toxicology

1. Alcohol intoxification

2. Ethanol toxicity
Ethanol is a 2-carbon–chain alcohol; the
chemical formula is CH2 CH3 OH. It is
ubiquitous throughout the world and is a
leading cause of morbidity across cultures.
It is one of the most commonly abused drugs.

3. Phatrmacokinetics
The primary route of absorption is oral,
although it can be absorbed by inhalation and
even percutaneously.
Ethanol is rapidly absorbed, and peak serum
concentrations typically occur 30-60 minutes
after ingestion. Its absorption into the body
starts in the oral mucosa and continues in the
stomach and intestine. Both high and low
concentrations of ethanol are slowly absorbed;
the co-ingestion of food also slows absorption.

4. Ethanol has a volume of distribution (0.6 L/kg)
and is readily distributed throughout the body.
Ethanol is primarily metabolized in the liver.
Approximately 90% of an ethanol load is
broken down in the liver; the remainder is
eliminated by the kidneys and lungs.
 In children, ethanol is cleared by the liver at
the rate of approximately 30 mg/dL/h, which is
more rapid than the clearance rate in adults.
In the liver, ethanol is broken down into
acetaldehyde by alcohol dehydrogenase
(ADH). Then, it is further broken down to
acetic acid by acetaldehyde dehydrogenase.

5. Acetic acid is fed into the Krebs cycle and is
ultimately broken down into carbon dioxide
and water. Also, a gastric isozyme of ADH
breaks down a significant amount of ethanol
before it can be absorbed; sex differences in
ADH may, in part, account for differences in
ethanol effects per given quantity consumed
between men and women.
Disulfiram reduces the rate of oxidation of
acetaldehyde by competing with the cofactor
nicotinamide adenine dinucleotide (NAD) for
binding sites on aldehyde dehydrogenase.

7. Pathophysiology
Ethanol exerts its actions through several
mechanisms. For instance, it binds directly to the
gamma-aminobutyric acid (GABA) receptor in
the CNS and causes sedative effects similar to
those of benzodiazepine.
 Furthermore, ethanol is also a glutamate
antagonist in the CNS.
Ethanol also has direct effects on cardiac muscle,
thyroid tissue, and hepatic tissue. However, the
exact molecular targets of ethanol and the
mechanism of action are still the subjects of
ongoing research

8. In young children, ethanol causes
hypoglycemia and hypoglycemic seizures;
these complications are not as common in
older patients.
Hypoglycemia occurs secondary to ethanol's
inhibition of gluconeogenesis and secondary to
the relatively smaller glycogen stores in the
livers of young children.
In toddlers who have not eaten for several
hours, even small quantities of ethanol can
cause hypoglycemia.

9. Ethanol use is also strongly linked to risk-taking
behaviors that can lead to major trauma,
minor trauma, illicit drug use, and teenage
pregnancy. Especially trauma due to motor
vehicle collisions or violent crimes
The concomitant use of ethanol and other
drugs is common, and combinations of ethanol
with other sedative-hypnotics or opioids may
potentiate the toxic effects.
Young children commonly ingest ethanol
when they drink a liquid not meant for
consumption, such as perfume or cleaning
agents.

10. Frequently, other chemicals in the ingested
substance are more toxic than the ethanol.
Therefore, a detailed physical examination is
important to evaluate for any signs and
symptoms caused by these other toxins. Also,
give special attention to the examination of the
oral cavity and airway because substances in
cleaning agents can cause chemical burns to
these areas.


11. SIGNS AND SYMPTOMS
Ethanol has a sedative effect, producing
general CNS depression, respiratory
depression, hypoxia and hypoglycemia.
In children, the classic triad of signs of ethanol
intoxication includes coma, hypoglycemia, and
hypothermia.
Mild vasodilatation leading to a modest
decrease in blood pressure
Flushed skin
 tachycardia

13. Chronic ethanol use can lead to the following:
Fetal alcohol syndrome
Chronic pancreatitis
Hepatic dysfunction
Hematologic disorders
Numerous electrolyte abnormalities
Hypertension
Cardiomyopathy
Malnutrition
Obesity

14. Work up
Blood glucose level
Blood electrolytes
Blood ethanol level. Clinical findings and
ethanol concentrations may be categorized as
follows (these are rough estimates only and
have not been validated in children):
Intoxication or inebriation - 100-150 mg/dL
Loss of muscle coordination - 150-200 mg/dL
Decreased level of consciousness - 200-300 mg/dL
Death - 300-500 mg/dL

16. Pregnancy Test
Serum salicylate and acetaminophen levels: In
intentional suicidal ingestions, the presence of
other toxic substances must be determined.
Urine drug levels: Older patients may have
ingested recreational drugs such as cocaine,
marijuana, benzodiazepines, amphetamines,
and opiates.
Methanol levels: These results can be helpful
if an ingestion of combined substances is
suspected. A positive methanol level can alert
the physician to a co-ingestion.

17. Arterial blood gases: The pH can help in ruling
out the co-ingestion of methanol and ethylene
glycol, because significant academia is
associated with those ingestions.
Serum calcium and magnesium levels: High
concentrations of ethanol and its chronic use
can deplete these cations.

