Drug Class: Non-steroidal Anti-Inflammatory Drug (NSAID)
Subclass: Cyclooxygenase 2 Inhibitors (COX-2 inhibiters)
Generic Name: Coxibs
Common Chemical Structure of Cox2 Inhibitors:
Selective COX- 2 inhibitors belong to two major structural classes: 1) Tricyclics (also known as ortho-aryl heterocycles or carbocycles); 2) Non-tricyclics. (Zarghi & Arfaei, 2011)
All of the compounds in this class possess 1, 2-diarylsubstitution on a central hetero or carbocyclic ring system with a characteristic methanesulfonyl, sulfonamido, azido, methanesulfonamide or pharmacophore-based tetrazole group on one of the aryl rings that plays a crucial role on COX-2 selectivity. Coxibs such as Celecoxib, Rofecoxib, Valdecoxib, belong to this common structural class (Singh et al., 2004).
Compounds belonging to this class can be sub-classified based on the size and type of the central heterocyclic or carbocyclic ring system (core). 4-, 5- and 6-membered rings and also bicyclic and tricyclic fused and Spiro ring systems have frequently been used as the central core for this group of compounds.(Zarghi & Arfaei, 2011)
These series of compounds lack the cyclic central core. Instead, they possess acyclic central systems such as olefinic, iminic, azo, acetylenic and ?, ?-unsaturated ketone structures. The central acyclic core may contain a two-membered or three membered chain structures which is the basic point for sub classification of these compounds. (Zarghi & Arfaei, 2011)
The coxibs have different chemical structures that could be responsible for their distinct pharmacokinetic properties. Celecoxib and valdecoxib possess a sulfonamide group, Rofecoxib and Etoricoxib have a methylsulfone moiety, and Lumiracoxib is a “phenylacetic acid” derivative with very close similarity to diclofenac.(Praticò & Dogné, 2005)
Mechanism of Action of NSAID Inhibitors:
COX existed in two distinct isoforms: COX-1 and COX-2 (Flower, 2003). COX-1 is the only isoenzyme found in platelets, leading to the formation of thromboxane A2 (TXA2). It also plays a role in the protection of the gastro intestinal (GI) mucosa, renal hemodynamics, and platelet thrombogenesis (DeMaria & Weir, 2003).
In contrast, COX-2 is highly expressed by cells involved in inflammation (e.g., macrophages, monocytes, and synoviocytes), and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters. COX-2 is primarily responsible for the synthesis of prostanoids involved in acute and chronic inflammatory states (Masferrer et al., 1994).
Both COX-1 and COX-2 catalyze the initial step in the conversion of arachidonic acid into prostaglandins, which are important mediators of pain and inflammation and which can be inhibited by NSAIDs (FitzGerald & Patrono, 2001).
Inflammatory prostaglandins are primarily derived from COX-2, while prostaglandins formed by COX-1 have in general a more homeostatic role in gastric cytoprotection and platelet function. Selective inhibition of COX-2 would provide anti-inflammatory effects without disrupting gastric cytoprotection and platelet function. Thus, selective inhibition of COX-2 will have therapeutic actions similar to NSAIDs without the GI side effects that are attributed to inhibition of COX-1. (Rao & Knaus, 2008)
Thromboxane A2 synthesized by COX-1 in platelets promotes vasoconstriction, smooth muscle proliferation, and platelet aggregation. Prostacyclin (PGI2), a product of arachidonic acid from COX-2 in vessel walls, plays an important role in the homeostatic defense mechanism that promotes vasodilatation and inhibition of platelet aggregation(Leval et al., 2004). NSAIDs block both COX isoforms and therefore inhibit TXA2 and PGI2 production to a similar extent, although there is some variation in the biochemical selectivity for each isoenzyme among different NSAID. (Dogné et al., 2004)
In contrast, Coxibs exhibit differing inhibitory effects on PGI2 production. Thus, coxibs may create an imbalance between TXA2 and PGI2 and shift away from the protective effects attributable to PGI2. This might be the dominant mechanism that can lead to an increased risk of thrombosis and cardiovascular disease. (Grosser, Fries, & FitzGerald, 2006)
Grosser and his colleagues (2008) pointed to concern regarding the cardiovascular (CV) safety of coxibs has been raised, particularly the increased risk of thrombotic events such as myocardial infarction (MI), unstable angina, sudden and unexplained death, and stroke (Grosser et al., 2006).
Also Shi and Kolotz (2008) showed epidemiological data suggest that coxibs and NSAIDs as a class all carry some variable potential CV risks, particularly when taken at high doses for prolonged periods of time. Therefore, the risks (CV) and benefits (GI) of coxibs must be carefully weighed before making therapeutic decisions.(Shi & Klotz, 2008)
Because of this increased risk of CVD, the Rofecoxib and Valdecoxib withdrawn from US market in September 2005, Lumiracoxib withdrawn from the Canadian and Australian market and not approved by the FDA, and Etoricoxib has not been approved by the FDA for the US and withdrawn from market in April of 2007 (Rao & Knaus, 2008).
Also Fleischmann and his colleagues (2006) showed chronic use of Lumiracoxib could increase liver enzyme levels, and according to the European Medicines Agency (EMEA) hepatic dysfunction represents a contraindication. Because of several cases of severe liver damage, Lumiracoxib was withdrawn from the Australian and Canadian market and the FDA recently denied the approval of this drug (Fleischmann et al., 2006). The only drug approved in USA was Celecoxib (Sons, 2015) thus, will be the center of our paper.
Brand Names: Celebrex
Therapeutic class: NSAIDs
Pharmacologic class: Cyclooxygenase-2 inhibitors
Chemical name: 4-5-(4-methylphenyl)-3 (trifluoromethyl)-1H-pyrazol-1-yl benzenesulfonamide and is a diaryl-substituted pyrazole.
The molecular weight is 381.38. Molecular formula is C17H14F3N3O2S.
This agent was approved by the US Food and Drug Administration (FDA), in December 31, 1998.
Available Forms Capsules: 50 mg; 100 mg; 200 mg; 400 mg
Celecoxib is compound from the; 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency.(Penning et al., 1997)
Mechanism of Action
Non selective inhibition of both COXs will inhibit many physiological responses such as inflammation, pain, clotting as well as gastrointestinal protection mediated by COX-1. So selective inhibition of COX-2 will results in the same physiological response without the gastrointestinal side effects like, gastric ulcers