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ARE ALL NSAIDS CREATED EQUAL? Comparison of toxicity of 3 common over-the-counter NSAID pain medications: Aspirin, Ibuprofen, and Naproxen By Lucie Jelinkova RELEVANCE AND OBJECTIVES I chose this topic to educate myself and my fellow students on the toxicity of common pain relievers. It is known that many people overmedicate on these substances, believing that since they are sold without prescription, they are harmless. The main objective of this presentation is to determine if one of 3 most commonly used NSAID pain relievers is better or worse than the others. In other words, is one a safer drug? Is it easier to overdose on one more than the other? Is long-term use more dangerous with one or the other? Is one better or worse for different populations? INTRODUCTION What are NSAIDs? NSAIDs stands for Non-steroidal Antiinflammatory Drugs. They can also be called NSAIAs (Non-steroidal Anti-inflammatory Agents) or NSAIMs (Non-steroidal Anti-inflammatory Medicines. The most common ones include Aspirin, Ibuprofen, and Naproxen. In the United States, these are available for purchase over the counter. These drugs provide analgesic (pain relieving), antipyretic (fever-reducing), and anti-inflammatory effects. INTRODUCTION WHAT ARE NSAIDs USED FOR? • • • • • • • • • Mild to moderate acute or chronic pain – mostly due to inflammation Fever, rheumatic fever Migraines and other types of headache Menstrual pain Low dose aspirin is given as a prevention for heart attack or stroke Post-surgery treatment Joint pain and other muscularskeletal pain Gout May be helpful in cancer prevention INTRODUCTION ASPIRIN • Also called acetylsalicylic acid • Provides analgesic, antipyretic, • • and anti-inflammatory effects Used at low doses for it’s antiplatelet effects to prevent excessive blood clotting to prevent heart attacks or strokes One of the most used medications in the world INTRODUCTION IBUPROFEN • Common names include • • • Advil and Motrin Also called iso-butylpropanoic-phenolic acid Provides analgesic, antipyretic, and antiinflammatory effects Has mild antiplatelet effects, as well as vasoconstriction effects INTRODUCTION NAPROXEN • Common names • • include Aleve, Midol XR, and many others Provides analgesic, antipyretic, and anti-inflammatory effects Over-the-counter in the United States only METHODS OF ACTION ASPIRIN • • • Aspirin works by inhibiting the production of prostaglandins, which are signaling molecules that sensitize pain receptors in the body It also inhibits the production of thromboxanes, molecules that play a role in thrombosis (clot formation) Aspirin accomplishes this inhibition by attaching an acetyl group to cyclooxygenase (COX), an enzyme that synthesizes prostaglandins and thromboxanes, and thus irreversibly deactivates it METHODS OF ACTION ASPIRIN • • • • • The COX enzyme exists in two isozymes: COX-1 and COX-2 Inactivation of COX-1 inhibits thromboxane, which leads to anticlotting effects Inactivation of COX-2 leads to production of antiinflammatory effects Aspirin inactivates both isozymes This pathway, with some modifications, is common to ibuprofen and naproxen as well http://archives.focus.hms.harvard.edu/2004/Oct15_2004/anesthesia.html METHODS OF ACTION IBUPROFEN • Ibuprofen works by • • inhibiting COX-1 and COX-2 as well As opposed to aspirin, the inactivation of COX enzymes by ibuprofen is reversible While aspirin binds COX covalently, ibuprofen reversibly competes for the same binding site METHODS OF ACTION NAPROXEN • • • Naproxen works as a COX inhibitor as well, reducing inflammation and promoting antiplatelet action Additionally, naproxen may be able to inhibit the proliferation of the influenza virus The shape of the naproxen molecule allows it to block a binding site on the virus’ nucleoprotein, preventing it from binding the ribosome, thus disabling the nucleoprotein function Influenza A virus NOW ONTO THE BAD STUFF… Reye’s Syndrome liver Bullous pemphigoid Peptic ulcer PROBLEMS The incredibly wide use of aspirin, ibuprofen, and naproxen provides us with a wide array of adverse effects These adverse effects can occur with misuse of the drugs, as well as with correct use This presentation will focus on the most prevalent and/or serious adverse effects PROBLEMS – NORMAL USE GASTROINTESTINAL EFFECTS – ALL NSAIDs One of the main adverse effects associated with the use of NSAIDs are gastrointestinal (GI) problems These problems arise with the COX-1 inhibition, which produces the antiplatelet property of NSAIDs Antiplatelet effect can produce GI ulceration and bleeding Aspirin appears to induce these effects more, due to the irreversible binding of COX, however all 3 drugs have been associated with GI effects Increased dosing, as well as NSAID combination increases risk Combining NSAIDs with alcohol increases risk Drugs that