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Liver Toxicity

Liver Toxicity. Andrew Dawson. Outline. Adverse Drug Reactions Definition & Types Examples Mechanisms Revisit some hepatic metabolism Paracetamol Hepatotoxicity Other examples. Toxicity Overview. Drug. Cellular Accumulation. Toxicity. Nucleic Acid Enzyme Transport Protein

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Liver Toxicity

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  1. Liver Toxicity Andrew Dawson

  2. Outline • Adverse Drug Reactions • Definition & Types • Examples • Mechanisms • Revisit some hepatic metabolism • Paracetamol Hepatotoxicity • Other examples

  3. Toxicity Overview Drug Cellular Accumulation Toxicity • Nucleic Acid • Enzyme • Transport Protein • Signalling Protein • Receptor • Autologous protein Carcinogenicity Phase I/II Bioactivation Necrosis Stabile Metabolites Toxic Metabolites Apotosis Bioinactivation Hypersensitivity Excretion

  4. Which ADRs are idiosyncratic, are dose-related? (or other?) A - Augmented (dose-related) B - Bizarre (idiosyncratic) C(?) - Statistical (no identifiable victim) D(?) – Delayed Sheep and goats and ….

  5. Acute ADRs including drug toxicity are commonly categorised into two groups A - Augmented (dose-related) B - Bizarre (idiosyncratic) Adverse Drug Reactions

  6. Type A & Type B ADRs

  7. Allergy Individual variation in pharmacokinetics enzyme polymorphism (perhexilene) renal or hepatic failure (sotalol, chlormethiazole) age (flucloxacillin) Individual variation in pharmacodynamics receptor polymorphism (TCAs) organ failure (hypothyroidism & digoxin) Drug interactions Type B reaction mechanisms

  8. Paracetamol Poisoning: Andrew Dawson

  9. Paracetamol overdose Would you like liver with that? • 24 yo woman takes 24 grams of paracetamol

  10. Objectives • Mechanism • Risk assessment • Treatment

  11. Objectives • Risk assessment • Mechanism • Simple • Advanced • Hepatic drug metabolism • Treatment • Pitfalls • Decontamination • ADR

  12. Paracetamol questions • By what mechanism does paracetamol cause problems in overdose? • Why does the body produce “toxic metabolites” • How can you estimate her risk of hepatic damage? • What is the relevance of alcohol ingestion to the risk of hepatotoxicity?

  13. Normally 85-90% metabolism by conjugation Minor oxidative pathways (P450 enzymes) produces the intermediate toxic metabolite glutathione required for further metabolism to non-toxic metabolites N-acetyl-p-benzoquinonimine

  14. 85% Conjugation P450 Glutathione NAPQI Paracetamol Mechanism N-acetyl-p-benzoquinonamine

  15. CONJUGATION Sulphation & Gluronidation PARACETAMOL P450 TOXIC INTERMEDIATEMETABOLITE SH NON TOXIC METABOLITES MECHANISM OF TOXICITY • When glutathione depleted - the toxic metabolite binds to sulphydryl- containing proteins in the liver cell • Causing cell death (toxic hepatitis)

  16. 90% Conjugation P450 Glutathione NAPQI NAPQI Paracetamol Toxicity

  17. Glutamine synthase Cytosol ADP-ribose pyrophosphatase-1 Glutamylcysteinylsynthetase GAPDH Glutathione S-transferase Methionineadenosyltransferase MIF tautomerase N-10-formyl-H4folate dehydrogenase Protein phosphatase Proteasome Tryptophan-2,3-dioxygenase Aldehyde dehydrogenase Carbamyl phosphate synthase-1 Glutamate dehydrogenase Mg2+ ATPase Ca2+/Mg2+-ATPase Na+/K+-ATPase Enzymes inhibited by binding with NAPQI

  18. NAPQI induced an adaptive defense response

  19. Paracetamol questions • By what mechanism does paracetamol cause problems in overdose? • How does the body produce “toxic metabolites” • How can you estimate her risk of hepatic damage? • What is the relevance of alcohol ingestion to the risk of hepatotoxicity?

  20. How the liver produces toxic metabolites • Phase I • Chemical modification - Oxidation, hydroxylation, etc… • pharmacological inactivation or activation, • facilitatedelimination • addition of reactive groups for subsequentphase II conjugation • Phase II • Conjugation – Inactive, water soluble

  21. Paracetamol questions • By what mechanism does paracetamol cause problems in overdose? • Why does the body produce “toxic metabolites” • How can you estimate her risk of hepatic damage? • What is the relevance of alcohol ingestion to the risk of hepatotoxicity?

  22. 85% Conjugation P450 Glutathione NAPQI takes 24 grams of paracetamol+ alcohol N-acetyl-p-benzoquinonamine

  23. Paracetamol questions • By what mechanism does paracetamol cause problems in overdose? • Why does the body produce “toxic metabolites” • How can you estimate her risk of hepatic damage? • What is the relevance of alcohol ingestion to the risk of hepatotoxicity?