18. Management
Maintain airways and respiration.
Correct hypotension.
Quickly correct hypoglycemia. In children, 2-4
mL/kg of 25% dextrose solution is usually
administered. A maintenance infusion of
dextrose-containing IV fluids is often required.
Correct any electrolyte abnormalities found with
laboratory studies. Routine empiric electrolyte
replacement is not helpful; only documented
electrolytic abnormalities should be corrected.

19. If the ingestion occurred within 1 hour of
presentation, placing a nasogastric tube and
evacuating the stomach contents can be helpful.
In patients with chronic ethanol abuse,
administer thiamine 100 mg IV/intramuscularly
to prevent neurologic injury.
Additional care: If other substances have been
co-ingested, initiate specific treatment for those
substances, if available. For instance, naloxone
can be used to reverse respiratory depression if
opiate co-ingestion is suspected.

20. The administration of medications to cause
emesis is not recommended because of the
rapid onset of CNS depression and risk of
aspiration.
The administration of activated charcoal is not
recommended for isolated alcohol ingestions
because it does not bind hydrocarbons or
alcohols. If the clinician suspects a
concomitant ingestion of other toxic products,
activated charcoal may be effective in
absorbing these toxins.

21. Forced diuresis is not helpful because 90% of
ethanol metabolism occurs in the liver, and
only 10% of the ethanol load is secreted in the
urine.
GABA-receptor antagonists such as naloxone
and flumazenil have little effect on the CNS or
respiratory depression caused by ethanol; their
use is not recommended in isolated ethanol
intoxication.
Patients who have impaired hepatic function
may require dialysis to clear an ethanol load.

22. Isopropyl alcohol
Isopropyl alcohol is commonly found as both a
solvent as well as a disinfectant. It can be found in
many mouthwashes, skin lotions, and rubbing
alcohol.
Because of its widespread availability, lack of
purchasing restrictions, and profound intoxicating
properties, it is commonly used as an ethanol
substitute.
Isopropanol is metabolized via alcohol
dehydrogenase to acetone.

23. The peak concentration of acetone is not
present until approximately 4 hours after
ingestion. Both the CNS depressant effects and
the fruity odor on the patient's breath are due
to acetone.
isopropanol is irritating to the GI tract.
Therefore, abdominal pain, hemorrhagic
gastritis, and vomiting can be observed.

24. Methanol
Methanol is widely used as an industrial solvent
and paint remover. It is also used in photocopying
fluid, and windshield-washing fluids.
Although toxicity primarily occurs from
ingestion, it can also occur from prolonged
inhalation or skin absorption.
Methanol is primarily metabolized in the liver via
alcohol dehydrogenase into formaldehyde.
Formaldehyde is subsequently metabolized via
aldehyde dehydrogenase into formic acid, which
ultimately is metabolized to FOLATE.

25.  Formate is toxic because it inhibits mitochondrial
cytochrome c oxidase, causing the symptoms of
hypoxia at the cellular level, and also causing
metabolic acidosis, among a variety of other
metabolic disturbances
metabolic acidosis is associated with
hypoventilation, pancreatitis, nausea, and
abdominal pain.
It is mainly toxic to eyes and the patient usually
complain of visual problem, hyperemia of the optic
disc. Over several days, the red disc becomes pale,
and the patient may become blind.

26. TREATMENT
The primary antidotal treatment of methanol
blocking alcohol dehydrogenase. This enzyme
can be inhibited by either ethanol or fomepizole.
Toxic alcohol levels are frequently not
immediately available. Thus, ideally, if methanol
poisoning is suspected, the patient should
receive a loading dose of fomepizole while the
levels are being obtained.

27. If ethanol is used, the recommended target
serum concentration is 100-150 mg/dL.
 Because ethanol inhibits gluconeogenesis,
hypoglycemia is common in patients on an
ethanol infusion. Thus, serum glucose levels
must be checked frequently, at least every 2
hours.
In addition, because it is difficult to attain a
steady serum concentration of ethanol, the
ethanol level also must be checked frequently,
and titrations made.

28. significant metabolic acidosis should be
treated with sodium bicarbonate infusions. If
methanol is suspected, folinic acid should be
administered at a dose of 1 mg/kg, with a
maximal dose of 50 mg. It should be repeated
every 4 hours. If folinic acid is not
immediately available, folic acid can be
substituted at the same dose.
Based on experimental studies, formate
appears to be excreted in the kidneys at a much
higher rate when the patient is not acidotic.

29. In addition, when the patient is not acidotic, formic
acid dissociates to formate at lower rates so that
less formate crosses the blood-brain barrier. Thus,
in methanol intoxication, correcting the acidosis
actually speeds up elimination of the toxic
compound and decreases toxicity.
Leucovorin (folinic acid) is active form of folate
and may be substituted for folic acid may act as an
adjunctive agent in methanol ingestion. It may
enhance elimination of toxic metabolite formic acid
produced when methanol is metabolized. Folic acid
should be administered for several days to enhance
folate-dependent metabolism of formic acid to
carbon dioxide and water.

30. Hemodialysis is frequently required in patients
with significant methanol ingestions.[13