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ACEM Primary Written > Anaesthetics: Pharmacology - Alcohol > Flashcards

Anaesthetics: Pharmacology - Alcohol Flashcards

1
Q

Mechanism of action of ethanol

A

Affects large number of proteins that participate in signalling pathways
Enhances action of GABA at GABA(A) receptors
Also inhibits ability of glutamate to open NMDA-associated cation channels (likely responsible for “blackouts” with alcohol intoxication)

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2
Q

Describe the absorption of ethanol

A

Rapidly absorbed from GIT, with peak levels within 30mins during fasting state (food ingestion delays absorption by delaying gastric emptying)

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3
Q

Describe the distribution of ethanol

A

Rapid and wide, with tissue levels approximating blood levels
Readily crosses BBB and placenta
Vd 0.5-0.7L/kg

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4
Q

What is the difference in peak concentrations of alcohol between sexes? What accounts for this?

A

Higher peak concentration in women due to lower TBW and differences in first-pass metabolism
Women also have lower amounts of gastric ADH

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5
Q

Describe the metabolism of ethanol

A

> 90% oxidised in liver (with remainder excreted through lungs and in urine)
Follows zero-order kinetics with two major pathways of metabolism:
- ADH pathway
- Microsomal ethanol oxidising system (MEOS)

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6
Q

How many g/hr of ethanol can an adult metabolise?

A

7g/hr

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7
Q

Describe the ADH and MEOS pathways of ethanol metabolism

A

Alcohol dehydrogenase and MEOS both convert ethanol to acetylaldehyde
MEOS only important at high concentrations when ADH becomes saturated due to depletion of NAD+
Aldehyde dehydrogenase then converts acetylaldehyde to acetate, which is then further metabolised to CO2 and H2O

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8
Q

Where is ADH found?

A

Cytosolic enzyme found mostly in liver, with small amounts in other organs including brain and stomach

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9
Q

What is the clinical significance of the genetic variation in ADH?

A

May confer more rapid metabolism of ethanol (e.g. in East Asian populations)

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10
Q

What is the clinical significance of the excess NADH production that results from ADH’s metabolism of ethanol?

A

Acute alcohol poisoning: causes lactic acidosis and hypoglycaemia
Chronic alcoholism: likely contributes to metabolic disorders

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11
Q

Which CYP450 enzymes are involved in MEOS?

A

2E1, 1A2, 3A4

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12
Q

What changes in metabolism of ethanol are induced with chronic use?

A

MEOS activity is increased, resulting in increased ethanol metabolism but also increased metabolism of other drugs eliminated by MEOS/CYP450, and increased generation of toxic byproducts (toxins, free radicals, H2O2)

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13
Q

Mechanism of action of disulfiram

A

Inhibits aldehyde dehydrogenase
Produces unpleasant reaction (facial flushing, nausea, vomiting, dizziness, headache) after drinking due to accumulation of acetylaldehyde

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14
Q

Mechanism of action of fomepizole

A

Inhibits alcohol dehydrogenase
Prevents conversion of methanol and ethylene glycol to their toxic metabolites

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15
Q

Describe the CNS effects of ethanol

A

Lower doses: sedation, anxiolysis
At higher doses: slurred speech, ataxia, impaired judgment, disinhibition
At even higher doses: coma, respiratory depression, death

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16
Q

Describe the CVS effects of ethanol

A

Significantly decreased myocardial contractility
Vasodilation (via depression of vasomotor centre, and direct smooth muscle relaxation by acetylaldehyde)

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17
Q

What effect does ethanol have on uterine smooth muscle?

