TOXIC ALCOHOLS Flashcards
TOXIC ALCOHOLS
Alcohol Substance Causing Toxicity Key Effects
Ethanol b-Hydroxybutyric acid
Acetoacetic acid
Metabolic acidosis
Methanol Formic acid
Lactic acid
Ketone
Metabolic acidosis
Hyperosmolality
Retinal damage
Neurologic dysfunction
Ethylene glycol Glycolic acid
Calcium oxalate
Metabolic acidosis
Hyperosmolality
Hypocalcemia
Cardiac, cerebral, renal
Diethylene glycol 2-Hydroxyethoxyacetic acid Metabolic acidosis
Hyperosmolality
Neurologic, renal
Propylene glycol Lactic acid Metabolic acidosis
Hyperosmolality
Isopropanol Isopropanol Hyperosmolality
Coma
Hypotension
METHANOL AND ETHYLENE GLYCOL – SOURCE?
Exposure
- Suicide/homicide
- Accidental
- Recreational]
MeOH
- USA - ~2100 cases, 11 deaths (2018)
- Windshield wiper fluid
- Varnish, paint thinner (huffing)
- Fuel – camping stoves
- Industrial – denaturant
- ‘Bootleg alcohol’ – moonshine
- Often repeat patients (retrospective
study of emergency department
found 113 visits by 18 patients)
Ethylene glycol (EG)
- USA - ~7200 cases, 19 deaths (2018)
- Antifreeze
- Natural gas industry
- Liquid cooled computers
- Household cleaning products
- Pesticides
- Industrial solvents (for paints, plastics)
METABOLISM
i.) Fomepizole
ii.) Ethanol
(both competitive inhibitors of ADH)
PHARMACOKINETICS
MeOH
- Km = 54mMol
- T½ without ADHi (14-30h)
- T½ with ADHi (43-96h)
- Hepatic 97%
Ethylene glycol
- Km = 40mMol
- T½ without ADHi (3-8h)
- T½ with ADHi (17-18h)
- Hepatic 80%, Renal 20%
Zero order – occurs when enzyme is
saturated
(rate is independent on [drug])
1st order – rate is directly proportional to
substrate concentration
(rate is dependent on [drug])
Note: EtOH becomes zero order at 1mM
(DUI – 17mM)
TOXICITY – HOW MUCH?
MeOH
Oral Exposure
- 30 mL can be toxic (> 6.2mM)
- 1-2mL/kg = median lethal dose
Inhalation and Dermal Exposure
- Well absorbed
EG
Oral Exposure
- ~1.4 ml/kg can be toxic (>3.2mM)
Inhalation and Dermal Exposure
- Poorly absorbed
Decontamination
- Within 1h, use NG tube and suction stomach
- No role for activated charcoal as it does not absorb alcohols
TOXICITY (METHANOL)
- Metabolic acidosis and visual problems are the hallmarks
- Formic acid (or formate)
- Inhibits cytochrome c oxidase (mitochondrial ETC)
- Stops OXPHOS, ATP production – tissue hypoxia
- In photoreceptors found in the retinal excessive cell death from
mitochondrial damage blindness, cells do not regenerate
https://bio.libretexts.org/
Formic acid - Decreased visual acuity,
photophobia, blurred vision - Abdominal pain
SYMPTOMS – TIMING (METHANOL)
Stage 1 (0 – 6 hours)
- Mimics ethanol intoxication (Isopropyl=EG>EtOH>MeOH)
- Inebriation (dizzy, ataxia, confusion)
- Gastric irritation (pain, nausea, vomiting)
- Absence does not rule-out toxic concentration
Stage 2 (6 – 30 hours)
- Latent period – critical
- Inebriation resolves
- May be asymptomatic (co-ingestion of EtOH common)
Stage 3 (6 – 72 hours)
- Toxicity
- Visual symptoms start to appear (blurred vision, blindness)
- Seizure, coma, cerebral edema, herniation
- Cardiac failure, respiratory arrest
TOXICITY – ETHYLENE GLYCOL
Metabolic acidosis and organ dysfunction primarily from glycolic and oxalic
acid
- Glycolic acid - overwhelms the buffering ability of HCO3
- in the blood
- Glycolic acid = Impairment of cellular respiration
- Oxalic acid - Calcium oxalate crystals produced which precipitate in
blood, clogging renal microcirculation, tubular necrosis (oxalic acid +
Ca2+)
- Hypocalcemia lead to myocardial dysfunction, renal failure
- Neurologic, cardiopulmonary and renal failure
SYMPTOMS – TIMING (ETHYLENE GLYCOL)
Stage 1 (30 min – 12 hours)
- Mimics ethanol intoxication
- Inebriation (dizzy, ataxia, confusion)
- Gastric irritation (pain, nausea, vomiting
- Early neurologic CNS depression, cerebral edema, seizure
Absence does not rule-out toxic concentration
Stage 2 (12-24 hours)
- Cardiopulmonary stage
- Cardiac dysfunction, shock
- Tachypnea, ARDS
Stage 3 (24-72 hours)
- Renal stage – failure
Stage 4
- Late neurologic damage
OSMOLAL AND ANION GAP
KEY: Osmolal gap decreases while anion gap increases.
