Liver Toxicity Andrew Dawson. Outline Adverse Drug Reactions Definition & Types Examples Mechanisms Revisit some hepatic metabolism Paracetamol Hepatotoxicity.

Liver Toxicity

Andrew Dawson

Outline• Adverse Drug Reactions

• Definition & Types

• Examples

• Mechanisms

• Revisit some hepatic metabolism

• Paracetamol Hepatotoxicity

• Other examples

Phase I/II Bioactivation

Bioinactivation

Toxicity Overview

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 A & Type B ADRs

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?

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

85% Conjugation

NAPQI

P450

Glutathione

Paracetamol Mechanism

N-acetyl-p-benzoquinonamine

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

90% Conjugation

NAPQI

P450

Glutathione

NAPQI

Paracetamol Toxicity

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

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 Summary of effects of alcohol alcohol