The Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

How Anti-Inflammatory Drugs Work

Nonsteroidal anti-inflammatory drugs (also called NSAIDs) are medicines that reduce pain, fever, and inflammation. They work by stopping a group of enzymes, called cyclooxygenase (abbreviated COX) enzymes, from making chemicals that act like hormones and cause swelling and pain.

You can take NSAIDs by mouth or in a cream or gel applied to the skin. Many NSAIDs are available over the counter and at prescription strength.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs (pronounced en-say-dids) are the most commonly used pain medications in adults. They are effective in decreasing pain (analgesia) and reducing inflammation and fever. NSAIDs also may slow the progression of arthritis and decrease the risk of clots forming in the blood vessels.

NSAIDs work by inhibiting the activity of cyclooxygenase enzymes, which produce chemicals that cause inflammation and swelling. They can be taken as pills that are sold without a prescription (over-the-counter or OTC) or in creams and gels.

NSAIDs are divided into categories based on their selectivity. They include acetylated salicylates (aspirin), non-acetylated salicylates, propionic acids (diclofennac, indomethacin), pyranic acids (meloxicam, piroxicam) anthranilic acid (nabumetone), phenylethylamines (naproxen, naproxen), and oxiclocoxib (Celebrex). The NSAIDs that favor COX-1 over COX-2 enzymes are more likely to cause gastrointestinal side effects, while those that prefer COX-2 have a higher risk of cardiovascular events. This is why NSAIDs are generally recommended for the shortest duration possible. Some NSAIDs can interact with certain drugs, such as the blood thinners warfarin and coumadin.

Inhibitors of cyclooxygenase enzymes (COX-1 and COX-2 inhibitors)

The enzyme cyclooxygenase (COX) catalyzes the conversion of polyunsaturated fatty acids to prostaglandins, which are then released into the circulation. Two COX isoforms, COX-1 and COX-2, have been identified. COX-1 is a constitutive enzyme whose levels remain relatively constant throughout the body. In contrast, COX-2 is an inducible enzyme whose levels increase rapidly in response to a number of stimuli including inflammatory mediators and cytokines.

Many of the most commonly used NSAIDs are non-selective and inhibit both COX-1 and COX-2. These drugs reduce inflammation and relieve pain, but they also cause gastrointestinal ulcers and bleeding. In contrast, selective NSAIDs such as celecoxib have fewer gastrointestinal side effects and do not promote clotting, but they may increase the risk of heart attack.

Indomethacin binds selectively to COX-2 because it has the 2′-methyl group that projects into a small hydrophobic pocket formed by Val-349, Ala-527, Ser-530, and Leu-531 in the COX-2 molecule. Mutagenesis of the ring amide to alanine or leucine reveals that binding to this pocket is responsible for the time-dependent inhibition of COX-2.

Nonpharmacologic approaches to inflammation

Immunological homeostasis is achieved by strict control of the production and activation of proinflammatory and anti-inflammatory molecular and cellular effectors that act synergistically to ensure the integrity of tissues. This equilibrium is disrupted by chemical, physical, and biological aggressions triggering an inflammatory response that leads to the development of immune-mediated lesions unless adequately countered.

A wide variety of pharmacological and nonpharmacological interventions modulate the neuroimmune axis, controlling inflammation by eliminating the aetiological agent or by their direct immunomodulatory effects. In particular, electrotherapy based on the use of light (low-level laser therapy), sound waves (ultrasound), radiation (radiotherapy), temperature (cryotherapy), mechanical forces (vibration), and others have been shown to have powerful effects on controlling inflammation and stimulating tissue repair. They can be used as adjuncts to standard pharmacological treatment and, in some cases, improve the efficacy of anti-inflammatories.

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