A

Relaxes

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18
Q

Describe the clinical effects of ethanol at increasing BAC

A

50-100: sedation, subjective “high”, slower reaction times
100-200: impaired motor function, slurred speech, ataxia
200-300: emesis, stupor
300-400: coma
>400: respiratory depression, death

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19
Q

Four mechanisms implicated in tissue damage due to chronic alcohol abuse

A
  1. Increased oxidative stress coupled with depletion of glutathione
  2. Damage to mitochondria
  3. Growth factor dysregulation
  4. Potentiation of cytokine-induced injury
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20
Q

17 toxic effects of chronic alcohol abuse

A
  1. Liver disease
  2. Chronic pancreatitis
  3. Gastritis
  4. Malnutrition
  5. Tolerance
  6. Physiologic dependence
  7. Psychological dependence
  8. Neurotoxicity
  9. Cardiomyopathy and heart failure
  10. Arrhythmia
  11. HTN
  12. Haematological disorders
  13. Fluid and electrolyte imbalances
  14. Steroid hormone imbalance
  15. Foetal alcohol syndrome
  16. Carcinogenesis
  17. Alcohol-drug interactions
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21
Q

What is the progression of liver disease seen with chronic alcohol use?

A

Alcoholic fatty liver -> alcoholic hepatitis -> cirrhosis -> liver failure

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22
Q

Who is more susceptible to alcohol-induced hepatotoxicity: women or men?

A

Women

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23
Q

Describe the pathogenesis of chronic pancreatitis due to alcohol abuse

A

Direct toxic effect on acinar cells
Alters pancreatic epithelial permeability and promotes formation of protein plugs and calcium carbonate stones

24
Q

What type of malnutrition is typically seen with chronic alcohol abuse?

A

Protein and vitamins (especially water-soluble)

25
Q

Four features of physical alcohol dependence

A
  1. Hyperexcitability
  2. Seizures
  3. Toxic psychosis
  4. Delirium tremens
26
Q

Six types of neurotoxicity seen with chronic alcohol abuse

A
  1. Symmetric peripheral nerve injury (initially distal limbs; most common)
  2. Gait disturbance, ataxia
  3. Dementia
  4. Demyelinating disease (rarely)
  5. Painless blurred vision (usually bilateral and symmetric, develops over several weeks and may be followed by optic nerve degeneration)
  6. Wernicke-Korsakoff syndrome
27
Q

Describe the features of Wernicke-Korsakoff syndrome

A

Associated with thiamine deficiency
Wernicke’s encephalopathy: characterised by triad of paralysis of extraocular muscles, ataxia, confusion (may progress to coma and death)
Korsakoff’s psychosis: even with thiamine replacement, most patients are left with chronic disabling memory disorder

28
Q

What type of cardiomyopathy is seen with chronic alcohol abuse? What is the effect of abstinence on this cardiomyopathy?

A

Dilated cardiomyopathy with ventricular hypertrophy and fibrosis
Cessation of drinking associated with decreased cardiac size and improved function

29
Q

What is the most common haematological disorder seen with chronic alcohol abuse?

A

Anaemia, usually due to alcohol-related folic acid deficiency or GI bleeding related iron deficiency anaemia

30
Q

What symptoms of steroid hormone imbalance are seen with chronic alcohol abuse?

A

Gynaecomastia
Testicular atrophy

31
Q

Seven features of foetal alcohol syndrome

A
  1. IUGR
  2. Microcephaly
  3. Poor coordination
  4. Underdevelopment of midfacial region (flattened face)
  5. Minor joint abnormalities

More severe cases:
6. Congenital heart defects
7. Mental retardation

32
Q

What is the likely mechanism of alcohol’s carcinogenesis?

A

Likely due to acetylaldehyde’s damaging effect on DNA, as well as ROS produced by MEOS

33
Q

There is increased risk of which five cancers with alcohol abuse?

A

Mouth
Pharynx
Larynx
Oesophagus
Liver

34
Q

Describe alcohol-drug interactions with acute vs chronic use, giving examples

A

Chronic use induces CYP450 enzymes: increased risk of hepatotoxicity with paracetamol
Acute consumption inhibits CYP450: decreases metabolism of phenothiazines, TCAs, sedative-hypnotics

35
Q

Describe the timeline and progression of alcohol withdrawal symptoms

A

Mild syndrome (increased HR and BP, tremor, anxiety, insomnia): begins 6-8hrs post cessation and improves within 1-2 days
More severe reactions (seizures, hallucinations): days 1-5
Delirium tremens: several days later

36
Q

When are longer vs shorter acting benzodiazepines preferred for use in the treatment of alcohol withdrawal?

A

Longer-acting for ease of dosing and slow tapering effect
Shorter-acting in setting of liver disease to prevent accumulation

37
Q

What is the molecular basis of alcohol withdrawal?

