Nonsteroidal antiinflammatory drugs

[SH4:p276-p277]

NSAID classification

• Conventional nonspecific COX inhibitors
• Selective COX-2 inhibitors

 

Characteristics of NSAIDs

PD - mechanism of action

• Decreased activation and sensitisation of peripheral nociceptors
• Attenuate inflammatory response
• Synergistic effects with opioids
• Preemptive analgesia (decreases neuronal sensitisation)

PD - effects

• Absence of cognitive changes
• Absence of depression of breathing
• Less N&V compared with opioids
• No pupillary changes
• Absence of dependence or addiction potential
• Ceiling effects
  --> Higher doses only increase risk of drug-induced toxicity

PK

• Long duration of action
• Less dose variability compared with opioids

Potential adverse effects of NSAIDs

• Inhibition of platelet aggregation
  --> Excessive bleeding
• Gastric ulceration
  --> Occurs even after brief use of NSAIDs
• Renal dysfunction
• Hepatocellular injury
• Asthma exacerbation
• Allergic reactions
• Tinnitus
• Urticaria
• Suppression of new bone formation

Cyclooxygenase

• Cyclooxygenase (COX) is an enzyme that catalyse the conversion of arachidonic acid into prostaglandins
  --> Two isoenzymes
• Inhibition of prostaglandin synthesis may also
  * Induce bronchospasm
  * Suppression of new bone formation

COX-1

• COX-1 enzyme is found primarily in
  * Gastric mucosa
  * Renal parenchyma
  * Platelets
• COX-1 is only slightly up-regulated in response to inflammation
• Essential in homeostatic process such as
  * GIT mucosa integrity
  * Renal function
  * Platelet aggregation

Prostaglandins (PG) involved depending on location

• Stomach --> PGE2, PGI2
• Kidney --> PGE2
• Platelet --> Thromboxane A2 (TXA2), PGI2

NB:

• PGI2 = prostacyclin
  * Produced by endothelium
  * Causes vasodilation, inhibits platelet adherence and aggregation
• PGE2
  * Causes vasodilation
  * PGE2 production in kidney is responsible for autoregulation of local circulation (and thus GFR) [WG21:p707]
• TXA2
  * Produced by platelet
  * Causes vasoconstriction and platelet aggregation

COX-2

• COX-2 enzyme is found in
  * sites of injury
• COX-2 is inducible
  --> Up-regulated 10-20 fold in response to inflammation
• COX-2 mediates
  * Inflammation
  * Fever
  * Pain
  * Carcinogenesis (tumour invasion, angiogenesis, and metastasis)

NB:

• Phospholipase A2 catalyse the conversion of membrane phospholipids into arachidonic acid

Usage

[COX-2 inhibitors]

• Analgesia
• Perioperative pain
• Protection against colorectal cancer
• Protection against dementia

Mechanism of action of NSAIDs

• NSAIDs suppresses COX-mediated production of prostaglandin E2
  --> Reduce post operative pain
• PGE2 is the primary inflammatory prostaglandin
  --> Directly activates and up-regulates the sensitivity of peripheral nociceptors
  * May also cross BBB and particate in spinal nociception
• Opioid requirements for postoperative management are decreased 20% to 50% by NSAIDs