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Acetaminophen, liver and astham

 Health Consequence of Acetaminophen (Paracetamol, APAP) 10/31/16 http://healthfully.org/rc/id5.html                                Acetaminophen hepatotoxicity far exceeds other causes of acute liver failure. A large population study of prenatal APAP found 80% 3-year olds with impaired physical-mental development, similarly a 3 fold increased risk for asthma, and for ADHD, and for pain a 2014 metastudy found it is no better than a placebo. 

1)  The dug called acetaminophen (in the United States, Canada, Japan, South Korea, & Iran) is called paracetamol elsewhere.  Sold for the relief of pain[1], fever, and headaches, because of aggressive marketing; It is the most widely sold over-the-counter drug, and is frequently added to prescription medications especially opioids[2].  It is found in over a 100 over-the-counter preparations and 65 prescription opiates.  U.S. sales total over $1 billion annually.  Because it is often abbreviated as APAP (acetyl-para-amino-phenol) on prescriptions and bottles, this tragically fools the user (see #4).  Read on and you will know why it’s, at best its slight benefits are not worth their many risks.[3] 

2)   Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by A. Cahn and P. Hepp in 1886.  But its unacceptable toxic effects, the most alarming being cyanosis[4], prompted the search for less toxic aniline derivatives.  Harmon Northrop Morse had already synthesized paracetamol at John Hopkins University in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried APAP on patients.  However its precursor phenacetin became popular.  APAP, the metabolite of phenacetin, was first marketed in the US in 1953, but took until the 70s for widespread usage as an alternative to NSAIDs such as aspirin, naproxen and ibuprofen.       

3)   APAP’s peak absorption 30-60 minutes after oral administration and its half-life is 2 hours.  Dosing is 10-15 mg/kg every 4 hours, 5 doses per day maximum.  Recommend maximum dose is 1,000 mgs, and 4,000 mg per day.  Like all  NSAIDs, it blocks prostaglandins, thus it is anti-inflammatory drug, though the opposite is believed.[5]   Like NSAIDs, pain reduction compared to a placebo is slight & ineffective for acute pain.  Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis” a 2014 metastudy found. 

4)  Uninformed users presume it is safe like aspirin and other NSAIDs, and thus will up the dosage as pain persists.  APAP is also added to a large number of prescription and over-the-counter medications; thus doubling the dosage.  APAP is the leading cause of drug acute liver failure (ALF) in the U.S.  My cousin spent 10 days in the hospital in the summer of 2009; he took Vicodin and Tylenol.  Dozens of opioids contain APAP (Vicodin, Darvocet, Percocet, at Rxlist).  APAP is in popular over-the-counter drugs include Tylenol, Excedrin, Coricidin-D and Nyquil for which 30 ml has 700 mgs of APAP.  In prescription drugs it is usually label as APAP; and thus 44% of ALF patients took both prescription and an over-the-counter drug.  “Eighty-one percent of unintentional patients [not suicide] reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes… survival rate 65%.”  The authors of the study concluded:  “..., acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States.”  In the December 2005 issue of the medical journal Hepatology, “the annual percentage of potentially fatal acute liver failure (ALF) cases caused by acetaminophen (TYLENOL) rose from 28 percent in 1998 to 51 percent in 2003.  In 2010, APAP caused 56,000 emergency-room visits, 26,000 hospitalizations, and 458 deaths.[6]  Given the voluntary nature of side effect reporting system, those figures are a gross underestimate, see Side Effect.  A well designed study using the biomarker for liver toxicity, alanine transaminase found that 39% of volunteers experienced an elevation of ALT[7] more than 3 times the upper limit, and a quarter of that number had 8 times the clinically significant level of ALT.  The reason is the CD44 gene found in 39% of volunteers.  One cause of toxicity is through depletion glutathione which is produced in the liver and is a cofactor in various liver reactions, and a very strong antioxidant which protects the liver, Wiki, at, and.

