Process of Inflammation: Process of inflammation can be summarized as given below.
- Initial causing release of mediators (histamine, serotonin, leukotrienes, SRS-A, lysosymal enzymes, lymphokines & prostaglandins).
- Increased vascular permeability & exudation.
- Leukocyte migration, Chemotaxis & Phagocytosis.
- Proliferation of connective tissue cells.
Role of complement system in the inflammation:
- Complement proteins are numbered C1 to C9.
- Complement system consists of two activating pathways:
b) Non-immunological activated alternate pathway.
- A major function of complement is to mask antigens & microbes with C3 fragments that directs them to cell containing C3 receptors, such as phagocytic cells.
- Complement activation: Release of IL-1 (cytokine), PGE2 & LTB4.
- This inhibition of complement system helps in following disease conditions:
e) Systemic lupus erythromatosus.
Pathogenesis of rheumatoid arthritis:
- An unknown initiation factor in the synovial joint causes the production of antigenic IgG, which stimulates the synthesis of the rheumatoid factors IgM, IgG, forming immune complexes.
- IgG aggregates activate complement system leading to the generation of chemotactic factors that attracts polymorphonuclear leukocytes into the cellular cavity.
- Leukocytes ingest immune complex to become rheumatoid arthritis cells, which discharges hydrolases results in further degradation of joints.
- All of this induce COX expression.
|Biosynthesis of eicosonoids|
Physiological role of different eicosoinoids:
- Heat: PGE1 & PGE2
- Vasodilation & Redness: PGE1, PGE2, PGD2 & PGA2
- Edema: PGE1, PGI1 & PGI2
- Pain : PGI2, PGE1 & PGE2
b) Thromboxanes & Prostacyclins:
- TXA2 (Synthesized in platelets): Similar to angiotensin II (Vasodilation).
- PGI2: Vasodilator & Bronchodilation.
- LTC4, LTD4 & LTE4: Slow reacting substance of anaphylaxis (SRS-A) (Bronchoconstrictor & Vasoconstriction).
- LTB4: Chemotactic in nature.
- COX-1 is constitutive enzyme. Present in resting cells (used for normal functions).
- COX-2 is inductive enzyme. Produced by cytokines at the time of inflammation.
- Drugs acting at COX-2 are more selective.
|Classification of NSAIDs|
- PGs cause hyperalgesia.
- NSAIDs do not change the pain induced by direct application of PGs but, block the pain sensitizing mechanism induced by bradykinin, TNFα, IL etc.
- Therefor more effective in inflammation induced pain.
- ILs, TNFα & interferrons causes PGE2 production in hypothalmus------> raises temperature threshold.
- Blocks the pyrogens (COX-2 enzymes).
4. Antiplatelet aggregation:
- TXA2 (COX-1) -----> Platelet aggregation.
- PGI2 -------> Antiplatelet
- NSAIDs inhibits both but TXA2 inhibition predominates.
- Inhibits PGE2 & PGI2.
- Decrease bicarbonate & mucus secretion.
- COX-1 dependent impairment of renal blood flow & decrease of glomerulation filteration rate-------> Increase renal insufficiency.
- JGA COX-2 dependent NA+ & water retention.
- Papillary necrosis on habitual intake.
- Gastric mucosal damage
- Edema & NA+ retention
- Delay of labour
Individual pharmacology & chemistry of each class of NSAIDs:
1. Salicylates (Aspirin): Only NSAID which inhibits COX-1 & COX-2 irreversibly.
Structure activity relationship (SAR) study of aspirin:
- Active moiety is salicylate ion.
- Toxicity is due to COOH group (removal of COOH results in analgesic activity only).
- OH at meta/para results in no activity.
- Substitution at 5 increases anti-inflammatory activity.
- Substitution by halogen on ring increase potency & toxicity.
- Displace following drugs: Oral anticoagulants, Methotrexate & Phenytoin.
- Inhibits following drugs: Thiazide & Frusemide.
2. Pyrazolones: All cause agranulocytosis.
a) Phenylbutazone: Strong anti-inflammatory but rather weak analgesic and antipyretic drug. Not used due to high toxicity.
b) Oxyphenbutazone: Metabolite of phenylbutazone but less irritant.
c) Dipyrone: Safer & lesser anti-inflammatory but more analgesic drug.
3. Accetic acid derivatives:
a) Indomethacin: Powerful anti-inflammatory (equal to aspirin). Although effective in rheumatoid arthritis but not used due to side effects.
Structural activity relationship (SAR) of indomethacin:
- Replacement of COOH group with other acidic group decrease activity.
- Acidity of COOH group is directly proportional to the activity.
- Amide analogues are inactive.
- N-benzoyl derivatives with F, Cl, CF3 at para ------> Most active drugs.
- At position 5: OCH3, F, N(CH3)2, CH3, COO results in more active than non substituted.
- N of indole ring is not essential.
- Alkyl at α postion to COOH is more active than aryl substitution.
Antiinflammatory + Analgesic + Antipyretic
d) Etodolac: Antiinflammatory + Analgesic
e) Tolmetic: Analgesic + Antipyretic
f) Ketorolac: Antiinflammatory
4. Oxicam derivatives:
a) Piroxicam: Antiinflammatory + Analgesic + Antipyretic. Better tolerated than aspirin.
b) Tenoxicam: Same as piroxicam.
5. Propionic acid derivatives:
- Safest of all NSAIDs.
- Accumulates in synovial fluid.
6. Non-acid NSAID: Nabumetone
- Prodrug which is basic in nature.
- Converted to methoxy napthylacetic acid.
- Lesser side effects.
- Phenacetin is a prodrug which is metabolized to paracetamol.
- N-accetyl benzoquinoneimine is the metabolite which is hepatotoxic.
- N-accetyl cysteine is given for the treatment of hepatotoxicity caused.
- Paracetamol inhibits the COX of CNS only & not of periphery hence only analgesic in nature & no gastric bleeding.
- Inhibits the functions of WBC.
- During inflammation-----> activation of WBC ----> production of cytokines ----> PG synthesis.
- Nimesulide inhibits the release of cytokine from WBC.
- Very strong anti-inflammatory.
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