Serial Anion Gap
§ Clinically significant poisoning will
cause elevation in anion gap
§ EG and MeOH – as parent
alcohol levels fall, acidic
metabolites rise
§ Note: inhibition of ADH
(fomepizole or EtOH) can delay
the elevation
§ Anion gap measure at baseline
then repeated 2-4h for ~6-12h
passed ingestion
MEASURING OSMOLAL GAP – CAUTION OR CONSIDERATION?
Standardization
§ Numerous different equations – what is the best?
§ No consensus on upper limit (10-20mOsm)
§ Ranges may vary between labs
Low sensitivity
§ Values span over a range ~20mOsm
§ Ethylene glycol level >20 mg/dL shift in osmolal gap only 3mOsm/L
§ Baseline is at lower end of normal – clinically significant intoxication within
‘normal’ gap
§ Later stages of intoxication as EG or MeOH are metabolized osmolal gap
may be absent
Low specificity
§ Elevated osmolal gap may be caused by any uncharged molecule (ie., EG,
MeOH, EtOH, ketoacidosis, renal failure, shock)
§ Thus an elevated osmolal gap doesn’t prove EG or MeOH intoxication
LACTATE GAP
§ EG and MeOH poisoning can
elevate lactate levels
§ Mitochondrial poison
§ Patients often low thiamine levels
§ Stress response
§ Generally, lactate is low (<5mM)
§ Does not fully account for elevated
anion gap (attributed to formate
and glyoxylate)
§ Issue with sensitivity of assays
used:
§ Portable blood gas (lactate
oxidase) cannot differentiate
§ Lab assay (GC spec) uses lactate
dehydrogenase
TREATMENT –
Goals
Call PADIS
1) Block the toxic metabolite formation (inhibit ADH –fomepizole, EtOH)
2) Correct pH to 7.2 (bicarbonate)
3) Eliminate toxic metabolites (dialysis)
- Delays in starting treatment can lead to worse outcomes…
TREATMENT – ALCOHOL DEHYDROGENASE INHIBITION
Fomepizole – preferred therapy (very expensive)
§ Initial dose 15mg/kg iv
§ 10mg/kg iv, 12h for 4 doses (2 days)
§ 15mg/kg iv, 12h
- stop when toxic alcohol levels or safe
- MeOH (<6.2mM)
- EG (<3.2mM)
- Elimination can take a long time
- Dialysis may be required to clear parent alcohol
Ethanol – 2nd line therapy if fomepizole is not available therapy
§ Dosing is tricky – target blood alcohol 22-23mM (0.08%, 17mM driving legally drunk)
§ Oral alcohol – loading dose (~17mmol/kg) maintenance dose (~1.4-2.8mmol/kg/hr
~1/2 standard drink per hour)
§ Monitor (ie., anion gap increases ADHi not adequate)
§ Hard alcohol might better than beer/wine (less volume)
§ Pregnancy – fomepizole preferable
TREATMENT
Dialysis
Bicarbonate
Dialysis
Goal – Remove toxic alcohols and metabolites
§ Metabolic acidosis (pH<7.15), anion gap >24mM
§ End-organ damage (coma, seizure, vision changes, renal failure)
§ MeOH (>15mM) or EG (>6mM) levels
§ Continue ADHi during dialysis
Bicarbonate
§ Normalizing pH to keep metabolites in ionized state
§ Prevent penetration into tissues
§ Increase urinary excretion
