Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of a drug class that inhibit the activity of cyclooxygenase (COX-1 or COX-2) enzymes. This confers them analgesic, antipyretic, and anti-inflammatory effects, as well as inhibition of platelet aggregation. Side effects depend on the specific drug but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.
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
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
Traditionally COX-2 was taught to be expressed by cells involved in inflammation such as macrophages, monocytes, and synoviocytes. 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.
This is however an overly simplified view. COX-2 is not an exclusively proinflammatory inducible enzyme. It is basally expressed in many organs such as the ovary, uterus, brain, spinal cord, kidney, cartilage, bone, and the gastrointestinal tract. It plays a more complex physiological role than previously recognised.
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: COX-2 expression in the spinal cord may facilitate nociceptive transmission, with prostaglandins acting on the CNS to cause central hyperalgesia. There is widespread induction of COX-2 expression in spinal cord neurons and other regions of the CNS following peripheral inflammation. COX-2 is expressed in the dorsal horn and is upregulated briefly following trauma in the corresponding segment. Prostaglandin E2 has a role in central pain sensitisation. It directly depolarises wide dynamic range neurons into the deep dorsal horn, and reduces the inhibitory tone of the neurotransmitter glycine onto neurons in the superficial layers of the dorsal horn thereby disinhibiting 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.
COX inhibitors antagonise central hyperalgesia in the dorsal horn through modulating the glutamatergic signalling from nociceptive C fibres to secondary neurons. COX-2 but not COX-1 inhibition suppresses inflammation-induced prostaglandin level rise the CSF.
Side Effects
Many of the side effects of NSAIDs are due to COX-1 suppression, such as gastrointestinal ulceration and bleeding, and platelet dysfunction. Selective COX-2 inhibitors were developed with the idea of avoiding the unwanted side effects that are elicited by COX-1 inhibition.
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.
The long term use of both traditional NSAIDs and COX-2 inhibitors confers cardiovascular risks. The mechanism for this relates to the previously unrecognised role of COX-2 expression in basal conditions, and the blockade of COX-2 dependent prostaglandins such as prostacyclin. Prostacyclin is reduced by over 60% by both traditional NSAIDs and COX-2 inhibitors. Prostacyclin is a potent inhibitor of platelet aggregation, and also plays a role in hypertension, atherogenesis, and cardiac dysfunction.
COX-2 is also involved in renal function, and so NSAIDs and COX-2 inhibitors can also cause peripheral oedema, hypertension, and inhibition of water and salt excretion leading to exacerbation of hypertension.
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
