaining and using

the drug. Daily activities revolve around the drug. The user will withdraw from family or

society to use the drug. Preference will be to spend time with drug-using friends.

What is harmful use? A pattern of psychoactive substance use that is causing damage to

health. The damage may be physical (as in cases of hepatitis from the self-administration of

injected drugs) or mental (e.g. episodes of depressive disorder secondary to heavy consumption

of alcohol). The diagnosis requires that actual damage should have been caused to the mental or

physical health of the user.

The above definition is a diagnostic definition for clinical purposes. A broader definition would

include patterns of use that are criticized by others and are associated with adverse social

consequences, e.g. arrest or marital problems.

Drug Abuse: Medical Perspective

The American Psychiatric Association defines substance abuse as having the following features:

 A maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to repeated use of substances. There may be a repeated failure to

fulfil major role obligations, repeated use in situations in which it is physically

hazardous, multiple legal problems, and repeated social and personal problems.

and

 The symptoms have never met the criteria for substance dependence for the class of substance.

This description stresses pattern of drug use resulting in impairment of function and

inappropriate or socially unacceptable behaviour, but without the characteristics of substance

dependence and without damage to the physical or mental health of the individual. This

definition would apply to individuals who have recently started using a drug.

Drug Abuse: Social Perspective

In contrast to the medical pharmacological model, the social deviance model of drug abuse

examines permissible and non-permissible behaviour. These judgements are based on custom

and tradition and continue to change as societal values change. In this definition, drug abuse

refers to the use, usually self-administration, of any drug in a manner that deviates from the

approved medical or social patterns within a given culture. The term conveys social disapproval

and does not necessarily include potential adverse effects.

Lesson B.2 DRUG DEPENDENCE AND DRUG ABUSE

_____________________________________________________________________________________

In applying this definition to our society, the following criteria can be established for drug abuse:

 The use of prohibited drugs.

 The use of any therapeutic drugs for other than its intended use.

 The intentional ingestion of any therapeutic drug in amounts greater than that prescribed, or taking the drug by routes other than those medically approved.

 Taking drugs in combination in order to obtain a greater pleasurable effect.

 The excessive use of licit (legal) social drugs (alcohol, caffeine, tobacco).

The social model mentions, for the most part, drugs as relates to therapeutic agents. The

definition should be expanded to include all substances of abuse, including glue (sniffing),

gasoline and solvents.

The social model may appear to be a list of "dos and don'ts", set arbitrarily, but drug abuse does

have significant social costs and the potential harm to the individual and society must be

considered. Societal issues such as excessive use of health care systems, dysfunctional families,

and the inability of the drug abuser to function in a productive manner must be considered.

As stated above, society will set different standards for different drugs. In North America, social

use of alcohol is accepted, but drunk driving is not. Some societies have banned alcohol on

religious grounds, yet some societies use hallucinogens for religious ceremonies. Different

societies set different standards. When in Rome, do nothing more than that which is accepted in

Rome (with apologies to the person who coined the original phrase).

Abuse Potential

The concept of abuse potential involves three main contributors: the intrinsic dependence

liability of the drug, the availability of the drug, and its inherent harmfulness to cause physical

and psychological effects.

Dependence liability is the tendency of the drug to produce physical and psychological

dependence. It varies from drug to drug as well as from individual to individual. Dependence

liability is determined by three factors:

1. Nature of the drug: Most, if not all, drugs are natural reinforcers, much the same as food,

water and sex. The pleasurable effects produced by a drug increases the probability that

the drug will be taken again. Heroin and cocaine produce intensely pleasurable effects and

have a high intrinsic dependence liability. The rapidity of the effect has a major role in the

development of dependence. The more immediate the response coupled with an intense

response will invariably lead to dependence and continued abuse.

Lesson B.2 DRUG DEPENDENCE AND DRUG ABUSE

_____________________________________________________________________________________

2. Route of administration: Drugs that can be administered by routes that give rapid

absorption and hence rapid effects have a greater potential for abuse than drugs which

produce the effect more slowly. For example, drugs that are taken by sniffing, inhalation

or intravenously are usually more abuse-prone that those taken orally.

