LIver 3 Flashcards
Most commob=n cause of drug recall
Drug-induced hepatotocicity
WHo is more affected by DILI’s?
Women
Hepatocellular DILI
↑ AST/ALT (preceds incr total bilirubin and ALP)
Usually occurs w/in 1yr of starting drug
Can result in fulminant hepatitis
Steotonecrosis DILI
↑ synth of FAhepatocytes engorged with FA, burst open
Inflammation
Fibrosis DILI
Mild, chronic hepatitisfibrosiscirrhosis if drug not d/c
Cholestatic DILI
Prevents proper elimination of bile by liveraccumulation
↑ ALP
Definition of hepatotoxicity
How can determine the pattern of injury?
General mechanisms of DILI
Intrinsic: predictable
direct hepatotoxin, which has 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
further classified into allergic or non-allergic type
Most common type of intrinsic DILI
Aectaminophen - Most common cause of acute liver failure
Extremely high AST/ALT levels (>3500)
Help distinguish from other drug induced hepatotoxicity (generally 5x ULN)
Excess actaminophen causes what?
With overdose, ↑ production of NAPQI exceeds capacity of glutathione stores
NAPQ Covalently binds to and modifies critical hepatic cell proteins
Results in hepatic necrosis and possibly death to the patient
Stages of Acetaminophen Toxicity
Acute toxicity Values
Toxic doses
Adults: >7.5g
Children: >150mg/kg
Gut Decontamination after acet toxicity
Syrup of Ipecac
Not contraindicated, but effectiveness beyond 1 hour is markedly diminished
Emesis induced within 1hr reduced serum levels by 50% ; No impact at 90 minutes
Activated charcoal
Superior to ipecac in reducing serum levels
Single dose should be administered within 1hour (Effectiveness after 1hr not known)
Should be considered to all patients with potential acetaminophen od before the 4hour nomogram evaluation
Avoid other gut decontamination measures
Anti-dote of acetaminophen toxicity?
Acetylcysteine
MOA of acetycysteine
Enhances glutathione stores (acts as substrate)
Promotes conjugation by nontoxic pathway
Nonogram for identifying acetaminophen toxicty
Rumack-Matthew nomogram(modified in North America)
Rumack-Matthew Nonogram
Predicts only the likelihood of AST/ALT >1000
Does not predict survival or death
Use of nomogram > 24hrs not recommended
Identifies patients who require aggressive management
Not reliable for extended release products
Acetycysteine Infusion Rates
Longer infusions may be superior if long delay in treatment (10-24hrs)
Treatment may be delayed up to 8 hours without increased risk
Allergic Type Idosyncratic DILI
Some cases of hepatotoxicity present with “allergic” type sx
Fever, rash, eosinophilia, etc
May have extrahepatic involvement as well
Symptoms may occur with increasing intensity with repeated exposure (sensitization)
Drugs associated with allergic-type idosyncratic
Anticonvulsants (phenytoin, phenobarb, CBZ)
Sulfonamide antibiotics
Allopurinol
Dapsone, minocycline, propythiourocil
Non-allergic Idiosyncratic DILI
Likely caused by toxic metabolites
Mechanism of production not always clear
Onset 1 week to > 1 year
Rechallenge: days to weeks (accumulation must occur?)
Drugs associated with non-allergic DILI
isoniazid, valproic acid, ketoconazole, methyldopa
Onset(Latency) of drug timing approach?
Short = 3–30 days
Moderate = 30–90 days
Long 90 = days
Management of suspected DILI
Immediate d/c of all potential hepatotoxins
Supportive care as needed
Acetylcysteine for acetaminophen poisonings
Potential other uses as well
Corticosteroids can be considered for ‘allergic’ rxns
“DRESS” [with eosinophilia & systemic sx]
No other antidotes exist
Serial biochemical measurements until the liver enzymes return to normal
Severe jaundice
significant indicator of mortality
referral to transplant center ASAP
How can liver dysfunction be quantified?
Child Pugh A = 5-6 points
Child Pugh B = 7-9 points
Child Pugh C = 10-15 points (severe)