5) Paracetamol poisoning  “Intravenous & oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose.[8] When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to inactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, thereby damaging liver cells. This may lead to severe liver damage and even death by acute liver failure.  In the treatment of acetaminophen overdose, acetylcysteine acts to maintain or replenish depleted glutathione reserves in the liver and enhance non-toxic metabolism of acetaminophen” Wiki.   Another mechanism is through the cytochromes P450 enzyme system which in the liver metabolizes drugs including APAP—see Wiki.  See auxiliary for more on P450.  If a drug or certain fruits such as grapefruits utilize that pathway, then a toxic accumulation can occur, especially in the 39% whose liver is sensitive to APAP; the same for those with acute neuropathy (kidney disease).   APAP, the best-selling NSAID has no significant benefits, causes well over 26,000 hospitalizations for liver failure yearly, has serious chronic side effect, yet is sold over the counter, and is the NSAID of first choice by most doctors, and is commonly added as a second ingredient to prescription drugs:  something is very wrong, very wrong with our corporate medical system, education of doctors, and our regulatory system.                                                                                                                                                                                                                                       

6)   “In 1998 the decreased use of aspirin in U.S. children was first suggested as a possible factor in the rising prevalence of asthma.”  Two years later it was linked to the use of APAP.  A study of 205,487 children age 6 to 7 years published in Lancet found a 323% increase in risk of asthma for those with high use group versus no use.  Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhino-conjunctivitis, and eczema at age 6 to 7 years” also meta-analysis of 425,140 subjects. A similar large study of teens came to the same conclusion.  Another study found that childhood asthma risk increased if APAP was taken during pregnancy.  Another study of 322,959 children in 113 centers found for highest exposure a 2.51 increase.  This review article describes the mechanisms through inhibition of both leukocyte myeloperoxidase & of GST role in lung growth.  A study in 2010 linked APAP to infertility.  An “Epidemiological studies have shown that acetaminophen by women during pregnancy is associated with increased risk of cryptorchidism [absence of testes] in boys” possible by lowering testosterone during the masculinization programming window.  This finding is supported by studies on human and rat fetal testes.  Developmental and behavior affects have been uncovered for APAP.  In a Norwegian study (Oct 2013) of 2.919 Norwegian mothers which same-sex sibling pairs who were used to adjust for familial and genetic factors, they found “substantially adverse development outcomes at 3 years of age… [including] attention deficit hyperactivity disorder [ADHD} or language disorder.… Poorer by comparison to sibling at 3 years of age were motor gross motor development by 76%, communications by 80%, internalizing behavior by 86%, higher levels of activity by 84%.  This was for mother who had taken APAP prenatal for more than 28 days; and smaller effect for 1-27 days of APAP--similar findings in another study.  APAP is associated with autism:  Acetaminophen use after measles-mumps-rubella vaccination was significantly  associated with autistic disorder when considering children 5 years of age or less… when considering only children who had post-vaccination sequelae (OR 8.23…)” at, also.  A Danish pregnancy cohort study of 64,322 consisting of 3 interviews followed by one at 6 months after childbirth:  Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development.”  APAP use during pregnancy was by the 7th year associated with a 29% increased incidence of hyperactivity (ADHD) and its severe form (HKD) 37% higher.  .  These serious health issues are ignored, thus pharma’s KOLs (key opinion leaders) who teach physicians that APAP is safe during pregnancy, for babies, and for children.  It is even more dangerous for adults because of its blockage of COX-2, which increases the risk of clotting[8] and the production of atheroma thus MIs and Stokes.

