13 - Toxic Alcohols Flashcards
1
Q
What is an osmol gap?
A
Difference between measured osmolality and calculated osmolarity
2
Q
What is osmolarity?
A
- Measure of total # of particles in 1 L of solution (molar concentrations)
- Usually calculated
3
Q
What is osmolality?
A
- Measure of total # of particles per kg of solution (molal concentrations)
- Usually measured
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
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)
6
Q
Formula for osmol gap
A
- d Osm = Osm (measured) - Osm (calculated)
- Normal range = 10 +/- 6 mOsm
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)
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)
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)
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)
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
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
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)
14
Q
Metabolic derangements of acute ethanol intoxication
A
- Hypoglycemia
- Metabolic acidosis (due to lactate and/or ketoacids)
- Hypomagnesemia
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
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
