Toxicity of Alcohols

Ethylene Glycol Isopropyl alcohol

Methanol
 Introduction
• Alcohols are hydrocarbons that contain a hydroxyl group
• A compound with two hydroxyl groups is called a diol or a glycol
• Toxic alcohols commonly refer to methanol, ethanol, ethylene glycol and isopropyl alcohol
• Less common but potentially toxic alcohols include diethylene glycol, benzyl alcohol and
the glycol ethers

Ethylene Glycol
Methanol Isopropyl alcohol
 Methanol
• Methanol is a clear colorless liquid with a faint alcoholic
odor with many commercial uses
✓ Antifreeze/ Anti icing agent in windshield wiping fluids
✓ gasoline additives as octane booster
✓ As solvent and extraction agent in many industries.
✓ Fuel source for camp stoves and chafing dishes
✓ Manufacture of acetic acid, formaldehyde, inorganic
acids, cleaning solutions, printing and duplicating
solutions, adhesives, enamels, stains, dyes, and
varnishes
✓ Varnish and paint removers
✓ Ethanol denaturant in the preparation of industrial
methylated spirits.
 Ethylene Glycol
• Ethylene glycol (EG) is a colorless, odorless, sweet-
tasting substance. It has many commercial uses:
✓ Coolant mixtures
✓ Antifreeze
✓ Air craft de-icing solutions
✓ Solvent (inks, pesticides and adhesives)
✓ Brake fluid
✓ Heat exchangers and condensers
✓ Glycerin substitute (as preservative, and in
manufacturing of paints, cosmetics, polishes,
and detergents).

