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Drug induces hepatotoxicity Flashcards

1
Q

Hepatotoxicity and drugs

A
  • 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
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2
Q

Drugs most frequently implicated with hepatotoxicity

A
  1. Acetominophen
  2. Isoniazide
  3. Phenytoin
  4. Valproate
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3
Q

Clinical features of drug related hepatotoxicity

A

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

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4
Q

Age as RF for DIH

A
  • 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
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5
Q

Gender as RF for DIH

A
  • FEMALES>males
    • HALTHONE
    • ISONIAZIDE
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6
Q

Genetic RF and DIH

A

Slow AND fast acetylators may be more succeptible to ISONIAZIDE hepatotoxicity

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7
Q

Enzyme induction as RF for DIH

A

Alcohol, rifampicin, other drugs →induce CYP450 2E1 →increase hepatotoxicity of acetaminophen, isoniazide, halthone

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8
Q

Diseases that may increase risk of DIH

A
  • RF
  • Diabetes
  • Obesity
  • Pregnancy
  • Pre-existing liver disease

Because they affect the way the liver metabolizes durgs

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9
Q

DOSE, CONC, DURATION retalted to what in terms of RF to DIH

A

nutrition

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10
Q

Mediators of DIH

A
  • 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
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11
Q

NON covalent interactions

A
  • inhibition of mitochondrial function
  • accumulation of ROS
  • lipid peroxidation
  • Depletion of reduced glutathione
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12
Q

Covalent interactions

A
  • 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
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13
Q

Intrinsic hepatotoxicity

A
  • 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
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14
Q

Idiosyncratic hepatotoxicty

A
  • 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
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15
Q

Hepatocellular necrosis

A
  • liver destruction
  • marked elevation of serum aminotransferases
    • preceed increase in serum bilrubin and modest increase in alkaline phosphatase
  • Izoniazide
  • Acetaminophen
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16
Q

Steatosis

A

Microvascular

  • modest elevation in aminotransferases
  • lactic acidosis
  • Valproic acid
  • Tetracyclines at high dose

Macrovascular

  • steroids
  • Methotrexate

Steatohepatitis

  • AMIODARONE
17
Q

Cholestasis

A

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
18
Q

Acetaminophen induced hepatotoxicity

A
  • 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
19
Q

Clinical features of acetaminophen overdose

A
  • 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

Gi (5 decks)

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