Nick Buckley: Paracetamol: More than Meets the Eye

Paracetamol poisoning

Nick BuckleyProfessorial Medicine Unit UNSWNSW Poisons Information Centre

South Asian Clinical Toxicology Research Collaboration (www.sactrc.org)

March 2013

Paracetamol poisoning for the distracted

90% Conjugation

NAPQI

P450

Glutathione

Free Radical

Paracetamol Toxicity

Paracetamol overdose – Would you like social media with that?

(or acetylcysteine)• A 24 yo woman takes 15 grams of

paracetamol• Paracetamol level at 12 hours

= 300 nmol/mL (45 mg/L)

The State of the art Hypertox

APAP-APP

Questions

M According to guidelines, should she be treated with acetylcysteine?MWhere is she? MWhat year is it?

M What is the risk of hepatotoxicity and death if she is treated with acetylcysteine?

M What is the risk of hepatotoxicity & death if she if not?

What threshold for treatment?

& ? “The high risk line” UK circa 1995

& Schmidt LE, Dalhoff K. Br J Clin Pharmacol 2001 Jan;51:87-91

& Rumack BH, Mathew H. Paediatrics 1975; 55:871-876

& Prescott LF et al Lancet 1971; 519-522

Treatment Nomograms

0 5 10 15 20

10

25

50

100

150200

300

Time

mg

/L

What threshold for treatment?

& Rumack BH, Mathew H. Paediatrics 1975; 55:871-876

& Prescott LF et al Lancet 1971; 519-522

Treatment Nomograms

0 5 10 15 20

10

25

50

100

150200

300

Time

mg

/L

MHRA (UK) – August 2012

& MHRA UK (estimated to prevent one death in UK every 37.5 years vs using 150 line)

& Rumack BH, Mathew H. Paediatrics 1975; 55:871-876

Treatment Nomograms

0 5 10 15 20

10

25

50

100

150200

300

Time

mg

/L

Questions

M According to guidelines, should she be treated with acetylcysteine?MWhere is she? MWhat year is it?

M What is the risk of hepatotoxicity & death if she if not?

M What is the risk of hepatotoxicity and death if she is treated with acetylcysteine?

Time to 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.

0

5

10

15

20

25

30

0 to 4, 4 to 8, 8 to 12, 12 to 16, 16 to 20, 20 - 24

CAOS theory – Individualised risk estimates are

as easy as Psi.

Sivilotti et al 2005

APAP-APP

Remaining ‘controversies’ in antidotes for paracetamol

poisoning?• What is the role of liver transplant???

King’s College criteria for transplant in

paracetamol induced liver disease

Arterial pH < 7·3 after adequate fluid

resuscitation.OR (all of)

Grade or IV encephalopathy and

Prothrombin time > 100 seconds and

Serum creatinine > 300 � mol/L

In a 24 hour period.

Q J Med 2008; 101:723–729

Survival curves depending ondecision to transplant with

"Kings criteria"

0 10 20 30 40 50 600

50

100

Transplanted

Not transplantedextrapolationsQALYs

Years

Su

rviv

al %

Other ‘first world problems’

• Slow release paracetamol preparations• Diagnosis of occult overdose

presentations with acute liver failure • Very Early vs 4-8 hour NAC treatment

Extended release OD

» MJA 2008; 188: 310-311

» James LP, Letzig L, Simpson PM etal. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metabolism and Disposition. 2009: 37(8); 1779-1784.

» James LP, Capparelli EV, Simpson PM etal. Acetaminophen-Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen Overdose. Nature. 2008: 84(6); 684-690.

Dose-related, long-half-life

Given acetylcysteine is about as proven an antidote as we

have – how does it work?• Antioxidant

– Direct– Conversion to cysteine –

• rate limiting step in glutathione synthesis

• “Free radical” scavenger

How quickly should you

scavenge free radicals?

Five decades of paracetamol poisoning - but still more than meets the eye or iphone

• New evidence still needed• No RCTs comparing different NAC regimens• Early risk prediction with adducts?• Duration of NAC in established

hepatotoxicity?• Better & earlier prediction of likely fatal

outcome• Decision support tools

• Risk prediction

Questions?