NSAIDS, mechanism

Herbette, L. G. Vecchiarelli, M. Tmmlitz, G., NSAID Mechanism of Action Membrane Interactions in the Role of Intracellular Pharmacokinetics, Vane, Botting, Botting, pp. 85-102 (1995). 

Aseptic meningitis Ibuprofen, sulindac, naproxen, tolmetin, ketoprofen, diclofenac, indomethacin, piroxicam, rofecoxib, celecoxib Rare. No obvious cross-reactivity of NSAIDs. Mechanism may be type III or IV hypersensitivity to drug... 

NSAIDs mechanism of action relays inhibition of production of prostanoids to prevent the inflammatory pain. Two cyclooxygenase enzymes contribute to the conversion of arachidonic acid to prostaglandin H2 cyclooxygenase-1 (COX-1) is a constitutive form of cyclooxygenase but COX-2 tends to be induced primarily by inflammation in most tissues. Many recent medications and investigations are directed at inhibiting COX-2 to relieve pain, such as celecoxib. 

Figure 48,2. NSAIDs mechanism of action (adapted from httpy/www.arcoxia.ae).

There are thought to be at least four different mechanisms of action for NSAIDs. Aspirin (and also bromoaspirin) covalently... 

Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body s synthesis of prostaglandins (Sections 7.11 and 27.4). There are two forms of the enzyme, COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only tire response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. 

A non-allergic mechanism imderlying precipitation of asthmatic attacks by aspirin in hypersensitive patients was proposed over 30 years ago [4]. It was founded on pharmacological inhibition of COX of arachidonic acid and explained a cross-reactivity between different NSAIDs varying in chemical structure. This COX theory was confirmed by several studies [11] and was further refined following discovery of the second COX isoenzyme - COX-2. At least two COX isoenzymes, COX-1 and COX-2, are coded by separate genes. Their role in inflammation, asthma and anaphylaxis has been reviewed previously [12]. 

Patients with chronic idiopathic urticaria, who develop cutaneous reactions in response to aspirin, display certain similarities in eicosanoid profile with AIA. The mechanism of the reactions is often related to COX-1 inhibition [18]. Therefore, aspirin and all drugs that inhibit COX-1 should be avoided in patients who already have had cutaneous reactions to NSAID. Coxibs are usually well tolerated, although occasional adverse reactions have been reported [19, 20]. For treatment of the reactions, antihistamines are usually sufficient, but in more severe cases adrenaline and corticosteroids may be warranted. 

The mechanisms of pain and the ability to control pain may vary in different pain states. This is of particular importance in consideration of a rational basis for the treatment of both inflammatory and neuropathic pain where the damage to tissue and nerve leads to alterations in both the peripheral and central mechanisms of pain signalling. In respect of existing drug therapies, this plasticity, the ability of the system to change in the face of a particular pain syndrome, explains the effectiveness of NSAIDs in inflammatory conditions and yet is also responsible for some of the limitations in the effectiveness of opioids in neuropathic pain. 

Non-selective NSAIDs [those that inhibit both cyclooxygenase-1 and -2 (COX-1 and COX-2)] cause gastric mucosal damage by two primary mechanisms (1) a direct toxic interaction and (2) systemic pharmacologic actions. 

Direct irritation of the mucosal lining by NSAIDs occurs because NSAIDs are weak acids. Topical irritation is therefore most pronounced with more acidic NSAIDs such as aspirin. While the direct irritant effects of NSAIDs play a contributory role in the development of NSAID-induced gastritis, this mechanism generally plays a minor role in the evolution of NSAID-induced PUD. 

Prostaglandins, through their effects on mucous cell secretion, basal bicarbonate secretion, and mucosal growth, are important factors in gastric healing and protection. Inhibition of prostaglandin production by NSAIDs compromises these important protective mechanisms. Finally, the antiplatelet effects of NSAIDs may worsen bleeding complications associated with PUD. 

NSAIDs are a reasonable alternative when acetaminophen fails to provide an acceptable analgesic response. Some authorities recommend NSAIDs over acetaminophen for patients presenting with severe pain or signs and symptoms of inflammation, but this is a matter of much contention. The rationale for this recommendation is that acetaminophen s central mechanism of action renders it ineffective against peripheral joint inflammation, and therefore, less effective.18 Consensus guidelines support the use of NSAIDs as an alternative to acetaminophen if clinical features of peripheral inflammation or severe pain are detected.11,12 Unfortunately there is no validated mechanism to identify patients who are more likely to respond to NSAIDs than acetaminophen. 

Gold salts have had a long history of use in rheumatoid arthritis.269,270 The development of orally active auranofin (also known as Ridaura (50), Figure 23) was a major improvement over the early injectable gold preparations which were polymeric (e.g., (51)—(53)). However, use has declined with the popularity of nonsteroidal antiinflammatory drugs (NSAIDS) such as indo-methacin a recent estimate of the commercial value for auranofin was 6 million. The mechanism... 

Leite AZ, Sipahi AM, Damiao AO, Coelho AM, Garcez AT, Machado MC, Buchpiguel CA, Lopasso FP, Lordello ML, Agostinho CL, Laudanna AA Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID A new mechanism. Gut 2001 48 163-167. 

Most peptic ulcers occur in the presence of acid and pepsin when HP, NSAIDs, or other factors disrupt normal mucosal defense and healing mechanisms. Acid is an independent factor that contributes to disruption of mucosal integrity. Increased acid secretion has been observed in patients with DU and may result from HP infection. Patients with GU usually have normal or reduced rates of acid secretion. 

Alterations in mucosal defense induced by HP or NSAIDs are the most important cofactors in peptic ulcer formation. Mucosal defense and repair mechanisms include mucus and bicarbonate secretion, intrinsic epithelial cell defense, and mucosal blood flow. Maintenance of mucosal integrity and repair is mediated by endogenous prostaglandin production. 

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