3. Amount used: The greater the dose and the frequency of use, the greater the potential for

development of dependence. For example, occasional use of alcohol in moderation (social

drinking) will rarely lead to dependence, but frequent, high-dose use will lead to

dependence.

The availability of a drug in society is a major factor in determining abuse potential. The more

widespread a drug, the more likely it is to be abused. Alcohol, which has only moderate intrinsic

dependence liability, is the most highly abused psychoactive substance in our society, largely

because it is readily available. Heroin, on the other hand, has very high intrinsic dependence

liability, but has posed a lower overall risk in North America as availability is controlled by law

and cost.

The inherent harmfulness of a drug refers to the potential of the drug to cause harm. If a drug is

perceived to be a serious risk to life and health, it will not be used even if widely available.

Methyl alcohol (wood alcohol) is widely available, and when consumed, it produces inebriating

effects similar to those produced by ethyl alcohol (beverage alcohol). However, methyl alcohol,

in small doses, can cause blindness and death and hence is not abused even though it is widely

available.

The following table lists characteristics of some common drugs of abuse in terms of their ability

to cause tolerance and dependence.

Lesson B.2 DRUG DEPENDENCE AND DRUG ABUSE

_____________________________________________________________________________________

TOLERANCE TO, AND DEPENDENCE ON, SOME PSYCHOACTIVE DRUGS

Drug Class Tolerance Physical

Dependence

Psychic

Dependence

Opiates

(e.g. morphine, codeine, heroin, methadone)

+ + +

CNS Depressants

(i) Ethanol

(ii) Sedative-hypnotics

(e.g. barbiturates, benzodiazepines)

CNS Stimulants

(i) Amphetamine-type drugs

(ii) Cocaine

Hallucinogens

(e.g. LSD, mescaline)

+ – +

Cannabis (THC) + + +

+ occurs

– does not occur

Lesson B.2 DRUG DEPENDENCE AND DRUG ABUSE

_____________________________________________________________________________________

Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. All of the following statements are correct except:

(A) Drug tolerance is defined as a state in which repeated administration of a given dose

of drug has progressively less pharmacological response.

(B) Physical dependence is an abnormal state produced by repeated administration of a

drug that leads to the appearance of a withdrawal syndrome when the drug is

stopped.

with the drug's effect and a craving for the drug.

(D) Drug use is reinforced by the pleasurable effect produced by a drug.

(E) Drug dependence rarely occurs under conditions where the drug is prescribed by a

physician.

2. The following criteria are all used to establish the social model of drug abuse except:

(A) The use of prohibited drug.

(B) The use of any therapeutic agent for purposes other than its intended use.

(D) The ingestion of any therapeutic drug in amounts greater than prescribed.

(E) The excessive use of legal drugs.

3. Which of the following statements is correct?

(A) Ethanol produces tolerance and psychic dependence, but not physical dependence.

(B) Opiates produce tolerance, but not physical and psychic dependence.

(D) Cannabis produces tolerance, psychic dependence and physical dependence.

(E) Amphetamines produce physical and psychic dependence, but not tolerance.

Lesson B.2
DRUG DEPENDENCE AND DRUG ABUSE
Objectives
Introduction
Drug dependence

Drug tolerance
Physical dependence
Psychological dependence

What is compulsive use?
What is harmful use?
Drug Abuse: Medical Perspective
Drug Abuse: Social Perspective
Abuse Potential

Dependence liability

Nature of the drug
Route of administration
Amount used

The availability of a drug
The inherent harmfulness

TOLERANCE TO, AND DEPENDENCE ON, SOME PSYCHOACTIVE DRUGS
Questions

Lesson B10.pdf

Lesson B.10 Dr. W.J. Racz

NICOTINE

Reference: A Primer of Drug Action, 12 th

ed.

Objectives

At the conclusion of this lesson, you should be able to: (1) state the mechanism of action of

nicotine at the level of the central and peripheral nervous systems, (2) state the effects of short-

term and long-term use of tobacco products, and (3) describe the potential for abuse of nicotine

in terms of tolerance and dependence.

