- Information
- AI Chat
Anti-inflammatory agents
The Human Body (PY4010)
Kingston University
Recommended for you
Preview text
Anti-inflammatory agents
NSAIDs They are analgesic (prevent pain), anti-pyretic (lowering raised temp/ fever) and anti-inflammatory (decrease immune response). Examples include: Aspirin, Ibuprofen, Etodolac, Meloxicam, Naproxen, Indomethacin. NSAIDs are used to treat Low grade pain Bone pain Fever Inflammation Responses are dependant on inhibitory profiles of different COXs Pharmacological mechanisms of NSAIDs Main therapeutic action is by inhibiton of COX. Older generation NSAIDs inhibit both COX1 and COX2. Newer COX2 selective agents as ‘super aspirins’. Paracetamol is generally not considered an NSAID because it has only minor anti-inflammatory activity. Paracetamol Analgesic without anti-inflammatory effects. Little inhibition of COX-1 or COX-2 in peripheral tissue. Weakly inhibits COX-3 in CNS. Causes liver damage in overdose. Antipyretic action Upon infection ⇒ Bacterial endotoxins during infections stimulate macrophages to release interleukin-1 (IL-1B). (IL-1B) acts on the hypothalamus to cause PGE release. Increase in PGE2 depresses temperature sensitive neurons. PGE elevates set point temperature (onset of fever). Upon taking NSAID ⇒ NSAID blocks PGE2 production so set point is lowered back to normal value and fever dissipates. NSAIDs have no effect on normal body temperature. Analgesic action
Upon infection ⇒ Prostaglandins sensitise and stimulate nociceptors. Oedema produced by inflammation also directly activates nociceptive nerve fibres. Prostaglandins interact synergistically with other pain producing substances to produce hyperalgesia (increased sensitivity to pain). Upon taking NSAID ⇒ Blockade of Prostaglandin breaks this cycle and leads to pain relief. Useful for pain associated with production of inflammatory agents.
Anti-inflammatory action
PGE2 and PGI2 have powerful acute inflammatory effects: Ateriolar dilatation (increased blood flow) Increase permeability in post-capillary venules Both processes increase influx of inflammatory mediators into interstitial space Upon taking NSAID ⇒ inhibition of PGE2 and PGI2 formation as this reduces redness and swelling. NSAIDs provide only ‘symptomatic relief’ - they do not cure the underlying cause of inflammation.
Systems
Cardiovascular system Skeletal GI tract CNS Genital tract Kidney and Body fluids Lung & Respiratory Skin
Cardiovascular
TXA2 has a major role in vascular haemostasis: platelet aggregation and vasoconstriction. NSAIDs decrease TXA2 levels and so increase bleeding time. Possibly problematic in surgery or childbirth. Where platelet aggregation is increased in disease, aspirin has a role in prophylactic treatment. PGI2/E2 and NO (nitric oxide) are endothelial mediators
Prostaglandins with acute inflammatory effects contribute to swelling and pain in arthiritis. Arteriolar dilatation, Increased microvascular permeability and Hyperalgesia (increased sensitivity to pain). NSAIDs thus diminish these effects but do not treat the cause.
GI tract
Prostaglandins important in protecting the gastric mucosa; stimulate mucus secretion and inhibit gastric acid secretion. NSAIDs decrease these cytoprotective mechanisms; bleeding and ulceration can result. Gastric side effects are the most common adverse reactions to older NSAIDs. COX2 selective inhibitors may be ‘gastric friendly’ as it is suggested that COX is expressed in gut. NSAIDs are acidic. In the GI tract they cause: Decreased mucus secretion Decreased HCO3- (bicarbonate) Increased Acid secretion Increased LT (leukotriene) production Increased blood loss Interfere with tissue healing (COX2 inhibition) Nausea, dyspepsia, GI contraction (COX1 inhibition)
COX2 selective agents
Examples: Celecoxib, Etoricoxib, Rofecoxib and Valdecoxib Etoricoxib is the most selective COX2 inhibitor. COX2 selective agents have no effect on TXA2 in platelets, but decrease PGI2 in blood vessels. Rofecoxib was withdrawn due to CV effects. Not suitable for RA/osteoarthiritis; use meloxicam, etodolac etc instead. COX2 inhibitor + NSAID ⇒ Ulcer Diclofenac (NSAID) is selective for COX2 but inhibits COX1 in GIT ⇒ ulcers. Less effective analgesic - less inhibition of COX3 in brain and spinal cord.
CNS
NSAIDs inhibit pyrexia (fever).
In overdose NSAIDs produce paradoxical hyperpyrexia, stupor and coma. Increased metabolism and increased metabolic acid production. Reye’s syndrome risk (brain & liver damage) when used in children with influenza or chicken pox. Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH > or = 7.
Genital tract
Prostaglandins cause pain and smooth muscle spasm during menstruation - NSAIDs used as treatment. Mefanamic acid reduces blood loss. NSAIDs may be useful in primary dysmenorrhoea. Prostaglandins (PGE2 and PGF2a) are important in uterine contractions in childbirth, thus NSAIDs delay contractions. Many NSAIDs increase postpartum blood loss because TXA2 production is prevented.
Lung & Respiratory
Prostaglandins (PGD2 and PGF2a) have both constrictor and dilatator effects on airway smooth muscle - but NSAIDs have no effect on normal airway tone. But NSAIDs must be avoided or used with caution in asthmatics - tend to be hypersensitive to aspirin or other NSAIDS and therefore wheeze. At toxic doses, aspirin initially stimulates respiration. Actions on respiratory centre and uncoupling of oxidative phosphorylation ⇒ medulla stimulated. Respiratory alkalosis caused by hyperventilation (CO2 washout from lungs).
Metabolised to 5-aminosalicylic acid (mesalazine) and sulfapyridine. Reduces the synthesis of eicosanoids by blocking the activity of cyclooxygenase and lipoxygenase. Cyclooxygenase and Lipxygenase activities are high in ulcerative colitis. Side effects include: ingestion/abdominal pain/diarrhoea/dizziness/coughing etc
Anti-inflammatory agents for gout
Gout is a type of arthiritis which is painful inflammation caused by accumulation of uric acid crystals in joints. Uric acid (from purines) is in the blood and is harmless at low levels. It is passed out with urine and faeces. 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 include Naproxen, Diclofenac and Indomethacin.
Mode of action of allupurinol - example
Don’t need to know
Mode of action of naproxen
Inhibits COX1/COX2 levels which lower PG levels ⇒ targets mediators engaged at the onset of inflammation. Exhibits analgesic, anti-inflammatory and antipyretic activity. Inhibits platelet aggregation. Side effects include: dizziness/nausea/indigestion/hives/etc Relatively risk neutral for CV events.
Anti-inflammatory agents
Module: The Human Body (PY4010)
University: Kingston University
- Discover more from:
