selective cox-2 inhibitors. pharmacology of selective cox-2 inhibitors (coxibs) discovery in early...
TRANSCRIPT
Selective COX-2 Selective COX-2 InhibitorsInhibitors
Pharmacology of Pharmacology of Selective COX-2 Inhibitors Selective COX-2 Inhibitors
(COXIBs)(COXIBs)
Discovery in early 1990: cyclo-Discovery in early 1990: cyclo-oxygenase (COX) existed in 2 distinct oxygenase (COX) existed in 2 distinct isoforms isoforms
While COX-1 and COX-2 are While COX-1 and COX-2 are structurally similarstructurally similar
COX-2 contains a side pocketCOX-2 contains a side pocket
Pharmacology of Pharmacology of Selective COX-2 Inhibitors Selective COX-2 Inhibitors
(COXIBs)(COXIBs)
Pharmacology of Pharmacology of Selective COX-2 Inhibitors (COXIBs)Selective COX-2 Inhibitors (COXIBs)
Pharmacology of Pharmacology of Selective COX-2 Inhibitors Selective COX-2 Inhibitors
(COXIBs)(COXIBs) Ratio of affinities to COX-1 and COX-Ratio of affinities to COX-1 and COX-
2 determines how “selective” 2 determines how “selective” a a compound iscompound is
NSAIDs inhibit COX-1 and COX-2 with NSAIDs inhibit COX-1 and COX-2 with different ratiosdifferent ratios
Differences in selectivity lead to Differences in selectivity lead to some variability in some variability in Clinical action Clinical action Safety profilesSafety profiles
Classification and Classification and Basic Differences of COXIBsBasic Differences of COXIBs
ClassificationClassification DrugDrug SelectivitySelectivity Chemical Chemical structurestructure
First First generationgeneration
CelecoxibCelecoxib
RofecoxibRofecoxib3030
272272SulfonamideSulfonamide
SulfoneSulfone
Second Second generationgeneration
ValdecoxibValdecoxib
EtoricoxibEtoricoxib
LumiracoxibLumiracoxib
6161
344344
433433
SulfonamideSulfonamide
SulfoneSulfonePhenylacetic Phenylacetic acid derivativeacid derivative
COX-1 vs COX-COX-1 vs COX-22
Cyclo-oxygenase I (COX-Cyclo-oxygenase I (COX-1)1)
Constitutive enzymeConstitutive enzyme
““House keeping” enzymeHouse keeping” enzyme
Expresses ubiquitouslyExpresses ubiquitously
Mediates physiological responsesMediates physiological responses
Cyclo-oxygenase I (COX-Cyclo-oxygenase I (COX-1)1)
Only isoenzyme found in plateletsOnly isoenzyme found in platelets
Thromboxane AThromboxane A22 (TXA (TXA22) formation) formation
Also plays a role inAlso plays a role in
Protection of GI mucosaProtection of GI mucosa
Renal hemodynamicsRenal hemodynamics
Platelet thrombogenesis Platelet thrombogenesis
Cyclo-oxygenase II (COX-Cyclo-oxygenase II (COX-22))
Highly expressed by cells Highly expressed by cells involved in inflammationinvolved in inflammation (eg. (eg. macrophage, monocytes, synoviocytes)macrophage, monocytes, synoviocytes)
Unregulated by bacterial Unregulated by bacterial lipopolysaccharides, cytokines, lipopolysaccharides, cytokines, growth factors, tumor promotersgrowth factors, tumor promoters
Cyclo-oxygenase II (COX-Cyclo-oxygenase II (COX-2)2)
““Inducible” formInducible” form
Primarily responsible for Primarily responsible for synthesis of prostanoids involved synthesis of prostanoids involved in acute and chronic in acute and chronic inflammatory states inflammatory states
COX-1 and COX-2COX-1 and COX-2
However, this distinction is somewhat However, this distinction is somewhat simplifiedsimplified
COX-2 also constitutively expressed under COX-2 also constitutively expressed under physiological conditions in severe tissues physiological conditions in severe tissues Brain Brain Spinal cordSpinal cord KidneyKidney Vascular endotheliumVascular endothelium
