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Year 4 - Toxicology > 13 - Toxic Alcohols > Flashcards

13 - Toxic Alcohols Flashcards

1
Q

What is an osmol gap?

A

Difference between measured osmolality and calculated osmolarity

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2
Q

What is osmolarity?

A
  • Measure of total # of particles in 1 L of solution (molar concentrations)
  • Usually calculated
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3
Q

What is osmolality?

A
  • Measure of total # of particles per kg of solution (molal concentrations)
  • Usually measured
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4
Q

Formula for calculated osmolarity (mOsm)

A
  • 2 * [Na+] + [glucose] + [BUN]
  • All concentrations in mmol/L
  • Or if concentrations in mEq/L and mg/dL:
    • 2 * [Na+ (mEq/L)] + [glucose (mg/dL)]/18 + [BUN (mg/dL)]/2.8
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5
Q

How can serum osmolality be affected?

A
  • May be increased by contributions of circulating alcohols and other low MW substances
  • These substances aren’t included in calculated osmolarity, so there will be a gap (delta Osm)
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6
Q

Formula for osmol gap

A
  • d Osm = Osm (measured) - Osm (calculated)

- Normal range = 10 +/- 6 mOsm

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7
Q

Describe ethanol elimination

A
  • 90-95% eliminated by enzymatic oxidation
  • 5-10% excreted unchanged (kidney, lung)
  • Michaelis-Menten kinetics (-dC/dt = Vmax*C / Km + C)
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8
Q

How much ethanol is eliminated in a human?

A
  • 100-125 mg/kg/h in occasional drinkers
  • Up to 175 mg/kg/h in habitual drinkers
  • Average-sized adult metabolizes 7-10 g/h, BAC level falls 15-20 mg/dL/h (in chronic drinkers it falls 30-40 mg/dL/h)
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9
Q

Described ethanol metabolism

A
  • First pass (ADH in gastric mucosa)
  • Liver metabolism
    • ADH (cytosol of hepatocytes)
    • CYP2E1 (endoplasmic reticulum)
    • Perioxidase-catalase system (perioxisomes)
    • ALDH (mitochondria)
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10
Q

Describe ethanol PD

A
  • Selective CNS depressant at low doses
  • General CNS depressant at high doses
  • MOA = multifactorial (increase of GABA-nergic function; inhibition of NMDA receptors and increase in dopamine release)
  • Functional tolerance (habituation)
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11
Q

At what BAC level can impairment begin to be detected? What are lethal doses of ethanol in adults and children?

A
  • In non-tolerant individuals, impairment of judgement can be detected at levels as low as 25 mg/dL
  • Lethal dose = 5-6 g/kg (non-tolerant); children = 3 g/kg
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12
Q

Signs and sx of acute ethanol intoxication

A
  • Flushed face, tachycardia, increased sweating
  • Mydriasis, muscular incoordination, ataxia
  • Altered consciousness
  • Euphoria, agitation
  • Sx of gastric irritation (N/V)
  • Death by respiratory depression
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13
Q

Stages of acute ethanol intoxication

A
  • 50 mg/dL = mild (decreased inhibition, slight incoordination)
  • 100 mg/dL = mild to moderate (slow reaction time, altered sensory ability)
  • 150 mg/dL = mild to moderate (altered thought processes, personality/ behaviour changes)
  • 200 mg/dL = moderate (mental confusion, N/V)
  • 300 mg/dL = severe (hypothermia, hypoglycemia, seizures)
  • 700 mg/dL = potentially lethal (unconsciousness, decreased reflexes, respiratory depression)
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14
Q

Metabolic derangements of acute ethanol intoxication

A
  • Hypoglycemia
  • Metabolic acidosis (due to lactate and/or ketoacids)
  • Hypomagnesemia
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15
Q

Management of intoxicated pt

A
  • Uncomplicated ethanol OD (monitoring, sedatives if pt antisocial)
  • Glucose, oxygen, thiamine
  • Confirm alcohol intoxication w/ levels
  • Finger stick glucose level
  • Electrolytes (magnesium)
  • Anion gap and osmol gap
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16
Q

Interventions for ethanol toxicity

A
  • Gastric lavage -> used if we suspect majority of alcohol is still in the stomach (possible b/c of pyloral spasm and alcohol causing delayed gastric emptying); depends on presentation and how long since ingestion
  • Hemodialysis -> effective, but rarely used for pure ethanol overdose; depends on level of intoxication
  • Emesis and activated charcoal not used
17
Q

Examples of chronic ethanol toxicity

A
  • Alcoholic liver disease
    • Fatty liver (90% of chronic drinkers, mobilization of fatty acids and inhibition of lipoprotein synthesis)
    • Alcoholic hepatitis (hepatocyte degeneration and necrosis)
    • Alcoholic cirrhosis (8-30% of chronic drinkers, hepatocyte destruction, progressive disease w/ poor prognosis)
  • Fetal alcohol syndrome
18
Q

