Toxicology by shimaji gurchima

By Shimaji Gurchima clinical pharmacy
3/19/2021
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Methanol & Ethanol Poisoning
3/19/2021 2
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Methanol poisoning
Methanol and ethylene glycol are two alcohols of
the most common causes of intoxication
Isopropyl alcohol (isopropanol,rubbing alcohol)
is another alcohol that is sometimes ingested
when ethanol is not available.
 It produces coma and gastrointestinal irritation,
nausea, and vomiting, but is not usually
associated with retinal or renal injury.
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Methanol has a high toxicity in humans.
 As little as 10 mL of pure methanol when drunk
is metabolized into formic acid, which can cause
permanent blindness by destruction of the optic
nerve.
methanol’s major effect is to cause central
nervous system depression
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Formic acid, the toxic metabolite of methanol,
is responsible for ocular toxicity in animal
models and is rightly presumed to
be responsible in human studies.
Serum methanol levels of greater than 20 mg/
dL correlate with ocular injury & result in the
blindness
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How methanol cause belindness?
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Methanol attack here

Methanol is converted to the toxic metabolites
formaldehyde and formate by alcohol
dehydrogenase and aldehyde dehydrogenase.
 The enzyme chiefly responsible for methanol
oxidation in the liver is alcohol
dehydrogenase.
Fomepizole, an alcohol dehydrogenase
inhibitor, is approved for the treatment of
methanol and ethylene glycol poisoning.
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Fomepizole appears to be safe during the short
time it is administered for treatment of methanol
or ethylene glycol poisoning.
The most common adverse effects are burning at
the infusion site, headache, nausea, and dizziness.
Intravenous ethanol is an alternative to
fomepizole.
It has a higher affinity than methanol for alcohol
dehydrogenase; thus,saturation of the enzyme
with ethanol reduces formate production.
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 Ethanol is used intravenously as treatment for
methanol and ethylene glycol poisoning.
The dose-dependent characteristics of ethanol
metabolism and the variability of ethanol
metabolism require frequent monitoring of blood
ethanol levels to ensure appropriate alcohol
concentration.
In cases of severe poisoning, hemodialysis can be
used to eliminate both methanol and formate
from the blood.
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Two other measures are commonly taken
I. Because of profound metabolic acidosis in
methanol poisoning, treatment with
bicarbonate often is necessary.
II. Since folate-dependent systems are
responsible for the oxidation of formic acid
to CO2 in humans folinic and folic acid are
often administered to patients poisoned with
methanol.
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The special susceptibility of humans to methanol
toxicity is due to metabolism to formate and
formaldehyde, not to methanol itsel
 The conversion of methanol to its toxic
metabolites is relatively slow, there is often a
delay of 6–30 hours before the appearance of
severe toxicity.
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Methanol has a quick and profound effect on
the body.
Once ingested the body changes methanol
into formaldehyde and formic acid.
Formic acid begins to build up in your body,
and when it does, it does serious damage to
your central nervous system.
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In addition, bicarbonate may help to decrease
the amount of active formic acid. Antidote
therapy, often using ethanol or fomepizole, is
directed towards delaying
methanol metabolism until the methanol is
eliminated from the patient's system either
naturally or via dialysis
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Methanol is the simplest alcohol, consisting of a
methyl group linked to a hydroxyl group.
physical Properties of Methanol
 It is a light, volatile, colorless, flammable liquid
with a distinctive odor similar to that of ethanol
(drinking alcohol).
Methanol is however far more toxic than ethanol.
In severe cases, the odor of formaldehyde may be
present on the breath or in the urine.
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Formaldehyde doesn't stick around long in your
body because it is so rapidly metabolized to
formic acid by the second enzyme in this
metabolic pathway. ...
The cells that make up the optic nerve are
exquisitely sensitive to formic acid, which is
why blindness is so closely associated
with methanol poisoning.
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Methanol is a poisonous chemical derived
through synthetic processes, while
commercial ethanol is produced by factory
fermentation of food crops.
Both substances can be used as energy sources,
but methanol serves mainly as a subject of
research and its use as a motor fuel in the U.S.
has been largely phased out.
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Methanol is both acidic and basic.
In Bronsted-Lowry approach, proton donors are
acid, proton acceptors are bases.
Methanol is a proton donor because it fairly
easily donates O-H proton to strong bases such as
sodium hydride
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The visual disturbance is frequently described as
“like being in a snowstorm” and can progress to
blindness.
