ANTI-INFLAMMATORY AND IMMUNOSUPPRESSANT DRUGS NSAIDs ANTIRHEUMATOID DRUGS

1. ANTI-INFLAMMATORY AND IMMUNOSUPPRESSANT DRUGS NSAIDs ANTIRHEUMATOID DRUGS DRUGS USED IN GOUT ANTAGONISTS OF HISTAMINE IMMUNOSUPPRESSANT DRUGS

3. NSAIDs NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

4. are among the most widely used drugs • major type of effects: • antiinflammatory • analgesic (reduction of pain) • antipyretic (lowering of a raised temperature) • mechanisms of action: • inhibition of cyclooxygenase (COX) • inhibition of biosynthesis of PGs and TXs • COX-1 = enzyme expressed in most tissues • involved in cell-cell signalling and in tissue homeostasis • COX-2= enzyme induced in inflammatory cells when they are activated , responsible for the production of prostanoid mediators of inflammation

5. Nonselective NSAIDs Selective and nonselective NSAIDs arachidonic acid inflammation physiological activation COX-1 COX-2 (constitutive form) Endoperoxides (inducible form) proinflammatory prostanoids prostanoids ensuring physiological functions Results from inhibition of prostanoids biosynthesis COX-2 inhibition COX-1 inhibition) Unwanted effects mainly on the GIT and kidney, decrease in pl.aggregation Antiinflammatory, analgesic and antipyretic effects

6. the antiinflammatory action of NSAIDs is mainly related to their inhibition of COX- 2 and it is probable that their unwanted effects are largery due to their inhibition of COX-1 All NSAIDsare analgesics and antipyretics but the degree of anti-inflammatory activity varies OTC drugs (over the counter)

7. Antipyretic effect normal state hypothalamic thermoregulatory centre PGs heat production heat lost NORMAL TEMPERATURE

8. Antipyretic effect hypothalamic thermoregulatory centre various pyrogens PGs heat lost heat production FEVER

9. Antipyretic effect hypothalamic thermoregulatory centre various pyrogens PGs stop aspirin heat production heat lost vasodilation sweating

10. Analgesic effect-- mechanisms in the periphery against pain associated with inflammation or tissues damage because of decrease in PGs production that sensitises nociceptors to inflammatory mediators (bradykinin) centralmechanisms (in the spinal cord) NSAIDs are effective in: arthritis pain of muscular and vascular origin headache, toothache, dysmenorrhoea in combination with opioids : decrease in postoperative pain

11. Antiinflammatory effect • NSAIDs reduce mainly components of the inflammatory and immune response in which the products of COX-2 action play a significant part: • vasodilatation • oedema • pain

12. Unwanted effects • gastrointestinal disturbances • dyspepsia, diarrhoea, nausea, vomiting • one in five chronic users: gastric damage (risk of • serious hemorrhage and/or perforation) • PGs inhibit acid secretion and have protecting action on • the gastric mucosa • skin reactions (from mild rashes, urticaria to more serious • reactions) • renal reactions • acute renal insufficiency reversible on stopping the drug • (due to inhibition of PGE2 mediated compensatory vasodilatation • that occurs in response to NORA and ANG II) • chronic NSAIDs consumption: analgesic nephropathy • chronic nephritis, renal papillary necrosis (renal hypertension, • malignancies)

13. THE SALICYLATES natural products that contain precursors of salicylic acid such as willow bark (glycoside salicin) acetylsalicylic acid sodium salicylate methylsalicylate used in topical applications diflunisal ASPIRIN (acetylsalicylic acid) pharmacokinetics well absorbed, highly bound to plasma proteins first-pass effect--converted to salicylic acid in low dose t1/2 = 4 h, first-order kinetics in high doses >4 g/day saturation pharmacokinetics (danger of overdosage !)pH of urine

14. Unwanted effects: • gastritis with focal erosions and bleeding • salicylism with repeated ingestion of large doses of s: • tinnitus, vertigo, decreased hearing • Reye´s syndrom in children: encephalopathy and • hepatopathy that can follow an acute viral illness (treated with • aspirin). RS has a 20-40% mortality • allergic reactions: skin rashes, worsening of asthma • IND: • antiplatelet effects: 325 mg/day • analgesic effects: 0.5 g 4-6times/day • for short-term analgesia • antiinflammatory effects: 3.5 - 4 g/day • for long-term treatment

15. PARACETAMOL an analgesic-antipyretic agent given orally, metabolised in liver (t1/2 =2-4 h) toxic doses (>5g) cause nausea and vomiting, then, after 24-48 h, potentially fatal liver damage by saturating normal conjugating enzymes causing the drug to be converted by mixed function oxidases to N-acetyl-p-benzoquinone imine. If this is not inactivated by conjugation with glutathione (in alcohol abusers), it reacts with cell proteins and kills the cells (hepatocytes) Agents which increase glutathion: acetylcystein i.v. or methionin orallycan prevent liver damage if given early IND: to lower temperature paracetamol is preferred because it lacks GIT unwanted effects and unlike aspirin, has not been associated with Reye´s syndrome in children

16. Ac Ac-sulfate Ac-glucuronide Cytochrome P450 Reactive electrophilic compound (Ac*) GSH Cell macromolecules (protein) Gs-Ac* Ac*-protein Hepatic cell death Ac-mercapturate

17. IBUPROFEN • analgesic, antipyretic and antiinflammatory action • without gastric toxicity • ind: acute pain for short-term analgesia • OTHER NSAIDs • used for antiinflammatory effects in acute or chronic • inflammatory conditions (e.g. rheumatoid arthritis and related • connective tissue disorders) • are given in higher doses then that for simple analgesia and • treatment may need to be continued for a long period • indomethacin, naproxen can also be used for severe pain • unrelated to inflammation • flurbiprofen, diclofenac

18. more selective for COX-2: nimuselide Coxibs: celecoxib (treatment of arthritis) rofecoxib (withdrown for cardiovascular disorders - IM)

19. ANTIRHEUMATOID DRUGS DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (DMARDs)

20. Rheumatoid disease (one of commonest chronic inflammatory conditions) is a common cause of disability. • The primary inflammatory cytokines, interleukin-1 and tumour necrosis factor-α , have a major role in pathogenesis • DMARDs improve symptoms and can reduce disease activity • as measured by: • reduction in number of swollen and tender joints • pain score • disability score • radiology • serum concentration of acute-phase proteins

21. The effects : • probably result from inhibition of excessive cytokine • liberation • are slow in onset • only have a part to play in progressive disease • are also toxic (the patient must be monitored) IND: rheumatoid + psoriatic arthritis

22. Drugs Unwanted effects Comments --------------------------------------------------------------------------- Immunosuppressantsblood dyscrasias MTX is usual methotrexate (MTX)carcinogenesis first-choice azathioprin opportunistic inf. DMARD cyclosporinMTX: cirrhosis mucositis cycl.: nephrotoxicity hypertension --------------------------------------------------------------------------------------- sulphasalazine blood dyscrasias s. is also used for (combination of rasheschronic inflammatory sulphonamidecolours urine/tearsbowel disease with a salicylate)orange

23. Drugs Unwanted effects Comments Gold compounds skin rashses inhibit mitogen- sodium aurotiomalate mouth ulcerations induced concentrated in macrophages lymphocyte and synovial cells in joints, proliferation effects appear slowly (in months) (maximum effects in 3-4months) penicillamine in 40% is known to have nauzea, vomiting, metal-chelating propert proteinuria and decreases IL-1 gener. chloroquine blurring of vision decreases leukocyte retinopathies chemotaxis, lyozomal enzyme release

24. Thank you for attention