Intoxication of paracetamol

Analytisch Diagnostisch Centrum, ADC

Department of Toxicology and Drug Research

drs. F.J.I.Faulborn, pharmacist

Overview

➲ intoxications; the basics ➲ farmaceutical, farmacological and chemical pro-

perties of paracetamol ➲ casus ➲ pathofysiologal aspects ➲ clinical symptoms ➲ the lab test of paracetamol

Intoxications, the basics

➲ “ “All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing poison.”- Paracelsus

Paracelsus a basic principle of toxicology.

Intoxications, the basics

➲ Several root cause: Auto-intoxication (antidepressiva, pain killers) Farmacotherapy ( interactions, wrong dosages) Druguse (alcohol, narcotics) Internet drugs

➲ NVIC (=National Vergiftigingen Intoxicatie Centrum, website vergiftigingen.info .)

Childrens to 4 yrs and adults of 18 – 65 yrs , are the focus groups Top 5 drug induced intoxication in Holland, 2012: paracetamol,oxazepam,

ibuprofen, vitamin D, quetiapine (brand: Serequel) In 2011, Holland (bron: CBS): 1647 cases of “ tentamen suicidii”, 15% man and

30 % woman

Still basics: farmacokinetics

➲ ADME: absorption, distribution, metabolisation, elimination process.

Continuing basics: ADME can be different for childrens, especially in case of intoxification

Continuing basics: the ADME in case of intoxification

➲ Absorption: in case of many tablets/capsules--> delayed f.e. valproinic acid: Tmax1-3 hr (normal) to 18 hrs. Cmax. Is also delayed with retardtablets

f.e. tramadol retard capsules: 1-2 hr.(normal vs. 5-6.5 hr (retard)

➲ Distribution: with lowered serum levels chance for re-distribution, f.e. chronic lithium accumulation in bone, brain and thyroid

➲ Metabolism: saturation, f.e. paracetamol ➲ Elimination: with high dosis --> slow down

elimation process f.e. Fenytoine due to enzym saturation

What to do with an intoxicated patient:

➲ Anamnese: what, why, how much, symptoms ➲ Identifying group: toxine syndromes/ toxidromes

hypnotics -sedatives-alcohol (hyporeflexie, hypotonic, coma, hypotension, hypothermic)

opioides -cocaine-methadon(hypoventilation, hypothermic, miosis, hypotension,

bradycardic)

anticholinergics -antihistaminca, antiparkinson, antipsychotica, antidepressiva, scopolamine (delirium,

tachycardic, dry+red skin, mydriasis, urineretention, convulsions, aritmias)

cholinergics - nicotine, pesticides, carbamates (diarrhea,

vomitting, urineretenton, miosis, bradycardic, lung oedema, salivation)

sympaticomimetics – cafeine, theophylline, amfetamines, decongestiva, epinephrine (agitation, anxiety,

paranoia, convulsions, mydriasis, hypertension, dry mouth, artimias, hypertermic)

serotonerg- SSRIs's, MAO's, TC's, LSD (tremors, hyperreflex, diarrhea,

fever, hypersalivation, sweating)

Matabolics of PCM

➲ 3 metabolic pathways: Glucuronidation (= 40 % of the metabobolism). Sulfation (= 20-40 % of the metabolism). N-ydroxyltion followed by Glutathion conjugation ( =15%).

➲ From this glutathion conjugation is 5-10 % of paracetamol transformed by CYP2E1 to NAPQI (= N-acetyl-p-benzo-quinone-imine)

➲ This NAPQI is toxic and binds to liver parenchym, destroying the liverfunction ➲ All 3 pathways yield final products that are inactive, nontoxic and eventually excreted by the kidneys.

➲ Acute toxic dose differs: ingestion < 100mg/kg--> no risks. With > 100mg/kg, risk of liver failure. With > 250mg/kg= 50% of liver failure. With > 350mg/kg= 100% liver failure.