COX-1 also be unregulated to a certain COX-1 also be unregulated to a certain degree in inflammationdegree in inflammation
Development of Development of COXIBsCOXIBs
Development of COXIBSDevelopment of COXIBS
Theoretically, selective inhibition Theoretically, selective inhibition of COX-2 would provideof COX-2 would provide
Anti-inflammatory effectsAnti-inflammatory effects
Without disrupting gastric Without disrupting gastric cytoprotection and platelet cytoprotection and platelet functionfunction
Development of COXIBSDevelopment of COXIBS
Hypothesis: selective inhibition Hypothesis: selective inhibition of COX-2 will haveof COX-2 will have
Therapeutic actions similar to Therapeutic actions similar to NSAIDsNSAIDs
Without GI side effectsWithout GI side effects
Thromboxane AThromboxane A22 (TXA (TXA22) ) & &
Prostacyclin (PGIProstacyclin (PGI22))
Thromboxane AThromboxane A2 2 (TXA(TXA22))
Synthesized by COX-1 in plateletSynthesized by COX-1 in platelet VasoconstrictionVasoconstriction Smooth muscle proliferationSmooth muscle proliferation Platelet aggregationPlatelet aggregation
Prostacyclin (PGIProstacyclin (PGI22))
In contrast, PGIIn contrast, PGI22, a product of , a product of arachidonic acid (AA) from COX-2 in arachidonic acid (AA) from COX-2 in vessel walls plays important role in vessel walls plays important role in homeostatic defense mechanism homeostatic defense mechanism that promotesthat promotes
VasodilatationVasodilatation
Inhibition of platelet functionInhibition of platelet function
NSAIDS and COXIBsNSAIDS and COXIBs NSAIDs block both COX-1 and COX-2 NSAIDs block both COX-1 and COX-2
production to a similar extentproduction to a similar extent
In contrast, COXIBs inhibits PGIIn contrast, COXIBs inhibits PGI22 productionproduction
Thus, COXIBs may create an imbalance Thus, COXIBs may create an imbalance between TXAbetween TXA22 and PGI and PGI22
This might be the dominant mechanism This might be the dominant mechanism that can lead to increased risk of that can lead to increased risk of thrombosisthrombosis
Therapeutic Therapeutic UseUse
Therapeutic UseTherapeutic Use
Postoperative painPostoperative pain Osteoarthritis (OA)Osteoarthritis (OA) Rheumatoid arthritis (RA)Rheumatoid arthritis (RA) Acute gouty arthritisAcute gouty arthritis Chemoprevention Chemoprevention
Its role in carcinogenesis, apoptosis and Its role in carcinogenesis, apoptosis and angiogenesisangiogenesis
Celecoxib approved for Rx of familial Celecoxib approved for Rx of familial adenomatous polyp (FAP)adenomatous polyp (FAP)
Clinical Clinical SafetySafety
Gastrointestinal Gastrointestinal
(GI) Tract(GI) Tract
Gastrointestinal (GI) TractGastrointestinal (GI) Tract
Common reported adverse events Common reported adverse events (AEs) were related to GI tract(AEs) were related to GI tract
DyspepsiaDyspepsia
DiarrheaDiarrhea
NauseaNausea
Abdominal painAbdominal pain
FlatulenceFlatulence
Gastrointestinal (GI) TractGastrointestinal (GI) Tract
Upper GI complications have also Upper GI complications have also occurred in pts treated with occurred in pts treated with COXIBsCOXIBs
PerforationPerforation
UlcersUlcers
BleedingsBleedings
PUBsPUBs
Gastrointestinal (GI) TractGastrointestinal (GI) Tract
Many large RCTsMany large RCTs COXIBs caused COXIBs caused
fewer GI AEs fewer GI AEs compared to NSAIDscompared to NSAIDs
