Local Hormones II: Anti-inflammatory agents

• NSAIDs

  Non-steroidal anti-inflammatory drugs
• Characteristics of NSAIDs

  • Analgesic (prevention of pain)
  • Anti-pyretic (lowering of raised temperature, fever)
  • Anti-inflammatory (decrease an immune response)
• Conditions NSAIDs are used to treat

  • Low grade pain (chronic inflammation, e.g. arthritis)
  • Bone pain (cancer metastases)
  • Fever (associated with infections)
  • Inflammation (decreases symptoms — oedema, redness, itch)
• COX

  Enzyme that converts arachidonic acid to prostaglandins and thromboxanes
• Older generation NSAIDs

  • Inhibit both COX1 and COX2, so aren't selective
• Newer COX2 selective agents


  • Inhibit COX2 activity without affecting COX1 activity, known as 'super aspirins'
• Paracetamol

  • Analgesic (can relief pain) without anti-inflammatory effects, as it has little inhibition of COX1 or COX2 in peripheral tissue
  • Weakly inhibits COX3 (variant of COX1 in the CNS), so maybe the pain lowering effects of paracetamol may be related to COX3 inhibition, but this doesn't explain all of its effects: there's evidence to suggest it affects 5HT as 5HT is also important for pain
• Other NSAIDs

  • etodolac
  • meloxicam
  • ibuprofen
  • naproxen
  • indomethacin
• Antipyretic action of NSAIDs

  1. Bacterial endotoxins stimulate macrophages to release interleukin-1 (IL1β)

  2. IL1β acts on the hypothalamus to cause PGE₂ release (via COX2)

  3. Increase in PGE₂ decreases temperature sensitive neurons

  4. PGE₂ then elevates set point temperature — this leads to the onset of fever

  5. NSAIDs block PGE₂ production so set point is lowered back to normal value and fever dissipates

  
• NSAIDs have no effect on normal body temperature, so doesn't reduce the normal body temperature
• Analgesic action of NSAIDs

  1. PGs sensitise and stimulate nociceptors (pain receptors)

  2. Oedema produced by inflammation directly activates nociceptive nerve fibres

  3. PGs interact synergistically with other pain producing substances (e.g. kinins, 5HT, histamine) to produce hyperalgesia (increased sensitivity to pain)

  4. Blockade of PG production breaks this cycle and leads to pain relief as it reduces the sensitivity to pain
• NSAIDs are useful for pain associated with production of inflammatory agents (PGs/TXs), e.g. arthritis, toothache, headache (as NSAIDs inhibits PGs-mediated vasodilatation)
• Anti-inflammatory action of NSAIDs

  1. PGE₂ and PGI₂ can cause arteriolar dilatation and increase permeability in post-capillary venules, leading to increased influx of inflammatory mediators into interstitial space

  2. Inhibition of their formation reduces redness and swelling

  
• NSAIDs provide only 'symptomatic relief' — they do not cure the underlying cause of inflammation e.g. help, but do not cure arthritis
• Aspirin can inhibit thromboxane production, which may promote bleeding, so caution must be taken when using it. NSAIDs shouldn't be used if there's bleeding as a result, as they could make it worse
• Cardiovascular effects of NSAIDs

  • TXA₂ has a major role in vascular haemostasis: it's important for platelet aggregation and vasoconstriction
  • NSAIDs decrease TXA₂ (COX1 product) levels and so increase bleeding time, which can be possibly problematic in surgery or childbirth
  • Where platelet aggregation is increased in disease, aspirin has a role in prophylactic treatment
  • TXA₂ and PGI₂ have a more static balance, but there is also something called an endothelium relaxing factor like NO (nitric oxide), which can also work to promote vasodilation and prevent platelet aggregation
  • Thrombo-resistance is conferred by endothelial mediators
  • When there's damage/bleeding, clotting factors/proteins are released, e.g. collagen and von Willebrand factor, and the cut is blocked, reducing blood loss
  • Inappropriate platelet aggregation leads to thrombus and ischaemia heart disease

  
• Why aspirin is beneficial in cardiovascular disorders

  1. Endothelial cells release PGI₂ while platelets release TXA₂, both of which act together to prevent too much bleeding occurring

  2. Platelets have no nuclei, so they can't make new stuff. So when they are inhibited, new platelets need to be released, so they can release TXA₂

  3. Endothelial cells have nuclei, so even if they're inhibited irreversibly, they can make new stuff

  4. When a person takes low dose (75 mg) aspirin to begin with, it inhibits both irreversibly

  5. But as time goes on, endothelial cells will release PGI₂, but platelets are not able to release more TXA₂

  6. Less irritant effects occur and the benefits of PGI₂ and PGE₂ are not lost

  
• Skeletal effects of NSAIDs

  • PGs with acute inflammatory effects contribute to swelling and pain in arthritis
  • NSAIDs diminish these effects, but do not treat the cause
• GI tract effects of NSAIDs

  • PGs (PGE₂/PGI₂) are important in protecting the gastric mucosa by stimulating mucus secretion, inhibiting gastric acid secretion
  • NSAIDs decrease these cytoprotective mechanisms, leading to bleeding and ulceration
  • Gastric side effects are the most common adverse reactions to older NSAIDs
  • COX2 selective inhibitors may be 'gastric-friendly', as it is suggested that COX1 is expressed in gut

  
• Mechanisms of GI side effects of NSAIDs

  1. Mediators of release of acid secretion are histamine, gastrin and acetylcholine (Ach)

  2. Gastrin can cause acid secretion by directly acting on the parietal cells. Ach can induce the same as well

  3. NSAIDs are acidic

  4. ↓ mucus secretion as PGE₂ production is being inhibited

  5. ↓ HCO₃⁻ as PGE₂ production is being inhibited

  6. ↑ acid secretion as PG is being taken away, so acid secretion's not going to be inhibited