Introduction

Nicotine is a naturally-occurring substance that is found in tobacco. Nicotine, caffeine and

alcohol are the three most used psychoactive drugs in society. Nicotine has no therapeutic value

other than in smoking cessation programs. It is extremely important, however, that tobacco use

results in a large number of health problems and is responsible for approximately 100 deaths

each day in Canada.

Use of tobacco products increased from the 1940’s until the 1970’s as it was considered “cool”

to smoke. This era also saw an increase in the number of women smoking. Over the last three

decades, the percent of the adult population who smoke steadily declined to where 27% of both

males and females over the age of 15 smoked in 1995. This is a high figure if one considers the

effects of smoking in causing cancer and its role in cardiovascular disease. The 27% of the male

population who currently smoke has declined from a higher 61% in 1965. It is not nicotine

which is responsible for the long-term effects of smoking, but other compounds found in tobacco

and tobacco smoke.

Pharmacology of Nicotine

Nicotine stimulates nicotinic receptors in the central nervous system, including the cerebral

cortex, producing increased psychomotor activity, cognitive function, attention and enhanced

memory. In large doses, it can cause agitation, tremors and seizures. The effects in the central

nervous system are mediated, at least in part, by nicotinic receptor mediated release of dopamine

and serotonin (another CNS transmitter).

In the peripheral nervous system, nicotine stimulates the sympathetic ganglia and thus drives the

sympathetic nervous system. This results in an increase in heart rate and blood pressure.

Nicotine has powerful reinforcing properties and it is nicotine in tobacco products that is

responsible for the dependence.

Lesson B.10 NICOTINE

______________________________________________________________________________

Nicotine exists in cigarette smoke in very small particles, and when inhaled, these droplets are

rapidly absorbed. Approximately 20% of the nicotine in a cigarette is absorbed following

“normal smoking” and inhaling of the smoke. Nicotine is absorbed as well, from the

gastrointestinal tract, oral mucosa and across the skin (transdermal) (nicotine is available as a

gum and as patches). Nicotine is distributed throughout the body and rapidly penetrates to the

brain. It readily crosses the placenta and may have deleterious effects on the fetus.

Nicotine is rapidly metabolized in the liver and the metabolites are excreted in the urine. The

half-life of nicotine in the body is about two hours.

Medical Use of Nicotine

The only medical use of nicotine is in smoking cessation programs. Nicotine is administered in

the form of a chewing gum or as transdermal patches. This approach is an attempt to maintain

the blood nicotine levels and satisfy the craving for a cigarette. The use of nicotine in a gum or

patch allows the tapering off of the nicotine dose.

Effects of Short-Term Use

In the non-smoker, a few puffs of a cigarette may result in dizziness, headache, nausea, vomiting

and abdominal cramps. The smoke may trigger coughing or gagging. These symptoms

disappear in the chronic user.

With regular use, nicotine produces mild euphoria, enhanced arousal, increased ability to

concentrate, a sense of relaxation, and of course, a reduction in the urge to smoke. Nicotine may

cause a small increase in heart rate and blood pressure. Nicotine may depress appetite.

Effects of Long-Term Use

Cigarette smoking is recognized as the major preventable cause of premature death in Canada.

Tobacco smoke contains nicotine, carbon monoxide, and thousands of other compounds, some of

which are carcinogens. The cost to society is staggering: out of every 1000 Canadians aged 20

who smoke, 500 will die from smoking-related diseases before the age of 70. In Canada, 21% of

deaths from all causes is attributable to cigarette smoking. The social and economic cost

estimates range from $9.5 to $12.3 billion per year in Canada. A portion of this cost is offset by

tobacco taxes, reduced health care costs to the elderly, and reduced pension payments, as these

people die a premature death.

Cardiovascular disease is caused by two components in cigarette smoke – nicotine and carbon

monoxide. Carbon monoxide reduces the capacity of the red blood cells to carry oxygen. Both

of these compounds increase the incidence of atherosclerosis (plaques in the vessel) and

formation of thrombi (blood clots). There is a 5- to 19-fold increase in risk of death due to

cardiac causes in the smoker. In Canada, 11,000 people per year will die of smoking-related

cardiovascular disease; this is one-third of deaths due to all cardiac causes.