➲ If the T1/2 >3,5 hr--> indication of liver failure, with abnormal INR/ PTT after 48 hr--> indicators for encephalopatie ➲ After 96 hr. → liver transplantation ➲ Paracetamol with alcohol one-time-only: less forming of toxic NAPQI, due to competition for binding to liverenzym

CYP2E1 ➲ If combined with chronic alcoholism: due to induced level of CYP2E1--> more toxic NAPQ1--> liver tissue damage

Casus, reviewing toxidromes

➲ Ambulance brings a man from the streets of Otrobanda, with no cognitive reaction, a breathing freq. of 6 and pin-point pupils.

→ Which toxidrome is this?

Casus 2

➲ A 2 jr. old girl is redireted by the GP after a convulson-episode to the hospital- pediatric department for further examination: a decrease in consciousness level and using amoxicilline, domperidon, both p.o.. As antipyretic she was using paracetamol suspension 40mg/ml, 4dd 1,5 ml

➲ Examination: BP 109/51; HR 180 b/min; T 35.9 C; sleepy and weak; pupils not reactive to light.

→ using medication and several hours after time with the GP

→ what to do?

Further casus 2

➲ Blood work/ Clinic lab: elevated ALAT = 49 u/l ( ref. < 42 u/l); elevated ASAT =53 u/l (ref.< 48 u/l)

➲ Toxicology screen showed PCM level of 566 mg/L at 8 hr

➲ Probability toxicity by nomogram:

➲ N-acetylcysteine (NAC) was initiated at 1.8g in 200ml DW 5% during 1 hr. Then 630 mg in 150 ml DW 5% over 4 hrs. Finally 1.2 g in 250ml DW 5% over 24 hrs. ( from internal medicine protocol)

➲ -->The PCM serum level and liver enzymes started to decrease after the NAC and she was able to respond on day 3 after admission.

➲ → domperidon was competing with the substrate

CYP2E1, with result accumulation of NAPQ1 and resulting in elevated liver enzymes

Protocol treatment PCM intox. ( “ Acute Boekje” en NVIC)

I deminishing absorption: gastric lavage within 1-2 hr. and administer 50 g active charcoal. After 4-6 hr co-admin laxantia ( osmotic type f.e. macrogol-elctrolytes)

II blind start with NAC: 150mg/kg IV in 15 min. Then

50mg/kg during 8 hrs. And at least continuing with same dosis till plasma PCM< 10mg/l

[side effect of NAC: anigio edema, bronchospasm, hypotension]

III if allergic for NAC: then methionine 35mg/kg p.o.

Each 4 hrs till max. 10g.

Clinical view, the symptoms

A: no symptoms B: after few hrs. motion sickness and vomiting C: after 18- 72 hrs. abdominal pain <-due to liver expansion D: after more than 24 to 36 hrs. liver function failure with

spiking levels of ALAT en ASAT; icterus E: after more than 48 hrs. breakdown of the coagulation

cascade/ INR-PTT, with internal bleeding and encephalopathie

F: after more than 96 hrs. of treatment and still high levels of INR, ALAT and ASAT--> liver tranplantation.

E:worst case scenario between 48 and 96 hrs. with no change --> fatal

Lab method PCM analisis

Sampling: 1-4 ml blood in EDTA flask with gel; min. after 4 hrs. of ingestion PCM

Transport: room temp. If stored: cooled at 8 C ( or freezed -20 C) Method of analysis: enzymatic colorimetric, spectrophotometric principle

→ rapid, reliable, convenient and specific. Test principle: enzymatic cleavage specific to the amide bond of PCM-->

p-aminophenol + acetate. This p-aminophenol is reactive with 2,5 dimethylphenol in the presence of Manganese--> yielding a colored compound.--> this yield an absorbance at 605 nm and is directly proportional to the concentration of PCM in the sample

[Lambert-Beer law: absorbance of an monochromatic light beam is proportional to the concentration of the number of absorbing molecules, when it passes through a medium of homogenous thinckness]

After reviewing :

intoxications; the basics farmaceutical, farmacological and chemical properties of PCM casus pathofysiologal aspects clinical sympthoms the lab test of PCM literature: J.of PW 2011;5, Intoxicaties op de SEH, C de Jong, Sia et al, paracetamol poisoning,

J.emerg.med, cot 2006, Behera et al,J.Anl.Bioanal.Tecn. 2012, 3;6, Farmacotherapeutisch Kompas