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Non steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs. They are used to alleviate pain, inhibit inflammation and reduce fever. NSAIDs achieve this by manipulating enzymes and interfering with different pathways in the body.
The three main effects of NSAIDs as mentioned above are primarily due to the principal action of NSAIDs which is the inhibition of cyclooxygenase (COX). This enzyme catalyzes the reaction between arachidonic acid and PGH2; the precursor of prostaglandins (PGD2, PGE2, PGI2) and thromboxanes (TXA2). These prostanoids produce different symptoms of the inflammatory response and therefore they need to be inhibited.
There are two main forms of COX - cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). COX-1 is a constitutive enzyme thus present in most cells mainly for tissue homeostatis, whereas COX-2 enzymes are induced at the inflammatory site, producing inflammatory mediators (Rang et al.)
Both enzymes contain two sites of catalytic activity: the cyclooxgenase site and the peroxidise site. However, the main focus here will be the cyclooxygenase active site.
This opening of the COX active site consists of amphipathic helices which forms the transmembrane domain. The active site itself is a long lipophillic channel with a catalytic crevice for the binding of the substrate. Along the channel Arginine 120 (Arg 120) is found where the channel is considerably confined because the ionic residue extends outwards forming hydrogen bonded networks with Tyrosine 335 (Tyr 335) and Glutamate 524 (Glu 524) and this is known as the constriction point. Different enzymes act via slightly different mechanism to inhibit the COX enzymes.
NSAIDs containing carboxylates form hydrogen bonds and electrostatic interactions with the guanidinium component of Arg120. This means that Arg120 anchors the NSAIDs and blocks the entry of the active site to prevent arachidonate, which in turn prevents the biosynthesis of prostaglandins.
Aspirin also travels along the lipophillic channel of the COX active site. However, aspirin inhibits COX enzymes irreversibly by modifying the enzyme covalently. It does this by acetylation of the hydroxyl group of Serine 530. This prevents the access for arachidonic acid in the upper proportion of the COX-1 channel to Tyrosine 385 by steric hindrance which in turn inhibits the synthesis of prostaglandins.
The catalytic site of COX-2 is larger than the COX-1 enzyme site thus the inhibition of COX-2 may not be inhibited by the acetylation of its active site as it can accept the substrate even when it is acetylated. This means that aspirin is more sensitive to COX-1 than COX-2, despite their structural similarity.
The inflammatory response consists of vasodilatation which results in the dilation and redness of blood vessels, increased permeability of the blood vessels, oedema and pain. NSAIDs act to reduce these symptoms by inhibiting COX-2 enzymes and this mechanism of COX inhibition is described above.
NSAIDs also have anti-pyretic effect and this affects prostaglandin production in the brain. The function of the hypothalamus is temperature regulation; ensuring heat production or heat loss in the body when necessary. Thus, when there is an onset of fever and the temperature of the body is raised, the body uses heat loss mechanisms such as sweating to ensure the elevated temperature is lowered back to the 'normal' temperature. An onset of fever can be caused by the release of interleukins-1 (IL-1) from leukocytes at the inflammatory site. These cytokines signal PGE2 to be synthesised in the hypothalamus, which induces the hypothermic response. Consequently, NSAIDs inhibit this production of PGE2 in the hypothalamus thus alleviating fever.
Moreover, NSAIDs have anti-analgesic effects and its mechanism of action is described here as it again involves the inhibition of PGE2. The presence of PGE2 induces pain by potentiating mediators such as histamine and bradykinin. These mediators sensitize afferent C fibres along the nociceptive pathway which cause the excitation of transmission neurons resulting in pain (Rang et al.) It is not wholly prostaglandins that cause the end reaction but it is their potential of to intensify the actions of these mediators. Therefore NSAIDs work by inhibiting PGE2 production and alleviating pain.
The mechanism of action of paracetamol somewhat varies from other NSAIDs because paracetamol shows no anti-inflammatory effects. Studies show that the drug does inhibit COX enzymes but this is dependent on the concentration levels of peroxides (Bertolini et al.) Moreover, the mechanism of action of the analgesic effect of paracetamol is unclear. At present, studies show that TRPV1, a nociceptive receptor is activated by anandamide. And it is thought that as paracetamol is metabolized to AM404 and this inhibits the uptake of this neurotransmitter (Bertolini et al.) thus alleviating pain.
Prostaglandins have a huge range of functions in human biology; therefore it is not surprising that the inhibition of them can lead to various side effects. One unwanted effect is gastrointestinal disturbances. This is induced by NSAIDs because COX-1 is inhibited. This means that normal gastric acid secretion is prevented because prostaglandins are usually responsible for this. Also, prostaglandins normally have a protective action on the mucosa and modulate intestinal blood flow. Therefore, with the removal of its protection, causes the GI tract to become aggravated and damaged by normal gastric acids.
Prostaglandins also have other roles, for example PGE2 is required in the aid of adequate renal blood flow. However NSAIDs inhibit this action of prostaglandins therefore one side effect of the long term usage of NSAIDs is damage to the kidney; analgesic nephropathy. This encompasses chronic interstitial nephritis and renal papillary necrosis.
Moreover, aspirin may trigger asthma in NSAID sensitive-asthma patients (Rang et al.) The mechanism of action by which this is caused is thought to be via the pathways of COX enzymes (Morwood et al.) Cysteinyl leukotrienes are products of the lipoxygenase pathway and mediators of asthma as they enhance the secretion of mucus in airways and bronchoconstriction. NSAIDs inhibit prostagladin production thus causing overproduction of cysteinyl leukotrienes which in turn leads to the manifestation of aspirin induced asthma. However, this mechanism does not fully explain NSAID sensitive asthma symptoms because studies have shown abnormalities only in nasal polyp tissue (Sousa et al.) and no other airways.
Aspirin changes the balance between prostanoids. TXA2 promotes platelet aggregation that causes blood clots and PGT2 inhibits aggregation. Therefore aspirin works by inhibiting COX-1 which synthesizes these prostanoids, thus reducing the risk of myocardial infarction. This anticoagulant component of aspirin is therefore useful but the risk is when the blood clot is reduced and there is extensive bleeding.
The use of NSAIDs reduces the risk for Alzheimer's Disease because it is thought that chronic inflammation causes neural damage. Therefore, inhibition of inflammatory mediators via COX enzymes, would inhibit inflammation. However, there is evidence which opposes this cause of neural damage (Breitner et al.) therefore the exact mechanism of action of NSAIDs is unknown. There are connections between NMDA receptor activity, the stimulation of COX-2 and cell death in Alzheimer's disease, thus further research is required on COX-2 inhibitors.
This discussion shows some of the mechanisms of actions of NSAIDs and the diversity of the roles and functions of the various prostaglandins in the human body. The main role of NSAIDs is the prevention of the synthesis of prostaglandins by inhibiting COX enzymes.
The effects of NSAIDs include anti-inflammatory effects, anti-pyretic effects, anti analgesic effects and some specific effects of aspirin such as anticoagulation.
Unwanted side effects of NSAIDs include gastric damage, renal damage, stimulating asthma in NSAID-sensitive-asthma.
Finally, some mechanisms are unclear because of the complex biosynthesis pathways, but further research is being carried out so the functions of each form of COX enzymes is known and used to find the best action of the drug without adverse side effects, for example the on going research for COX-2 inhibitors which should prevent gastric damage.