“Traditional NSAIDs” versus “COXIBs” Iraj Salehi-Abari “Traditional NSAIDs” versus “COXIBs” Iraj Salehi-Abari MD., Internist Rheumatologist salehiabari@sina.tums.ac.ir NSAIDs

In the name of God the merciful and compassionate

Iraj Salehi-Abari Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used type of medication to treat arthritis and other painful musculoskeletal disorders They have been used for more than 3 decades Nowadays there are over 20 NSAIDs available NSAIDs

Introduction: Aspirin (ASA) was the first NSAIDs to be used Iraj Salehi-Abari Introduction: Aspirin (ASA) was the first NSAIDs to be used Nowadays there are many non-salicylate NSAIDs: Traditional ( classic ) COXIBs NSAIDs

NSAIDs are: Anti-inflammatory Analgesic Antipyretic Iraj Salehi-Abari Op/Os

Prostanoid synthetic pathways: Phospholipase A2 Membrane phospholipids =============== Arachidonic acid Cyclooxygenase Arachidonic acid =============== Prostaglandin G2 PGH synthase Prostaglandin G2 ============= Prostaglandin H2 (PGH2) PGH2  PGD2, PGE2, PGF2 PGH2  PGI2 PGH2  TxA2

NSAIDs; mechanism of action Iraj Salehi-Abari NSAIDs; mechanism of action PG-mediated effects: The primary effect of NSAIDs is to inhibit Cyclooxygenase, therefore Prostaglandins will not be produced, . . . NonPG-mediated effects NSAIDs

Prostanoid synthetic pathways: Phospholipase A2 Membrane phospholipids =============== Arachidonic acid CyclooNSAIDs xygenase Arachidonic acid =======NSAIDs======= Prostaglandin G2 PGH synthase Prostaglandin G2 ============= Prostaglandin H2 (PGH2) PGH2  PGD2, PGE2, PGF2 PGH2  PGI2 PGH2  TxA2

Cyclooxygenase (COX): Iraj Salehi-Abari Cyclooxygenase (COX): COX catalyzes the formation of Prostaglandins, Prostocyclin and Thromboxane from Arachidonic acid NSAIDs

Functions of Prostaglandins: Iraj Salehi-Abari Functions of Prostaglandins: Activation of the inflammatory response Sensitize spinal neurons to pain Acts on thermoregulatory center of hypothalamus to produce fever NSAIDs

Functions of Prostaglandins: Iraj Salehi-Abari Functions of Prostaglandins: Vasoconstriction and platelet aggregation in damaged vessels and vasodilation in normal vessels Vasodilation and promotion of blood flow in kidney  increased GFR Inhibition of acid synthesis and promotion of mucus secretion in stomach NSAIDs

Functions of Prostaglandins: Iraj Salehi-Abari Functions of Prostaglandins: Uterine contraction and induction of labor Reduction of intraocular pressure Regulation of calcium movement Inhibition of Apoptosis NSAIDs

Cyclooxygenase (COX): Iraj Salehi-Abari Cyclooxygenase (COX): There are two types of COX enzyme: COX-1 COX-2 A splice variant derived from the COX-1 gene has been described as COX-3 NSAIDs

COX-1: It is expressed in most tissues As a “Housekeeping” enzyme Iraj Salehi-Abari COX-1: It is expressed in most tissues As a “Housekeeping” enzyme Regulating normal cellular Processes: Gastric cytoprotection Vascular homeostasis Platelet aggregation Kidney function NSAIDs

COX-2: It is usually undetectable in most tissues Iraj Salehi-Abari COX-2: It is usually undetectable in most tissues Its expression is increased during states of “Inflammation” NSAIDs

Iraj Salehi-Abari COX-1 inhibition: Inhibition of COX-1 isoenzyme by the NSAIDs produces the side (adverse) effects of NSAIDs NSAIDs

Iraj Salehi-Abari COX-2 inhibition: Inhibition of COX-2 isoenzyme by the NSAIDs produces the effects of: Anti-inflammatory Analgesic Antipyretic NSAIDs

Traditional NSAIDS vs COXIBs: Iraj Salehi-Abari Traditional NSAIDS vs COXIBs: Nowadays NSAIDs are divided into: “Traditional” NSAIDs: “COXIBs” NSAIDs

“Traditional” NSAIDs: Iraj Salehi-Abari “Traditional” NSAIDs: “Trditional” or “Classic” NSAIDs are non-selective inhibitors of Cyclooxygenase and they inhibit both the COX-1 and COX-2 isoenzymes NSAIDs

“Traditional” NSAIDs: Iraj Salehi-Abari “Traditional” NSAIDs: Salicylate (acetylated): Aspirin Salicylates (non-acetylated): Diflunisal, Salsalate,… Propionic acids: Ibuprofen, Naproxen, Ketoprofen,... Acetic acids: Diclofenac, Tolmetin, Indomethacin,… Oxicams (enolic acids): Meloxicam, Piroxicam,… Fenamates (anthranilic acids): Mefenamic acid,… Non-acidic (naphthylalkanone): Nabumetone NSAIDs

“COXIBs: “COXIBs” are a new class of NSAIDs Iraj Salehi-Abari “COXIBs: “COXIBs” are a new class of NSAIDs They are COX-2 selective inhibitors They have been developed to reduce the risk of GI ulcers and bleeding, But they increase the cardio (cerebro)-vascular accidents NSAIDs

COXIBs (selective COX-2 inhibitors) Iraj Salehi-Abari COXIBs (selective COX-2 inhibitors) Celecoxib (Celebrex): available in USA Etoricoxib (Arcoxia) Lumiracoxib (Prexige) Parecoxib NSAIDs

Precautions with COXIBs Iraj Salehi-Abari Precautions with COXIBs Rofecoxib (Vioxx) and Valdecoxib (Bextra) were taken off the market in 2004, due to increased risk of heart attack and stroke in that people who took these medicatons NSAIDs

Iraj Salehi-Abari Attention please: In Amir Alam Hospital Rheumatology Unit (AAHRU) high dose COXIBs have been used for a very short period of time and when it was discovered that with medium to high doses their side effects are significant, (specially cardio (cerebro)- vascular), They have been not used most of time since 2002. NSAIDs

NSAIDs; mechanism of action Iraj Salehi-Abari NSAIDs; mechanism of action PG-mediated effects: The primary effect of NSAIDs is to inhibit Cyclooxygenase, therefore Prostaglandins will not be produced, . . . NonPG-mediated effects NSAIDs

NonPG-mediated effects Iraj Salehi-Abari NonPG-mediated effects NSAIDs insert into biological membranes and interfere with cell function They inhibit PMN function They interfere with the PMN – EC adherence They decrease the expression of L-selectin They inhibit iNOS and decrease NO NSAIDs

Iraj Salehi-Abari Attention please: There is individual variation in response to NSAIDs in both Efficacy and Adverse effects Aspirin is an irreversible inhibitor of platelet aggregation NSAIDs

Iraj Salehi-Abari Attention please: NSAIDs with a short half life (< 6 hours), no enterohepatic circulation and lower cardio (cerebro)-vascular accidents may be the best choices for older patients Naproxen may be the safest for people with coronary artery disease NSAIDs