7)  APAP wasn’t proven to be a COX-2 inhibitor until 2008.  “The variance with other studies occurs because of method of analysis whole cell versus broken cell preparation….  Thus the myth of APAP as a weak prostaglandin inhibitor persists. [9] … maximal ex-vivo inhibitions were 56% (COX-1)[10] and 83% (COX-2)” at. Thus APAP is a NSAID, and like all NSAIDS but aspirin they  increase the risk for ischemic events including MIs.  Allow me to go over briefly the COX-2, Vioxx story.  Vioxx was used in a trial to see if it prevents Alzheimer’s disease like aspirin.  The seniors given Vioxx had over a 4 fold increase in MIs (heart attacks), and thus the trial was stopped early.  That an increase in heart attacks didn’t show up in other trials is because Merck selected younger, healthy volunteers.  A warning letter by the FDA resulted in the block-buster being “voluntarily being removed in Nov. of 2004, but by then estimated 160,000 MIs occurred and 55,000 deaths.  Sales were $2.5 billion yearly.  Unfortunately the FDA left one COX-2 inhibitor on the market, Celebrex, though it was by then banned in Canada and the EU.  For an excellent account of the disaster Marcia Angell’s The Truth About the Drug Companies, p 265-276.  (Note the Wikipedia article of 05 on Vioxx has been scrubbed, as too the one on Celebrex).   Use of NSAIDs or acetaminophen at high frequency or dose is associated with a significantly increased risk for major cardiovascular events”AHA 2006.   The AHA warns that for all NSAIDs but aspirin[11] regular usage greatly increases incidence of heart attacks—see  FASEB (concluding sentence). 

8)   So why is pharma so big on acetaminophen?  Think like a pharma executive, thus business strategies are measured by profit; I call this tobacco ethics.  A drug which causes an assortment of chronic conditions is a winner, while one that prevent chronic conditions--such as aspirin--is subjected to criticism based upon what I and others call tobacco science.  Many physicians found out that the NSAIDs inhibit like Vioxx COX-2, therefor they cause MIs.[12]  This entails that some doctors are hesitant to recommend the long-term usage of NSAIDs.  Believing that APAP isn’t an NSAID, they are far more willing to prescribe APAP than an NSAID such as Motrin or Aleve.  Here is where it gets ugly:  A doctor following treatment guidelines will prescribe for the typical patient who has had a heart attacked patented drugs costing over $70,000 a year (for high cholesterol, arrhythmia, three for hypertension, and an anticoagulant).  APAP is also causes asthma, coronary heart disease, autism, ADHD, and hypertension; thus billions are made treating side effects of the leading NSAID and APAP.   The FDA is an extension of big pharma and APAP sales are over $1 billion annually.  The FDA’s advisor board in 1977 recommended a packaging warning:  Do not exceed the recommended dosage because severe liver damage may occur."  This was implemented in 2010.  It took until 2014 for the FDA to request that manufacturers lower the dose to 325 mgs (yes, a mere request).  Acetaminophen’s history is another example of pharma’s tobacco ethics which results in their ability to influence the FDA and politicians.  They frame the practices of medicine through their KOLs (key opinion leaders) treatment guidelines, medical textbooks, and continuing education of doctors.  Seeing through the eyes of a pharma executive provides the best explanation of our drugged world; thus APAP is a blockbuster.

9). It is as Prof. Ben Goldacre state, “The devil is in the details.”  This negative assessment is of an industry that has consistently put profits before people and has manipulated the practice of medicine to cause great harm; it is their business model and their fiduciary duty.  There is a chorus of critics.  Three things I highly recommend: 1) to click on my collection of YouTube documentaries (each with a short description) on bad pharma.  2) To read Prof. Peter Gotzsche, Deadly Medicines and Organized Crime, How Pharma has Corrupted Healthcare.  It won a medical book merit award by the British Medical Association, has a forwards written by BMJ’s former editor-in-chief and another by the JAMA’s Deputy Editor.  3) To click on link and read my 4 page explanation as to Why Physicians Give Junk Treatment.  It removes the blame from physicians who are practicing medicine in a very corrupt system.  As Prof. Goldacre says:  “A perverse system produces perverse results.”  Goldacre is a founder of the AllTrials movement.  Having uncovered a liar, much that goes as around as established “truths”, ain’t.  Based on personal experience & several hours searching the literature, I have come to believe that NSAIDs lack significant analgesic effect.  If you break a toe and need relief, don’t reach for an NSAID.  Unlike an opioid, taking 3 pills at once doesn’t work better than one for major chronic pain. 



