Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

Paola Patrignani; Stefania Tacconelli; Annalisa Bruno; Carlos Sostres; Angel Lanas


Expert Rev Clin Pharmacol. 2011;4(5):605-621. 

In This Article

Mechanism of Action of Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs are a chemically heterogeneous group of compounds that provide unmistakable and significant health benefits in the treatment of pain and inflammation.[1] However, their use is associated with increased risk of gastrointestinal (GI) and cardiovascular (CV) effects.[2–5] Both therapeutic and adverse effects of NSAIDs are mainly due to the inhibition of prostanoid biosynthesis.[1] Prostanoids (i.e., prostaglandin [PG]E2, PGD2, PGF, thromboxane A2 [TXA2] and prostacyclin [PGI2]) are special second messengers owing to their ability to cross the cell membrane, diffuse through the extracellular space, and interact with high-affinity G-protein-coupled receptors located on the same cell or in neighboring cells.[6] Prostanoids play important roles in many cellular responses and pathophysiologic processes, such as modulation of the inflammatory reaction and its resolution, erosion of cartilage and juxta-articular bone, GI cytoprotection and ulceration, angiogenesis and cancer, hemostasis and thrombosis, renal hemodynamics and progression of kidney disease, as well as atheroprotection and progression of atherosclerosis.[7]

Prostanoids are generated intracellularly from arachidonic acid (AA) mainly through, but not exclusively, the activity of phospholipase A2.[8] Once released, intracellular free AA is transformed to PGH2 by the activity of prostaglandin H (PGH) synthases (named cyclooxygenase [COX]-1 and COX-2); then, PGH2 is metabolized to the prostanoids by different synthases expressed in a tissue-specific fashion (Figure 1).[6]

Figure 1.

Cyclooxygenase pathways of arachidonic acid metabolism. Prostanoids are generated from arachidonic acid stored within the cell membrane and esterified to glycerol in phospholipids. A receptor-dependent event initiates phospholipid hydrolysis, mainly through the activity of phospholipase A2. Once released, intracellular free arachidonic acid is transformed to prostaglandin H2 by the activity of prostaglandin H synthases (named COX-1 and COX-2). Prostaglandin H2 is metabolized to the prostanoids by different synthases expressed in a tissue-specific manner.
COX: Cyclooxygenase; DP: Prostaglandin D receptor; EP: Prostaglandin E receptor; FP: Prostaglandin F receptor; IP: Prostacyclin receptor; PG: Prostaglandin; PGI2: Prostacyclin; PLA2: Phospholipase A2; TP: Thromboxane A2 receptor; TxA2: Thromboxane A2.

Cyclooxygenase isozymes are homodimers and each monomer is a heme-containing glycoprotein. COX-1 and COX-2 share the same catalytic activities[9] (i.e., the COX activity that oxidizes AA to PGG2 and the peroxidase activity that reduces PGG2 to the unstable endoperoxide, PGH2). However, they are differently regulated catalytically, transcriptionally and post-transcriptionally.[10] The COX-1 gene has the structural features of a 'housekeeping' gene and it is constitutively expressed in almost all tissues. By contrast, COX-2 is an immediate early gene.[9,10]COX-2 expression is controlled at various levels such as gene transcription and post-transcriptional events.[11,12] Transcriptional activation of COX-2 occurs quickly and transiently in response to a wide range of stimuli including pathogens, cytokines, nitric oxide (NO), irradiation, growth factors and various extracellular ligands.[11]

In general, COX-1-dependent prostanoids play an essential homeostatic role in physiological functions (such as GI cytoprotection, platelet aggregation and vascular smooth muscle tone modulation),[13,14] while COX-2-dependent prostanoids play dominant roles in pathophysiologic processes such as inflammation and cancer, and physiological processes such as endothelial vasoprotection.[13,14]

