Selective COX-2 Inhibitors. Pharmacology of Selective COX-2 Inhibitors (COXIBs) Discovery in early...

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