Liver Toxicity Andrew Dawson. Outline Adverse Drug Reactions Definition & Types Examples Mechanisms Revisit some hepatic metabolism Paracetamol Hepatotoxicity.
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Outline• Adverse Drug Reactions
• Definition & Types
• Examples
• Mechanisms
• Revisit some hepatic metabolism
• Paracetamol Hepatotoxicity
• Other examples
Sheep and goats and ….Which ADRs are idiosyncratic, are dose-
related? (or other?)
A - Augmented (dose-related)
B - Bizarre (idiosyncratic)
C(?) - Statistical (no identifiable victim)
D(?) – Delayed
Acute ADRs including drug toxicity are commonly categorised into two groups
A - Augmented (dose-related)
B - Bizarre (idiosyncratic)
Adverse Drug Reactions
Type B reaction mechanisms
• 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
Objectives
• Risk assessment• Mechanism
• Simple• Advanced• Hepatic drug metabolism
• Treatment• Pitfalls• Decontamination• ADR
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?
N-acetyl-p-benzoquinoni
mine
Normally 85-90% metabolism by conjugation
glutathione required for further metabolism to non-toxic metabolites
Minor oxidative pathways (P450 enzymes) produces the intermediate toxic metabolite
MECHANISM OF TOXICITY
• When glutathione depleted - the toxic metabolite binds to sulphydryl- containing proteins in the liver cell
• Causing cell death (toxic hepatitis)
PARACETAMOLPARACETAMOL
TOXIC TOXIC INTERMEDIATEINTERMEDIATEMETABOLITEMETABOLITE
NON TOXICNON TOXICMETABOLITESMETABOLITES
Sulphation &Sulphation &GluronidationGluronidationCONJUGATIONCONJUGATION
P450P450
SHSH
Enzymes inhibited by binding with NAPQI
• Glutamine synthase
• Cytosol ADP-ribose pyrophosphatase-1
• Glutamylcysteinyl synthetase
• GAPDH
• Glutathione S-transferase
• Methionine adenosyltransferase
• 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
NAPQI induced an adaptive defense response
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?
How the liver produces toxic metabolites
• Phase I
• Chemical modification - Oxidation, hydroxylation, etc…
• pharmacological inactivation or activation,
• facilitated elimination
• addition of reactive groups for subsequent phase II conjugation
• Phase II
• Conjugation – Inactive, water soluble
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?
85% Conjugation
NAPQI
P450
Glutathione
takes 24 grams of paracetamol
+ alcohol
N-acetyl-p-benzoquinonamine
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?
Increase Conjugation
Children, the pill
NAPQI
Induced P450: chronic
alcohol, antiepileptics,
barbiturates
Glutathione depletion: chronic ingestion
paracetamol, malnutrition
Factors alter risk
Blocked P450:acute
alcohol, cimetidine
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
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
• Single ingestion• Known time
• Best or worst case scenario
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
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
PARACETAMOLPARACETAMOL
TOXIC TOXIC INTERMEDIATEINTERMEDIATEMETABOLITEMETABOLITE
NON TOXICNON TOXICMETABOLITESMETABOLITES
Sulphation &Sulphation &GluronidationGluronidationCONJUGATIONCONJUGATION
P450P450
SHSH
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.
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.
Decontamination:Risk /Benefit
• Dose
• Time
• Method
• Nothing
• Emesis
• Charcoal
• Lavage
• Whole Bowel Irrigation
N-acetyl-p-benzoquinoni
mine
Normally 90% metabolism by conjugation
glutathione required for further metabolism to non-toxic metabolites
Minor oxidative pathways (P450 enzymes) produces the intermediate toxic metabolite
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
NAC
• Aim to start Rx within 8 hours
• Early toxicity– Glutathionine precursor– SH donor
• Late toxicity– ?Free radical scavenging– ?Haemodynamic– ?Other
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
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.
Halothane hepatitisHalothane 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.
Ecstasy – Toxic metabolites + Ecstasy – Toxic metabolites + Oxidative stress from Oxidative stress from
hyperthermiahyperthermia
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
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
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