Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective

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Abstract

Owing to the efficacy in reducing pain and inflammation non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most popularly used medicines, confirming their position in the WHO’s Model List of Essential Medicines. With escalating musculoskeletal complications, as evident from 2016 Global Burden of Disease data, NSAID usage is evidently unavoidable. Apart from analgesic, anti-inflammatory and antipyretic efficacies, NSAIDs are further documented to offer protection against diverse critical disorders including cancer and heart attacks. However, data from multiple placebo-controlled trials and meta-analyses studies alarmingly signify the adverse effects of NSAIDs in gastrointestinal, cardiovascular, hepatic, renal, cerebral and pulmonary complications. Although extensive research has elucidated the mechanisms underlying the clinical hazards of NSAIDs, no review has extensively collated the outcomes on various multiorgan toxicities of these drugs together. In this regard, the present review provides a comprehensive insight of the existing knowledge and recent developments on NSAID-induced organ damage. It precisely encompasses the current understanding of structure, classification and mode of action of NSAIDs while reiterating on the emerging instances of NSAID drug repurposing along with pharmacophore modification aimed at safer usage of NSAIDs where toxic effects are tamed without compromising the clinical benefits. The review does not intend to vilify these ‘wonder drugs’; rather provide a careful understanding of their side-effects which would be beneficial in evaluating the risk-benefit threshold while rationally using NSAIDs at safer dose and duration.

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Most cited references 203

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Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.

J R Vane (1971)

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Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

C Bombardier, L Laine, A Reicin … (2000)

Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

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Cyclooxygenases 1 and 2.

J R Vane, Y Bakhle, R. M. Botting (1998)

Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.

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Author and article information

Contributors

Uday Bandyopadhyay

Journal

Journal ID (nlm-ta): Biochem Pharmacol

Journal ID (iso-abbrev): Biochem. Pharmacol

Title: Biochemical Pharmacology

Publisher: Elsevier Inc.

ISSN (Print): 0006-2952

ISSN (Electronic): 1873-2968

Publication date PMC-release: 10 July 2020

Publication date (Electronic): 10 July 2020

Electronic Location Identifier: 114147

Affiliations

[a ]Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal 736101 India

[b ]Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India

[c ]Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kankurgachi, Kolkata, West Bengal 700054 India

Author notes

[* ]Corresponding author: Dr. Uday Bandyopadhyay Division of Molecular Medicine, Bose Institute, P-1/12, CIT Road, Scheme VIIM, Kankurgachi, Kolkata West Bengal 700054, India udayb@ 123456jcbose.ac.in

[1]

Present address: National Institute of Biomedical Genomics, P.O.: N.S.S., Kalyani, West Bengal 741251 India

Article

Publisher ID: S0006-2952(20)30383-X Publisher ID: 114147

DOI: 10.1016/j.bcp.2020.114147

PMC ID: 7347500

PubMed ID: 32653589

SO-VID: 0c903e59-4de2-4dae-8d65-2f9b96c30597

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 27 April 2020

Date revision received : 3 July 2020

Date accepted : 7 July 2020

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Subject: Article

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: nsaid, non-steroidal anti-inflammatory drug,pghs, prostaglandin-endoperoxide synthase,pg, prostaglandin,fda, us food and drug administration,ic, inhibitory concentration,p450, cytochromes p450,pla, phospholipase,tx, thromboxane,lte, leukotriene,mos, mitochondrial oxidative stress,etc, electron transport chain,o2.-, superoxide,cvd, cardiovascular disease,tnf-α, tumor necrosis factor-alpha,nf-κb, nuclear factor kappa-light-chain-enhancer of activated b cells,icam-1, intercellular adhesion molecule 1,mapk, mitogen activated protein kinase,pkc, protein kinase c,drp1, dynamin-related protein 1,lps, lipopolysaccharide,hmgb1, high mobility group box 1,damp, danger associated molecular pattern,medal, multinational etoricoxib and diclofenac arthritis long-term trial,gi, gastrointestinal,mi, myocardial infarction,hf, heart failure,vigor, vioxx gastrointestinal outcomes research,approve, adenomatous polyp prevention on vioxx trial,precision, prospective evaluation of celecoxib integrated safety versus ibuprofen or naproxen,nansaids, non aspirin nsaids,adma, asymmetric dimethyl arginine,enos, endothelial nitric oxide synthase,ckd, chronic kidney disease,aki, acute kidney injury,gfr, glomerular filtration rate,ppar, peroxisome proliferator-activated receptor,crescent, celecoxib rofecoxib efficiency and safety in cormorbidities evaluation trial,ich, intracerebral haemorrhage,aerd, aspirin-exacerbated respiratory disease,cap, community acquired pneumonia,cys-ltes, cysteinyl leukotrienes,nsaid,cyclooxygenase,prostaglandin,inflammation,mitochondria,organ damage,apoptosis,gastropathy

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: nsaid, non-steroidal anti-inflammatory drug, pghs, prostaglandin-endoperoxide synthase, pg, prostaglandin, fda, us food and drug administration, ic, inhibitory concentration, p450, cytochromes p450, pla, phospholipase, tx, thromboxane, lte, leukotriene, mos, mitochondrial oxidative stress, etc, electron transport chain, o2.-, superoxide, cvd, cardiovascular disease, tnf-α, tumor necrosis factor-alpha, nf-κb, nuclear factor kappa-light-chain-enhancer of activated b cells, icam-1, intercellular adhesion molecule 1, mapk, mitogen activated protein kinase, pkc, protein kinase c, drp1, dynamin-related protein 1, lps, lipopolysaccharide, hmgb1, high mobility group box 1, damp, danger associated molecular pattern, medal, multinational etoricoxib and diclofenac arthritis long-term trial, gi, gastrointestinal, mi, myocardial infarction, hf, heart failure, vigor, vioxx gastrointestinal outcomes research, approve, adenomatous polyp prevention on vioxx trial, precision, prospective evaluation of celecoxib integrated safety versus ibuprofen or naproxen, nansaids, non aspirin nsaids, adma, asymmetric dimethyl arginine, enos, endothelial nitric oxide synthase, ckd, chronic kidney disease, aki, acute kidney injury, gfr, glomerular filtration rate, ppar, peroxisome proliferator-activated receptor, crescent, celecoxib rofecoxib efficiency and safety in cormorbidities evaluation trial, ich, intracerebral haemorrhage, aerd, aspirin-exacerbated respiratory disease, cap, community acquired pneumonia, cys-ltes, cysteinyl leukotrienes, nsaid, cyclooxygenase, prostaglandin, inflammation, mitochondria, organ damage, apoptosis, gastropathy

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective

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Most cited references 203

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.

Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

Cyclooxygenases 1 and 2.

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