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 OBJECTIVESI chose this topic to educate myself and my

fellow students on the toxicity of common pain relievers. It is known that many people over-medicate 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 Anti-inflammatory 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.

INTRODUCTIONWHAT 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 muscular-skeletal pain

• Gout

• May be helpful in cancer prevention

• Etc.

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-butyl-propanoic-phenolic acid

• Provides analgesic, antipyretic, and anti-inflammatory 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 ACTIONASPIRIN• 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 anti-inflammatory 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 ACTIONNAPROXEN• 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 use of NSAIDs, particularly post-surgery

PROBLEMS – NORMAL USEREYE’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 USECARDIOVASCULAR 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 USERENAL 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 - OVERDOSEASPIRIN 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

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