B2.071 - Pharmacokinetics Of Acetominophen Flashcards
What are the 3 routes that acetominophen can be metabolized by
Glucuronosyl transferase
Sulfo transferase
Cytochrome
In a normal therapeutic dose which route does acetaminophen take most often
Glucuronosyltransferase
With a therapeutic amount of acetominophen rank which routs it will take starting with most often to least
Glucuronyl > Sulfo > Cytochrome then GSH > Cytochrome then binds with protein
Which pathways caps out first
Sulfotransferase
What does GSH do
Detoxifies the NAPQI intermediate
Liver GSH levels are inversely proportional to what
Liver protein adductor
What does NAPQI do toxicity wise in the liver
Damages the mitochondrial membranes through protein modification
Why does acetaminophen toxicity happen
50% intentional
50% unintentional
Why are there so many intentional overdose
Common suicide attempt method
What are some ways to prevent intentional acetaminophen overdose
Suicide prevention, counseling
Education
Lower dosage
Blister packs
What are some of the ways people unintentionally overdose on acetaminophen
Many OTC products have it
Many opioids have it
What are 3 aspects of pharmacokinetic variability
Genetics
Expression
Inhibition
What are some polymorphic genes that affect acetaminophen toxicity
UGTs - Gluc pathway
GST - GSH pathway
CYP2E1
Nearly all polymorphic drug metabolizing enzymes show
Diminished or no activity
What are ways diminished activity could cause both more or less tolerance to acetaminophen toxicity
UGT and GST diminished activity will make it more toxic
diminished CYP2E1 activity may decrease hepatotoxicity
What are some inducers of CYP2E1
Ethanol, isoniazid
What are some drugs that inhibit conjugation of acetaminophen and will enhance hepatotoxicity
Phenobarbital and phenytoin
Does ethanol inhibit hepatotoxicity or promote it
Both, ethanol is a competing substrate of CYP2E1 so it can protect against hepatotoxicity
But
Chronic ethanol use will induce CYP2E1 enhancing acetaminophen hepatotoxicity
How does nutritional status affect how acetaminophen is metabolized
Production of cofactors requires ATP
What can alter responses to drugs?
Age BMI Other drugs Diet Social Habits Genetics Disease processes
What contributes to intra individual responses to drugs
Changes in BMI, other drugs, diet, social habits, disease
What primarily contributes to inter individual variability
Genetic differences
What are potential treatment targets for acetaminophen overdose
Prevent absorption
Inhibit NAPQI
Enhance scavenging of NAPQI
Remove from systemic circulation
How do you prevent absorption of acetaminophen
Gastrointestinal lovage and activated charcoal
