Download Paracetamol self poisoning_ahd (Specific toxin)

Liver Toxicity
Andrew Dawson
Outline
• Adverse Drug Reactions
• Definition & Types
• Examples
• Mechanisms
• Revisit some hepatic metabolism
• Paracetamol Hepatotoxicity
• Other examples
Toxicity Overview
Phase I/II
Bioactivation
Bioinactivation
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
Adverse Drug Reactions
Acute ADRs including drug toxicity are commonly
categorised into two groups
A - Augmented (dose-related)
B - Bizarre (idiosyncratic)
Type A & Type B ADRs
A
B
Pharmacologically
predictable
Dose-dependent
+
-
+
-
Incidence & morbidity
High
Low
Mortality
Low
High
Treatment
Adjust dose(?) Stop
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
Paracetamol Poisoning:
Andrew Dawson
Paracetamol overdose
Would you like liver with that?
• 24 yo woman takes 24 grams of paracetamol
Objectives
• Mechanism
• Risk assessment
• Treatment
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?
Normally 85-90% metabolism by
conjugation
Minor oxidative
pathways (P450
enzymes)
produces the
intermediate toxic
metabolite
N-acetyl-pbenzoquinonimin
e
glutathione required for further
metabolism to non-toxic
metabolites
Paracetamol Mechanism
85% Conjugation
NAPQI
Glutathion
e
N-acetyl-p-benzoquinonamine
MECHANISM OF TOXICITY
PARACETAMOL CONJUGATION
Sulphation &
Gluronidation
P450
TOXIC
INTERMEDIATE
METABOLITE
SH
NON TOXIC
METABOLITES
• When glutathione depleted - the
toxic metabolite binds to
sulphydryl- containing proteins in
the liver cell
• Causing cell death (toxic
hepatitis)
Paracetamol Toxicity
90% Conjugation
NAPQI
NAPQI
Glutathione
Enzymes inhibited by binding
with NAPQI
•
Glutamine synthase
•
Protein phosphatase
•
Cytosol ADP-ribose pyrophosphatase-1
•
Proteasome
•
Glutamylcysteinyl synthetase
•
Tryptophan-2,3-dioxygenase
•
GAPDH
•
Aldehyde dehydrogenase
•
Glutathione S-transferase
•
Carbamyl phosphate synthase-1
•
Methionine adenosyltransferase
•
Glutamate dehydrogenase
•
Mg2+ ATPase
•
Ca2+/Mg2+-ATPase
•
Na+/K+-ATPase
•
•
MIF tautomerase
N-10-formyl-H4folate dehydrogenase
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?
takes 24 grams of paracetamol
+ alcohol
85% Conjugation
NAPQI
N-acetyl-p-benzoquinonamine
Glutathion
e
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?
Factors alter risk
Increase
Conjugation
Children, the pill
Glutathione
depletion:
chronic ingestion
paracetamol,
malnutrition
NAPQI
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
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
PARACETAMOL CONJUGATION
P450
TOXIC
INTERMEDIATE
METABOLITE
SH
NON TOXIC
METABOLITES
Sulphation &
Gluronidation
• Increased conjugation
• children, oral contraceptive
• Induced P450
• chronic alcohol, antiepileptics,
barbiturates
• Blocked P450:acute alcohol, cimetidine
• Glutathione depletion: chronic
ingestion paracetamol, malnutrition
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
Normally 90% metabolism by
conjugation
Minor oxidative
pathways (P450
enzymes)
produces the
intermediate toxic
metabolite
N-acetyl-pbenzoquinonimin
e
glutathione required for further
metabolism to non-toxic
metabolites
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 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 +
Oxidative stress from hyperthermia
Phase I/II
Bioactivation
Bioinactivation
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
Summary of effects of alcohol