3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
 3.1.3.6. NSAIDs 

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

[Chris Flynn]

RPG Chaps

R = renal dysfunction

P = platelet dysfunction

G = gastric irritation and ulceration

C = CNS irritation (e.g. in aspirin overdose --> tinnitus, hyperventilation, N&V)

H = hepatocellular damage

A = Asthma

P = Pregnancy (ductus arteriosus changes)

S = Skin rash

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