prostaglandins

• Arachidonic acid: a polyunsaturated 20 carbon fatty acid
• Leukotrienes = formed from arachidonic acid by action of the lipoxygenase (LOX) enzymes
• prostaglandins formed by cyclooxygenase (COX) action on arachidonic acid
• Leukotrienes LTB4, LTC4, LTD4, LTE4 = bronchoconstrictors in asthma + promote inflammation
• Pyrogens (floating pathogen derived biochemical substances) lead to the production of cytokines and subsequent prostaglandins.
• PGI2 and PGE2 are hyperalgesic = increase sensitivity of receptors to painful stimuli (pharmacological action of prostanoids)
• mifepristone (RU 486, progesterone receptor antagonist) in combination with a prostaglandin is used for medical abortion
• in smooth muscle; PGI2, PGE2 relax/TXA2 contracts (vascular). PGF2a, LTC4 contract (bronchial). PGE2, PGF2a contract (uterine). PGE2, PGF2a contract (GIT)
• PGI2 and PGE2 increase renal blood flow and increase water (+Na/K) excretion. TXA2 decreases renal blood flow and decreases glomerular filtration rate
• NSAIDs (block production of PGI and PGE) have side effects of reducing renal blood flow and excretion of water and salt so patients with tendency to heart or kidney failure may have these worsened. NSAIDs in combination with phenacetin, and paracetamol can cause renal failure (analgesic nephropathy).
• analgesic nephropathy = chronic interstitial nephritis = long term NSAIDS with phenacetin (and/or its metabolite paracetamol) in combo with aspirin, caffeine, or codeine. In 60s-70s, combined analgesic use exceeded 10% population in some states, especially among middle aged women with chronic headache. Easily available as Vincent's or Bex powders (phenacetin with aspirin and caffeine).
• COX-1 constitutive in most cells. COX-2 inducible in inflammatory cells. 2 upregulated by other stimuli eg stress on endothelial cells
• NSAIDs started with using willow bark (salicylic acid). Pure aspirin marketed in 1899. (isolated acetyl salicylic acid). Phenylbutazone introduced ~1950. Indomethacin ~ 1963. Mainly to treat pain and inflammation of arthritis. All carry an increased risk of gastric and duodenal ulceration,
• Risk of having a bleeding or perforated ulcer while taking NSAIDs long term = 1-2% per year (U.S. ARAMIS)
• In Aus study of 87 arthritis patients taking NSAIDs, 18% had a peptic ulcer at baseline endoscopy
• Selective inhibitors of COX-2 (don't target COX-1, gastric mucosa is fine then). 50% less likely to cause ulcerative complications, but can still occur. Celecoxib available. Rofecoxib (Vioxx) off the market because it increased risk of vascular thrombosis.
• When the thromboxane pathway is upregulated, the prostacyclin pathway is downregulated. Ie, when COX is inhibited, more leukotrienes are created.
• Ulcer complication events with naproxen (non-selective) = 1.4/100 patient years vs rofecoxib (COX-2 selective) = 0.6/100 py. Relative Risk (95% confidence interval) = 0.4 (0.2-0.8x the naproxen risk).
• Low dose aspirin = extensively used to reduce risk of myocardial

  infarction and cerebral thrombosis.

  Mode of action is blocking platelet thromboxane production so platelets do not aggregate

  Optimal dosage is about 75-100 mg once daily (cf. 600 mg for a headache)

  Gastric ulceration is less likely at these doses, but still occurs in around 5-10% patients each 6 months.