  7. ↑ LT (leukotriene) production as the cyclooxygenase pathway has been inhibited

  8. ↑ blood loss

  9. Interfere with tissue healing (COX2 inhibition)

  10. Causes nausea, dyspepsia and GI contraction (COX1 inhibition)
• COX-2-selective agents

  • Examples include celecoxib, etoricoxib, rofecoxib and valdecoxib
  • Etoricoxib is most selective COX2 inhibitor
  • They have no effect on TXA₂ in platelets, but decrease PGI2₂ in blood vessels
  • Rofecoxib was withdrawn due to CV effects
  • Not suitable for RA/osteoarthritis; use meloxicam, etodolac, etc. instead
  • COX2 inhibitor ≠ NSAID ≠ ULCER
  • Diclofenac (an NSAID) is selective for COX2, but inhibits COX1 in GIT ≠ ulcers
  • Less effective analgesic — less inhibition of COX3 in brain and spinal cord

  
• CNS effects of NSAIDs

  • NSAIDs inhibit pyrexia - therapeutic use
  • In overdose, NSAIDs produce paradoxical hyperpyrexia, stupor and coma
  • ↑ metabolism and ↑ metabolic acid production. increase metabolism can produce heat
  • Reye's syndrome risk (brain & liver damage) when used in children with influenza or chicken pox
  • Can cause somnolence, confusion and fulminant hepatitis
• Genital tract effects of NSAIDs

  • PGs cause pain and smooth muscle spasm during menstruation, so NSAIDs are used as treatment
  • Mefenamic acid reduces blood loss
  • NSAIDs may be useful in primary dysmenorrhoea
  • PGs (PGE₂ and PGF₂α) are important in uterine contractions in childbirth, thus NSAIDs delay contractions
  • Many NSAIDs increase postpartum blood loss because TXA₂ production is prevented

  
• Respiratory effects of NSAIDs

  • PGs (PGD₂, PGF₂α) have both constrictor and dilatator effects on airway smooth muscle, but NSAIDs have no effect on normal airway tone
  • NSAIDs must be avoided or used with caution in asthmatics as 20% asthma patients wheeze when given aspirin or other NSAIDs because they are hypersensitive to these drugs
  • At toxic doses, aspirin initially stimulates respiration due to actions on respiratory centre and uncoupling of oxidative phosphorylation and medulla stimulated, leading to respiratory alkalosis caused by hyperventilation (leads to CO2 washout from lungs)
• Renal effects of NSAIDs

  • Vasodilator PGs (E₂/I₂) regulate renal blood flow, thus NSAIDs reduce renal blood flow and chronic renal injury may result
  • Effectiveness of some antihypertensive drugs is reduced by concurrent treatment with NSAIDs
  • Inhibition of COX2 ↓ sodium excretion and ↑ intravascular volume, leading to an average BP rise of 3/2 mmHg, but this varies
  • Low dose aspirin doesn't seem to interfere with antihypertensive therapy, but regular use should be avoided
  • PGI₂ mediates renin release, which is counter-regulated by PGE₂, which decreases Na⁺ reabsorption, if Na⁺ reabsorption increases
• Other indications of NSAIDs

  • Decrease colonic polyps and prevent colon cancer
  • May decrease Alzheimer's disease risk
  • Post-operative pain relief
  • Renal colic — upper part of abdominal pain/groin usually caused by kidney stones

  
• Use of NSAIDs with warfarin will increase GI bleeding
• Ulcerative colitis

  Inflammation of the bowel
• Aims of treatment for ulcerative colitis

  • Reduce symptoms, known as inducing remission (a period without symptoms)
  • Maintain remission
• First-line treatment options for ulcerative colitis

  Aminosalicylates (sulfasalazine and mesalazine) - reduce inflammation for mild or moderate ulcerative colitis, useful in the long term to maintain remission
• Mechanism of action of sulfasalazine

  1. Metabolised to 5-aminosalicylic acid (mesalazine) and sulfapyridine

  2. Reduces the synthesis of eicosanoids by blocking the activity of cyclooxygenase and lipoxygenase

  3. Cyclooxygenase and lipoxygenase activities are high in ulcerative colitis
• Side effects of sulfasalazine

  • Indigestion, feeling or being sick, abdominal pain, diarrhoea
  • Dizziness, headache, difficulty sleeping, tinnitus
  • Coughing; itchy rash, may affect your taste and cause sore mouth
• Gout

  A type of arthritis caused by the accumulation of uric acid crystals in joints
• Cause of gout

  1. Uric acid (from purines) is in the blood and is harmless at low levels

  2. High levels of uric acid in the blood (hyperuricemia) cause tiny grit-like crystals to collect in the joints which irritate the joint tissues, causing inflammation, and pain
• Examples of anti-gout drugs


  • naproxen
  • diclofenac
  • indomethacin
• Mode of action of naproxen

  1. Inhibits COX1/COX2 levels which lower PG levels - targets mediators engaged at the onset of inflammation

  2. Exhibits analgesic, anti-inflammatory and antipyretic activity

  3. Inhibits platelet aggregation (inhibits platelet TXA2)

  
• Side effects of naproxen

  • Dizziness, nausea, indigestion, blurred vision, diarrhoea, abnormal liver function test, water retention, ringing in the ears, hives
• Naproxen is relatively risk neutral for CV events (heart attacks are rare)
• Aspirin action on COX

  Acts irreversibly on COX, removing it so the cell has to make new COX. Other NSAIDs act reversibly, which is significant in its use as prophylactic in cardiovascular disease