3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.6. NSAIDs
 3.1.3.6.1. COX-2 inhibitors 

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  • Withdrawn from the market in October 2004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