Physical findings in early methanol poisoning are
generally nonspecific
-such as inebriation and
- gastritis, and
-possibly an elevated osmolar gap.
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The development of bradycardia, prolonged
coma, seizures, and resistant acidosis all imply a
poor prognosis.
The cause of death in fatal cases is sudden
cessation of respiration.
The first treatment for methanol poisoning, as in
all critical poisoning situations, is support of
respiration.
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There are three specific modalities of treatment
for severe methanol poisoning.
I. Suppression of metabolism by alcohol
dehydrogenase to toxic products.
II. Hemodialysis to enhance removal of methanol
and its toxic products.
III. Alkalinization to counteract metabolic acidosis.
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ETHANOL POISONING
• Alcohol, primarily in the form of ethyl alcohol
(ethanol), has occupied an important place in
the history of humankind for at least 8000
years.
• Alcohol is also the most commonly abused
drug in the world, and the cause of vast
medical and societal costs.
• Approximately 75% of the adult population
drinks alcohol regularly in the United States .
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BASIC PHARMACOLOGY OF ETHANOL
Pharmacokinetics
• Ethanol is a small water-soluble molecule that
is absorbed rapidly from the gastrointestinal
tract.
• After ingestion of alcohol in the fasting state,
peak blood alcohol concentrations are reached
within 30 minutes.
• The presence of food in the stomach delays
absorption by slowing gastric emptying.
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Distribution is rapid, with tissue levels
approximating the concentration in blood.
The volume of distribution for ethanol
approximates total body water (0.5–0.7 L/kg).
 After an equivalent oral dose of alcohol, women
have a higher peak concentration than men, in
part because women have a lower total body
water content and in part because of differences
in first-pass metabolism.
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• In the central nervous system (CNS), the
concentration of ethanol rises quickly, since the
brain receives a large proportion of total blood
flow and ethanol readily crosses biologic
membranes.
• Over 90% of alcohol consumed is oxidized in
the liver; much of the remainder is excreted
through the lungs and in the urine.
• At levels of ethanol usually achieved in blood,
the rate of oxidation follows zero-order kinetics.
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Microsomal Ethanol
oxidatizing system

• Two major pathways of alcohol metabolism to
acetaldehyde have been identified
Acetaldehyde is then oxidized to acetate by a
third metabolic process.
• Alcohol dehydrogenase and aldehyde
dehydrogenase are inhibited by fomepizole and
disulfiram, respectively.
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A. Alcohol Dehydrogenase Pathway
• The primary pathway for alcohol metabolism
involves alcohol dehydrogenase (ADH), a
family of cytosolic enzymes that catalyze the
conversion of alcohol to acetaldehyde.
• These enzymes are located mainly in the liver,
but small amounts are found in other organs
such as the brain and stomach.
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There is considerable genetic variation in ADH
enzymes, affecting the rate of ethanol metabolism
and also appearing to alter vulnerability to
alcohol-abuse disorders.
 For example, one ADH allele (the ADH1B*2
allele), which is associated with rapid conversion
of ethanol to acetaldehyde, has been found to be
protective against alcohol dependence in several
ethnic populations and especially East Asians.
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• Some metabolism of ethanol by ADH occurs
in the stomach in men, but a smaller amount
occurs in women, who appear to have lower
levels of the gastric enzyme.
• This difference in gastric metabolism of
alcohol in women probably contributes to the
sex-related differences in blood alcohol
concentrations.
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• During conversion of ethanol by ADH to
acetaldehyde, hydrogen ion is transferred from
ethanol to the cofactor nicotinamide adenine
dinucleotide (NAD+) to form NADH
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B. Microsomal Ethanol-Oxidizing System (MEOS)
• This enzyme system, also known as the mixed
function oxidase system, uses NADPH as a
cofactor in the metabolism of ethanol.
• It consists primarily of cytochrome P450 2E1,
1A2, and 3A4.
• During chronic alcohol consumption, MEOS
activity is induced.
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• As a result, chronic alcohol consumption
results in significant increases not only in
ethanol metabolism but also in the clearance of
other drugs eliminated by the cytochrome
P450s that constitute the MEOS system, and in
the generation of the toxic byproducts of
cytochrome P450 reactions (toxins, free
radicals, H2O2).
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C. Acetaldehyde Metabolism
Much of the acetaldehyde formed from alcohol
is oxidized in the liver
The a reaction catalyzed by mitochondrial
NAD dependent aldehyde dehydrogenase
(ALDH).
