NSAIDs and Prostaglandin (PG) Synthesis Inhibition

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Chapter: Essential pharmacology : Nonsteroidal Anti-inflammatory Drugs And Antipyreticanalgesics

In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation. This is now considered to be the major mechanism of action of NSAIDs.



In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation. This is now considered to be the major mechanism of action of NSAIDs. Prostaglandins, prostacyclin (PG I2) and thromboxane A2 (TXA2) are produced from arachidonic acid by the enzyme cyclooxygenase which exists in a constitutive (COX1) and an inducible (COX2) isoforms; the former serves physiological ‘house keeping’ functions, while the latter, normally present in minute quantities, is induced by cytokines and other signal molecules at the site of inflammation generation of PGs locally which mediate many of the inflammatory changes. However, COX2 is constitutively present at some sites in brain and in juxtaglomerular cells: may serve physiological role at these sites. Most NSAIDs inhibit COX1 and COX2 nonselectively, but now some selective COX2 inhibitors have been produced. Features of nonselective COX1/COX2 inhibitors (traditional NSAIDs) and selective COX2 inhibitors are compared in Table 14.1


Aspirin inhibits COX irreversibly by acetylating one of its serine residues; return of COX activity depends on synthesis of fresh enzyme.


Beneficial actions due to PG synthesis inhibition


·      Analgesia: prevention of pain nerve ending sensitization

·        Antipyresis

·        Anti-inflammatory

·        Antithrombotic

·        Closure of ductus arteriosus in newborn


Other NSAIDs are competitive and reversible inhibitors of COX, return of activity depends on their dissociation from the enzyme which in turn is governed by the pharmacokinetic characteristics of the compound.


Analgesia PGs induce hyperalgesia by affecting the transducing property of free nerve endings—stimuli that normally do not elicit pain are able to do so. NSAIDs do not affect the tenderness induced by direct application of PGs, but block the pain sensitizing mechanism induced by bradykinin, TNFα, interleukins (ILs) and other algesic substances. They are, therefore, more effective against inflammation associated pain.


Antipyresis NSAIDs reduce body temperature in fever, but do not cause hypothermia in normothermic individuals. Fever during infection is produced through the generation of pyrogens including, ILs, TNFα , interferons which induce PGE2 production in hypothalamus—raise its temperature set point. NSAIDs block the action of pyrogens but not that of PGE2 injected into the hypothalamus. The isoform present at this site appears to be COX2 (possibly COX3 also). However, fever can occur through non-PG mediated mechanisms as well.


Shared toxicities due to PG synthesis inhibition


1. Gastric mucosal damage

2. Bleeding: inhibition of platelet function

3. Limitation of renal blood flow : Na+ and water retention

4. Delay/prolongation of labour

5. Asthma and anaphylactoid reactions in susceptible individuals


Anti-inflammatory The most important mechanism of anti-inflammatory action of NSAIDs is considered to be inhibition of PG synthesis at the site of injury. The anti-inflammatory potency of different compounds roughly corresponds with their potency to inhibit COX. However, nimesulide is a potent anti-inflammatory but relatively weak COX inhibitor. PGs are only one of the mediators of inflammation; inhibition of COX does not depress the production of other mediators like LTs, PAF, cytokines, etc. Inflammation is the result of concerted participation of a large number of vasoactive, chemotactic and proliferative factors at different stages, and there are many targets for anti-inflammatory action.


Activated endothelial cells express adhesion molecules (ECAM 1, ICAM1) on their surface and play a key role in directing circulating leucocytes to the site of inflammation (chemotaxis). Similarly, inflammatory cells express selectins and integrins. Certain NSAIDs may act by additional mechanisms including inhibition of expression/ activity of some of these molecules and generation of superoxide/other free radicals. Growth factors like GMCSF, IL6 and lymphocyte transformation factors may also be affected. Stabilization of leucocyte lysosomal membrane and antagonism of certain actions of kinins may be contributing to NSAID action.