[1] The mechanism for pain reduction is through the reduction of inflammation by blocking only 50% of COX2 & COX1 enzymes (prostaglandins), Goodman & Gilman’s pharmacology textbook 2007 edition, p. 693).  Thus APAP is a “mild analgesics” p  681. 

[2] The supposed agonistic effect of APAP with opioids, assuming only moderate publish bias is purportedly due to the conversion of arachidonic acid that facilitate effects of opioids on K+ channels.  However this causal relationship is far from established and PhARMA, relying upon audience ignorance, has as their norm used bio-pathways to sell their products to physicians.  APAP should not be included with opioid medications since most people will take an opioid repeatedly until pain is reduced, and 39% are susceptible at much lower doses to APAP’s toxic effect on the liver.  A number of nations have acted to limit this deadly cocktail.       

[3] I have after years of study, I found at the effort to protect the public is a fašade; thus I don’t, and won’t put in my body unnatural chemicals called drugs.  Pharma does all it can to burry what it knows, and the FDA is part of the regulatory fašade. 

[4]  Cyanosis is a blue or purple coloration of the skin due to the tissues near the skin surface being low in oxygen.   

[5] One of the reasons leading to such controversial findings may lie in the fact that acetaminophen elicits no measurable inhibition of PG [prostaglandins COX-1 & COX -2] formation in broken cell preparations but a profound suppression in intact cells  [54 & 82%]. Despite these findings, acetaminophen is still regarded as a weak inhibitor of peripheral COX-1 and COX-2 enzymes (2) at.

[6] This is based upon a very, very imperfect reporting system where the side-effect from sent to the FDA is forwarded to the drug manufacturer, and eventually after evaluation a report totally side effects is sent to the FDA.  Because it is contrary to the manufacturer’s fiduciary obligation to accurately report issues with their drugs, this method is designed to fall short, see my article.  Side Effects rarely cause a drug being removed from the market until it goes off patent, and black box warning have little effects.   

[7] Alanine aminotransferase (ALT) is used to monitor liver toxicity.  In this study of  14 days of 145 volunteers, 39 received a placebo, and of the remaining 106 volunteers 38  had greater than 3 fold increase of ALT, of them 27 had 5 times the upper limit, and 8 had over 8 times the upper limit.  The study’s ranging in age from 18 to 45—older people would be at greater risk. The volunteers received 4 grams (the maximum recommended dosage).   The intended duration of the study was 14 days.  The author commented that their review of previously published studies supported their observations.  Worst Pills Best Pills Newsletter article September, 2006, also published at http://healthfully.org/nsaids/id8.html.   

[8] On the other hand, PTGS2 (COX-2) is a more important source of prostaglandins, particularly prostacyclin which is found in blood vessel lining. Prostacyclin relaxes or unsticks platelets, so drugs that block this mechanism - like Celebrex (celecoxib) and other coxibs (Rofecoxib) - increase risk of cardiovascular events due to clottingWiki.

[9] One of the reasons leading to such controversial findings may lie in the fact that acetaminophen elicits no measurable inhibition of PG formation in broken cell preparations but a profound suppression in intact cells. (7) . Despite these findings, acetaminophen is still regarded as a weak inhibitor of peripheral COX-1 and COX-2 enzymes (2)--at. 

[10] A 56% inhibition of COX-1 is insufficient to block thromboxane, and thus prevent the platelets from forming clots. Thus blocking COX 1 prevents clots, while COX-2 blocking promotes clots (see #7), and blocking just COX-2 thus promotes clots, and thus MIs.     

