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Flashcards in Lesson B8 - Pharmacology Deck (54)

The major reason for the extensive use and abuse of
alcohol is

its ready availability and the permissive attitudes of society


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



Ten to 13 ml of absolute alcohol is the amount metabolized by

the liver each hour.


Ethanol is absorbed rapidly from the

stomach and the upper small intestine (the major site of


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.


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.


Over 95% of ethanol in the body is eliminated by biotransformation, primarily in the



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


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)


Ethanol is classified as a general central nervous system (CNS)



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.


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.


Ethanol produces dose-dependent depression of CNS function:

disinhibition → sedation → hypnosis → general anesthesia →



Low dose: Disinhibition (inhibition of an inhibitory pathway in the CNS).
This is usually manifested by increased social
interaction, e.g



High dose: Sedation → hypnosis → general anesthesia → coma →



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”.


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


At lower alcohol
concentrations, alcohol binds to the GABA receptor and augments

GABA-mediated neuronal


Alcohol is a CNS depressant, but at low dose the response observed is one of



Drinkers feel gregarious,

jovial, relaxed and more self-confident.


As the dose increases, the individual may demonstrate exaggerated

emotional responses


Blackouts: This is the phenomenon where the drinker does not remember events while under
the influence of



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


Drinking and driving: Alcohol is one of the major causes of

automobile accidents.


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



The other risks associated with excessive use of alcohol is associated with

depression, coma and death.


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 –

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.


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 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.



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


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 ethanol, and frequency of ethanol administration.


It is important to note that, normally, minimal tolerance develops to the

lethal dose of


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




1. between ethanol and sedative hypnotics
2. ethanol and general anesthetics


The basis of physical dependence on ethanol primarily involves the CNS. Withdrawal from
ethanol (CNS depressant) produces

excitability of the CNS (arousal, stimulation).


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.


Psychological dependence is defined as a compulsion that requires periodic or continuous
administration of a drug to produce pleasure or to

avoid discomfort.


The dependence liability is



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.


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



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


Epidemiologic and laboratory animal studies have demonstrated that ethanol is a



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.


Drugs Used in the Treatment of Alcoholism: Disulfiram and Calcium Carbimide (Calcium

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).


1AIngestion of ethanol and other CNS depressants leads to an additive effect or
synergism of CNS depression.

B) Ethanol inhibits biotransformation (metabolism) of certain drugs


Alcohol and Drug Interactions-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