  24. Increase Conjugation Children, the pill Glutathione depletion: chronic ingestion paracetamol, malnutrition Induced P450: chronic alcohol, antiepileptics, barbiturates NAPQI Factors alter risk Blocked P450:acute alcohol, cimetidine

  25. Paracetamol Risk? • 24 yo woman takes 24 grams of paracetamol • Complains of nausea and vomiting, loose bowel motion and abdominal pain. • Paracetamol level • 16 hours = 334 nmol/mL

  26. Risk Assessment for Treatment • Ideally a paracetamol blood level nomogram. • Those on or above the treatment line will require treatment. • Single ingestion • Known time • Best or worst case scenario

  27. Risk by dose • Single • > 200mgs/kg or > 10 grams • Staggered • > 200 mgs/kg or > 10 grams in 24 hours • > 150 mgs/kg or > 6 grams in each 24 hours (48 hours) • > 100 mgs/kg or > 4 grams per day chronic at risk

  28. CONJUGATION Sulphation & Gluronidation PARACETAMOL P450 TOXIC INTERMEDIATEMETABOLITE SH NON TOXIC METABOLITES Factors that may alter risk • Increased conjugation • children, oral contraceptive • Induced P450 • chronic alcohol, antiepileptics, barbiturates • Blocked P450:acute alcohol, cimetidine • Glutathione depletion: chronic ingestion paracetamol, malnutrition

  29. Paracetamol: Treatment • N–acetylcysteine • Glutathione precursor • Antioxidant • Protection from toxicity • Before 8 hours complete protection • 8–24 hours incomplete protection but lower mortality • After 24 hours - shown to decrease mortality in established hepatotoxicity.

  30. Paracetamol: 3 Cases • A 16-year-old female (50 Kg): 1 hour following the ingestion of 10 grams of paracetamol. • A 16-year-old female (50 Kg): 15 hours following the ingestion 12 grams of paracetamol. • A 16-year-old female (120 Kg): 1 hour following the ingestion of 10 grams of paracetamol.

  31. Decontamination:Risk /Benefit • Dose • Time • Method • Nothing • Emesis • Charcoal • Lavage • Whole Bowel Irrigation

  32. Normally 90% metabolism by conjugation Minor oxidative pathways (P450 enzymes) produces the intermediate toxic metabolite glutathione required for further metabolism to non-toxic metabolites N-acetyl-p-benzoquinonimine

  33. Time to N-acetylcysteine (hours) and hepatotoxicity (%) Smilkstein MJ et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319:1557-1562

  34. NAC • Aim to start Rx within 8 hours • Early toxicity • Glutathionine precursor • SH donor • Late toxicity • ?Free radical scavenging • ?Haemodynamic • ?Other

  35. N-acetylcysteine • 150mg/kg over 15 minutes • 200 ml 5% dextrose i.v. infusion • 50mg/kg over 4 hours • 500ml of 5% dextrose • 100mg/kg over 16 hours • 1L of 5% dextrose

  36. Acute auto-immune hepatitis • A 40 year old woman • Has a drainage of a surgical wound abscess under general anaesthesia • A few days later she has jaundice and severely deranged liver function tests.

  37. Halothane hepatitis Halothane is metabolized by cytochrome P450 2E1 to a chemically reactive trifluoroacetyl radical, which has been shown to covalently modify lysine residues in a range of target proteins Chemical modification of protein(s) leads to the immune response associated with halothane hepatitis.

  38. Ecstasy – Toxic metabolites + Oxidative stress from hyperthermia

  39. Drug Cellular Accumulation Toxicity • Nucleic Acid • Enzyme • Transport Protein • Signalling Protein • Receptor • Autologous protein Carcinogenicity Phase I/II Bioactivation Necrosis Stabile Metabolites Toxic Metabolites Apotosis Bioinactivation Hypersensitvity Excretion

  40. Spectrum of manifestations of drug induced hepatotoxicity • Acute hepatitis – paracetamol, isoniazid, troglitazone • Chronic hepatitis – diclofenac, methyldopa • Acute cholestasis – erythromycin, flucloxacillin • Mixed hepatitis/cholestasis – phenytoin • Chronic cholestasis – chlorpromazine • Fibrosis - methotrexate • Microvesicular steatosis – valproate • Veno-occlusive disease - Cyclophosphamide

  41. Examples of risk factors for drug induced hepatotoxicity • Methotrexate – alcohol, obesity, diabetes, psoriasis • Isoniazid – viral hepatitis, alcohol, acetylator phenotype, rifampicin • Paracetamol – alcohol, fasting • Valproate – other anticonvulsants, genetic metabolic defects • Diclofenac – female, osteoarthritis

  42. Summary of effects of alcohol

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