1. “Traditional NSAIDs” versus “COXIBs”
Iraj Salehi-Abari
“Traditional NSAIDs” versus “COXIBs”
Iraj Salehi-Abari MD.,
Internist
Rheumatologist
NSAIDs

3. In the name of God the merciful and compassionate

4. 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

5. 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

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

9. 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

10. 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

11. 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

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

13. 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

14. 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

15. 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

16. 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

18. 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

19. 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

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

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

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

23. “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

24. “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

25. “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

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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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