Drug interactions with ethanol

A
  • Acute intoxication -> transient increase in plasma level or other agents (ex: phenytoin)
  • Alcoholism -> enzymatic induction, increased clearance (shorter t1/2) of phenytoin, methadone, tolbutamide, isoniazid, and warfarin
  • Additive effects w/ antihistamines, barbiturates and sedative-hypnotics
  • Increased acetaminophen hepatotoxicity (alcohol-APAP syndrome)
  • Cimetidine increases alcohol levels (decrease in first pass and inhibition of P450)
  • “Antabuse reaction” = sick feeling (tolbutamide, carbamates, metronidazole)
19
Q

What is alcohol withdrawal? What is the treatment?

A
  • Syndrome that ranges from mild to severe effects (ie: from agitation to delirium and seizures)
  • Habituation of organism to CNS depressant effects, uncompensated state of overstimulation (upregulation of NMDA receptors)
  • Symptomatic tx
20
Q

Tx of alcoholic patients

A
  • Diagnosis
  • Serotonin uptake inhibitors
  • Naltrexone
  • Acamprosate calcium (Campral)
  • Bromocriptine
  • Litihum
  • Disulfiram (inhibits metabolism?; not a great option)
  • Non-pharms
21
Q

Describe absorption and distribution of methanol

A
  • Absorption -> rapid from oral route (peak w/in 30-60 mins); also through inhalation and skin
  • Distribution -> Vd = 0.6-0.7 L/kg
22
Q

Methanol elimination

A
  • Zero-order kinetics at high concentrations
  • First-order at low concentrations (t1/2 = 1-3 h)
  • 10-20% eliminated unchanged by lungs
  • 3% unchanged in urine
  • Primarily liver metabolism
23
Q

Methanol metabolism

A
  • Affinity of ADH for ethanol is 4x greater than affinity for methanol
  • Conversion of formaldehyde to formic acid is very rapid (t1/2 = 1-2 minutes)
  • No accumulation of formaldehyde in blood
  • Formate metabolism is dependent upon presence of tetrahydrofolate to form 10-formyl tetrahydrofolate that can be metabolized to water and CO2
  • t1/2 of formate is as long as 20 h in humans
24
Q

What are the toxic metabolites of methanol?

A

Formaldehyde and formic acid

25
Q

Describe ocular toxicity of methanol

A
  • Caused directly by formic acid
  • Acidosis increases toxicity by favouring diffusion (vision can improve if acidosis is corrected)
  • Inhibition of retinal and optic nerve mitochondrial function
  • Occurs when formate concentration > 20-30 mg/dL
  • Retina = primary site of toxicity
  • Sx = blurred vision, “snow field” vision, reduced pupillary response to light
26
Q

Methanol tx

A
  • Standard supportive care
  • Correction of acidemia (IV sodium bicarb)
  • Fomepizole or ethanol
  • IV folinic acid (leucovorin)
  • Hemodialysis (t1/2 of formate = 165 min)
    • Action serum level for hemodialysis = > 25 mg/dL (> 7.8 mmol/L)
27
Q

Methanol tx priorities

A
  • Circumstances
  • Time after ingestion
  • Ethanol co-ingestion
  • Evaluation of acidosis, osmol gap, ethanol and methanol levels, anion gap
28
Q

Folic acid vs. folinic acid (leucovorin)

A
  • Folic acid reduced in vivo to tetrahydrofolic acid by dihydrofolic acid reductase
  • Folinic acid is 5-formyl tetrahydrofolic acid (preferred since doesn’t require metabolic reduction)
29
Q

Describe ethylene glycol elimination

A
  • 80% elimination by hepatic metabolism

- 20% unchanged in urine

30
Q

What is the action serum level of ethylene glycol for hemodialysis

A

> 25 mg/dL (> 4.03 mmol/L) w/ acidosis or renal insufficiency (renal insufficiency caused by precipitation of calcium oxalate)

31
Q

Ethylene glycol tx

A
  • Ethanol (serum concentration of 100 mg/dL)
  • Fomepizole (competitive inhibitor of ADH)
  • Thiamine and pyridoxine (100 mg and 50 mg IV q6h)
  • Folates
  • Hemodialysis
  • If osmol gap reveals that there is another alcohol besides ethanol, doesn’t matter which one b/c the tx is the same
  • *Intervention only different for ethanol, everything else the same; also doesn’t matter the amount
32
Q

Dosing of fomepizole

A
  • Loading dose = 15 mg/kg
  • 10 mg/kg q12h x 4 doses
  • 15 mg/kg q12h

Year 4 - Toxicology (22 decks)

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