1. Selective COX-2 Inhibitors

2. Pharmacology of Selective COX-2 Inhibitors (COXIBs)
Discovery in early 1990: cyclo-oxygenase (COX) existed in 2 distinct isoforms
While COX-1 and COX-2 are structurally similar
COX-2 contains a side pocket

3. Pharmacology of Selective COX-2 Inhibitors (COXIBs)

4. Pharmacology of Selective COX-2 Inhibitors (COXIBs)

5. Pharmacology of Selective COX-2 Inhibitors (COXIBs)
Ratio of affinities to COX-1 and COX-2 determines how “selective” a compound is
NSAIDs inhibit COX-1 and COX-2 with different ratios
Differences in selectivity lead to some variability in
Clinical action
Safety profiles

6. Classification and Basic Differences of COXIBs
Drug
Selectivity
Chemical structure
First generation
Celecoxib
Rofecoxib 30
272
Sulfonamide
Sulfone
Second generation
Valdecoxib
Etoricoxib
Lumiracoxib 61
344
433
Phenylacetic acid derivative

7. COX-1 vs COX-2

8. Cyclo-oxygenase I (COX-1)
Constitutive enzyme
“House keeping” enzyme
Expresses ubiquitously
Mediates physiological responses

9. Cyclo-oxygenase I (COX-1)
Only isoenzyme found in platelets
Thromboxane A2 (TXA2) formation
Also plays a role in
Protection of GI mucosa
Renal hemodynamics
Platelet thrombogenesis

10. Cyclo-oxygenase II (COX-2)
Highly expressed by cells involved in inflammation (eg. macrophage, monocytes, synoviocytes)
Unregulated by bacterial lipopolysaccharides, cytokines, growth factors, tumor promoters

11. Cyclo-oxygenase II (COX-2)
“Inducible” form
Primarily responsible for synthesis of prostanoids involved in acute and chronic inflammatory states

13. COX-1 and COX-2 However, this distinction is somewhat simplified
COX-2 also constitutively expressed under physiological conditions in severe tissues
Brain
Spinal cord
Kidney
Vascular endothelium
COX-1 also be unregulated to a certain degree in inflammation

14. Development of COXIBs

15. Development of COXIBS
Theoretically, selective inhibition of COX-2 would provide
Anti-inflammatory effects
Without disrupting gastric cytoprotection and platelet function

16. Development of COXIBS
Hypothesis: selective inhibition of COX-2 will have
Therapeutic actions similar to NSAIDs
Without GI side effects

17. Thromboxane A2 (TXA2) & Prostacyclin (PGI2)

18. Thromboxane A2 (TXA2) Synthesized by COX-1 in platelet
Vasoconstriction
Smooth muscle proliferation
Platelet aggregation

19. Prostacyclin (PGI2)
In contrast, PGI2, a product of arachidonic acid (AA) from COX-2 in vessel walls plays important role in homeostatic defense mechanism that promotes
Vasodilatation
Inhibition of platelet function

20. NSAIDS and COXIBs
NSAIDs block both COX-1 and COX-2 production to a similar extent
In contrast, COXIBs inhibits PGI2 production
Thus, COXIBs may create an imbalance between TXA2 and PGI2
This might be the dominant mechanism that can lead to increased risk of thrombosis

22. Therapeutic Use

23. Therapeutic Use Postoperative pain Osteoarthritis (OA)
Rheumatoid arthritis (RA)
Acute gouty arthritis
Chemoprevention
Its role in carcinogenesis, apoptosis and angiogenesis
Celecoxib approved for Rx of familial adenomatous polyp (FAP)

24. Clinical Safety

25. Gastrointestinal (GI) Tract

26. Gastrointestinal (GI) Tract
Common reported adverse events (AEs) were related to GI tract
Dyspepsia
Diarrhea
Nausea
Abdominal pain
Flatulence

27. Gastrointestinal (GI) Tract
Upper GI complications have also occurred in pts treated with COXIBs
Perforation
Ulcers
Bleedings
PUBs

28. Gastrointestinal (GI) Tract
Many large RCTs
COXIBs caused fewer GI AEs compared to NSAIDs
However, most, if not all, of the GI benefits will be lost in pts who take low-dose aspirin

29. Cardiovascular (CV) System

30. Cardiovascular (CV) System
First evidence that COXIBs might increase CV risk emerged from VIGOR study
Rofecoxib group: 5-fold increase in thromboembolic events (primarily
acute MI)

31. Kidney

32. Kidney COX-2 also constitutively expressed in kidney
Is regulated in response to alterations in intravascular volume
COXIBs may transiently
Decrease urinary Na+ excretion
Can induce mild to moderate BP elevation

33. Kidney COXIBs and NSAIDs Similar effects for kidney damage
Renal insufficiency
Na+ retention with HT
Peripheral edema
Hyperkalemia
Papillary necrosis

34. Other Adverse Events (AEs)

35. Other (Common) Adverse Events
Dizziness
Headache
Flu-like symptoms
Fatigue
Anxiety
Insomnia

36. Other Adverse Events
As a sulfonamide, celecoxib can cause cutaneous adverse reactions without warning even in pts with no history of sulfonamide allergy
Rash
Urticaria
Photoallergic dermatitis
Serious and potentially fetal AEs
Exfoliative dermatitis
Steven Johnson syndrome
Toxic epidermal necrolysis

37. Other Adverse Events
Etoricoxib mg/day for up to 1 yr, the most frequently reported lab AEs
Increased level of SGOT
Increased level of SGPT
1-2.1%
Hepatic dysfunction presents a contraindication
During long-term Rx with COXIBs, LFTs should be regularly monitored

38. Other Adverse Events
Lumiracoxib withdrawn due to severe liver damage

39. Conclusions

40. Conclusions
CV risks of COXIBs apparently increase with dose and duration of exposure
If COXIBs indicated
The lowest effective dose
For a limited time
BP as well as renal and hepatic function advisably monitored

41. Conclusions COXIBs should not be prescribed in pts with
Ischemic heart disease
Cerebrovascular disorders (stroke)
Peripheral arterial disease