COX-2 inhibitors

[SH4:p277]

Examples of COX-2 inhibitors

Celecoxib

(Celebrex)

• The first selective COX-2 inhibitor to become available clinically (in 1998)
• Celecoxib 200mg daily for osteoarthritis
• Celecoxib 100-200mg BD for rheumatoid arthritis

Rofecoxib

(Vioxx)

• Used for acute post-operative pain
• Loading dose 50mg followed by 25mg daily
• 12.5-25mg daily for osteoarthritis
• Withdrawn from the market in October 2004
  * Due to doubling of MI and CVA risks, found in a study designed to ascertain possible protective effect against colon cancer.

Valdecoxib

• 40mg before surgery and another 40mg after surgery if necessary
• For OA and RA --> valdecoxib 10mg daily
• Primary dysmenorrhoea --> valdecoxib 20mg BD or 40mg daily
• Parecoxib is a prodrug of valdecoxib

Parecoxib

• The only COX-2 inhibitors that is availabe as a parenteral form
• For postoperative pain relief, parecoxib 40mg 1 hour before surgical procedure and another 40mg after surgery if necessary
• Parecoxib is a prodrug that is converted to valdecoxib in vivo.

Structures

• Celecoxib = sulfonamide
• Rofecoxib = sulfone
• Valdecoxib = sulfonamide

Pharmacodynamics

COX-2 inhibitors

• No effect on platelet aggregation
• Decreased GIT side effects (compared with nonspecific NSAIDs)
• Increased risk of acute myocardial infarction and cerebrovascular accident
  * In patients treated chronically with selective COX-2 inhibitors
• Analgesia is not more superior than historically older drugs

COX-2 enzymes are constitutively expressed in brain and spinal cord
--> Up-regulated after persistent noxious inputs
--> Inhibition of COX-2 in spinal cord may be important for decreasing postinjury hyperalgesia

Side-effects

Gastrointestinal toxicity

• Presumably COX-1 maintains GIT integrity by producing prostaglandins
  --> Inhibition of COX-1 leads to GIT toxicity
• 15-30% incidence of gastric or duodenal ulcers in patients taking NSAIDs regularly
• Use of selective COX-2 inhibitors reduces GIT toxicity by 50% (compared to nonspecific NSAIDs)
• Concomitant therapies which reduce ulcers include:
  * Histamine-2 receptor antagonists
  * Proton pump inhibitors
  * Misoprostol (a synthetic prostaglandin E1 analogue)

NB:

• See [Stomach] for acid secretion physiology
• No evidence that NSAID contribute to GORD
• Corticosteroid (blocks COX-2 but not COX-1)
  --> Not considered to cause ulcers
  * But still impair healing of pre-existing ulcers

Coagulation effects

• Platelet aggregation depends on thromboxane A2 (TXA2)
• Platelets do not contain COX-2
  --> All synthesis of TXA2 in platelets is mediated by COX-1
• Conventional nonspecific NSAIDs inhibits COX-1
  --> Platelet aggregation impaired
  * Aspirin even irreversibly inhibits COX-1
• COX-2 inhibitors do not appear to have any significant interactions with anticoagulant drugs
• COX-2 inhibitors do not affect platelet aggregation, bleeding time or postoperative blood loss

Cardic effects

• COX-2 inhibitors
  * Selectively suppress prostaglandin I2 (PGI2, vasoprotective)
  * Does not inhibit thromboxane A2 (procoagluant)
  --> Risk of a thrombotic episode or a myocardial infarction is increased
• COX-2 inhibitors may possibly have a protective role by mediating delayed preconditioning against myocardial infarction and stunning

Hypertensive effect

• Prostaglandins counteract the response to vasoconstrictor hormones
  --> Influence sodium balance by natriuretic effect
  * ?? By influencing GFR?
• By inhibiting prostaglandin production
  --> NSAIDs can increase BP
  * But effect is quite small (about 5 mmHg)

Renal effects

[RD5:p728]

• NSAIDs has no adverse effects on renal function in healthy individuals
• Prostaglandin participate in the autoregulation of renal blood flow and glomerular filtration, and influence tubular transport of ions and water

NSAIDs and renal damage

• Phenacetin causes tubulointerstitial nephritis
  --> Was withdrawn from the market
• Paracetamol is a phenacetin metabolite
  * Been associated with an increased incidence of end-stage renal disease (ESRD)
• Aspirin is the only NSAID without risk of adverse renal effects

GFR

• PGE2 causes vasodilation in kidney
  * In patients with decreased GFR, PGE2 is required to keep GFR up
  * PGE2 is involved in autoregulation of blood vessels in kidney
• Nonselective NSAIDs inhibits synthesis of PGE2
  --> In renal impairment, NSAIDs can lead to decreased GFR and Na+ retention
  --> Systemic hypertension and oedema
• Inhibition of synthesis of vasodilating PGE2 can also lead to
  * Renal medullary ischaemia

