Lesson B9.pdfLesson B.9 Dr. W.J. Racz CANNA.docx

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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2
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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3
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.
(C) In 1978, the U.S.A. sponsored a program to destroy
marijuana crops in Mexico using
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.
(C) The absorption of THC from the gastrointestinal tract is
rapid and complete.
(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
(C) α
(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.
(C) Irreversible damage to the myocardium (heart muscle).
(D) Physical dependence.
(E) Psychological dependence.
Lesson
B.9CANNABISReferenceObjectivesIntroductionHistoryClassifi
cation of MarijuanaLegalPharmacologicalPharmacologyMedical

Uses of MarijuanaNon-Medical Use of Cannabis and Cannabis
ProductsEffects of Short-Term Use – Low to Moderate
DosesCNSCardiovascularRespiratoryGastrointestinalOther
effectsEffects of Short-Term Use – Higher DosesCNSCannabis
and impaired drivingEffects of Long-Term UsePsychological
effectscardiovascular effectsrespiratory systemOther areas of
concernTolerance and DependencePotential for AbuseQuestions
Lesson B8.pdf
ALCOHOL (ETHANOL)
Reference: A Primer of Drug Action, 12th ed.
Objectives
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)
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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.
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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.

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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.
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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.
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.
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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

_____________________________________________________
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7
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
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8
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.
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9
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.

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10
Questions
Instructions
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.
(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.
(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.
(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.8ALCOHOL
(ETHANOL)ReferenceObjectivesIntroductionEthanol Content
of Alcoholic BeveragesAbsorption of EthanolDistribution of
EthanolMetabolism and ExcretionPharmacology and Toxicology
of AlcoholMedical Uses of Ethyl Alcohol (Ethanol)Central
Nervous SystemRELATIONSHIP BETWEEN BLOOD

ETHANOL CONCENTRATIONAND PHARMACOLOGIC
EFFECT*Mechanism of Neuronal Action of AlcoholEffects of
Short-Term Use – Low DoseEffects of Short-Term Use – Higher
DosesAdverse Effects of Short-Term UseBlackoutsPsychiatric
effectsDrinking and drivingViolenceother risksAdverse Effects
of Long-Term UseCentral nervous systemThe peripheral
nervous systemEthanol DependenceTolerance to, and
Dependence on, EthanolMechanism
Cross-tolerance
Physical dependenceWithdrawal from ethanolPsychological
dependencePotential for AbuseEffects on the Cardiovascular
SystemEffects on the Gastrointestinal TractEffects on the
LiverEffects on the Embryo/FetusPrincipal featuresAssociated
featuresDrugs Used in the Treatment of Alcoholism: Disulfiram
and Calcium Carbimide (Calcium Cyanamide)Alcohol and Drug
InteractionsQuestions
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
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
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2
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
ANTIPSYCHOTIC AND
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3
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.
ANTIPSYCHOTIC AND
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4
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:
ANTIPSYCHOTIC AND
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5
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
R
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.
ANTIPSYCHOTIC AND
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6
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
ANTIPSYCHOTIC AND
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7
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
ANTIPSYCHOTIC AND
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8
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.

ANTIPSYCHOTIC AND
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9
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.
ANTIPSYCHOTIC AND
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10
Questions
Instructions

1. All of the following drugs are correctly matched with an
appropriate therapeutic use except:
(A) Haloperidol – schizophrenia.
(B) Chlorpromazine – schizophrenia.
(C) Lithium – manic-depressive disorder.
(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.
(C) Blockade of norepinephrine 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.
(C) Blockade of monoamine oxidase C.
(D) Blockade of monoamine oxidases A and B.
(E) Blockade of monoamine oxidases A and C.
ANTIPSYCHOTIC AND
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11
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.
(C) 1 day.
(D) 2 days.
(E) 2 weeks.
Lesson B.6CLASSIFICATION OF MENTAL DISORDERS
ANTIPSYCHOTIC AND ANTIDEPRESSANT
DRUGSReferences
ObjectivesPsychosesOrganicFunctionalAffective (Mood)
DisordersNeurosesAntipsychotic DrugsMechanism of Action of
Antipsychotic DrugsAntipsychotic actionExtrapyramidal
movement disordersEndocrine effectsOther Receptors Blocked
by Phenothiazine AntipsychoticsCholinergic (muscarinic)
receptorsBlockade of serotonin receptorsBlockade of histamine
receptorsBlockade of α-adrenoceptorsOther Antipsychotic
DrugsSecond-Generation AntipsychoticsClozapineLithium
CarbonateClinical Pharmacology of LithiumMonitoring of

Serum Concentration of LithiumAdverse Effects of
LithiumAntidepressant AgentsReactive (secondary)
depressionMajor depression (endogenous)Depression associated
with manic-depressive disorderTheory of the Causes of Major
DepressionTypes of AntidepressantsTricyclic
antidepressantsSecond-generation (atypical)
antidepressantsSelective serotonin reuptake inhibitors
(SSRI’s)Drugs that block Serotonin and norepinephrine
uptakeMonoamine oxide (MAO) inhibitorsPhenelzine and
tranylcypromineAction of Antidepressants on Biogenic Amine
NeurotransmittersChoice of AntidepressantsAdverse
EffectsTricyclic antidepressantsSSRI’sMAO
inhibitorsQuestions
Lesson B7.pdf
STIMULANT DRUGS
th
ed
Objectives

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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2
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).
_____________________________________________________
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3
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.
_____________________________________________________
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4
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.
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.
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.
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
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5
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
_____________________________________________________
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6
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
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7
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.
_____________________________________________________
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8

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.
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).

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9
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).
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.

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10
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.
_____________________________________________________
_____________
11

Questions
Instructions
(A) Amphetamines are synthetic compounds.
(B) Cocaine is extracted from the leaves of the cocoa plant.
(C) Naturally occurring amphetamines are more effective than
synthetic amphetamines.
(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.
(C) Insomnia.
(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.
(C) Cocaine is one of the most popular recreational drugs.
(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.
(C) Cocaine – blocks adenosine receptors.
(D) Methylphenidate – used to prevent seizures.
(E) Amphetamine – widely prescribed for appetite control.
Lesson B.7STIMULANT
DRUGSReferenceObjectivesAmphetaminesHistoryChemistryPh
armacologyAmphetamine AbuseEffects of Short-Term Use –
Low DoseEffects of Short-Term Use – Higher DosesEffects of
Long-Term UseThe Amphetamine RunTolerancePhysical
DependencePsychological (Psychic) DependencePotential for
AbuseCocaineHistoryPharmacologyTherapeutic Uses of
CocaineMetabolismCocaine AbuseEffects of Short-Term – Low
DosesEffects of Short-Term – Higher DosesEffects of Long-
Term UseThe Cocaine BingeCocaine DependencePotential for
AbuseCaffeinePharmacologyEffects of Short-Term Use – Low
DoseEffects of Short-Term Use – High DoseEffect of Long-
Term UseTolerance and DependencePotential for
AbuseQuestions
Lesson B5.pdf
Lesson B.5 Dr. G.S. Marks

CLASSIFICATION OF THE MAJOR PSYCHOACTIVE
DRUGS
th
ed.
Objectives
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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2
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.
(c) Caffeine: Caffeine is a blocker (competitive antagonist) of
adenosine at its receptors
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.

Lesson B9.pdfLesson B.9 Dr. W.J. Racz CANNA.docx

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