selectively alter COX-2 only are being developed Other types of bleeding or microbleeding can occur with the PROBLEMS – NORMAL USE REYE’S SYNDROME – ASPIRIN Aspirin consumption in children with a viral infection has been associated with development of Reye’s syndrome Reye’s syndrome can occur without aspirin as well, cause of this illness is unknown This syndrome causes severe encephalopathy (swelling of brain) and liver damage Evidence of aspirin as a causative agent in Reye’s syndrome is weak, however, use of aspirin is not recommended for children and teenagers for viral illnesses in the US for this reason Symptoms are thought to be caused by damage to liver mitochondria – which is where aspirin could be the causative agent PROBLEMS – NORMAL USE CARDIOVASCULAR EFFECTS – IBUPROFEN Ibuprofen has been correlated with increased blood pressure with prolonged use Effect may be more pronounced in combination with other drugs, particularly hydrochlorothiazide, a drug prescribed for hypertension in congestive heart failure CV effects have been associated with other NSAIDs as well, though not in such a degree as ibuprofen PROBLEMS – NORMAL USE RENAL CANCER – IBUPROFEN and NAPROXEN A 2005 study published in the Archives of Internal Medicine has reported an increase of renal cell cancer (RCC) in those frequently taking ibuprofen and naproxen Prolonged use of these drugs correlated with an increased risk of RCC Aspirin intake was not associated with RCC risk Study did not provide an explanation as to why non-aspirin NSAIDs increases risk of RCC PROBLEMS – NORMAL USE OTHER PROBLEMS – ALL There is a plethora of other problems associated with aspirin, ibuprofen, and naproxen Nausea, headache, indigestion, diarrhea, dizziness Erectile dysfunction Skin problems, such as severe blistering Edema of skin tissue, hives Hyperkalemia Miscarriage Etc. PROBLEMS - OVERDOSE ASPIRIN Overdose can be acute or chronic, chronic overdose has a much higher mortality rate Toxic dose is considered to be greater than 150mg per kg of body weight – for a 60kg person (~135lb), that is 9g of aspirin or over 27 325mg tablets Potentially lethal dose is greater than 500mg per kg of body weight Toxicity occurs from salicylate poisoning Serious symptoms include cerebral edema, elevated blood pH, acidosis, hypoglycemia, seizures, coma, death PROBLEMS - OVERDOSE IBUPROFEN Can be acute or chronic Toxic dose is considered to be greater 100mg per kg of body weight – for 60kg person, that is 30 200mg tablets Lethal dose not determined Most symptoms occurring during overdose can be directly linked to excess COX inactivation Symptoms include GI bleeding, seizures, acidosis, heart failure, liver failure, renal failure, etc PROBLEMS - OVERDOSE NAPROXEN Symptoms are similar to that of aspirin and ibuprofen overdose They include: GI distress and bleeding, heart failure, severe headaches, seizures, coma, death LD50 for rats is 543mg per kg of body weight, for dogs it is over 1000mg per kg of body weight DISCUSSION It is important to note that the majority of adverse effects are rare – these drugs can vastly improve life quality of many people Adverse effects are correlated with overuse, prolonged use, and combination of with other drugs and/or alcohol HOWEVER Despite the low probability of experiencing adverse effects, it is imperative patients remain informed or risks OTC drugs, such as NSAIDs should be consumed with considerable caution CONCLUSION It appears that all three drugs – Aspirin, Ibuprofen, and Naproxen – have their sets of risks that should be considered It appears that not one of these drugs is particularly better than the others, however, perhaps aspirin may be more dangerous to children, whereas ibuprofen may be more dangerous for people with cardiovascular risk factors Each drug should be considered carefully before ingesting Risk factors for adverse effects should be considered as well REFERENCES http://www.ncbi.nlm.nih.gov/pubmedhealth Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 231(25):232-5, 1971. Lejal N, Tarus B, Bouguyon, E, et al. Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of Influenza A virus. Antimicrob Agents Chemother. 57(5):2231-42, 2013. http://www.reyessyndrome.org/facts.html Rainsford KD. Discovery, mechanisms of action and safety of ibuprofen. Int J Clin Pract Suppl. 135:3-8, 2003. Gurwitz JH, Everitt DE, Monane M, et al. The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons. J Gerontol A Biol Sci Med Sci. 51(2):M74-9, 1996. Argentieri J, Morrone K, Pollack Y. Acetaminophen and Ibuprofen overdosage. Pediatr Rev. 33(4):188-9, 2012. http://www.drugs.com/monograph/aspirin.html http://www.drugs.com/pro/naproxen.html http://www.drugs.com/ibuprofen.html Cho E, Curhan G, Hankinson S, et al. Prospective Evaluation of Analgesic Use and Risk of Renal Cell Cancer. Arch Intern Med. 171(16):1487-93, 2011.