B2.071 Acetaminophen Pharmacokinetics Flashcards
therapeutic dose (1.5 g) distribution through pathways
Glucuronride- 0.85 g Sulfate- 0.45 g NAPQI - 0.08 g GSH - 0.07 g Protein Adducts - 0.01 g
max therapeutic dose (4 g) distribution through pathways
Glucuronride- 3 g Sulfate- 0.5 g NAPQI - 0.4 g GSH - 0.3 g Protein Adducts - 0.04 g
double max therapeutic dose (8 g) distribution through pathways
Glucuronride- 4.5 g Sulfate- 0.5 g NAPQI - 2 g GSH - 1.6 g Protein Adducts - 0.4 g
toxic/lethal dose (8 g) distribution through pathways
Glucuronride- 4.5 g Sulfate- 0.5 g NAPQI - 12 g GSH - 2 g Protein Adducts - 9 g
what is the primary substrate that prevents NAPQI binding to protein?
glutathione
GSH depletion = protein binding
how do APAP protein adducts initiate toxicity?
the change in structure of the proteins (with addition of the NAPQI) alter the function, resulting in hepatotoxicity
in what order do the different APAP metabolic pathways deplete?
sulfation
glucuronidation
GSH scavenging of NAPQI
what cellular component does NAPQI primarily act against?
mitochondria
modifies their proteins, makes them leaky
unleashes mediators of toxicity and initiated oncotic necrosis
what is one reason for unintentional overdoses?
polypharmacy
taking multiple meds for symptoms that contain APAP and then taking APAP itself
how is APAP overdose related to opioids?
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
what is the APAP dose limit set by the FDA?
325 mg per pill
what are 3 primary reasons for pharmacokinetic variability?
genetics
expression
inhibition
genetics
genetic variation in genes coding for drug metabolizing enzymes often decrease activity
expression
drugs or chemical exposures from diet, social habits, or the environment can upregulate the expression of drug metabolizing enzymes
inhibition
drugs or chemical exposures from diet, social habits, or the environment can inhibit drug metabolizing enzymes
which APAP metabolizing genes are polymorphic
2 UGTS
1 GST
CYP2E1
how can polymorphic APAP metabolizing genes have a negative effect
polymorphic enzymes usually show diminished or no activity
decreased activity of UGT or GST will enhance hepatotoxicity
inducers
increase expression of proteins involved in drug disposition
inducers of CYP2E1
chronic ethanol and anti TB drug isoniazoid
induction increases sensitivity to APAP hepatotoxicity
inhibitors of APAP conjugation
phenobarbital
phenytoin
inhibit glucuronidation as competitors
acute ethanol
competing substrate of CYP2E1, may protect against hepatotoxicity
why is chronic ethanol use an inductor of CYP2E1?
induction requires multiple or chronic exposures to the inducer
how does nutrient restriction affect APAP metabolism?
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)
what factors can alter response to drugs?
age BMI other drugs diet social habits genetics disease processes
active form of APAP
APAP itself
what are 2 primarily used treatments for APAP overdose
- prevent absorption by GI lavage w activated charcoal
2. increase/replenish haptic GSH with NAC
how is NAC used against APAP overdose?
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