Nonsteroidal anti-inflammatory drugs comprise traditional NSAIDs (tNSAIDs) and NSAIDs selective for COX-2 (coxibs).[15] They are indicated for pain and stiffness in inflammatory rheumatoid arthritis (RA) and for management of pain in osteoarthritis (OA). They act as anti-inflammatory and analgesic agents by inhibiting COX-2-dependent prostanoids in the cells at an inflammatory site and in the spinal cord. In general, NSAIDs provide only symptomatic relief from the pain and inflammation associated with the disease and do not arrest the progression of pathological injury to tissue. Both nonselective NSAIDs and coxibs are widely prescribed because they are significantly more effective than acetaminophen in terms of managing pain and thus improving quality of life (QOL).[16] However, their concomitant inhibition of COX-1 and/or COX-2 in cells of the GI and CV systems translates into increased risk of upper GI bleeding (UGIB), atherothrombosis and hypertension.[3–5] Thus, the guidelines for OA recommend that where acetaminophen or topical NSAIDs are ineffective for pain relief, then substitution with an oral NSAID/COX-2 inhibitor should be considered, but they should be used at the lowest effective dose for the shortest possible period of time.[201] Similarly, guidelines for RA recommend the use of nonselective NSAIDs/COX-2 selective inhibitors for the treatment of arthritic pain.[17] Physicians prescribe NSAIDs in varying dosage levels dependent on the severity of the disease. They often prescribe higher doses of NSAIDs for patients with RA because the condition leads to a significant degree of swelling and stiffness in the joints. Lower NSAID doses are typically used in clinical practice for OA and muscle injuries, since there is less swelling and no warmth in the joints. Typically, several types of NSAIDs have to be administered before determining the most effective medication to relieve the discomfort.

Nonsteroidal anti-inflammatory drugs are grouped on the basis of their pharmacodynamic features – that is COX-1/COX-2 selectivity.[15] This is assessed in vitro and ex vivo (i.e., after drug administration) using human whole blood assays that evaluate the effects of drugs on platelet COX-1 and monocyte COX-2 levels.[18,19]

Nonsteroidal anti-inflammatory drugs are not specific drugs targeted at one COX isozyme but are selective drugs that affect only one or both isoforms depending on the dose administered.[15] The degree of COX selectivity of an NSAID, defined by its potency to inhibit COX-1 and COX-2 activities by 50% in vitro, is a chemical feature of the different drugs. We can group NSAIDs as being more selective in vitro for COX-1, such as naproxen and ibuprofen, and those more selective for COX-2, which are the majority of NSAIDs (Figure 2).[15,20] Among the NSAIDs more potent at inhibiting COX-2 than COX-1 in vitro, it has been shown that COX-2 selectivity is a continuous variable and some tNSAIDs show comparable experimental COX-2 selectivity to some coxibs (e.g., diclofenac and celecoxib).[15] However, it has to be noted that the degree of COX-isozyme selectivity found in vivo depends on the dose administered.[15,20] Finally, an important determinant of the clinical effects of drugs in vivo (both therapeutic and toxic effects) depends on the pharmacokinetic features of the different drugs such as half-life, and type of formulations such as slow-release or plain, which can influence the extent and duration of patient exposure to COX-isozyme inhibition. An intense area of research is to clarify the determinants of marked variability in how different people react to these drugs, based on their genetic background.

Figure 2.

Degree of selectivity for COX-2 by the different NSAIDs in vitro expressed as ratio of IC50 values for COX-1 and COX-2. The degree of COX selectivity of NSAIDs, defined by their potency to inhibit by 50% COX-1 and COX-2 activities in vitro. Higher values of COX-1/COX-2 IC50 ratio (>1) mirror higher selectivity versus COX-2. Lower values (<1) mirror higher selectivity for COX-1. IC50 is the concentration of the drug required to inhibit the activity of COX-1 and COX-2 by 50%.
COX: Cyclooxygenase; IC50: 50% inhibitory concentration.


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