[11] “TheSerhan’s group showed that acetylation of COX-2 by low dose aspirin leads to its biosynthesis of 15R-hydroxyelcosatetraenoic acid.  This intermediate is then converted by transcellular metabolism to the anti-inflammatory lipoxin 15-epi-lipoxin A4 in leukocytes’--AHA, and. This distinguish aspirin from other NSAIDs by the production of lipoxin

[12] Oddly they believe as told by KOLs that for Celebrex  and Aleve (naproxen) the risk is small based on very week evidence and widely prescribe and recommend them in addition to APAP. 


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Acetaminophen (Paracetamol, APAP):  It is the most widely sold over-the-counter drug for the relief of pain[1], fever, and  headaches.  It is found in over a 100 over-the-counter of which 65 are with an opiate.  As a mild analgesic APAP’s inclusion with an opiate cannot be justified given its severe side effect of causing live damage.  The annual percentage of potentially fatal acute liver failure (ALF) cases caused by acetaminophen rose from 28 percent in 1998 to 51 percent in 2003.  A major cause is that acetaminophen is indicated as APAP on most opiate prescriptions and the common use of the over-the-counter Tylenol as a second drug for relieve of pain.  In a well-designed study it was found that 39% of those taking the recommended dosage of APAP had 3 to 8 times the upper limit for ALT a marker for liver toxicity.  APAP in 2010 caused 56,000 emergency-room visits, 26,000 hospitalizations and 1,600 liver failures, and this is based on a system designed to grossly underestimate the severity of the problem. New FDA limits and warning goes into effect in 2014.  A study of 205,487 children age 6-7 found that the use of APAP is associated with a 323% increase in the risk of asthma.  The medical literature on liver toxicity goes back to the 1960s.  Aspirin at 975 mgs to start and as needed thereafter is a much safer and more effective choice.      Development  al and behavior affects have been uncovered.     In a Norwegian study (Oct 2013) of 2.919 Norwegian mothers which same-sex sibling pairs who were used to adjust for familial and genetic factors, they found “substantially adverse development outcomes at 3 years of age… [including] attention deficit hyperactivity disorder or language disorder. … Poorer by comparison to sibling at 3 years of age were motor gross motor development by 76%, communications by 80%, internalizing behavior by 86%, higher levels of activity by 84%.  This was for mother who had taken APAP prenatal for more than 28 days; and smaller effect for 1-27 days of APAP--similar findings in another study.    APAP is associated with autism:  Acetaminophen use after measles-mumps-rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less… when considering only children who had post-vaccination sequelae (OR 8.23…)” at, also   A Danish pregnancy cohort study of 64,322 consisting of 3 interviews followed by one at 6 months after child birth:  Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development.”  APAP use during pregnancy was by the 7th year associated with a 29% increased incidence of hyperactivity (ADHD) and its severe form (HKD) 37% higher.  Though believed to not be an NSAID, and thus not to significantly inhibit the COX-1 and COX-2 prostaglandins, APAP does based on whole cell assays.  Thus APAP is an NSAID and like NSAIDs increases incidents of ulcers and heart attacks (aspirin is the exception).  Aspirin is the only NSAID whose benefits are greater than the side effects.    




[1] The mechanism for pain reduction is through the reduction of inflammation by blocking only 50% of COX2 & COX1 enzymes and inhibiting the production of prostaglandins (Goodman & Gilman’s pharmacology textbook 2007 edition, p. 693).  This is why in they are classified as “mild analgesics” (G & G at 681).  A better method of assaying places the inhibition of COX 1 at 54% and COX-2 at 82%, see footnotes 4. 




 

We certainly are in a health care crisis, ... If we had set out to design the worst system that we could imagine, we couldn't have imagined one as bad as we have.”

Harvard Professor and former editor of the New England Journal of Medicine Marcia Angell quote

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Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for medical advice, diagnosis, and treatment.