Nonsteroidal Anti-Inflammatory Drugs
Cyclooxygenase Enzymes
The COX enzyme is responsible for the formation of prostanoids from arachidonic acid. The specific reactions catalysed are the conversion of arachidonic acid to prostaglandin G2, and the conversion of prostaglandin G2 to prostaglandin H2.
One end of the COX enzyme has a membrane binding domain along with an epithelial growth factor domain, and the other end is the active enzymatic site.
COX has two isoforms. They differ only in the amino acid at site 523 with COX1 having isoleucin, and COX2 having valine. Both COX isoenzymes act on arachidonic acid, but the difference lies in genes that produce them and the factors that trigger those genes.
- COX-1 is a "housekeeping" enzyme that is constantly expressed in nearly all tissues such as platelets, gastrointestinal tract, kidney, endothelium, uterus, and brain. It is involved in the mediation of physiological responses. For example is involved in cytoprotection of the stomach, platelet aggregation, and facilitating blood flow through tissues especially the stomach and kidney.
- COX-2 is expressed by cells involved in inflammation such as macrophages, monocytes, and synoviocytes; and also in the central nervous system. The expression is triggered by tissue damage in order to promote repair. It is the primary enzyme that is responsible for the synthesis of prostanoids in acute and chronic pathological inflammatory states. The expression is regulated by several mediators e.g. lipopolysaccharide, proinflammatory cytokines, and growth factors. Glucocorticoids inhibit COX-2 expression.
Prostaglandins
Prostaglandin H2 has its own actions or can be converted to other prostaglandins such as PGE2, PGI2, PGD2, PGF2, and TXA2.
- PGE2 produces fever, vasodilation with resulting lowering of blood pressure and promoting blood flow to the kidney and gastrointestinal tract, diuresis, and in the uterus it causes smooth muscle contraction.
- PGH2 increases blood pressure, i.e. it competes against PGE2.
- PGI2 has the same effects on the gastrointestinal tract as PG2. If fact all PGs have the same effect on the gastrointestinal tract.
- PGI2 inhibits the uterus, i.e. it competes against PGE2
- PGI2 inhibits platelet aggregation, i.e. it competes against thromboxane (TXA2).
- TXA2 promotes platelet aggregation.
Peripheral sensitisation: Prostaglandins regulate the sensitivity of polymodal nociceptors that are present in nearly all tissues. Many of these nociceptors can't be easily activated by physiological stimuli such as light pressure or slight increase in temperature. However, with tissue trauma and the release of prostaglandins, "silent" polymodal nociceptors are able to become excitable to pressure, temperature changes, and acidosis. This results in hyperalgesia and in some cases allodynia. This may be through effects on transient receptor potential vanilloid 1 (TRPV1) in sensory neurons, and tetrodotoxin-resistant sodium channels in dorsal root ganglia. Therefore, at least part of the analgesic action of COX inhibitors is thought to be due to the prevention of peripheral sensitisation.
Central sensitisation: prostaglandins also act on the central nervous system to cause central hyperalgesia. COX inhibitors antagonise central hyperalgesia in the dorsal horn through modulating the glutamatergic signalling from nociceptive C fibres to secondary neurons. COX-2 is expressed in the dorsal horn and is upregulated briefly following trauma in the corresponding segment. COX-2 expression in the spinal cord may facilitate nociceptive transmission.
Pharmacology of NSAIDs
The original NSAIDs operate on locations of the COX enzyme that are identical in both isoenzymes. This results in blocking of both the inflammatory effects of COX2 and the normal physiological effects of COX1. This results in potential side effects particularly on the kidney and stomach.
The COX2-inhibitors bind to a site on COX2 that isn't present or accessible on COX1. which reduces the side effects related to COX1 inhibition.
NSAIDs bind non-competitively to COX, for example ibuprofen. Aspirin on the other hand binds covalently, which means that the antagonistic effects only cease when the receptor or membrane are replaced. Indomethacin, a old NSAID that is no longer available in New Zealand, evolves from non-competitive binding to permanent binding.
Side Effects
Many of the side effects of NSAIDs are due to COX-1 suppression, such as gastrointestinal ulceration and bleeding, and platelet dysfunction.
COX-1 inhibition is also the mechanism for aspirin hypersensitivity and unrelated NSAIDs in some patients with asthma and in some patients with chronic urticaria-angioedema. In these cases, COX-1 inhibition results in activation of the lipoxygenase pathway which induces bronchospasm and nasal obstruction.
Nomenclature
The naming scheme of NSAIDs is related to the base molecule from which they are derived.
- pyrroleACetic - diclofenAC, ketorolAC
- PROpionic - ibuPROfen, naPROxen
- sALicylates - acetylesALicylic acid
- OXycams - pirOXicam
- indoleACetic - indomethACin