• It may be ingested as an alcohol substitute by

alcoholics, in suicide attempts, and accidentally by
children.
 Isopropanol
• Isopropanol is a colorless liquid with a
bitter taste. It has many commercial
uses :
✓ Synthesis of acetone, glycerin
✓ Solvent for oils, gums and resins
✓ Deicing agent
✓ Rubbing alcohol (Most rubbing
alcohol contains 70% isopropanol)
✓ as solvents in various industrial
products like hair care products,
skin lotion and aerosols
 Pharmacokinetiks
• Exposure to alcohols and glycols may occur dermally,
pulmonary and GI
• Rapidly absorbed by the gastrointestinal route (mean
absorption half-life for methanol is 5 min, Pulmonary
absorption depends on vapor pressure
• Time to peak concentration after GI route
– Ethylene glycol = 1 - 4 hrs
– Methanol, isopropyl alcohol = 30 - 60 minutes (Depending
on the presence or absence of food)
• All distribute well throughout the different body compartments
(VD is 0.5-0.8 L/kg).
• Binding affinities to plasma and tissue proteins are variable
(methanol>ethylene glycol >isopropanol)
 Pharmacokinetiks (cont’d)
• Liver enzymes deal with metabolism. Methanol and EG are
metabolized by alcohol dehydrogenase (ADH) and aldehyde
dehydrogenases(FMD ,and ALDH), while Isopropanol is
metabolized by alcohol dehydrogenase.
• Toxicity of EG and methanol is attributed mainly to their toxic
metabolites, resulting from oxidation of parent compounds. unlike
methanol and EG, the toxic effects are mediated by isopropanol
rather than its metabolite
 Pharmacokinetiks (cont’d)
• Elimination half-life of methanol is 12 to 20 hours
and for its toxic metabolite; formic acid averages 20
hours.
• Persistence of formic acid provides a biomarker to
monitor and assess occupational and poisoning
exposure to methanol.
• Formate metabolites is mainly execrated in urine.
• The volatility of methanol contributes to its
pulmonary excretion (10-20%).
 Pharmacokinetiks (cont’d)
• Ethylene glycol’s minimal lethal dose of EG for an adult is 1.0 to 1.5 mL/kg or 100
mL.
• Elimination half-life of 3-8 hours. Liver metabolizes 80% of the absorbed dose of
EG, and proximal tubules reabsorb 80% of filtered EG. Twenty percent of the EG
is excreted unchanged by the kidneys.
• EG is oxidized by alcohol dehydrogenase to glycolaldehyde and then to glycolic
acid.
• Glycolic acid is then converted to glyoxalic acid. The final end products include
oxalic acid, glycine, oxalomalic acid, and formic acid.
• Accumulation of these metabolites contributes to toxicity rather than EG itself,
pyridoxine (vitamin B6) and thiamine (vitamin B1) act as cofactors in glyoxalate
• Isopropanol is rapidly metabolized to acetone via alcohol dehydrogenase.
Acetone is predominantly renally excreted. 20% is excreted unchanged.
 Pathophysiology
• In methanol toxicity, formic acid inhibits cytochrome C oxidase activity in
mitochondria, thus preventing oxidative metabolism.
• Acidosis is main feature in methanol poisoning which is facilitated by both
direct and indirect effects of formic acid.
• Formic acid directly delivers a proton as it dissociates to formate and hydrogen
ions. Second, formic acid interferes with cellular metabolism, shifting aerobic
to anaerobic glycolysis and lactate , which worsens acidosis. Worsening
acidosis increases formate transfer across blood-brain barrier, leading to CNS
effects and also hypotension.
• Clinical symptoms result from damage to the CNS, eye, and GIT. Onset of
symptoms ranges from 40 minutes to 72 hours with an average of 24 hours.
Clinical presentation is characterized by early, latent, and delayed stages.
• Early stages of methanol intoxication are mild and transient, manifesting as
mild euphoria, and drowsiness followed by a latent interval phase lasting from
6 to 30 hours during which period metabolism of methanol occurs. Sensorium
remains essentially clear, with blurred vision as the only symptom.
 Pathophysiology (cont’d)
• Late phase leads to severe systemic toxic effects resulting from worsening
acidosis and accumulation of toxic metabolites.
• CNS manifestations include headache, vertigo, lethargy, and confusion.
• Severe toxicity leads to development of Parkinson-like extrapyramidal
syndrome characterized by rigidity, bradykinesia, mild tremor, and lethargy
with coma and convulsions indicating development of cerebral edema.
• Death may occurs due to respiratory failure or, rarely, to circulatory collapse.
• Ocular symptoms are highly variable and may include blurred vision, impaired
pupillary response to light, decreased visual acuity, photophobia, visual field
defects (snow Field),or progression to complete blindness which may be
irreversible in up to 25 to 33% of patients.
• Other clinical findings include GI symptoms such as nausea, vomiting, and
abdominal pain resulting from pancreatitis. Myoglobinuria is a rare
complication of methanol poisoning, which can lead to acute kidney injury
 Pathophysiology (cont’d)
• In ethylene glycol poisoning, multifactorial. mechanisms are involved; metabolic
acidosis resulting from accumulation of EG metabolites (aldehydes, glycolate,
oxalate, and lactate), tissue necrosis resulting from tissue deposition of calcium
oxalate crystals, and altered osmolality of extracellular fluid.
• Clinical features may be divided into three stages depending on the time elapsed
since ingestion:
• 1: Neurologic stage (0.5–12 Hours After Ingestion): patients experience nausea
and vomiting resulting from gastric irritation and inebriation with euphoria. Within
4-12 hours EG oxidized acidic metabolites accumulate leading to metabolic
acidosis. Acidic metaboloites cross BBB leading to
• CNS depression and alteration of consciousness, hyporeflexia, nystagmus, slurred
speech and ataxia, myoclonic jerks and occasionally, seizures. Symptoms are
progressing to coma in severe intoxication.
• 2: Cardiopulmonary Stage (12–24 Hours After Ingestion): Patients develop
hyperventilation to compensate for severe metabolic acidosis and severe hypoxia,
hypoglycemia, hypotension and reflex tachycardia. Most deaths occur during this
stage due to pulmonary oedema, acute respiratory distress, multiorgan failure,
and heart failure.
• 3: Renal Stage(24–72 Hours After Ingestion): This stage is characterized by
crystalluria, flank pain, then oliguric renal failure and acute tubular necrosis renal
failure, and rarely bone marrow suppression. In severe poisoning, renal failure
appears early and progresses to anuria.
 Pathophysiology (cont’d)
• Symptoms of isopropanol intoxication usually start within 30
minutes of ingestion. Symptoms range from GI side effects
such as nausea, vomiting, abdominal pain, gastritis, and
hematemesis to CNS side effects, including headache,
dizziness, confusion, and stupor.
• Sever intoxication results of profound CNS depression
associated with hypotension, tracheobronchitis, acute renal
failure, seizures, coma, and death.
 Diagnosis
• Methanol overdose should be considered in patients presenting with altered
mental status with visual disturbances, abdominal pain with high anion gap
metabolic acidosis, and increased osmolar gap (OG) (Measured Serum Osmolarity -
Calculated Serum Osmolarity), Osmolality is calculated by using the formula: 2 (Na)
+ (blood urea nitrogen/2.8) + (glucose/18). OG is a useful indicator for assessing
poisoning with higher alcohols. Normally, the value of the gap is 10 to 15 mOsm/kg.
• Laboratory tests include CBC, serum electrolytes, calcium, phosphate, lactate,
serum osmolality, anion gap, arterial blood gas, and urinalysis in addition to
measurement of methanol and ethanol levels.
 Diagnosis (cont’d)
• EG poisoning should be suspected in
patients presenting with altered mental
status, severe metabolic acidosis with
high anion gap and OG, hypocalcaemia,
and urine analysis showing oxalate
crystals. Calcium oxalate monohydrate crystals

