AssessmentsNon-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 56-year-old man comes to the clinic because of shortness of breath that began this morning. He reports a one-week history of progressively increasing pain in his left leg. His left leg is edematous and the calf muscles are tender to palpation. For years, he has been using celecoxib for his rheumatic disease. The use of celecoxib may contribute to the patient’s leg pain and dyspnoea in which of the following ways?
Content Reviewers:Yifan Xiao, MD
Contributors:Evan Debevec-McKenney, Sam Gillespie, BSc, Ursula Florjanczyk, MScBMC, Filip Vasiljević, MD
Non-steroidal anti-inflammatory drugs or NSAIDs are mainly used to treat inflammation, pain, and fever. These conditions are related to an increased production of pro-inflammatory chemicals called prostaglandins.
So, during inflammation, your immune cells use an enzyme called phospholipase A2 to take membrane phospholipids and make a 20-carbon polyunsaturated fatty acid, called arachidonic acid.
Arachidonic acid is a substrate for an enzyme called cyclooxygenase or COX.
The enzyme cyclooxygenase exists in two different isoforms: COX-1 and COX-2.
COX-1 is a constitutive enzyme, meaning that it’s always active, while on the other hand, COX-2 is an inducible enzyme, meaning that it must be turned on to function. This is usually triggered by immune cells and vascular endothelial cells during inflammation.
Both enzymes produce prostaglandin E2 (PGE2) and prostacyclin (PGI2), which cause vasodilation and attract different immune cells to the area.
They also act on neurons that detect pain, called nociceptors, and make them more sensitive to stimuli by lowering their threshold for activation.
Prostaglandin E2 also has other effects like causing uterine contractions, decreasing the secretion of acid, and increasing the production of protective mucus in the stomach.
Aspirin is taken perorally and most of the absorption occurs in the ileum.
Since aspirin irreversibly prevents the platelets from synthesizing new COX-1 enzymes, aspirin’s effect will persist until there are enough new platelets produced that are able to produce COX-1 enzymes. This leads to increased bleeding time without affecting PT or PTT.
Salicylate works by inhibiting COX-2, thereby reducing prostaglandin production, leading to decreased inflammation, pain, and fever; so, it’s commonly used to treat headaches and musculoskeletal pain.
It’s important to note that the effects of aspirin are dose-dependent: low doses under 300 mg/day work as an antiplatelet medication; medium doses between 300 and 2400 mg/day work as an antipyretic and analgesic; and high doses over 2400 mg/day work as an anti-inflammatory medication.
Okay, moving on to non-selective COX inhibitors, which reversibly inhibit both COX-1 and COX-2. Common medications in this class include ibuprofen, naproxen, ketorolac, indomethacin, sulindac, meloxicam, and many others.
Just like aspirin, these medications also inhibit COX-1 and have an antiplatelet effect, but because they’re reversible inhibitors, their effect is transient so they won’t provide the same benefit as aspirin.
Next, these medications also inhibit COX-2, which reduces inflammation, pain, and fever, so they have the same indications as aspirin.
However, ibuprofen, naproxen, and indomethacin are also used to reduce inflammation during an acute gout attack, where aspirin should be avoided since it competes with uric acid for excretion in the kidneys, which might worsen the symptoms of gout.
Since it doesn’t affect COX-1, it lacks the antiplatelet effect seen in aspirin. On the other hand, it doesn’t compete with aspirin for COX-1 like the reversible nonselective COX inhibitors, so it can be combined with aspirin without decreasing its antiplatelet effect.
Reversible inhibitors of COX-1 cause less gastrointestinal problems when compared to aspirin, and selective COX-2 inhibitors like celecoxib causes the least GI side effects since they don’t affect COX-1.
In the kidneys, all NSAIDs inhibit COX-2 which decreases the level of prostaglandins that dilate the renal artery, causing a reduction in renal blood flow. This reduced blood flow tricks the kidney into thinking the blood pressure is low, so in order to increase it, they activate the renin-angiotensin-aldosterone system, which can lead to hypertension.
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