W5_L11_Local hormones2;Anti-inflammatory drugs.pptx

Local hormones 2: Anti-inflammatory Agents Dr Omar Janneh Email: [email protected] Tel: 0208 725 5614 Office: Jenner Wing, First Floor, Corridor 4, Room: 1.118 Learning objectives • Describe the mechanism of action and uses of non-steroidal antiinflammatory drugs • Outline the major side effects...

Local hormones 2: Anti-inflammatory Agents Dr Omar Janneh Email: [email protected] Tel: 0208 725 5614 Office: Jenner Wing, First Floor, Corridor 4, Room: 1.118 Learning objectives • Describe the mechanism of action and uses of non-steroidal antiinflammatory drugs • Outline the major side effects of NSAIDs • Outline and compare the mechanisms of other anti-inflammatory agents used to treat gout, ulcerative colitis and inflammatory diseases of joints Outline of Lecture on anti-inflammatory drugs Basics • Pharmacological mechanism of action of action:  Antipyretic action  Analgesic action  Anti-inflammatory reaction  Systems Pharmacology – Cardiovascular system – Skeletal – Gastrointestinal – CNS – Genitals – Kidney & body fluids – Lung & respiratory • Anti-inflammatory agents for ulcerative colitis, and joint pains NSAIDs: Basics • Archetypal NSAID is aspirin (ASA) • NSAIDs are: – Analgesic (prevention of pain) – Anti-pyretic (lowering of raised temperature, fever) – Anti-inflammatory (decrease an immune response) • NSAIDs are used to treat: – Low grade pain (chronic inflammation, e.g. arthritis) – Bone pain (cancer metastases) – Fever (associated with infections) – Inflammation (symptoms- oedema, redness, itch) Responses are dependent on inhibitory profiles of different COXs Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs Summary: cardinal signs of Inflammation Pharmacological Mechanisms of NSAIDs • Main therapeutic action is by inhibition of COX: – COX converts AA to PGs and TXs – Aspirin acts irreversibly on COX; others act reversibly and this is significant in its use as a prophylactic in cardiovascular disease – Older generation NSAIDs inhibit both COX-1 and COX-2 – Newer COX-2 selective agents as ‘super aspirins’? – Paracetamol is a special case Paracetamol – not an NSAID • Analgesic without anti-inflammatory effects • Little inhibition of COX-1 or COX-2 in peripheral tissue • Weakly inhibits COX-3 in CNS – this doesn’t explain all of its effects Other NSAIDs include etodolac, meloxicam, ibuprofen, naproxen, indomethacin, etc. Antipyretic Action • Bacterial endotoxins produced during infections stimulate macrophages to release interleukin-1 (IL-1β) • IL-1β acts on the hypothalamus to cause PGE2 release (via COX-2)….. – ↑PGE2 depresses temperature sensitive neurons • PGE2 elevates set point temperature - onset of fever • NSAIDs block PGE2 production so set point is lowered back to normal value and fever dissipates • NSAIDs have no effect on normal body temperature Analgesic Action • PGs sensitise and stimulate nociceptors • Oedema produced by inflammation also directly activates nociceptive nerve fibres • PGs interact synergistically with other pain producing substances (e.g. kinins, 5-HT, histamine) to produce hyperalgesia (↑ sensitivity to pain) • Blockade of PG production breaks this cycle and leads to pain relief • Useful for pain associated with production of inflammatory agents (PGs/TXs), e.g. arthritis, toothache, headache (as NSAIDs inhibits PGs-mediated vasodilatation) • COX-1, COX-2 and COX-3 inhibition in CNS Anti-inflammatory Action • PGE2 and PGI2 have powerful acute inflammatory effects: – Arteriolar dilatation (blood flow) – Increase permeability in post-capillary venules – Both processes increase influx mediators into interstitial space of inflammatory • 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 • ↓ COX-2 generated PGs; effects develop gradually Systems Pharmacology of NSAIDs • • • • • • • • Cardiovascular system Skeletal Gastrointestinal tract CNS Genital tract Kidney and body fluids Lung & respiratory Skin Cardiovascular • TXA2 - major role in vascular haemostasis – platelet aggregation – Vasoconstriction • NSAIDs decrease TXA2 (COX-1 product) 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 Thrombo-resistance conferred by endothelial mediators Platelets Vessel lumen PGI2/E2 NO - Prevents platelet aggregation Vascular Endothelial Cells NO = nitric oxide Platelets aggregate and adhere at site of vessel damage Damaged Endothelium collagen Von Willebrand factor (vWF) TXA2 Vessel lumen Platelets ↑platelet aggregation; ↓blood loss Vascular endothelial cells Inappropriate platelet aggregation → thrombus and ischaemia heart disease Why is aspirin beneficial in cardiovascular disorders? Constitutively Active (COX-1) Inducible COX-2 Endothelial cell COX Platelet COX PGI2 TXA2 anti-aggregatory vasodilator pro-aggregatory vasoconstrictor Why is aspirin beneficial in cardiovascular disorders? Inducible (COX-2) + low doses of aspirin Constitutively Active (COX-1) Endothelial cell Platelet X X PGI2 TXA2 anti-aggregatory vasodilator pro-aggregatory vasoconstrictor COX COX Why is aspirin beneficial in cardiovascular disorders? OVER TIME new protein synthesis - New COX, recovery endothelial cell no protein synthesis in platelets - no new