Lung disease is also increased by smoking. There is a smoker’s syndrome, characterized by

Lesson B.10 NICOTINE

______________________________________________________________________________

difficulty in breathing, wheezing, chest pain, congested lung, and increased lung infections.

There is an increased risk of emphezema and other forms of chronic obstructive lung disease.

The cancer risk associated with smoking has now been defined beyond doubt. Anyone who

claims that there is no cancer risk with smoking, is either a fool, an idiot, or both. Thirty percent

of all cancers are estimated to be caused by cigarette smoke. Cigarette smoke is known to

increase the risk of cancer of the lung, the oral cavity and throat, the bladder, and the uterus.

The effects of passive smoke are also associated with an increased risk of cardiovascular disease

and cancer to the individual exposed to passive smoke (a non-smoker in the presence of

smokers). It is estimated that 300 Canadians will die this year from lung cancer induced by

passive smoke. The number of deaths due to cardiovascular disease is even greater.

In children “passive smoke” increases the risk of bronchitis and pneumonia, asthma and sudden

infant death syndrome.

Tolerance and Dependence

Biological tolerance does not appear to occur to any great extent. Most smokers will smoke to

keep nicotine blood levels at a certain range (30 to 40 nanograms/millilitre). The number of

cigarettes smoked each day is the number needed to keep the nicotine at this level. It is

noteworthy that the smoker is in a state of nicotine withdrawal upon awakening in the morning.

Physical and psychological dependence both occur to nicotine. Withdrawal from smoking

involves a number of symptoms. These are irritability, restlessness, anxiety, insomnia, fatigue,

inability to concentrate, and an extreme urge to smoke. The latter two may persist for months.

Cessation-of-smoking programs usually involve counselling and pharmacological support.

Potential for Abuse

Nicotine is a powerful reinforcer and has a high degree of abuse liability. Individuals will begin

smoking because of peer pressure, or because it is the chic thing to do. Health Canada and the

Royal Society of Canada both state that tobacco products meet all the requirements of addicting

substances. Attempts at cessation of smoking often fails, the craving of nicotine is so great.

Nicotine replacement programs (gum or patches) with counselling and support are somewhat

more successful than cessation without adjunctive therapy.

Lesson B.10 NICOTINE

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Questions

The following are typical questions you would be expected to answer after reviewing this lesson.

Instructions

Each of the questions or incomplete statements below is followed by several suggested answers

or completions. Select the one that is best in each case.

1. Which of the following statements is correct?

(A) Nicotine is the component in cigarette smoke responsible for the lung cancer risk.

(B) Carbon monoxide is the component in cigarette smoke which is responsible for the

dependence potential.

cause cardiovascular disease.

(D) Tolerance invariably develops to the euphoric effect of nicotine.

(E) Nicotine is removed by the filters on cigarettes.

2. Which of the following is correctly matched?

(A) Nicotine – acts directly on blood vessels.

(B) Carbon monoxide – reduced oxygen-carrying capacity of red blood cells.

(D) Cigarette tars – responsible for increase in risk of cardiovascular disease.

(E) Tobacco use – responsible for 60% of all deaths from all causes.

3. All of the following statements are correct except:

(A) Approximately 300 Canadians die each year from passive smoke-induced lung cancer.

(B) Regular use of nicotine products produces mild euphoria.

(D) Physical dependence does not occur with the use of nicotine.

(E) Psychological dependence occurs rapidly to nicotine-containing products

Lesson B.10 NICOTINE

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4. Which one of the following pairs is correctly matched?

(A) Nicotine – acts at the postganglionic sympathetic nerve endings.

(B) Nicotine – releases norepinephrine in the CNS.

(D) Nicotine – 100% absorbed from a cigarette during smoking.

(E) Nicotine – low dependence liability.

Lesson B.10
NICOTINE
Reference
Objectives
Introduction
Pharmacology of Nicotine
Medical Use of Nicotine
Effects of Short-Term Use
Effects of Long-Term Use

Cardiovascular disease
Lung disease
cancer
passive smoke

Tolerance and Dependence
Potential for Abuse
Questions