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MCM Test 4 > B2.071 Acetaminophen Pharmacokinetics > Flashcards

B2.071 Acetaminophen Pharmacokinetics Flashcards

1
Q

therapeutic dose (1.5 g) distribution through pathways

A 
Glucuronride- 0.85 g
Sulfate- 0.45 g
NAPQI - 0.08 g
GSH - 0.07 g
Protein Adducts - 0.01 g
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2
Q

max therapeutic dose (4 g) distribution through pathways

A 
Glucuronride- 3 g
Sulfate- 0.5 g
NAPQI - 0.4 g
GSH - 0.3 g
Protein Adducts - 0.04 g
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3
Q

double max therapeutic dose (8 g) distribution through pathways

A 
Glucuronride- 4.5 g
Sulfate- 0.5 g
NAPQI - 2 g
GSH - 1.6 g
Protein Adducts - 0.4 g
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4
Q

toxic/lethal dose (8 g) distribution through pathways

A 
Glucuronride- 4.5 g
Sulfate- 0.5 g
NAPQI - 12 g
GSH - 2 g
Protein Adducts - 9 g
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5
Q

what is the primary substrate that prevents NAPQI binding to protein?

A

glutathione

GSH depletion = protein binding

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6
Q

how do APAP protein adducts initiate toxicity?

A

the change in structure of the proteins (with addition of the NAPQI) alter the function, resulting in hepatotoxicity

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7
Q

in what order do the different APAP metabolic pathways deplete?

A

sulfation
glucuronidation
GSH scavenging of NAPQI

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8
Q

what cellular component does NAPQI primarily act against?

A

mitochondria
modifies their proteins, makes them leaky
unleashes mediators of toxicity and initiated oncotic necrosis

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9
Q

what is one reason for unintentional overdoses?

A

polypharmacy

taking multiple meds for symptoms that contain APAP and then taking APAP itself

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10
Q

how is APAP overdose related to opioids?

A

many opioids have been compounded with APAP for synergistic effects
individuals who are opioid tolerant or engage in excessive use can suffer from APAP overdose

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11
Q

what is the APAP dose limit set by the FDA?

A

325 mg per pill

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12
Q

what are 3 primary reasons for pharmacokinetic variability?

A

genetics
expression
inhibition

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13
Q

genetics

A

genetic variation in genes coding for drug metabolizing enzymes often decrease activity

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14
Q

expression

A

drugs or chemical exposures from diet, social habits, or the environment can upregulate the expression of drug metabolizing enzymes

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15
Q

inhibition

A

drugs or chemical exposures from diet, social habits, or the environment can inhibit drug metabolizing enzymes

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16
Q

which APAP metabolizing genes are polymorphic

A

2 UGTS
1 GST
CYP2E1

17
Q

how can polymorphic APAP metabolizing genes have a negative effect

A

polymorphic enzymes usually show diminished or no activity

decreased activity of UGT or GST will enhance hepatotoxicity

18
Q

inducers

A

increase expression of proteins involved in drug disposition

19
Q

inducers of CYP2E1

A

chronic ethanol and anti TB drug isoniazoid

induction increases sensitivity to APAP hepatotoxicity

20
Q

inhibitors of APAP conjugation

A

phenobarbital
phenytoin
inhibit glucuronidation as competitors

21
Q

acute ethanol

A

competing substrate of CYP2E1, may protect against hepatotoxicity

22
Q

why is chronic ethanol use an inductor of CYP2E1?

A

induction requires multiple or chronic exposures to the inducer

23
Q

how does nutrient restriction affect APAP metabolism?

A

production of cofactors for glucuronidation and sulfation require ATP
in nutrient restriction, ATP used for more critical functions, decreasing capacity for APAP conjugation
GSH synthesis decreased during nutrient restriction as well (also can be used up on other metabolites and ROS)

24
Q

what factors can alter response to drugs?

A 
age
BMI
other drugs
diet
social habits
genetics
disease processes
25
Q

active form of APAP

A

APAP itself

26
Q

what are 2 primarily used treatments for APAP overdose

A
  1. prevent absorption by GI lavage w activated charcoal

2. increase/replenish haptic GSH with NAC

27
Q

how is NAC used against APAP overdose?

A

oral and IV formulations
IV preferred
large initial dose followed by additional doses every 4 hours for 15-20 doses
should be given within 8 hours of ingestion

MCM Test 4 (19 decks)

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