Module 6: Drug Induced Liver Injury (TRAT) Flashcards
Dr. Covert EXM VI
How is liver function assessed?
-Enzymes: LFT
-Synthetic function test: tells how well the liver is functioning
-Cholestatic/Gallbladder function: help to clear Bilirubin -> if impaired it can cause elevated bilirubin -> Jaundice
Symptoms and Signs of Drug-induced liver injury
-abdominal pain
-ascites
-coagulopathy (liver responsible for producing the clotting factors)
-Varices (dilated blood vessels, type of upper GI bleed)
-Jaundice
-Puritis (itching, may be due to bilirubin)
-Splenomegaly
-Hepatomegaly
LFT test explained
-Enzymes: LFT
AST: Aspartate Transaminase
ALT: Alaline Aminotransferase
ALP: Alkaline Phosphatase
an acute injury of the hepatocytes will cause an increase in these enzymes in the blood
-but will not tell how severe the damage is
Which test indicates how well the liver is functioning?
Synthetic Function
-Albumin
-clotting factor
-platelets
-INR
Types of DILI
-Cytotoxic = Hepatocellular
directly to liver cells
drug binds protein/cellular material
immunologic: fever, rash, eosinophilia
-Cholestatic:
inhibition of bile excretion
Neoplasm: steroids, hormones
Which levels are elevated in cytotoxic and cholestatic DILI?
-cytotoxic: AST and ALT (10-500x)
-cholestatic:
ALP (3-10x)
T-bili and direct bilirubin (2-20x)
What are the drugs causing cytotoxic DILI?
-Isoniazid (used for TB)
-Valproic acid (use: epilepsy, seizure, bipolar)
-Acetaminophen
-Macrolides
-Nitrofurantoin
-Tetracycline
-Antivirals
-Azoles
-Analgesics
Both: Amiodarone
What are the drugs causing cholestatic DILI?
-Penicillins (cephalosporins)
-Sulfonamides
-Steroids
Both: Amiodarone
Which drugs may cause cytotoxic and cholestatic DILI?
-Amiodarone
-statins
-TCA
Which drugs are known to have a long time of onset?
> 1 year
-Amiodarone
-Macrolides
-Nitrofurantion
-Tetracyclines
Which drugs are known to have a shorter time of onset?
-3-12 weeks (1-2 months)
Isoniazid
Valproic acid
1-4 weeks (after completion)
Amox/Clav
24-72 h
Hypersensitiviy (Sulfonamides)
What is the most common way to counter DILI?
1: stop the offending agent
there are not many counteracting agents
Antidote for Cytotoxic DILI
-N-acetyl cysteine
decreases the risk of the need of a liver transplant
Antidote for Immune-mediated/hypersensitivity DILI
20-80 mg prednisone X 8-12 weeks
Antidote for Cholestatic DILI
-Ursodilol (Actigall)
promotes the excretion of bilirubin
Which drug is an antidote for liver injury caused by Methotrexate or Bactrim?
Folic acid agents
-Methotrexate and Bactrim are folic acid antagonists
replenish folic acid stores, rescue cells exposed to antagonists
-Leucovorin 1 mg = Levoleucovorin 0.5 mg
Antidote for Valproic acid-induced liver injury
L-Carnitine (supplement)
-MOA: repletion of deficit ( of L-Carnitine) caused by VPA injury
-dosing: 50-300 mg/kg IV q 3-6 h
-ADR:N/V, seizure risk
Antidote for Acetaminophen-induced liver injury
N-acetylcysteine
-MOA: replenishes glutathione
-dosing:
IV (ACAP + other DILI): 21h regimen for acety
PO (ACAP): 72h regimen
ADR:
PO: N/V
IV: Itching, flushing, hypersensitivity reactions (due to loading dose - may pretreat with Benadryl)
N-acetylcysteine dosing
-IV (ACAP + cytotoxic): 21h regimen
LD: 150 mg/kg over 1h
then 50 mg/kg over 4h
then 100 mg/kg over 16h
-PO (ACAP): 72h regimen (over 3 days)
LD: 140 mg/kg
then maintenance 70 mg/kg q 4h for 17 doses
Which tool is used to assess the risk of a liver injury after an acetaminophen overdose?
Rumack-Matthew Monogram
-if below the line, the risk for a liver injury is low
-if above, they might have a liver injury -> use N-acetylcysteine
Which enzyme produces the toxic metabolite in an acetaminophen-induced liver injury?
CYP2E1
-other metabolites are produced via Conjugation of sulfate or glucuronide (non-toxic)
-in an overdose, the non-toxic is saturated -> and the toxic pathway starts increasing
-glutathione is used in the toxic pathway -> depletion
What is the role of glutathione in acetaminophen metabolism?
-glutathione is used to metabolize the toxic metabolite NAPQI -> conjugation of glutathione making it non-toxic
-starts accumulation after the non-toxic pathway is saturated
-NAC is a source of glutathione
What is the antidote for cholestatic injury?
Ursodeoxycholic acid (not used often)
-MOA: helps to dissolve cholestatic or bile acid deposits
-not often seen due to DDIs with bile acid sequestrants (reduce Ursodilol absoprtion)
-dosing: 300 mg BID
-ADR: N/V
Which patient population may often need a liver transplant?
-chronic, untreated DILI
-acute Acetaminophen toxicity (often due to Tylenol leading to liver transplant)
most patients completely recover
Which antidote has a dosing ratio of 1:1?
Leucovorin 1 mg = Levoleucovorin 0.5 mg
for Methotrexate induced liver injury
Which drug may also be used for other DILI’s than acetaminophen?
IV N-acetylcysteine
Which molecule is replenished with N-acetylcysteine
Glutathione
