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Nsaids and Cardiovascular Diseases: Role of Reactive Oxygen Species

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Nsaids and Cardiovascular Diseases: Role of Reactive Oxygen Species UC Davis UC Davis Previously Published Works Title NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species. Permalink https://escholarship.org/uc/item/0hv9b1cm Authors Ghosh, Rajeshwary Alajbegovic, Azra Gomes, Aldrin V Publication Date 2015 DOI 10.1155/2015/536962 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2015, Article ID 536962, 25 pages http://dx.doi.org/10.1155/2015/536962 Review Article NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species Rajeshwary Ghosh,1 Azra Alajbegovic,1 and Aldrin V. Gomes1,2 1 Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA 2Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA Correspondence should be addressed to Aldrin V. Gomes; [email protected] Received 22 December 2014; Revised 3 March 2015; Accepted 3 March 2015 AcademicEditor:MarkJ.Crabtree Copyright © 2015 Rajeshwary Ghosh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs worldwide. NSAIDs are used for a variety of conditions including pain, rheumatoid arthritis, and musculoskeletal disorders. The beneficial effects of NSAIDs in reducing or relieving pain are well established, and other benefits such as reducing inflammation and anticancer effects are also documented. The undesirable side effects of NSAIDs include ulcers, internal bleeding, kidney failure, and increased risk of heart attackand stroke. Some of these side effects may be due to the oxidative stress induced by NSAIDs in different tissues. NSAIDs have been shown to induce reactive oxygen species (ROS) in different cell types including cardiac and cardiovascular related cells. Increases in ROS result in increased levels of oxidized proteins which alters key intracellular signaling pathways. One of these key pathways is apoptosis which causes cell death when significantly activated. This review discusses the relationship between NSAIDs and cardiovascular diseases (CVD) and the role of NSAID-induced ROS in CVD. 1. Introduction which comprise one class, inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. A second Nonsteroidal anti-inflammatory drugs (NSAIDs) are the class of NSAIDs (celecoxib and rofecoxib) targets only the most widely used over-the-counter drugs as well as the most COX-2 pathway and is termed as COX-2 selective inhibitors prescribed class of drugs for a variety of conditions including (also known as coxibs). COX selectivity is one of the pains, rheumatoid arthritis, osteoarthritis, musculoskeletal determining factors that is considered when administrating disorders, and other comorbid conditions [1]. Millions of NSAIDs to a patient. Administration of nonselective NSAIDs people suffer from pain resulting in the prolonged use of has been associated with side effects like peptic ulcer disease NSAIDs being common. Besides reducing or relieving pain and gastrointestinal bleeding [10]. COX-2 selective NSAIDs NSAIDs have been shown to be useful as anticancer agents in have been shown to exhibit gastroprotective effects unlike various kinds of cancers [2–4]. However, NSAIDs also have the nonselective NSAIDs and are thus useful in patients undesirable side effects including ulcers [5], bleeding [6], kid- with painful gastrointestinal conditions [10–12]. Another ney failure [7, 8], and increased risk of heart attack and stroke class of semiselective NSAIDs (indomethacin, meloxicam, [8, 9]. One of the mechanisms which has been associated with and diclofenac) have a higher affinity for COX-2 but tend to the adverse effects of NSAIDs is the generation of oxidative inhibit the COX-1 pathway also [13]. However, irrespective stress. The present review focuses on NSAIDs-induced ROS of their mechanism of action, prolonged exposure to any generation leading to cardiovascular diseases (CVD). class of NSAIDs has been shown to have potential adverse effects on cardiovascular events in patients with or without 2. Types of NSAIDs preexisting cardiovascular conditions, depending on the NSAIDs may be classified according to their mechanism of duration and dosage of these drugs [14, 15](Table1). Patients action.NonselectiveNSAIDslikeibuprofenandnaproxen, with preexisting cardiovascular conditions such as coronary 2 Table 1: List of NSAIDs with their recommended doses and levels in the circulation. Recommended dosages Levels in the circulation (Mandg/mL) Generic name Chemical name (may vary depending on Trade name (dose dependent) the age and condition) Zorvolex, Cataflam, Cambia, Voltaren, {2-[(2,6-Dichlorophenyl)amino]phenyl *5 M (1.5 g/mL) and 7 M(2.0g/mL) Voltaren gel, Arthrotec Diclofenac 25 mg–150 mg/day acetic acid [for 50 mg and 75 mg doses, respectively] (combinedwithmisoprostol),Flector,Zipsor, Pennsaid [1-(4-Chlorobenzoyl)-5-methoxy-2- Tivorbex, Indocin, Indocin SR, Indomethacin 25 mg–200 mg/day *3 M–6 M(1to2g/mL) methyl-1H-indol-3-yl]acetic acid Indo-Lemmon, Indomethagan **2 Mto22M (0.43 to 5.62 g/mL) Ketoprofen 2-(3-Benzoylphenyl) propanoic acid 25 mg–300 mg/day Oruvail, Nexcede [50 mg dose] Advil, Motrin and Nurofen, Vicoprofen *97 M–291 M(20–60g/mL) [400 mg Ibuprofen 2-(4-Isobutylphenyl) propanoic acid 100 mg–800 mg/day (combinedwithhydrocodone),Duexis dose] (combined with famotidine) Naprosyn, EC-Naprosyn, Naprapac (copackaged with lansoprazole), Aleve, *377 M(95g/mL) (2S)-2-(6-Methoxy-2-naphthyl) propanoic 250 mg–1000 mg/day Accord, Anaprox DS, Anaprox Antalgin, Naproxen [500 mg dose once every 12 h or 1000 mg acid (bothoralandIV) Apranax, Treximet (combined with dose for 5 days] sumatriptan succinate) and Vimovo (combined with esomeprazole magnesium) {(1Z)-5-Fluoro-2-methyl-1-[4- Oxidative Medicine and Cellular Longevity **1.4 M–6 M (0.5–2.0 g/mL) [constant Sulindac (methylsulfinyl)benzylidene]-1H-inden-3- 200mg–400mg/day Clinoril for all doses] yl}acetic acid 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1- Ketorolac 10 mg–40 mg/day **39 M(10g/mL) Toradol, Sprix carboxylic acid 4-Hydroxy-2-methyl-N-(2-pyridinyl)-2H- *5 Mto6M (1.5 to 2 g/mL) [single Piroxicam 1,2-benzothiazine-3-carboxamide 1,1- 0.2 mg–20 mg/day 20 mg dose] 9 Mto24M(3–8g/mL) Feldene dioxide [for 20 mg repeated doses] Oxidative Medicine and Cellular Longevity Table 1: Continued. Recommended dosages Levels in the circulation (Mandg/mL) Generic name Chemical name (may vary depending on Trade name (dose dependent) the age and condition) N-(4-Nitro-2- **10 Mto20M (2.86 to 4.58) mg/L Sulide, Nimalox, Mesulid, Xilox, Nise, Nexen, Nimesulide 100 mg twice daily phenoxyphenyl)methanesulfonamide [100 mg] [175] Nidolon ** 164 M(41g/mL) [250 mg doses] 2 ,4 -Difluoro-4-hydroxy-3- Diflunisal 250 mg–1000 mg 348 M(87g/mL) [500 mg doses] and Dolobid biphenylcarboxylic acid 496 M(124g/mL) [single 1000 mg dose] **60 M (14 mg/L) [0.65 mg/kg of Flurbiprofen 2-(2-Fluoro-4-biphenylyl)propanoic acid 50 mg–300 mg/day Ansaid flurbiprofen IV] [176] 2-[(2,3- 250 mg followed by Mefenamic acid *83 M(20g/mL) [250 mg single doses] Ponstel Dimethylphenyl)amino]benzoic acid 500 mg every 6 hours [1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol- Tolmetin 5mg–1800mg/day **156 M(40g/mL) [400 mg oral dose] Tolectin, Tolectin DS, Tolectin 600 2-yl]acetic acid The table lists only those NSAIDs that have been mentioned in Table 3 along with their recommended doses and respective concentrations in the circulation. Most of the information regarding the dosages and levels in serum or plasma of the NSAIDs has been taken from the FDA approved site, http://www.drugs.com. Nimesulide is the only NSAID in the list that is not available in the USA. References for the plasma concentrations of flurbiprofen and nimesulide are given in the table. *Serum concentrations, **Plasma concentrations. 3 4 Oxidative Medicine and Cellular Longevity Membrane phospholipid Phospholipase A2 COOH (cytosolic/secreted) (induced by Lipoxygenase pathway thrombin, injury/inflammation, Leukotriene CH3 hormones like epinephrine, Arachidonic acid angiotensin II) Cyclooxygenase pathway ∗ Valdecoxib, celecoxib, rofecoxib(Coxibs) COXIBS NSAIDS Homeostasis disruption Cytokines IL-1, COX-1 Naproxen, ibuprofen, COX-2 IFN-, growth TXA2 PGI2 (constitutive) ketoprofen (inducible) factors Platelet aggregation NSAIDS Prostaglandin G2 PGG2 Atherosclerosis, COX-1, COX-2 acute myocardial infarction, Prostaglandin H2 thrombosis PGH2 PGE synthase ne synthase PGF synthase Thromboxa PGI synthase PGD synthase ∗ TXA2 PGI2 PGD2 PGE2 Prostacyclin (brain) PGF2 (endothelium) neurophysiological TXB2 functions (platelets) Potent inhibitor (smooth muscle) of platelet Potent activator aggregation, Protein degradation Protein synthesis and stimulator of vasodilator platelet aggregation, vasoconstrictor Homeostasis maintained by PGF2 and PGE2 Figure 1: Inhibition of cyclooxygenase pathway by NSAIDs. Coxibs as well as nonselective NSAIDs inhibit the formation of the metabolites of the cyclooxygenase pathway thereby disrupting the homeostasis maintained by these metabolites. Coxibs cause an imbalance between the levels of thromboxane and prostacyclin being more favorable towards thromboxane and decreasing prostacyclin levels leading to the aggregation of platelets and causing thrombosis. artery disease,
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