ALCOHoLS

INTRODUCTION
 ETHANOL, a sedative-hypnotic drug, is the most
important alcohol of pharmacologic interest, It has
few medical applications
but its abuse causes major medical and
socioeconomic problems.

 METHANOL and ETHYLENE GLYCOL are also of

toxicologic importance
ETHANOL
A. Pharmacokinetics
After ingestion, ethanol is rapidly and
completely absorbed;
The drug is then distributed to most body
tissues, and its volume of distribution
is equivalent to that of total body water (0.5–0.7
L/kg)
Two enzyme systems metabolize ethanol to
acetaldehyde
Alcohol dehydrogenase (ADH)
 This family of cytosolic,
NAD+-dependent enzymes, found mainly
in the liver and gut,
accounts for the metabolism of low to
moderate doses of ethanol.
 The reaction has ZERO ORDER KINETICS,
resulting in a fixed capacity for ethanol
metabolism of 7–10 g/h
 Genetic variation in Alcohol
dehydrogenase affects the
rate of ethanol metabolism and
vulnerability to alcohol-use disorders.
2. Microsomal ethanol-oxidizing
system (MEOS)
 At blood ethanol levels higher than 100
mg/dL, the liver microsomal mixed function
oxidase system that catalyzes most phase I
drug metabolizing reactions contributes
significantly to ethanol metabolism .
 Chronic ethanol consumption induces
cytochrome P450 enzyme synthesis and
MEOS activity; this is partially responsible for
the development of tolerance to ethanol.
 The primary isoform of cytochrome P450
induced by ethanol—converts acetaminophen
to a hepatotoxic metabolite.
Acetaldehyde formed from the oxidation of ethanol by either
ADH or MEOS is rapidly metabolized to acetate by aldehyde
dehydrogenase, a mitochondrial enzyme found in the liver and
many other tissues.
Aldehyde dehydrogenase is inhibited by disulfiram and other drugs,
including metronidazole, oral hypoglycemics, and some cephalosporins.
Some individuals, primarily of Asian descent, have genetic deficiency of
aldehyde dehydrogenase.
After consumption of even small quantities of ethanol, these individuals
experience nausea and a flushing reaction from accumulation of
acetaldehyde.
Acute Effects ------ CNS
The major acute effects of ethanol on the CNS are
Sedation
Loss of inhibition,
Impaired judgment,
Slurred speech,
Ataxia.
impaired judgment, and a condition usually called
intoxication or drunkenness
 Like other sedative-hypnotic drugs, alcohol is a CNS depressant.
At high blood concentrations, it induces coma, respiratory
depression, and death
Blood alcohol concentration (BAC) and
clinical effects in non-tolerant
individuals.
Acute effects...
Additive CNS depression occurs with
concomitant ingestion of ethanol and a
wide variety of CNS depressants,
including
SEDATIVE HYPNOTICS
OPIOID AGONISTS
and drugs that block MUSCAIRINIC
and H1 HISTAMINE receptors
Acute effects…
The molecular mechanisms underlying the complex CNS effects of
ethanol are not fully understood
Specific receptors for ethanol have not been identified.
Rather, ethanol appears to modulate the function of a number of
signaling protein

1. It facilitates the action of GABA at GABAA receptors

2. inhibits the ability of glutamate to activate NMDA (N-methyl-d-
aspartate) receptors
3. modifies the activities of adenylyl cyclase, phospholipase C,and ion
channels.
Acute effects... HEART