The product of this reaction is acetate which
can be further metabolized to CO2 and water,
or used to form acetyl-CoA.
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Oxidation of acetaldehyde is inhibited by
disulfiram, a drug that has been used to deter
drinking by patients with alcohol dependence.
When ethanol is consumed in the presence of
disulfiram, acetaldehyde accumulates and causes
an unpleasant reaction of facial flushing, nausea,
vomiting, dizziness, and headache.
Several other drugs (e.g., metronidazole,
cefotetan, trimethoprim) inhibit ALDH and can
cause a disulfiram-like reaction if combined with
ethanol.
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Pharmacodynamics of Acute Ethanol Consumption
A. Central Nervous System :
 The CNS is markedly affected by acute alcohol consumption.
 Alcohol causes -sedation,
-relief of anxiety and,
At higher concentrations,
 slurred speech,
 ataxia,
 impaired judgment, and
 disinhibited behavior, a condition usually called intoxication or
drunkenness.
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• For chronic drinkers who are tolerant to the
effects of alcohol, higher concentrations are
needed to elicit these CNS effects.
• For example, an individual with chronic
alcoholism may appear sober or only slightly
intoxicated with a blood alcohol concentration of
300–400 mg/dL, whereas
this level is associated with marked intoxication
or even coma in a non-tolerant individual
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Blood alcohol concentration (BAC) and clinical effects in non-
tolerant individuals
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B. 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.
C. Smooth Muscle
 Ethanol is a vasodilator, probably as a result of
both CNS effects (depression of the vasomotor
center) and direct smooth muscle relaxation
caused by its metabolite, acetaldehyde.
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• 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. How?????
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CLINICAL PHARMACOLOGY OF
ETHANOL
Alcohol is the cause of more preventable
morbidity and mortality than all other drugs
combined with the exception of tobacco.
Polymorphisms associated with a relative
insensitivity to alcohol and presumably thereby a
greater risk of alcohol abuse have been identified
in genes encoding an α (alpha)subunit of the
GABAA receptor, an M2 muscarinic receptor, a
serotonin transporter, adenylyl cyclase, and a
potassium channel.
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• The link between a polymorphism in an opioid
receptor gene and a blunted response to
naltrexone raises the possibility of genotype-
guided pharmacotherapy for alcohol
dependence.
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MANAGEMENT OF ACUTE ALCOHOL INTOXICATION
• Nontolerant individuals who consume alcohol
in large quantities develop typical effects of
acute sedative-hypnotic drug overdose along
with the cardiovascular effects previously
described (vasodilation, tachycardia) and
gastrointestinal irritation.
• The most important goals in the treatment of
acute alcohol intoxication are to prevent severe
respiratory depression and aspiration of
vomitus.
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• The average blood alcohol concentration in
fatal cases is above 400 mg/dL; however, the
lethal dose of alcohol varies because of
varying degrees of tolerance.
• Electrolyte imbalances often need to be
corrected and metabolic alterations may
require treatment of hypoglycemia and
ketoacidosis by administration of glucose.
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• Thiamine is given to protect against Wernicke-
Korsak off syndrome.
• Patients who are dehydrated and vomiting should
also receive electrolyte solutions.
• If vomiting is severe, large amounts of potassium
may be required as long as renal function is
normal.
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MANAGEMENT OF ALCOHOL WITHDRAWAL
SYNDROME
• Abrupt alcohol discontinuation in an individual
with alcohol dependence leads to a
characteristic syndrome of motor agitation,
anxiety, insomnia, and reduction of seizure
threshold.
• The severity of the syndrome is usually
proportionate to the degree and duration of
alcohol abuse.
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Time course of events during the alcohol withdrawal
syndrome.
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Thank for your
attention!!!
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REFERENCES SOURCES
1 Katzung s Basic clinical Pharmacology 13th
Eddition
Page
Methanol poisoning 532-536 of 1739 pages
Ethanol poisoning 522-526 of 1739 pages
>> >> 529-530 of 1739 pages
2 Abramson, S, Singh, AK. “Treatment of the
alcohol intoxications: ethylene glycol,
methanol and isopropanol”. . vol. 9. 2000. pp.
695-701.
Kraut, JA, Kurtz, I. “Toxic alcohol
ingestions: clinical features, diagnosis, and
management”. . vol. 3. 2008. pp. 208-225
Internet source
(from web site)
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