Dr. Nayira A. Abdel Baky Associate Professor Pharmacology and Toxicology

1. Acetaminophen N-acetyl-P-aminophenol (APAP) Dr. Nayira A. Abdel Baky Associate Professor Pharmacology and Toxicology

2. ACETAMINOPHEN -Acetaminophen is contained in more than 100 over-the-counter drug preparations and is routinely reported as the most common pharmaceutical agent involved in overdose. -Acetaminophen was fourth among the top 25 substance categories with the highest number of fatalities (208 cases). -Hepatic failure due to acetaminophen overdose the most common cause of liver failure requiring transplantation in the United Kingdom and in the United States. -Acetaminophen toxicity is an example of saturation of deactivation pathways.

3. ACETAMINOPHEN -Therapeutic dose = 4 gm/24 hour in adults and 90mg/kg in childeren As little as 7.5g can be toxic (exceptions: patients who are taking enzyme inducer as anticonvulsants or rifampin, patients with history of chronic ethanol abuse, fasting, malnutrition, or HIV infection or patient with reduced ability to conjugate toxin. -The safety of acetaminophen depends on the availability of antioxidant such as reduced glutathione (GSH) and other thiol-containing substances required to detoxify NAPQI.

4. Met pathways of APAPUnder normal metabolic conditions and recommended doses 1- Hepatic glucuronide conjugation(40-65%) Hepatic sulfat conjugation(20 - 45%) 91-93% inactive metabolites excreted in the urine. 2- Excretion of unchanged APAP in the urine (2%). 3- Oxidation by cytochrome P450 to NAPQI(5%)  GSH combines with NAPQI  nontoxic cysteine/mercaptate conjugates  excreted in urine. Hepatic glucuronide conjugation(40-65%) Hepatic sulfat conjugation(20 - 45%)

5. Mechanism of Toxicity The ingested APAP undergo oxidative metabolism by CYP- 450 to reactive intermediate metabolite(N-acetyl –P-benzoquinone imine=NAPQI) which is rapidly bounded to glutathion ,detoxified through conjugation pathway ,and excreted. In the presence of adequate GSH stores , there is no fear from any toxicity. However, overdose of APAP saturate the conjugation pathways and NAPQI overwhelms the GSH detoxifi-cation mechanism , finally leading to liver necrosis and may be death.

6. Acetaminophen Metabolism Glucuronyl transferase Sulf otransferase

7. In Other Words: If too much acetaminophen is around 1-Saturation of glucuronidation and sulfation pathways 2-Amount of APAP metabolized by p450 cytochromes to NAPQIincreases. 3-Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol containing substances. 4-In OD: Rate and quantity of NAPQI formation overwhelms GSH supply and regeneration (glutathione levels fall to less than 30% of normal):  elimination of NAPQI prolonged  free NAPQI binds critical intracellular proteins with sulfhydryl groups (hepatocyte membranes)  cellular dysfunction and cell death and liver necrosis .

8. Renal toxicity -Organ dysfunction results everywhere in the body where local oxidative metabolism (via CYP-450) creates NAPQI that cannot be detoxified  direct organ toxicity. -Cytochrome P-450 enzymes produce NAPQI in the renal tubules  NAPQI binds cellular macromolecules  acute tubular necrosis. -25% of hepatotoxic cases Hepatorenal Syndrome &Volume depletion

9. Other organs damaged -Heart myocarditis -Pancreas  pancreatitis -It is controversial whether these entities are part of multisystem organ failure (MSOF) either from i-Fulminant hepatic failure (FHF) ii- Local accumulation of toxic metabolites.

