Liver 3 Flashcards
DILI
What is the most common reason for drug recall?
drug-induced hepatoxicity
-women more commonly affected
-acute or chronic
-~50% of all acute liver failure
What can increase the risk of hepatoxicity from herbal products?
exceeding recommended doses
What risk do environmental toxins pose to the liver?
can predispose a patient to a hepatic reaction when a drug is added
Why is DILI classification difficult?
drugs may cause > 1 pattern of damage
cause not always possible to determine
different types may occur at once
MOA not always understood
What should be considered in the diagnosis of DILI?
temporal relationship to drug use
exclusion of other causes of liver damage
What is the definition of hepatoxicity?
clinically significant abnormalities of liver tests
-ALT > 3x ULN and total bilirubin > 2x ULN
How can we determine the pattern of hepatic injury?
evaluate the ratio of ALT to ALP to determine predominant cause
-R >/5=hepatocellular injury
-2<R>5=mixed
-R<2=cholestatic</R>
What are the general mechanisms of DILI?
intrinsic: predictable
-direct hepatotoxin, inherent propensity to induce injury in all individuals; dose dependent or time dependent & reproducible
idiosyncratic: unpredictable
-causes injury in a small # of uniquely susceptible patients; variable presentation (allergic or non-allergenic)
What is the most common cause of acute liver failure?
acetaminophen
-extremely high AST/ALT levels (>3500)
=helps distinguish from other drug induced hepatoxicity
Describe normal metabolism of acetaminophen, and then what occurs with excessive acetaminophen.
normally:
-90% glucuronidated or sulfated, 2% metabolized by CYP
with excessive acetaminophen:
-glucuronidation & sulfation become saturated
-CYP becomes primary metabolic pathway
–>product of reaction=NAPQI (toxic)
–>NAPQI normally detoxified by glutathione
-with OD, NAPQI production exceeds glutathione stores
=hepatic necrosis and possible death
What are the 4 stages of acetaminophen toxicity?
stage 1 (within 24h)
-GI sx
stage 2 (24-72h)
-resolution of stage 1 sx
-onset of RUQ pain, increased bilirubin, PT, transaminases
stage 3 (72-96h)
-asymptomatic to fulminant hepatic failure
-AST and ALT peak (up to 100x normal)
-death at 3-5 days after ingestion
stage 4
-recovery stage, if survive stage 3
-symptoms subside and transaminases normalize
-survivors do not have chronic hepatic dysfunction
What are the toxic doses of acetaminophen?
adults: > 7.5g
children: > 150mg/kg
True or false: the clinical presentation of acetaminophen toxicity shows a fast onset
false
delayed=early recognition is essential
What is the Rumack-Matthew nomogram?
helps identify who should receive acetylcysteine
-does not predict survival or death
-use >24h not recommended
-not reliable for extended release products
What is the antidote of choice for acetaminophen toxicity?
acetylcysteine
What is the MOA of acetylcysteine?
enhances glutathione stores
When is acetylcysteine given?
if serum concentration exceeds the “treatment line” on the Rumack-Matthew nomogram
What is the benefit of acetylcysteine?
reduce risk of hepatoxicity
-all regimens
How long can treatment with acetylcysteine be delayed without increased risk of hepatoxicity?
up to 8h
Aside from acetylcysteine, what are some other potential options for acetaminophen toxicity?
Syrup of Ipecac
-not CI, but effectiveness beyond 1hr is diminished
activated charcoal:
-superior to ipecac in reducing serum levels
-no data on clinical benefit
-should be administered within 1hr, should be considered to all pts before the 4hr nomogram evaluation
Describe allergic-type DILI.
presents with allergic type sx
-fever, rash, eosinophilia, etc
sx may occur with increasing intensity with repeated exposure
What are some drugs associated with allergic-type DILI?
anticonvulsants
sulfonamides
allopurinol
dapsone, minocycline, PTU
Describe non-allergic DILI.
likely caused by toxic metabolites
-MOA not clear
-onset: 1wk to > 1yr
What are some drugs associated with non-allergic DILI?
isoniazid
valproic acid
ketoconazole
methyldopa
