Pharmacology & Chemistry of Non Steroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are one of the most prescribed drugs worldwide. You will get definitely fair amount of questions for this section in the GPAT. In this article, complete harmacology of NSAIDs along with their chemistry is discussed.

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).
• Vasodilation.
• Increased vascular permeability & exudation.
• Leukocyte migration, Chemotaxis & Phagocytosis.
• Proliferation of connective tissue cells.

The most common source of chemical mediators include neutrophills, basophills, mast cells, platelets, macrophages & lymphocytes.

Role of complement system in the inflammation:

• Complement proteins are numbered C1 to C9.
• Complement system consists of two activating pathways:

          a) Antibody mediated classical pathway.
          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:

           a) Rheumatoid arthritis  b) Gout  c) Osteoporosis  d) Ankylosing spondilitis
           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:

Biosynthesis of eicosonoids

Physiological role of different eicosoinoids: 

a) Prostaglandins:

• Heat: PGE1 & PGE2
• Vasodilation & Redness: PGE1, PGE2, PGD2 & PGA2
• Edema: PGE1, PGI1 & PGI2
• Pain : PGI2, PGE1 & PGE2

Misoprostol: PGE2 agonists (Inhibits gastric secretions).

b) Thromboxanes & Prostacyclins:

• TXA2 (Synthesized in platelets): Similar to angiotensin II (Vasodilation).
• PGI2: Vasodilator & Bronchodilation.

c) Leuktrienes:

• LTC4, LTD4 & LTE4: Slow reacting substance of anaphylaxis (SRS-A) (Bronchoconstrictor & Vasoconstriction).
• LTB4: Chemotactic in nature.

Cycloxygenase enzyme: 

• 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

Classification of NSAIDs

Pharmacological effects of NSAIDs:

1. Analgesia: 

• 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.

2. Antipyresis:

• ILs, TNFα & interferrons causes PGE2 production in hypothalmus------> raises temperature threshold.
• Blocks the pyrogens (COX-2 enzymes).

3. Antiinflammatory: Most important mechanism is inhibition of PGs.

4. Antiplatelet aggregation:

• TXA2 (COX-1) -----> Platelet aggregation.
• PGI2 -------> Antiplatelet
• NSAIDs inhibits both but TXA2 inhibition predominates.

5. Gastric/mucosal damage:

• Inhibits PGE2 & PGI2.
• Decrease bicarbonate & mucus secretion.

6. Renal effects:

• 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.

7. Common adverse effects of NSAIDs:

• Gastric mucosal damage
• Bleeding
• Edema & NA+ retention
• Delay of labour
• Asthma

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.

Drug interactions of aspirin:

• 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.

b) Sulindac: Its a prodrug.

c) Diclofenac:
    Antiinflammatory + Analgesic + Antipyretic

Diclofenac

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:

a) Ibuprofen:

Ibuprofen

• Safest of all NSAIDs.
• Accumulates in synovial fluid.

b) Naproxem c) Ketoprofen d) fenoprofen e) Flurbiprofen.

6. Non-acid NSAID: Nabumetone

•  Prodrug which is basic in nature.
• Converted to methoxy napthylacetic acid.
• Lesser side effects.

7. Para-aminophenol derivatives: Paracetamol (Acetaminophen)

Paracetamol

• 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.

8. Nimesulide:

Nimesulide

• 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.

If you have any doubt you are free to make a comment below. we will be happy to solve your query. All the best for your preparation.

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