Significant depression of myocardial

contractility has been observed in
individuals who acutely consume
moderate amounts of alcohol,
ie, at a blood concentration above
100 mg/dL.
Acute effects… Smooth Muscle
Ethanol is a vasodilator, probably as a result of both CNS effect
(depression of the vasomotor center) and direct smooth muscle
relaxation caused by its metabolite, acetaldehyde.
In cases of severe overdose, hypothermia—caused by vasodilation—
may be marked in cold environments
Ethanol also relaxes the uterus and—before the introduction of
more effective and safer uterine relaxants (eg, calcium channel
antagonists) — was used intravenously for the suppression of
premature labor.
Consequences of Chronic Alcohol
Consumption
 Chronic alcohol consumption profoundly affects the function of
several vital organs—particularly the liver—and the nervous,
gastrointestinal, cardiovascular, and immune systems
 Chronic consumption of large amounts of alcohol is associated
with an increased risk of death.
 Deaths linked to alcohol consumption are caused by liver
disease, cancer, accidents, and suicide.
A. Liver and Gastrointestinal
Tract
 Liver disease is the most common medical complication of
alcohol abuse; an estimated 15–30% of chronic heavy drinkers
eventually develop severe liver disease.
 Alcoholic fatty liver, a reversible condition,may progress to
alcoholic hepatitis and finally to cirrhosis and liver failure.
 In the United States, chronic alcohol abuse is the leading cause
of liver cirrhosis and of the need for liver transplantation
Concurrent infection with hepatitis B or C virus increases the
risk of severe liver disease.
Liver and gastrointestinal
effects…
 Other portions of the gastrointestinal tract can also be
injured.
 Chronic alcohol ingestion is by far the most common cause of
chronic pancreatitis in the Western world.
 Individuals with chronic alcoholism are prone to gastritis and
have increased susceptibility to blood and plasma protein loss
during drinking, which may contribute to anemia and protein
malnutrition.
 Alcohol also injures the small intestine, leading to diarrhea,
weight loss, and multiple vitamin deficiencies.
 2.Tolerance and dependence
Tolerance may result from ethanol-induced up-
regulation of a pathway in response to the
continuous presence of ethanol. Dependence may
result from over-activity of that same pathway
after the ethanol effect dissipates and before the
system has time to return to a normal ethanol-free
state
Both psychological and physical dependence
are marked.
3. Neurotoxicity
 The most common neurologic abnormality in
chronic alcoholism is generalized symmetric
peripheral nerve injury, which begins with
distal paresthesias of the hands and feet.
Degenerative changes can also result in gait
disturbances and ataxia
 Wernicke-Korsakoff syndrome is a relatively
uncommon but important entity characterized
by paralysis of the external eye muscles,
ataxia, and a confused state that can progress
to coma and death. It is associated with
thiamine deficiency but is rarely seen in the
absence of alcoholism.
4. Endocrine System & Electrolyte
Balance
 Chronic alcohol use has important effects
on the endocrine system and on fluid and
electrolyte balance.
 Clinicalreports of gynecomastia and
testicular atrophy in alcoholics with or
without cirrhosis suggest a derangement in
steroid hormone balance
5. Cardiovascular system
Excessive chronic ethanol use is
associated with an increased incidence of
hypertension, anemia,
and dilated cardiomyopathy.
Acute drinking for several days
(“binge” drinking) can cause arrhythmias.
6. Fetal alcohol syndrome
Ethanol use in pregnancy is
associated with teratogenic effects
that include
1. mental retardation (most
common),
2. growth deficiencies,
3. Microcephaly
4. and a characteristic
underdevelopment of the midface
region.
7. Neoplasia
Ethanol is not a primary carcinogen, but its
chronic use is associated with an increased
incidence of
1. Neoplastic diseases in the gastrointestinal
tract
2. a small increase in the risk of breast cancer.
8. Immune system
Chronic alcohol abuse has complex effects on
immune functions because
1. it enhances inflammation in the liver and
