NSAIDs: Non-Steroidal Anti inflammatory Drugs.

NSAIDs

Non-Steroidal Anti-inflammatory Drugs.

• The pharmacological agents which relieve pain lower elevated body temperature and also produces an anti-inflammatory effect by inhibiting an enzyme cyclooxygenase (COX) are known as analgesic-antipyretic or NSAIDs.


• NSAIDs as name indicate lack steroidal nucleus and hence also lack side effects of steroids and hence are safer for use to relieve minor pains.


• Mechanism of action of NSAIDs-


• Any injury to cell cause rupture of cell membrane causing a release of Arachidonic Acid which is a component of the cell membrane.


• The released Arachidonic acid is get converted to the Prostaglandins by actions of a group of enzymes called as "Cyclo-oxygenases".


• The formed prostaglandins cause "nociception" i.e. activation of pain stimulus.


• The formed prostaglandins get circulated through the blood to the hypothalamus and cause shifting of thermal conditions of the body on higher side by acting on temperature regulating center.


• The prostaglandins are known to be main culprits behind the "Inflammation".


• Inflammation is characterized by Swelling, Redness of affected area, Heat on affected area.


• Pathogenesis of inflammation –1) Increased capillary permeability: Exodution of capillary fluid in extracellular space: Swelling.2) Chemotaxis –accumalation  WBCs at the site of injury. (Movement of WBCs (Blood) under chemical signal of body): Redness and Heat at affected area.
  
  3) Suppuration – formation of pus from cell debris
  
  4) Nociception – activation of pain.




• NSAIDs inhibit cyclooxygenase enzyme (COX) an enzyme involved in the synthesis of prostaglandin from arachidonic acid and hence relieve from pain, hyperpyrexia, and inflammation.


• Cyclooxygenase (Prostaglandin Synthetase.):


• Cyclooxygenase exist in 3 isoforms i.e. COX-I, COX-II & COX-III


• COX-I is involved in sercreation of gastric mucus while COX-II mediate inflammatory response.


• Non-selective COX inhibitors inhibit both COX-I & COX-II threby causes gastric acidosis.


• Selective COX-II inhibitors inhibit only COX-II, thereby does not cause gastric acidosis


• Anti-pyretic drugs poorly inhibits COX-II peripherally due to the presence of peroxides but inhibit COX-III in hypothalamus in brain to reduce elevated body temperature up to normal


• Protelytic enzymes viz. chymopapain, serratiopeptidase cause breckdown of collgen at the site of inflammation , when combines with conventional NSAIDs i.e.Nonselective COX- inhibitors increases vascular permeability and reduces swelling.

Classification of NSAIDs:

1) Non-selective COX inhibitors or conventional NSAIDs

1.  Salicylic acid derivatives e.g. Aspirin, sodium salicylate, methyl salicylate


2.  P-amino phenol derivatives e.g. Paracetamol, phenacetin


3. Pyrazolone derivatives e.g. Phenylbutazone, oxyphenbutazone


4. Indole derivatives e.g.Indomethacin, sulindac


5. Propionic acid derivatives e.g. Ibuprofen, naproxen, ketoprofen, fenoprofen


6. Anthranilic acid derivatives / Fenamates e.g. mefenamic acid, flufenamic acid


7. Arylacetic acid derivatives eg. Diclofenac, ketorolac, Flufenac


8. Oxicams e.g. Piroxicam, tenoxicam, meloxicam, Lornoxicam

2) Selective COX –II inhibitors e.g. Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib 

3) sulfanilamide e.g.Nimesulide

4) Anti-inflammatory Potentiator e.g. serratiopeptidase, chymotrypsin, Rutoside(Rutin), Bromelain

5) Miscellaneous e.g. Gold

PHARMACOLOGICAL  ACTIONs OF NSAID’S:  

Prototype drug: Aspirin.

1) Analgesic, Antipyretic and anti-inflammatory action:-

• The analgesic action of NSAID’S is predominantly peripheral i.e. inhibition of prostaglandin synthesis and release.


• They are mainly effective for relieving dull pains related to joints, muscles, nerves, bodyache and toothache.


• NSAID’S reduce elevated body temperature up to normal in fever by resetting thermostatic center in the hypothalamus at a higher level thus their antipyretic action is central.


• It exerts anti-inflammatory action at higher doses (i.e. aspirin 3-6 g/day). Signs of inflammation like pain tenderness, redness and localized swelling are suppressed.

2) Respiration:-

• Salicylates are respiratory stimulants, salicylates stimulate respiration by


• Direct action on medullary respiratory center.


• Indirect action by increasing plasma carbon dioxide concentration.

3) Gastrointestinal Tract:-

• The ingestion of salicylates may produce dyspepsia, epigastric distress, nausea and vomiting as a result of gastric irritation.


• sometimes may produce peptic ulceration with G.I bleeding leading to hematemesis (hemat-blood, emesis-vomitting) at high dose.


• The action is due to two facts,


• 1) Aspirin (Acetyl Salicylic Acid) is itself acid, on an empty stomach if taken causes gastric acidosis.


• 2) Aspirin being a nonselective COX inhibitor inhibits both COX-I and COX-II, as COX-I is needed to maintain gstric integrity of gastric mucosa their lack leads to the gastric ulceration.

4) Blood System:-

• Salicylates reduce platelet aggregation (at low dose), promotes fibrinolysis, prolongs bleeding time by interfering with the formation of thromboxanes (TXA2); a chemical mediator essential for platelet aggregation.


• Hence act as "Antiplatelet" at low dose i.e. 75mg.

5) Uricosuric Effect:-

• Salicylate in small dose  1-2g/day increases plasma urate level by blocking tubular secretion of uric acid. i.e. uric acid retention.


• Salicylates in large doses 5-6g/day increases urate excretion by inhibiting reabsorption of uric acid.  i.e. causing uric acid excretion.


• