Drugs & Liver Flashcards
Phase I: converts drug into reactive metabolite (e.g., CYP enzymes)
- may cause hepatocyte injury/death
Phase II: Conjugation: Adds large polar groups to metabolite to make it water soluble and pharmacologically inert
- Glucuronide
- Sulfate
- Glutathione
- Methyl
Phase III: Excretion via ATP-dependent excretory transporters into bile canaliculi
Phases of Hepatic Drug Metabolism
- phase I reactions that take place on the cytoplasmic side of the endoplasmic reticulum membrane
- account for the majority of phase I reactions (vs. mitochonchondrial-type)
Microsomal-Type Phase I reactions
- Catalyzes conjugation of drug metabolites within the cytoplasm of hepatocytes
UDP Glucuronyl Transferases (UDP-GT or UGT)
Inhibition of CYP3A activity
- increases bioavailability of drug
Grapefruit Juice
Overall increase in hepatotoxicity:
- Speeds up Phase I: Increases CYP2E1 activity.
- Slows down Phase II: Inhibits the rate of glutathione (GSH) synthesis; Impairs mitochondrial transport of GSH
- Increased hepatotoxicity when associated with alcohol intake are acetaminophen, isoniazid, cocaine, methotrexate, and vitamin A
Chronic Alcohol
- An overall decrease in CYP activity may occur in elderly patients –> increases risk of overdose
- Infants may show considerable immaturity of the supply of drug metabolizing; CYP enzymes may be low to undetectable at birth and develop over time
Effect of Age on drug metabolism
- 80% of reactions
- Predictable
- Dose dependent
Direct Hepatotoxicity
- can be due to immune response to drug
- Tend to be systemic: get fevers and rash
- If rechallenge with medication: reaction will be more brisk and severe
Idiosyncratic DILI
Labs
- Elevated transaminases: AST, ALT
- Followed by elevated Bilirubin
- Alkaline phosphatase relatively spared
Histology
- Hepatocellular necrosis or apoptosis, steatosis, and cellular degeneration
- High infiltration of inflammatory cells
DILI at Hepatocellular Level
- Toxicity is likely to occur with single ingestions greater than 250 mg/kg, or those greater than 12 g over a 24-hour period.
- Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract.
- Serum concentrations peak between one-half and two hours after an oral therapeutic dose.
- Peak serum concentrations are reached within 4 hours
Acetaminophen/Tylenol Toxicity
- May be asymptomatic.
- Nausea, vomiting, diaphoresis, pallor, lethargy, and malaise.
- Laboratory studies are typically normal.
Stage I (0.5 to 24 hours) of Acetaminophen/Tylenol Toxicity
- Of patients that develop hepatic injury, over 50% will show aminotransferase elevation within 24 hours; all will have elevations by 36 hours.
Symptoms:
- Right upper quadrant pain.
- Elevations of prothrombin time (PT) (deficient in Factor VII)
- elevations in total bilirubin, oliguria, and renal function abnormalities
Stage II (24 to 72 hours) of Acetaminophen/Tylenol Toxicity
**Death most commonly occurs in this stage, usually from multiorgan system failure
- Liver function abnormalities peak from 72 to 96 hours after ingestion.
- Jaundice, hepatic encephalopathy, a marked elevation in hepatic enzymes, and a bleeding diathesis.
- Plasma ALT and AST often exceed 10,000 IU/L, prolonged PT / INR, hypoglycemia, lactic acidosis, and hyperbilirubinemia (primarily indirect).
- Acute renal failure due to acute tubular necrosis.
Stage III (72 to 96 hours) of Acetaminophen/Tylenol Toxicity
- Patients who survive stage III enter a recovery phase that usually begins by day 4 and is complete by 7 days after overdose.
- When recovery occurs, it is complete; chronic hepatic dysfunction is not a sequela of acetaminophen poisoning
Stage IV (4 days to 2 weeks) of Acetaminophen/Tylenol Toxicity
Therapy for Acetaminophen overdose
- Mech: GI decontamination
- must take w/in 4 hours of suspected ingestion
Activated charcoal (AC)