A

Thought to be related to GABA receptor downregulation with prolonged exposure to ethanol

38
Q

Three medications used to manage alcohol dependence and their mechanisms of action

A
  1. Naltrexone: mu opioid receptor antagonist
  2. Acamprosate: many actions (weak NMDA antagonist, GABA(A) activators; also acts on serotonergic, noradrenergic, dopaminergic pathways)
  3. Disulfiram: aldehyde dehydrogenase inhibitor
39
Q

Adverse effect of naltrexone

A

Dose-dependent hepatotoxicity (should not be used in combination with disulfiram)

40
Q

Distribution and elimination of acamprosate

A

Widely distributed
Renal elimination

41
Q

Describe the pharmacokinetics of disulfiram

A

Rapidly and completely absorbed from GIT but takes 12hrs for full action
Slow elimination (effects may persist for days after cessation)

42
Q

Disulfiram inhibits the metabolism of which three drugs besides alcohol

A

Phenytoin
Oral anticoagulants
Isoniazid

43
Q

Adverse effect of disulfiram

A

Small increase in hepatic transminases

44
Q

Four other drugs that have disulfiram-like effects on alcohol metabolism

A

Metronidazole
Certain cephalosporins
Sulfonylureas
Chloral hydrate

45
Q

Describe the pharmacokinetics of methanol

A

Absorption: may be absorbed through skin, respiratory tract or GIT
Distribution: distributed in body water
Metabolism: oxidised to formaldehyde, formic acid and CO2 (occurs slowly: appearance of severe toxicity may be 6-30hrs post ingestion)

46
Q

Describe the reactions involved in metabolism of methanol

A

Methanol -> formaldehyde (catalysed by alcohol dehydrogenase)
Formaldehyde -> formate (catalysed by aldehyde dehydrogenase)
Formate -> CO2 + H2O (catalysed by folate-dependent mechanisms)

47
Q

Where is methanol used?

A

In production of many synthetic compounds and commercial solvents

48
Q

Describe the clinical presentation of methanol toxicity

A

Early: inebriation, gastritis, elevated osmolar gap
Severe: odour of formaldehyde on breath or in urine, visual disturbance (like “being in a snowstorm”; may progress to blindness), HAGMA
Late: progresses to bradycardia, prolonged coma, seizures, resistant acidosis, death from sudden cessation of respiratory

49
Q

What metabolite is especially responsible for toxic effects of methanol?

A

Formate

50
Q

What serum level of methanol warrants treatment and at what level is haemodialysis indicated?

A

> 20mg/dL: warrants treatment
50mg/dL: needs haemodialysis

51
Q

Describe three methods of treating methanol poisoning. What is one further method which lacks evidence?

A
  1. Suppression of metabolism by ADH: either via ADH inhibitor fomepizole or by ethanol (higher affinity for ADH than methanol)
  2. Haemodialysis
  3. Alkalinisation (to counter-act metabolic acidosis)

May also administer folic acid to try to enhance folate-dependent oxidation of formate to CO2

52
Q

Why does the dose of fomepizole need to be increased throughout treatment of methanol overdose?

A

Induces its own metabolism

53
Q

What is ethylene glycol?

A

Polyhydric alcohol used in heat exchangers, antifreeze and industrial solvents

54
Q

Describe the metabolism of ethylene glycol

A

Ethylene glycol -> glycolaldehyde (catalysed by alcohol dehydrogenase)
Glycoaldehyde -> glycolic acid

55
Q

Which ethylene glycol metabolites are toxic?

A

Both glycoaldehyde and glycolic acid

56
Q

Describe the clinical presentation of ethylene glycol poisoning

A

First few hours: transient excitation followed by CNS depression
After 4-12hrs: severe metabolic acidosis
Eventual deposition of oxalate crystals in renal tubules, causing delayed renal insufficiency

57
Q

How is ethylene glycol poisoning treated?

A

As per methanol toxicity:
- ADH inhibitors (fomepizole, ethanol acting as competitive antagonist)
- Haemodialysis
- Alkalinisation to counter metabolic acidosis

ACEM Primary Written (160 decks)

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