1. Tylenol and Hepatotoxicity Emmanuelle Mirsakov Pharm.D. Candidate 2007 USC School of Pharmacy 11-23-06

2. Importance Acetaminophen (Tylenol) [APAP] is a common constituent of OTC (over the counter) pain relievers Acetaminophen (Tylenol) [APAP] is a common constituent of OTC (over the counter) pain relievers Prescription pain relievers often come in combination with APAP (e.g. Vicodin (hydrocodone and APAP)) Prescription pain relievers often come in combination with APAP (e.g. Vicodin (hydrocodone and APAP)) Current guidelines set the maximum adult daily dose of APAP to 4g/day (3g/day for elderly) Current guidelines set the maximum adult daily dose of APAP to 4g/day (3g/day for elderly) Overdosing on acetaminophen is easier than with other pain relievers. Exceeding the max by only 20 percent for even one day can result in liver injury and rapidly deteriorating liver function in healthy people; the kidneys can also be affected. Overdosing on acetaminophen is easier than with other pain relievers. Exceeding the max by only 20 percent for even one day can result in liver injury and rapidly deteriorating liver function in healthy people; the kidneys can also be affected.

3. Mechanism of Action Despite massive experimental literature, and the detailed understanding of the mechanism of APAP’s toxic effect, some aspects still are controversial and unclear. Despite massive experimental literature, and the detailed understanding of the mechanism of APAP’s toxic effect, some aspects still are controversial and unclear. The controversy: The controversy: –There have been cases of liver damage from normal doses (<4g/day) of APAP

4. Mechanism in a Nut Shell Background Cytochrome P450 enzymes (liver metabolism) Cytochrome P450 enzymes (liver metabolism) Enzymes in the liver chew up drugs for removal from the body Enzymes in the liver chew up drugs for removal from the body Liver injury not due to drug itself but to the formation of a toxic metabolite ( a by-product) Liver injury not due to drug itself but to the formation of a toxic metabolite ( a by-product) Toxic metabolite: N-acetyl-p-benzoquinine imine [NAPQI] Toxic metabolite: N-acetyl-p-benzoquinine imine [NAPQI]

5. Mechanism in a Nut Shell Normal Majority of APAP is broken down (metabolized) by a process called glucoronidation [adding sugar groups on to detoxify the substance] & Sulphation [ adding sulfate groups on]; excreted as urine Majority of APAP is broken down (metabolized) by a process called glucoronidation [adding sugar groups on to detoxify the substance] & Sulphation [ adding sulfate groups on]; excreted as urine A small fraction of APAP is metabolized (broken down) by the liver (CytP450 enzymes), producing the toxic metabolite. A small fraction of APAP is metabolized (broken down) by the liver (CytP450 enzymes), producing the toxic metabolite. Normally we have a substance called glutathione (GSH) in our liver (stored there). Normally we have a substance called glutathione (GSH) in our liver (stored there). GSH combines with the toxic metabolite to detoxify it and help it leave the body GSH combines with the toxic metabolite to detoxify it and help it leave the body

6. Mechanism in a Nut Shell When Things Go Bad When there is more toxic metabolite than GSH then damage to the liver can happen (hepatotoxicity) When there is more toxic metabolite than GSH then damage to the liver can happen (hepatotoxicity) –Controversial as to why/how –In addition, the imbalance alone is not enough to cause the damage, but is a necessary pre-requisite.

7. Mechanism in a Nut Shell When Things Go Bad What can cause this imbalance? (genetic factors) What can cause this imbalance? (genetic factors) –Baseline of GSH in the liver –Level of liver enzymes to produce the metabolite ** The dose of APAP that will lead to damage is variable and unpredictable from patient to patient

8. Mechanism in a Nut Shell When Things Go Bad What can cause this imbalance? (external factors) What can cause this imbalance? (external factors) –Overdose –Drug interactions (Isoniazide) –Long-term alcoholism –Fasting/poor nutrition

9. Overdose Too much APAP ingested; more NAPQI by- product produced Too much APAP ingested; more NAPQI by- product produced NAPQI leads to liver damage (attacks the liver cells) NAPQI leads to liver damage (attacks the liver cells)