10. Factors which adversely affect APAP metabolism -Toxicity is increased in patients with induction of the P450 system through drugs such as smooking, rifampicin, phenobarbital, isoniazid, phenytoin, carbamazepine . -Drugs such as sulfa and AZT (zidovudine) potentiate acetaminophen hepatotoxicity by competing for glucuronidation pathways resulting in increased cyp2E1-dependent metabolism of acetaminophen - -This also occurs in patients with low glutathione reserves, as a product of: -Genetic variation -HIV +ve -Malnutrition, or fasting -Alcohol-related or other liver disease -Frequent dosing interval of APAP

11. Glutathione stores are determined by: -Age -Diet -Liver disease -Fasting prior ingestion -Chronic malnutrition -Anorexia -Gastroenteritis -Chronic alcoholism -HIV Glutathione replacement by sulfhydryl compounds: -Eating -NAC GSH stores

12. History & clinical presentation -The course of acetaminophen toxicity generally is divided into 4 phases. Clinical evidence of end-organ (hepatic , occasionally renal) toxicity is often delayed 24 hours post-ingestion. -Because antidotal therapy is most effective when initiated within 8 hours post-ingestion, the clinician must obtain an accurate history of the time(s) of ingestion, the quantity, and formulation of acetaminophen ingested, and any co-ingestants, which may delay APAP absorption (eg, anticholinergic drugs or opioids). -Because a patient's history may be inaccurate, the serum acetaminophen concentration is important for diagnosis and treatment, even in the absence of symptoms. After a single ingestion, APAP antidote (NAC therapy) is guided by the serum APAP concentration.

13. Clinical presentation Phase 1(few hrs after ingestion up to 24 hr) :Malaise , nausea , vomiting and diaphoresis. Phase 2 (24-72 hrs after ingestion) : Increase in liver enzymes(transaminases are peaking), serum bilirubin , prothrombin time are increased , and pain in the right upper abdominal quadrant. Phase 3 (72-96 hrs after ingestion) :Hepatic necrosis is characterized by;peak in the liver function, altered consciousness, hypoglycemia, jaundice , and coagulation abnormalities(coagulopathy), and encephalopathy. Hepatic failure can develops in 4th or in the 5th day if hepatic damage is sever and death can occcur. Myocardial necrosis, pancreatitis , heamolytic anemia and skin rashes may develop but are rare. Phase 4 (96 hours-14 days after ingestion) : Resolution of liver dysfunction and liver enzymes abnormalities reaching resolution, and healing of the pathologic liver damage. If hepatic damage is massively sever, sepsis and death may occure at 5-10 days

14. Diagnosis -In patient with a history of acetaminophen overdose, a serum acetaminophen level should be measured between 4 and 24 hours after ingestion. -The value obtained should be evaluated according to the Rumack-Matthew nomogram for determining the risk of hepatotoxicity and need for therapy. -Rumack-Matthew nomogram is semi-logarithmic plot of plasma acetaminophen levels vs. time. It is based only on acute ingestion. This nomogram assumes that acetaminophen absorption is completed by 4 hours and that elimination occurs with a half-life of 4 hours. -Acetaminophen levels are measured ≥ 4hrs after ingestion and 4 hrs later; if either level is above the Rumack-Matthew line of toxicity, treatment is required.

15. Laboratory analysis 1-Determination of plasma APAP level. 2-Monitoring liver profile including serum ALT, AST , bilirubin , glucose , prothrombin time, platelet count…etc 3- Determination of kideny functions by measuring plasma creatinine and BUN. 4-ECG for assessment of myocardial injury. 5- Urine analysis.

16. Management Steps General measures If the patient is presented to ER within 4 hrs of ingestion -Gastric lavage -Activated charcoal ,cathartics (saline sulfate are prefered to enhance sulfate metabolic pathway). -Glucose, bicarbonate, Vit K for elevated prothrombin time <8 hours -Take level of APAP after four hours (Peak concentration at 4 hrs then hepatic metabolism) -Start N-aceylcysteine (antidote) if APAP concentration is high =APAP is on or above nomogram line. -When NAC is administered anytime within 8 hours of ingestion, it is nearly 100 % protective against hepatotoxicity. Therefore, NAC should be given whenever a potentially toxic acetaminophen level is measured above the line on the nomogram - Patients should be advised to return to hospital if vomiting or abdominal pain develop or reoccur.