Dysmenorrhoea Involvement of PGs in dysmenorrhoea has been clearly demonstrated: level of PGs in menstrual flow, endometrial biopsy and that of PGF2α metabolite in circulation are raised in dysmenorrhoeic women. Intermittent ischaemia of the myometrium is probably responsible for menstrual cramps. NSAIDs lower uterine PG levels—afford excellent relief in 60–70% and partial relief in the remaining. Ancillary symptoms of headache, muscle ache and nausea are also relieved. Excess flow may be normalized.


Antiplatelet aggregatory NSAIDs inhibit synthesis of both proaggregatory (TXA2) and antiaggregatory (PGI2) prostanoids, but effect on platelet TXA2 (COX1 generated) predominates therapeutic doses of most NSAIDs inhibit platelet aggregation: bleeding time is prolonged. Aspirin is highly active; acetylates platelet COX irreversibly in the portal circulation before it is deacetylated by first pass metabolism in liver. Small doses are therefore able to exert antithrombotic effect for several days. Risk of surgical bleeding is enhanced.


Ductus arteriosus closure During foetal circulation ductus arteriosus is kept patent by local elaboration of PGE2 and PGI2. Unknown mechanisms switch off this synthesis at birth and the ductus closes. When this fails to occur, small doses of indomethacin or aspirin bring about closure in majority of cases within a few hours by inhibiting PG production. Administration of NSAIDs in late pregnancy has been found to promote premature closure of ductus in some cases. Prescribing of NSAIDs near term should be avoided.


Parturition Sudden spurt of PG synthesis by uterus probably triggers labour and facilitates its progression. Accordingly, NSAIDs have the potential to delay and retard labour. However, labour can occur in the absence of PGs.


Gastric mucosal damage Gastric pain, mucosal erosion/ulceration and blood loss are produced by all NSAIDs to varying extents: relative gastric toxicity is a major consideration in the choice of NSAIDs. Inhibition of COX1 mediated synthesis of gastroprotective PGs (PGE2, PGI2) is clearly involved, though local action inducing back diffusion of H+ ions in gastric mucosa also plays a role. Deficiency of PGs reduces mucus and HCO3¯ secrection, tends to enhance acid secretion and may promote mucosal ischaemia. Thus, NSAIDs enhance aggressive factors and contain defensive factors in gastric mucosa—are ulcerogenic. Paracetamol, a very weak inhibitor of COX is practically free of gastric toxicity and selective COX2 inhibitors are safer. Stable PG analogues (misoprostol) administered concurrently with NSAIDs antagonise their gastric toxicity.


Renal effects Conditions leading to hypovolaemia, decreased renal perfusion and Na+ loss induce renal PG synthesis which brings about intrarenal adjustments by promoting vasodilatation, inhibiting tubular Cl¯ reabsorption (Na+ and water accompany) and opposing ADH action.


NSAIDs produce renal effects by at least 3 mechanisms:


·      COX1 dependent impairment of renal blood flow and reduction of g.f.r. can worsen renal insufficiency.

·      Juxtaglomerular COX2 (probably COX1 also) dependent Na+ and water retention.

·      Ability to cause papillary necrosis on habitual intake.


Renal effects of NSAIDs are not marked in normal individuals, but become significant in those with CHF, hypovolaemia, hepatic cirrhosis, renal disease and in patients receiving diuretics or antihypertensives: Na+ retention and edema can occur; diuretic and antihypertensive drug effects are blunted.


Involvement of PG synthesis inhibition in analgesic nephropathy is uncertain.


Anaphylactoid reactions Aspirin precipitates asthma, angioneurotic swellings, urticaria or rhinitis in certain susceptible individuals. These subjects react similarly to chemically diverse NSAIDs, ruling out immunological basis for the reaction. Inhibition of COX with consequent diversion of arachidonic acid to LTs and other products of lipoxygenase pathway may be involved, but there is no proof.


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