Hyperkalaemia

• NSAIDs indirectly depress renin and aldosterone secretion by inhibiting renal prostaglandin I2 synthesis
  --> Hypoaldosteronism
  --> Hyperkalaemia
• Hyperchloraemic metabolic acidosis with hyperkalaemia is an effect of NSAIDs in patients with pre-existing renal disease

Allergic-type interstitial nephritis

• NSAIDs can cause an allergic interstitial nephritis
  * Usually occurs several months to 1 year after starting treatment
  * Manifests as acute renal failure
• Can also be caused by penicillin

Analgesic nephropathy

• Analgesic nephropathy consists of renal papillary necrosis and chronic interstitial nephritis
• Mechanism unknown
• Paracetamol and NSAIDs are possible causes

NB:

• Renal papilla is exposed to highest concentration of solutes, and has a lowest perfusion than the rest of kidney

Factors that increase the risk of NSAID-induced nephrotoxicity

• Hypovolaemia
• Pre-existing renal disease
• Congestive heart failure
• Sepsis
• Combination with other nephrotoxic drugs or radiographic contrast material
• Diabetes mellitus
• Cirrhosis

Hepatic effects

• NSAIDs can cause increases in plasma level of liver transaminases

Allergy

• Sulfonamide hypersensitivity is a contraindication for celecoxib and valdecoxib

Aseptic meningitis

• Can occur after NSAIDs (esp ibuprofen) and H2 antagonists
• This syndrome is more common in females with underlying autoimmune or collagen vascular disease
• May be an acute hypersensitivity reaction

Bone healing

• NSAIDs may impair bone healing
• NSAIDs are not recommended in spinal fusion surgery

Pharmacokinetics

• COX-2 inhibitors are distinct compounds which have different pharmacokinetics
• Different from non-specific NSAIDs, COX-2 inhibitors are:
  * Highly lipophilic
  * Neutral
  * Non-acidic molecules
  * Limited solubility in aqueous media

Absorption

• Well absorbed from GIT
• Low first-pass hepatic extraction
• Only parecoxib is available for IV/IM administration

Distribution

• Celecoxib = Widely distributed into the tissues
• Rofecoxib = Not as well distributed as celecoxib

Celecoxib

• Protein binding = 98%
• Vd = 400L

Rofecoxib

• Protein binding = 87%
• Vd = 86-89L

Valdecoxib

• Protein binding = 86%
• Vd = 98%

Metabolism

• Celecoxib = metabolised by CYP450 to hydroxy, carboxylic acid, and glucuronide derivatives
• Rofecoxib = metabolised mainly by cytosolic reduction in the liver
  --> Interaction with other P450 inhibitors is unlikely
• Parecoxib = rapid amide hydrolysis
  --> Valdecoxib is the active metabolite
• Valdecoxib = metabolised mainly by hepatic cytochrome P450
  --> To 1-hydroxyvaldecoxib

NB:

• Both parecoxib and valdecoxib are INHIBITORS of P-450
  --> Potential for inhibiting metabolism of other drugs (e.g. propofol, midazolam)
• But single dose parecoxib does not alter propofol or midazolam pharmacokinetics

Elimination

Celecoxib

• Elimination half-time = 12 hours
• <2% of celecoxib is excreted unchanged in urine

Rofecoxib

• Elimination half-time = 17 hours
• <1% of rofecoxib is excreted unchanged in urine

Valdecoxib

• Elimination half-time = 8-11 hours

Clinical

Usage

Analgesic efficacy

COX-2 inhibitors are useful in pain due to
* Osteoarthritis
* Rheumatoid arthritis
* Acute gout
* Dysmenorrhoea
* Dental pain
* Perioperative pain with orthopaedic surgery

Perioperative pain management

NSAIDs has a ceiling effect for postoperative analgesia
* Unlike opioids

Protection against colorectal cancer

• COX-2 expression increases significantly in most human colorectal cancers
• Chronic use of aspirin and other conventional NSAIDs reduces risk of colorectal cancer by 40-50%
• Celecoxib decreases the number of polyps in familial adenomatous polyposis

Protection against dementia

• Risk of developing Alzheimer's disease is decreased in patients who use NSAIDs.

COX-2 inhibitors vs nonspecific NSAIDs

• Primary advantage of COX-2 inhibitors
  --> Lack of effects on platelet function
• Also safer in patients with:
  * Asthma
  * Gastritis or gastric ulcer

Interactions

• Most common drug interaction is oral anticoagulants and NSAIDs
  --> Increased risk of GIT haemorrhage
• COX-2 inhibitors may increase plasma warfarin and lithium concentration
• NSAIDs and potassium-sparing diuretics may increase the risks of hyperkalaemia
• NSAID-induced decreases in GFR may also decrease the clearance of:
  * Digoxin
  * Lithium
  * Aminoglycoside antibiotics