Management of Paracetamol poisoning.pptx

the importance of knowing the hazardous medicine in our home

1. Paracetamol poisoning Prepared by: Julios Qayssar Adlan . Clinpharm . MPH Pharmacy department AQWCH

2. Poisoning mechanism The main toxicity following paracetamol poisoning is acute liver injury which results from the formation of a toxic metabolite of paracetamol, N-acetyl-p-benzoquinone imine (NAPQI). In adults taking therapeutic doses, paracetamol is metabolized into two major non-toxic metabolites – sulphate and glucuronide conjugates – which account for 30% and 55% of paracetamol metabolism. NAPQI, is formed in small amounts following a therapeutic dose of paracetamol. It is a highly reactive toxic metabolite formed by cytochrome P450 2E1 and is responsible for the hepatocellular injury that occurs with paracetamol toxicity. The small amounts of NAPQI produced after therapeutic doses are detoxified by irreversible glutathione-dependent conjugation reactions to two non-toxic metabolites. In overdose, the increased formation of NAPQI depletes glutathione and once glutathione is depleted by more than two-thirds it covalently binds to critical cellular proteins. It is hypothesized that this results in loss of activity of critical proteins and eventually hepatic cell death. To summarize, NAPQI is toxic, in therapeutic doses glutathione can make it in non-toxic. In overdose the glutathione mechanism is overwhelmed.  Hence NAC works as a glutathione donor preventing NAPQI accumulation

3. Management Resuscitation: Rarely required: in massive overdoses (high levels > 800mg/L can cause coma and a lactic acidosis) or delayed presentation with hepatic failure. Attention to airway, breathing and circulation. And lastly Correct hypoglycemia . Risk Assessment: Dose Formulation ingested, Acute vs staggered vs repeated supratherapeutic ingestion Time of ingestion Symptoms: abdominal pain, nausea, vomiting Investigations: All patients: Serum paracetamol concentration ALT/AST Those patients with acute liver injury also require: Venous blood gas – pH and lactate EUC (Electrolytes, Urea & Creatinine ) Glucose C oagulation Calcium / Magnesium / Phosphate  

4. Toxic dose is considered to be ( 150mg/kg )

5. Rumack –Matthew nomogram It plots serum concentration of acetaminophen against the time since ingestion, in order to predict possible liver toxicity and allow a clinician to decide whether to proceed with N-Acetylcysteine (NAC) treatment. It is a logarithmic graph starting 4 hours after ingestion; at this time the absorption of acetaminophen is considered likely to be complete. This nomogram allows for timely management of an acetaminophen overdose. Generally, a serum plasma concentration (APAP) of 140–150 μg /mL (or mg/L) at 4 hours post-ingestion indicates the need for NAC treatment .( 150mg/kg as toxic dose ) This nomogram is not used alone if the patient has altered mental status or if the history is not reliable; rather, an additional line should be drawn and plotted to see if the slope of the line remains at or above the nomogram. Additionally, a formal half-life may also be determined, by measuring concentration first upon admission of the patient and again 4 hours later; from these measurements, half-life can be calculated. If half-life is more than 4 hours, then treatment is necessary to prevent hepatotoxicity and liver failure. The original line, sometimes referred to as the Rumack –Matthew line, starts at 200 μg /mL at 4 hours and was published in 1975 by Barry H. Rumack and Henry Matthew. When the NAC study began in 1976, the U.S. Food and Drug Administration (FDA) required a line that was 25% below the original. This line is referred to as the treatment line and starts at 150 μg /mL at 4 hours. It is the usual line used in the United States to determine treatment of acetaminophen overdose after the publication of the NAC study in 1981. With early NAC and supportive therapy, 66% of patients will recover; the remainder will progress to fulminant hepatic failure and require liver transplantation, after which 70% of patients will survive at least one year

6. References Cairney DG, Beckwith HK, Al-Hourani K, Eddleston M, Bateman DN, Dear JW. Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine. Clin Toxicol (Phila) 2016; 54(5): 405-10. Chiew AL, Fountain JS, Graudins A et al.  Summary statement: new guidelines for the management of paracetamol poisoning in Australia and New Zealand.  MJA 2015; 203(5):215-218 Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of acetylcysteine. British journal of clinical pharmacology. 2016;81(3):471-81. Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol (Phila). 2017;55(10):1055-65. Chiew AL, Isbister GK, Page CB, Kirby KA, Chan BSH, Buckley NA. Modified release paracetamol overdose: a prospective observational study (ATOM-3). Clin Toxicol (Phila). 2018;56(9):810-9. Chiew AL, Reith D, Pomerleau A, Wong A, Isoardi KZ, Soderstrom J, et al.  Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand.  The Medical journal of Australia. 2020;212(4):175 – 83