COX, no recovery platelet X PGI2 anti-aggregatory vasodilator Platelets cannot synthesise more COX TXA2 pro-aggregatory vasoconstrictor Less irritant effects, benefits of PGI2 and PGE2 not lost Skeletal • PGs with acute inflammatory effects contribute to swelling and pain in arthritis – Arteriolar dilatation – Increased microvascular permeability – Hyperalgesia – increased sensitivity to pain • NSAIDs thus diminish these effects, but do not treat the cause GI Tract • PGs (PGE2/PGI2) important in protecting the gastric mucosa – stimulate mucus secretion – 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 • COX-2 selective inhibitors may be ‘gastric-friendly’, as it is suggested that COX-1 is expressed in gut – See examples of COX-2 selective inhibitors later Prostanoids modulate the action of Other Agents EP3 EP3 Aspirin inhibits the synthesis of PGE2 Site of action of aspirin and ibuprofen No need to memorise this pathway. Note the site of action of the drugs and put that into context of the gastroprotective effects attributed to PGE2 and TXA2 Summary of the effects of aspirin on the GI Tract • NSAIDs = acidic • • • • • ↓ mucus secretion ↓ HCO3↑ acid secretion ↑ LT production ↑ blood loss • Interfere with tissue healing (COX-2 inhibition) • Nausea, dyspepsia, GI contraction (COX-1 inhibition) COX-2-selective agents Examples: Celecoxib, etoricoxib, rofecoxib, valdecoxib, , Etoricoxib is most selective COX-2 inhibitor • They have no effect on TXA2 in platelets, but decrease PGI2 in blood vessels • Rofecoxib – withdrawn due to CV effects • Not suitable for RA/osteoarthritis; use meloxicam, etodolac, etc. instead • COX-2 inhibitor + NSAID → ULCER • Diclofenac (an NSAID) - selective for COX-2, but inhibits COX-1 in GIT → ulcers • Less effective analgesic - less inhibition of COX-3 in brain and spinal cord CNS • NSAIDs inhibit pyrexia - therapeutic use • In overdose NSAIDs produce paradoxical hyperpyrexia, stupor and coma - ↑ metabolism and ↑ metabolic acid production • Reye’s syndrome risk (brain & liver damage) when used in children with influenza or chicken pox • Somnolence, confusion and fulminant hepatitis Reye’s syndrome Aspirin shouldn’t be used in children with influenza or chicken pox; use paracetamol instead Without pre-existing hepatic disease Treatment: Urine alkalinisation increases the excretion of aspirin Genital Tract • PGs cause pain and smooth muscle spasm during menstruation - NSAIDs used as treatment – Note mefanamic acid reduces blood loss – NSAIDs may be useful in primary dysmenorrhoea • PGs (PGE2 and PGF2α) - important in uterine contractions in childbirth, thus NSAIDs delay contractions • Many NSAIDs increase postpartum blood loss because TXA2 production is prevented Respiratory • PGs (PGD2, PGF2α) 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 – ca. 20% asthma patients wheeze when given aspirin or other NSAIDs because they are hypersensitive to these drugs • 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) Kidney • Vasodilator PGs (E2/I2) regulate renal blood flow PGI2: mediates renin release • Thus, NSAIDs reduce renal blood flow – Chronic renal injury may result Counter-regulated by: PGE2 :↓ Na+ reabsorption, if Na+ reabsorption increases  Effectiveness of some antihypertensive drugs is reduced by concurrent treatment with NSAIDs  Inhibition of COX-2 ↓ sodium excretion and ↑intravascular volume  Average BP rise = 3/2 mmHg, but varies  Low dose aspirin doesn’t seem to interfere with antihypertensive therapy, but regular use should be avoided 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 Drug treatment of ulcerative colitis • Ulcerative colitis = inflammation of bowel Aims of treatment: • Reduce symptoms, known as inducing remission (a period without symptoms) • Maintain remission • First-line treatment options: aminosalicylates (sulfasalazine and mesalazine) • ↓ inflammation for mild or moderate ulcerative colitis. • Short-term treatment of flare-ups. • Useful in the long term to maintain remission. Mechanism of action of sulfasalazine • Metabolised to 5-aminosalicylic acid (mesalazine) and sulfapyridine • Reduces the synthesis of eicosanoids by blocking the activity of cyclooxygenase and lipoxygenase • 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 Anti-inflammatory agents for gout • Gout (a type of arthritis): accumulation of uric acid crystals in joints • Painful inflammation caused by build up of uric acid in joints • Uric acid (from purines) is in the blood and is harmless at low levels • Soluble uric acid prevents damage to blood vessel linings? • Passed out with the urine and faeces • High levels of uric acid in the blood (hyperuricemia) cause tiny gritlike crystals to collect in the joints which irritate the joint tissues, causing inflammation, and pain • Examples of anti-gouts drugs: naproxen, diclofenac and indomethacin Mode of action of allopurinol 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 (inhibits platelet TXA2). Side effects of naproxen • Dizziness, nausea, indigestion, blurred vision, diarrhoea, abnormal liver function test, water retention, ringing in the ears, hives • Relatively risk neutral for CV events (heart attacks are rare)