10. Overdose Four Mistakes Account for Most Overdoses of Acetaminophen: 1. Acetaminophen is in so many products that many people exceed the recommended dose by inadvertently taking two of them together. 2. Thinking that “more is better,” many people purposely take more than the recommended dose or take the next dose too soon after the previous one. 3. Many people combine acetaminophen with alcohol. Alcohol increases production of the enzyme that makes acetaminophen toxic to the liver. If you drink alcohol and take acetaminophen you can overdose even at recommended doses. 4. Many people continue taking Tylenol for longer than recommended

11. Rescue for Overdose N acetylcysteine (NAC) [Acetadote] N acetylcysteine (NAC) [Acetadote] –Given within 8 hours of APAP dose, the mortality is zero –Given within 24 hours it still has some beneficial effects –How does it work?  Unknown; thought to act by providing substrate for conjugation with the toxic metabolite –Other uses:  Mucolytic therapy in patients with abnormal or viscid mucous secretions

12. Drug Interaction Isoniazid {treatment of tuberculosis} Isoniazid {treatment of tuberculosis} –Activates the liver enzymes (specifically: Isoniazid is an inducer of CYP 2E1) –So more toxic metabolite is formed and the GSH is depleted and can no longer inactivate the increased amounts of NAPQI –The NAPQI attacks the liver cells and leads to cell death

13. Long-Term Alcoholism Long-term alcohol consumption induces the CYP2E1 enzyme system, leading to more production of NAPQI Long-term alcohol consumption induces the CYP2E1 enzyme system, leading to more production of NAPQI

14. Fasting/Poor Nutrition Fasting has been shown to deplete hepatic (liver) GSH stores Fasting has been shown to deplete hepatic (liver) GSH stores Hepatotoxicity has been observed in fasting individuals after intake of APAP in modest overdoses Hepatotoxicity has been observed in fasting individuals after intake of APAP in modest overdoses

15. Some Common Tylenol Products OTCRX   Tylenol   Excedrin   Pamprin   Cold/cough preparations: 1) 1)NyQuil 2) 2)DayQuil   Vicodin   Norco   Fioricet   Endocet   Lortab   Percocet   Darvocet * For a more extensive list please refer to attachment at the end of the handout

16. Duty of a Health Care Provider Educate patients and fellow health care providers about products that contain Tylenol and factors that can increase the risk of toxicity Educate patients and fellow health care providers about products that contain Tylenol and factors that can increase the risk of toxicity Do not exceed 4g/day; <3g/day for the elderly Do not exceed 4g/day; <3g/day for the elderly Look for risk factors (poor nutritional status, abuse potential, alcoholism, polypharmacy) Look for risk factors (poor nutritional status, abuse potential, alcoholism, polypharmacy)

17. Duty of a Health Care Provider Educate minority groups and elderly about Tylenol products and their dangers Educate minority groups and elderly about Tylenol products and their dangers –These patient populations are more likely to buy OTC medications and self-treat Recognize depressed patients (look for complaints of pain with no source causing it; suicidal ideation) Recognize depressed patients (look for complaints of pain with no source causing it; suicidal ideation)

18. Conclusions Tylenol is not a benign pain killer Tylenol is not a benign pain killer It is found in combination with many products It is found in combination with many products Tylenol toxicity can happen at “safe” doses, esp. if there are additional risk factors Tylenol toxicity can happen at “safe” doses, esp. if there are additional risk factors Education of patients and providers is essential Education of patients and providers is essential Be a good friend, educate your loved ones about the dangers of Tylenol Be a good friend, educate your loved ones about the dangers of Tylenol

19. No Joking Matter Acetaminophen is the active ingredient in more than 400 over-the-counter (OTC) and prescription products—including Tylenol and other analgesics (pain relievers), cough medicines, and sleep aids. Acetaminophen is the active ingredient in more than 400 over-the-counter (OTC) and prescription products—including Tylenol and other analgesics (pain relievers), cough medicines, and sleep aids. Each year, overdoses of acetaminophen account for more than 56,000 emergency room visits and an estimated 458 deaths from acute liver failure, reports a recent issue of the Harvard Women's Health Watch. Each year, overdoses of acetaminophen account for more than 56,000 emergency room visits and an estimated 458 deaths from acute liver failure, reports a recent issue of the Harvard Women's Health Watch.