pancreas
2. inhibits immune function in other tissues.
3. Heavy use predisposes to infectious pneumonia.
Treatment of Acute
and Chronic
Alcoholism
Clinical findings of acute alcohol
intoxication
Treatment of Acute Alcohol intoxication
 Acute alcohol poisoning is a medical emergency due to the risk of death
from respiratory depression or aspiration of vomit if vomiting occurs while the
person is unresponsive.
 Emergency treatment strives to stabilize and maintain an open airway and
sufficient breathing.
 Treat low blood sugar, with intravenous sugar solutions as ethanol induced low
blood sugar unresponsive to glucagon.
 Administer the vitamin thiamine to prevent Wernicke–Korsakoff syndrome,
which can cause a seizure (more usually a treatment for chronic alcoholism,
but in the acute context usually co-administered to ensure maximal benefit).
 Apply hemodialysis if the blood concentration is dangerously high
(>400 mg/dL), and especially if there is metabolic acidosis.
 Provide oxygen therapy as needed via nasal cannula or non-rebreather mask.
Treatment of Chronic Alcoholism
 Alcoholism is a complex sociomedical problem, characterized by a high relapse rate. Several CNS
neurotransmitter systems appear to be targets for drugs that reduce the craving for alcohol
 Acamprosate acts by antagonizing the actions of glutamate, a neurotransmitter which is
hyperactive in the post-withdrawal phase. By reducing excessive NMDA activity which occurs at
the onset of alcohol withdrawal, acamprosate can reduce or prevent alcohol withdrawal related
neurotoxicity.
 Naltrexone is a competitive antagonist for opioid receptors, effectively blocking the effects
of endorphins and opioids. Naltrexone is used to decrease cravings for alcohol and encourage
abstinence. Alcohol causes the body to release endorphins, which in turn release dopamine and
activate the reward pathways; hence in the body reduces the pleasurable effects from consuming
alcohol
 Nalmefene also appears effective and works in a similar manner.
 Disulfiram prevents the elimination of acetaldehyde, a chemical the body produces when breaking
down ethanol. Acetaldehyde itself is the cause of many hangover symptoms from alcohol use. The
overall effect is discomfort when alcohol is ingested: an extremely fast-acting and long-lasting,
uncomfortable hangover.
OTHER ALCOHOLS
methanol
 Class:
 industrial solvent found in many commercial solvents including “canned heat”
and windshield-washing fluid.
 Mechanism of Action:
 methanol & its metabolites are much more potent toxins than ethanol
 Side Effects:
 blurred vision with relatively clear sensorium that may take up to 30 hours to
develop after absorption
 formaldehyde may be detectible on the breath
 bradycardia, retinal damage, prolonged coma, seizures, respiratory depression
 metabolic acidosis with an elevated anion gap & osmolar gap
 a decrease in serum bicarbonate.
methanol
 Treatment of Poisoning:
 i.v.ethanol to suppress methanol metabolism by alcohol
dehydrogenase to its toxic products (formaldehyde &
formic acid)
 The formation of formaldehyde is reduced by prompt
intravenous administration of FOMEPIZOLE, an inhibitor
of alcohol dehydrogenase, which competitively inhibits
alcohol dehydrogenase oxidation of
methanol
 hemodialysis
 treatment of the acidosis with bicarbonate.
B. Ethylene Glycol
 Industrial exposure to ethylene glycol (by
inhalation or skin absorption) or self-
administration (eg, by drinking antifreeze
products) leads to severe acidosis and renal
damage from the metabolism of ethylene
glycol to oxalic acid.
 Prompt treatment with intravenous
fomepizole or ethanol may slow or prevent
formation of this toxic metabolite
Isopropyl alcohol (rubbing alcohol)
 Indications:
 found in rubbing alcohol & alcohol swabs
 ingestion of isopropyl alcohol is potentially fatal.
 Side Effects:
 unresponsive reflexes
 low urine output
 uncoordinated movements
 slowed breathing, nausea/vomiting, low blood pressure, dizziness, stupor, coma
 Treatment for Poisoning:
 ABCs (treating breathing difficulties & maintaining blood pressure)
 treating any hypoglycemia
 administering activated charcoal
 gastric lavage
 hemodialysis