Non-steroidal anti-inflammatory drugs
How do NSAIDs influence Furosemide action?
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, Justin Ling, MD, MS, Evan Debevec-McKenney, Sam Gillespie, Ursula Florjanczyk, MS
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.
NSAIDs work by decreasing the production of prostaglandins, thereby reducing inflammation, relieving pain, and reducing fever.
In order to understand how NSAIDs work, first we need to talk briefly about inflammation, which is the body’s response to a harmful stimulus, such as infection or injury.
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.
Finally, they stimulate the hypothalamus to increase the body temperature, causing fever.
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.
So, in conditions such as inflammation, pain, or fever, NSAIDs can be used to inhibit cyclooxygenase and decrease the production of prostaglandins.
Alright, now let’s start with aspirin, also known as acetylsalicylic acid, which works by irreversibly inhibiting both COX-1 and COX-2.
Aspirin is taken perorally and most of the absorption occurs in the ileum.
Since thromboxane A2 is a platelet activator, this makes aspirin useful as an antiplatelet medication.
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.
Next, in the liver, aspirin is metabolized into salicylate, which doesn’t have the antiplatelet effect, but it does have anti-inflammatory properties.
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.
Low doses or “baby aspirin” in the form of 81 mg tablets are used long-term to help prevent heart attacks, strokes, and blood clot formation in people at high risk of developing blood clots.
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.
If taken together with aspirin, they will even compete for the binding sites on COX-1, which results in a decrease in the antiplatelet effect of 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.
Now moving on to selective COX-2 inhibitors, the main medication in this group is celecoxib.
Celecoxib reversibly inhibits COX-2, so it can treat pain and inflammation like the other NSAIDs.
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.
For side effects, both aspirin and the nonselective COX inhibitors can cause problems by blocking COX-1 in many parts of the body.
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.