However, most, if However, most, if not all, of the GI not all, of the GI benefits will be lost benefits will be lost in pts who take in pts who take low-dose aspirinlow-dose aspirin
Cardiovascular Cardiovascular (CV) System(CV) System
Cardiovascular (CV) Cardiovascular (CV) SystemSystem
First evidence that COXIBs might First evidence that COXIBs might increase CV risk emerged from increase CV risk emerged from VIGOR studyVIGOR study
Rofecoxib group: 5-fold increase in Rofecoxib group: 5-fold increase in thromboembolic events (primarily thromboembolic events (primarily
acute MIacute MI) )
KidneyKidney
KidneyKidney
COX-2 also constitutively expressed COX-2 also constitutively expressed
in kidneyin kidney
Is regulated in response to alterations Is regulated in response to alterations in intravascular volume in intravascular volume
COXIBs may transiently COXIBs may transiently Decrease urinary NaDecrease urinary Na++ excretion excretion Can induce mild to moderate BP Can induce mild to moderate BP
elevationelevation
COXIBs and NSAIDs COXIBs and NSAIDs
Similar effects for kidney damageSimilar effects for kidney damage Renal insufficiencyRenal insufficiency
NaNa++ retention with HT retention with HT
Peripheral edemaPeripheral edema
HyperkalemiaHyperkalemia
Papillary necrosisPapillary necrosis
KidneyKidney
Other Adverse Other Adverse Events (AEs)Events (AEs)
Other (Common) Adverse Other (Common) Adverse EventsEvents
DizzinessDizziness
HeadacheHeadache
Flu-like symptomsFlu-like symptoms
FatigueFatigue
AnxietyAnxiety
InsomniaInsomnia
Other Adverse EventsOther Adverse Events
As a sulfonamide, celecoxib can cause As a sulfonamide, celecoxib can cause cutaneous adverse reactions without cutaneous adverse reactions without warning even in pts with no history of warning even in pts with no history of sulfonamide allergysulfonamide allergy RashRash UrticariaUrticaria Photoallergic dermatitisPhotoallergic dermatitis Serious and potentially fetal AEsSerious and potentially fetal AEs
Exfoliative dermatitisExfoliative dermatitis Steven Johnson syndromeSteven Johnson syndrome Toxic epidermal necrolysisToxic epidermal necrolysis
Other Adverse EventsOther Adverse Events
Etoricoxib 30-90 mg/day for up to 1 yr, Etoricoxib 30-90 mg/day for up to 1 yr, the most frequently reported lab AEsthe most frequently reported lab AEs Increased level of SGOTIncreased level of SGOT Increased level of SGPTIncreased level of SGPT 1-2.1%1-2.1%
Hepatic dysfunction presents a Hepatic dysfunction presents a contraindicationcontraindication
During long-term Rx with COXIBs, LFTs During long-term Rx with COXIBs, LFTs should be regularly monitoredshould be regularly monitored
Other Adverse EventsOther Adverse Events
Lumiracoxib withdrawn due to Lumiracoxib withdrawn due to severe liver damagesevere liver damage
ConclusionsConclusions
ConclusionsConclusions
CV risks of COXIBs apparently CV risks of COXIBs apparently increase with increase with dosedose and and durationduration of of exposureexposure
If COXIBs indicatedIf COXIBs indicated The lowest effective doseThe lowest effective dose For a limited timeFor a limited time
BPBP as well as as well as renalrenal and and hepatic hepatic functionfunction advisably monitored advisably monitored
ConclusionsConclusions
COXIBs should not be prescribed in COXIBs should not be prescribed in pts withpts with
Ischemic heart diseaseIschemic heart disease
Cerebrovascular disorders (stroke)Cerebrovascular disorders (stroke)
Peripheral arterial diseasePeripheral arterial disease