• Other laboratory abnormalities include

hypocalcaemia causing QT prolongation
on electrocardiogram and microscopic
hematuria, low bicarbonate, leukocytosis,
and increased protein in the CSF.
Calcium oxalate dihydrate crystals
 Diagnosis (cont’d)

• Isopropanol poisoning can be diagnosed in patients with

normal acid-base parameters, and hyperosmolarity which is
the most common laboratory abnormality associated with
isopropanol poisoning
 Treatment
• Management of methanol toxicity involves preventing serious
complications that can result from accumulation of toxic metabolites
of methanol. Initial step in treatment is focused on preventing the
development of metabolic acidosis, ophthalmologic abnormalities,
and coma if they have not already supervened, or correcting the acid-
base disturbance if present.
• If the patient is comatose, initial supportive care include ABC’s steps.
• Gastric lavage may be considered if the patient presents within 1 hour
of ingesting methyl alcohol ,while activated charcoal is probably of
little use as it does not absorb significant amounts of methyl alcohol.
• Hemodialysis effectively removes methanol and formic acid, corrects
metabolic acidosis, and shortens the hospital stay. Hemodialysis is
continued until the serum methanol concentration is undetectable,
and OG is normal.
 Treatment (cont’d)
• Metabolic acidosis should be
corrected immediately with
intravenous sodium bicarbonate.
• Folic acid supplementation plays an
important role in the management of
methanol toxicity as enhance the
metabolism of formic acid to less
toxic metabolites.
• Ethanol and fomepizole should be
administered rapidly as soon as
methanol ingestion is suspected to
prevent the formation and
accumulation of formate.
 Treatment (cont’d)
• Fomepizole acts as competitive Inhibitor of alcohol dehydrogenase (in vitro:
80,000 times affinity for ADH than methanol) that inhibits the metabolism of
methyl alcohol to its toxic metabolites. Fomepizole is given I.V. at a loading
dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 2 days. After 48
hours, dose should be increased to 15 mg/kg every 12 hours till the symptoms
resolve
• It is approved by FDA for treatment of methanol poisoning in 2000.

• Ethanol is another competitive inhibitor bind to alcohol dehydrogenase.

Ethanol can be given oral or I.V. as 10% ethanol. The loading dose of ethanol is
0.6 - 0.7 g ethanol/kg, and the maintenance dose is 66 mg ethanol/kg/hr for
nondrinkers and 154 mg ethanol/kg/hr for alcoholics. It is used in some areas
of the world as specific antidote in treatment of methanol toxicity even it is
not approved by FDA.
 Treatment (cont’d)
• Administration of fomepizole is preferred over ethanol for many reasons. It is easier to
administer and has a longer duration of action, whereas ethanol dosing is complex and is
associated with errors, and ethanol should be dosed for every hour compared with every 12
hours administration of fomepizole.
• Fomepizole administration is not associated with neither CNS depression nor hypoglycemic
effect if compared with ethanol administration. Disadvantages of fomepizole administration
include higher costs and hypersensitivity reaction.
• Other supportive measures include intravenous fluids and antiseizure medications for
control of seizures.
 Treatment (cont’d)
• In treatment of EG poisoning, the main aim is to prevent the formation of
toxic metabolites or dialytic removal of toxins and their metabolites.
Indications for gastric emptying and guidelines for administration of
sodium bicarbonate are the same as those given for methanol.
• Antidotes used are fomepizole and ethanol, similar to treatment of
methanol poisoning.
• If the patient is hypocalcemic, 10 mL of calcium gluconate 10% should be
given IV.
• Pyridoxine 100 mg and thiamine 100 mg IM or IV should be administered
daily to facilitate metabolism of ethylene glycol by nontoxic pathways.
• An EG level of 50 mg/dL is an indication for hemodialysis or peritoneal
dialysis
 Treatment (cont’d)

• In treatment of Isopropanol poisoning, supportive

measures (including ABC’s steps, gastric lavage, activated
charcoal, and induction of emesis) are generally sufficient if
patient is not comatose or hypotensive. It is reasonable to
initiate hemodialysis if the patient presents with
hypotension and coma or isopropanol blood level is 150-200
mg/dL.