Drug induces hepatotoxicity Flashcards
Hepatotoxicity and drugs
- induce all forms of acute/chronic liver disease
- not a common adverse drug reaction
- most common reason for drug approval withdrawal
- 50% of acute liver failure in the US
Drugs most frequently implicated with hepatotoxicity
- Acetominophen
- Isoniazide
- Phenytoin
- Valproate
Clinical features of drug related hepatotoxicity
mild asymptomatic changes in serum transaminases and bilrubin → acute hepatitis, prolonged cholestatic disease, cirrhosis, fatty liver, tumors, granulomas, fulminnat hepatic failure which requires liver transplantation
Age as RF for DIH
- increases with age
- HALTHONE hepatitis more likely in pt >60
- ISONIAZIDE hepatotoxicity more likley in pt >60
-
EXCEPTIONS
- VALPROIC ACID, SALICYCLATE
- more common in <3yrs
- VALPROIC ACID, SALICYCLATE
Gender as RF for DIH
-
FEMALES>males
- HALTHONE
- ISONIAZIDE
Genetic RF and DIH
Slow AND fast acetylators may be more succeptible to ISONIAZIDE hepatotoxicity
Enzyme induction as RF for DIH
Alcohol, rifampicin, other drugs →induce CYP450 2E1 →increase hepatotoxicity of acetaminophen, isoniazide, halthone
Diseases that may increase risk of DIH
- RF
- Diabetes
- Obesity
- Pregnancy
- Pre-existing liver disease
Because they affect the way the liver metabolizes durgs
DOSE, CONC, DURATION retalted to what in terms of RF to DIH
nutrition
Mediators of DIH
- reactive metabolites of drugs
- formed thru phase 1 metabolic reactions
- hepatocytes are exposed to a large conc. of toxic metabolites
- formed by CYP450 enzyme system
- Hepatotoxicity may result gtom covalent ad non covalent interaction of drug/metabolite with target molecules
NON covalent interactions
- inhibition of mitochondrial function
- accumulation of ROS
- lipid peroxidation
- Depletion of reduced glutathione
Covalent interactions
- binding electrophilic rwactive metabolites with celular macromolecules →hepatic necrosis
- NAPQI (a metabolite of acetaminophen)
- binding to proteins →immunogens →imunological reactions →disruption of cell membrane
- HALTHONE hepatotoxicity
Intrinsic hepatotoxicity
- predictable; dose dependent
- occurs in everyone who takes a toxic dose
- includes drugs that cause direct toxic injury
- distinctive patterns, with damage occuring after brief latency of hours to weeks
- Acetaminophen
- Methotrexate
Idiosyncratic hepatotoxicty
- less predictable; dose-independent
- caus hepatic damage in a small number of ppl
- uniquely succeptible people
- Variable pathological pattern of lesions
- Delayed onset of weeks to months
- related to HS or metabolic abnormality
- long incubation period
- lesions are assciated with rash, fever, eosinophilia
- HALTHONE
- ISONIAZID
- CHLORPROMAZINE
Hepatocellular necrosis
- liver destruction
- marked elevation of serum aminotransferases
- preceed increase in serum bilrubin and modest increase in alkaline phosphatase
- Izoniazide
- Acetaminophen
Steatosis
Microvascular
- modest elevation in aminotransferases
- lactic acidosis
- Valproic acid
- Tetracyclines at high dose
Macrovascular
- steroids
- Methotrexate
Steatohepatitis
- AMIODARONE
Cholestasis
Hepatocanalicular:
- Chloropromazine
Canalicular
- Contraceptive
- Steroids
Both
- biliary obstruction with elevated bilrubin in serum
- alkaline phosphatase is more elevated than aminotransferases
- Jaundice and itching
- most cases are mixed
Acetaminophen induced hepatotoxicity
- dose related hepatotoxin
- usually safe in therapeutic doses of <3g/day
- large doses (1–15g/day) →severe hepatic necrosis
- centrilobular
- Metabolized by phase 2 conjugation reactions mostly (glucorination,sulfation)
- Small amount metabolized by phase 1 →reactive intermediate; NAPQI →detoxified by glutathione conjugation
- very high doses →large amounts of NAPQI →toxicity
- high risk groups with more succeptible patients
Clinical features of acetaminophen overdose
- range from no symptoms to mild symptoms like N/V abdominal pain and pallor to sever symptoms like coma and metabolic acidosis with large doses
- PT and serum transaminases and bilrubin rise 16-24 hrs post ingestion
- peak hepatotoxicity at 72-120 hrs
- jaundice, coagulopathy, hepatic failure, renal failure, encephalopathy, coma if untreated
- must asses aceta levels in blood
- TREATMENT: N-acetylcysteine
