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

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 provides 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.

Keywords: Apoptosis; Cyclooxygenase; Gastropathy; Inflammation; Mitochondria; NSAID; Organ damage; Prostaglandin.

Graphical abstract

Fig. 1

Classification of non steroidal anti-inflammatory drugs (NSAIDs) based on structure.

Fig. 2

Classical applications and emerging uses of NSAIDs.

Fig. 3

NSAID-PGHS-prostanoid axis. PGHS-1/2 isoenzyme mediated prostanoid biosynthesis from arachidonic acid. Arachidonic acid is produced from phospholipids of the plasma membrane under the action of phospholipase A₂. In addition to prostaglandin (PG) and thromboxane (Tx) formation by PGHS isoforms in a cell and tissue-specific manner, leukotrienes (LTEs) are other immune mediators which are produced by the enzyme 5- lipoxygenase (5-LO). Each prostanoid interacts with its specific receptor as indicated in the figure.

Fig. 4

Overview of NSAID-induced mitochondrial reactive oxidants production leading to cellular pathology. NSAID triggers electron leakage from complex I of the electron transport chain (ETC) leading to incomplete reduction of molecular oxygen followed by superoxide (O₂^.-) production. O₂^.- is the precursor of most reactive oxygen species (ROS); itself rapidly being converted to H₂O₂ by superoxide dismutase (SOD2). In the presence of transitional metals (such as Fe²⁺), H₂O₂ can be converted to hydroxyl radical (HO·). H₂O₂ may be scavenged by glutathione peroxidise (GPx) in presence of GSH. The oxidised glutathione (GSSG) is reduced back to GSH by glutathione reductase (GR) in presence of NADPH. Amplification of ROS causes fall of mitochondrial membrane potential (ΔΨm). Reactive radicals react with biomolecules like membrane lipids, proteins and mtDNA producing lipid peroxides, protein carbonyls and DNA damage. Cytochrome C gets released from damaged mitochondrial to cytosol through outer mitochondrial membrane (OMM) permeabilization and activate apoptotic pathway. All these events together contribute to a wide range of cellular pathologies. Dotted arrows indicate detrimental reactions involving free radicals.

Fig. 5

Effect of NSAIDs on different target organs. The action of NSAIDs on major organs including stomach, small intestine, heart, liver, kidney, respiratory tract and brain is mainly mediated through PGHS-dependent prostanoid modulation and alteration of mitochondrial functional integrity leading to mitochondrial oxidative stress (MOS) generation, depolarization of mitochondrial transmembrane potential (ΔΨm) and consequent cell death. However, in heart, low dose aspirin actually offers cardioprotection through anti-thrombotic effect. Upward arrows indicate upregulation/elevation; downward arrows indicate downregulation/depletion.

Fig. 6

Structural representation of some NSAID prodrugs.