17. Patients with enhanced risk ( on B line) -Patients who regularly consume alcohol in excess -Those who are malnourished. -Those who regularly take enzyme-inducing drugs (e.g. carbamazepine, phenytoin, phenobarbitone, primidone, St John's Wort and rifampicin) -Those with conditions causing glutathione depletion (e.g. malnutrition, eating disorders, malabsorption states and HIV infection) Those people may be at higher risk of liver damage even from lower plasma paracetamol concentrations than others. The plasma paracetamol concentration for such patients should be considered in relation to treatment line B on the graph.

18. Nomogram Normal treatment line B B Start N-acetylcysteine (NAC) if Paracetamol level at 4 hours above the treatment line.However start treatment with NAC immediately - do not wait for the level - if any of the following are present: 1-If more than 150 mg/kg (or 12g in an adult) of paracetamol has been ingested. 2-Or the overdose is staggered. 3-Or the patient is a late presenter (>15hrs post ingestion) having already taken a significant overdose. 4-If the patient has taken a significant overdose (based on the history), but the initial Paracetamol level is below the treatment line then repeat the level four hours later as there can be delayed absorption.

19. Cont.;Management >8 hours Urgent action required because the efficacy of NAC declines progressively from 8 hours after the overdose Therefore, if > 150mg/kg or > 12g (whichever is the smaller) has been ingested, start NAC immediately, without waiting for the result of the plasma paracetamol concentration >24 hours Still benefit from starting NAC

20. Acetaminophen hepatotoxicity antidote -The antidote is N-acetyl cysteine (NAC) (Mucomyst). -NAC acts as antidote through several mechanisms including: i-It acts as a precursor to cysteine, and then to glutathione, repleting glutathione stores ii-It provides sulfhydryl donors to which NAPQI can bind and be detoxified. iii-It may also enhance sulfation of any remaining acetaminophen resulting in the reduction in the amount of NAPQI that is produced. iv-It has also been shown to improve survival in patients with hepatic failure by acting as a free radical scavenger, enhancing oxygen uptake and utilization in peripheral tissues, including the brain, and by improving microcirculation.

21. How is NAC administered? -The NAC protocol (orally): 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg administered every 4 hours for a total of 1330 mg/kg over 72 hours. -NAC solution should be diluted from the 20% solution to a 5% solution in juice or a carbonated beverage to maximized palatability. It stills smells and tastes pretty bad. -Vomiting frequently complicates oral NAC administration, and antiemetics such as high-dose metoclopramide, up to 1-2 mg/kg, and ondansetron may be necessary to help the patient retain the NAC. -Slow instillation through a nasogastric tube may also aid in NAC retention. -Intravenous NAC protocols: (1) 150 mg/kg of IV NAC over 15 minutes; this is followed by 50 mg/kg IV over 4 hours, followed by 100 mg/kg over 16 hours. (2)140mg/kg IV over 1 hour followed by 12 doses of 70 mg/kg administered every 4 hours.

22. What should I do with a patient with a “chronic” ingestion of acetaminophen over several days? -The nomogram is meant just for single acute overdose and does not apply in the setting of multiple supra therapeutic doses of acetaminophen. -Evaluation of these patients includes assessment of hepatotoxicity (elevated aspartate aminotransferase [AST], alanine aminotransferase [ALT], PT, and international normalized ratio [INR], as well as the presence of any unmetabolized acetaminophen. -NAC treatment should be initiated if acetaminophen is still measurable or there is evidence of hepatotoxicity and should be continued until at least 24 hours after the last dose of acetaminophen or until the patient is improved.

23. Special considerations for a pregnant patient and children -Acetaminophen has been shown to cross the placenta and to cause hepatotoxicity in a fetus, which has functioning mixed-function oxidase liver enzymes (14-16 weeks). -Pregnant patient should receive NAC for treatment with no delay. Delay may associate with fetal death. -Children may fare better after ingestion of acetaminophen because of an enhanced capacity for sulfation in their livers. -It was suggested that using 2-hours acetaminophen levels to predict toxicity risk in children after the ingestion of liquid acetaminophen formulas.