Ethiopia Mulat,MSC candidate in pharmacology,UOG

2. METHANOL TOXICITY

3. OUTLINE

4. History
• First used by Egyptians by pyrolysis of wood
• Robert Boyle isolated pure methanol in 1661
• Jean-Baptist Dumas and Eugene Peligot determined its elemental
composition in 1834
 The name methylene,from the Greek words methu,"wine," and
hyle, "wood“
 Methyl derived in 1840 from methylene, and then applied to
describe methyl alcohol; shortened to methanol in 1892 by the
International Conference on Chemical Nomenclature

5. PHYSICO-CHEMICALPROPERTIES OF
METHANOL
• Clear
• Colorless
• Flammable
• Poisonous
• Highly polar liquid with slight alcohol odor
• Miscible with water, alcohol, ether, ketones and
most other organic solvents.
• Burns with a non-luminous, bluish flame

6. Cont…
• Boiling point: 65°C
• Melting point: 97.8°C
• Vapour pressure at 25°C: 125 mmHg (16.2 KPa)
at 20°C: 94 mmHg
• Explosive limits (vol.% in air): 6.0 to 36.5
• Autoignition temperature: 470°C (878°F)

7. Chemical structure
• Formula: CH3OH
• Molecular weight: 32.04

8. Hazardous characteristics
• Dangers associated with vapour, its dispersion,
and possible ignition
• The liquid is flammable and, at normal room
temperatures, it evolves vapours which form
explosive mixtures over a wide range of
concentrations.
• The extent of danger from inhaling vapours
depends on the concentration and the duration
of the exposure.

9. USES OF METHANOL
Clinical use
• Clinically methanol can be rarely applied to
skin as antiseptic for cleaning and astringent
purposes

10. General applications
 Precoursor for chemicals
 Energy carrier
 Fuel for vehicles

11. Cont…
• Denaturant for ethanol
• A solvent
• Automobile coolant antifreeze
• Mixed with water and injected into high performance diesel and gasoline
engines for an increase of power

12. Common sources
• There are several sources of human physiological
methanol.
• Fruits, vegetables, and alcoholic beverages are likely the
main sources of exogenous methanol in the healthy
human body.
• Metabolic methanol may occur as a result of
fermentation by gut bacteria and metabolic processes
involving S-adenosyl methionine.
• Low levels of methanol in the body are maintained by
physiological and metabolic clearance mechanisms.

13. physiological methanol biogenesis

14. Other sources
• Earth's atmosphere
• Plant-emitted gaseous methanol
• Natural gas and coal
• Demethylesterification of pectin
homogalacturonan by PME with methanol
formation

15. Demethylesterification of pectin
homogalacturonan

16. TOXICOKINETICS
• Absorption
• Methanol is readily absorbed from the gastrointestinal
and respiratory tracts, and also by the percutaneous
route.
Distribution
• After absorption, It is widely distributed in total body
water with a volume of distribution of 0.6 to 0.7 L/kg.
• There is no protein binding.
• Undissociated formic acid readily crosses the blood-
brain barrier.
• It is distributed poorly in fatty tissues.

17. Metabolism
• Majority of methanol is converted to formaldehyde,
principally in the liver, by alcohol dehydrogenase.
• Formaldehyde is then converted to formate by
aldehyde dehydrogenase .
• The oxidation of formaldehyde to formate occurs by at
least 3 separate pathways with the participation of
 P450 monooxygenases
 Mitochondrial aldehyde dehydrogenase 2 (ALDH2)
 Gene encoding ADH5, χχ ADH, also called ADH3 or
formaldehyde dehydrogenase (FDH).

18. Pathways of conversion of
formaldehyde into water and CO2.

19. Cont…

20. Elimination and excretion
• 30% of the ingested dose is excreted
unchanged by the respiratory tract.
• The kidney excretes less than 5% of
unchanged methanol.
• Urine formate excretion >70 mg/24 hours
confirms the diagnosis of methanol
intoxication.
• This compares with an average urinary
formate concentration of 2 to 30 mg/L in
non-exposed subjects

21. Major interactions that increase toxic
level of methanol
• Use of methanol with other drugs or over the
counter products at the same time may change
the effect of methanol.
• This may increase the risk for side-effects or
cause the drug not to work properly.
• Drugs which cause disulfiram-like reactions
upon ingestion of alcohol results in an
unintended effect

22. Mechanism of methanol toxicity

23. Sources of exposure
– cleaning materials
– solvents
– paints
– varnishes
– fuels
– formaldehyde solutions
– antifreeze
– gasohol
– windshield washer fluid (30-40% methanol)
– duplicating fluids

24. TOXIC CONCENTRATION
• As little as 10 mL of pure methanol can cause
permanent blindness by destruction of
the optic nerve.
• 30 mL is potentially fatal
• The median lethal dose is 100 mL (i.e. 1–
2 mL/kg body weight of pure methanol.
• The reference dose for methanol is 2 mg/kg
in a day
• Toxic effects begin hours after ingestion, and
antidotes can often prevent permanent
damage.

25. Clinical presentation
Acute Exposure symptoms
• Persons acutely exposed to high levels of
methanol via ingestion, inhalation, or
extensive skin contact may develop severe
metabolic, ocular, and neurologic toxicity.
• After a latent period of 12 to 24 hours,
methanol toxicity may result in progressive
visual disturbance and impairment of
consciousness due to the gradual build-up of
toxic metabolites.

26. Cont…
Chronic Exposure symptoms
• Persons chronically exposed to airborne
methanol at levels insufficient to cause
systemic acidosis may complain of eye
irritation and visual blurring, upper
respiratory irritation, headache,nausea, and
lightheadedness—all of which are reversible
under these conditions.
• Chronic short-term cutaneous exposures may
result in skin irritation

27. Complications
• It is associated with blindness, metabolic acidosis, coma, seizure,
cardiovascular collapse, respiratory failure and death.
Vision loss
• The mechanism by which the methanol causes toxicity to the visual
system is not well understood. 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.
• Movement disorders
• Parkinsonian motor impairment has been described in some long-
term survivors of methanol poisoning.
• This is thought to be due to formic acid’s predilection for
accumulating in high concentrations within the putamen, but the
reasons for this phenomenon are unclear.
• One proposed reason is that formic acid has the ability to impair
dopaminergic pathways and increase enzymatic activity of dopa-B-
hydroxylase.

28. Cont…
Anion gap and Metabolic acidosis
• The anion gap is the difference between the
sum of the measured cations and the sum of the
measured anions.
• Normally, the anion gap is about 12–
16mmol/L

29. Cont…
• The generation of formate and lactate contributes to the
anion gap during methanol intoxication.
Most seriously intoxicated patients with a serum bicarbonate
level ,18mEq/L had serum methanol concentrations over
50mg/dL (500mg/L).
• Mortality correlates best with severity of acidosis and
formate concentration
• Formate accounts for up to 50% of the early bicarbonate
deficit lead to ion gap acidosis.

30. Antidote treatment of methanol
toxicity
• There are two alternative antidotes, both of which act by
blocking the alcohol dehydrogenase-mediated metabolism of
methanol: ethanol, fomepizole.
• (i) Ethanol
• Effective because it has a much greater affinity for alcohol
dehydrogenase than methanol.
• A blood ethanol concentration of 100 mg/dL (22 mmol/L) will
almost completely block methanol metabolism.
• However, ethanol is sometimes technically difficult to
administer because of its rapid and unpredicatable rate of
metabolism .
• A loading dose followed by titrated maintenance therapy is
necessary.

31. Cont…
• Ethanol and fomepizole can be administered to
delay methanol metabolism until the methanol is
eliminated from the patient’s
• These antidotes work via competitive inhibition;
ethanol and fomepizole are metabolized by ADH,
just as methanol is, but the enzyme has a higher
affinity for both antidotes than it does for
methanol.
• For example, the affinity of ADH for ethanol is 10-
20 times greater than it is for methanol.
• The use of fomepizole is limited because of its
high cost and lack of availability

32. Cont…
• Suggested dosing of alcohol
• 1 mL/kg of 95% ethanol
• 10 mL/kg of 10% ethanol in 5% dextrose over 30 minutes
• Maintenance dose
• 0.1 – 0.2 mL/kg/hour of 95% ethanol
• 1-2 mL/kg of 10% ethanol in 5% dextrose over 30 minutes
• In an emergency, an equivalent amount of any alcoholic drink
may be administered orally.
• The maintenance dosing needs to be adjusted according
blood ethanol concentration, ideally measured hourly, to
maintain the concentration >100 mg/dL.

33. Fomepizole

34. Cont…
• Fomepizole inhibits alcohol dehydrogenase,
which catalyzes the metabolism of ethanol,
methanol and ethylene glycol

35. Cont…
• Fomepizole is easily administrated
intravenously as a loading dose of 15 mg/kg,
followed by bolus doses of 10 mg/kg every
12 hours.
• After 48 hours, the bolus doses should be
increased to 15 mg/kg every 12 hours
because of induced metabolism over time.
• No side effects have been reported with this
dosage regimen and effectiveness is clearly
demonstrated.

36. References
• Armstrong, Henry E (1892). "The International Conference on Chemical
Nomenclature". Nature. 46 (1177):569. Bibcode:1892Natur..46...56A.
• Arora V, Nijjar IB, Multani AS et al.: MRI findings in methanol intoxication: a report of two cases. Br J Radiol.
2007;80:e243–e246.
• Azmak D: Methanol related deaths in Edirne. Legal Med. 2006;8:39–42.
• Berger, Sandy (30 September 2006). "Methanol Laptop Fuel". Compu·Kiss. Retrieved 22 May 2007.
• Bessell-Browne RJ, Bynevelt M. Two cases of methanol poisoning: CT and MRI features. Australasian Radiol
2007;51:175.
• Boyle discusses the distillation of liquids from the wood of the box shrub in: Robert Boyle, The Sceptical
Chymist (London, England: J. Cadwell, 1661), pp. 192–195.

37. REFERENCES
• Brent J, McMartin KE, Phillips S, et al. Fomepizole for the treatment of methanol poisoning.
N Engl J Med 2001;344:424.
• Evaluation of the Fate and Transport of Methanol in the Environment Archived 16 May 2016
at the Portuguese Web Archive, Malcolm Pirnie, Inc., January 1999.
• Goodman & Gilman. The pharmacological bases of therapeutics, 12th
• Guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002;40:415.
• International Programme on Chemical Safety ,Poisons Information
Monograph335:http://www.inchem.org/documents/pims/chemical/pim335.htm#2.2
• Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: mechanism of toxicity,
clinical course, diagnosis and treatment. Med Toxicol 1986;1:309.
• Katzang .Basic and clinical pharmacology,13th edition

38. The end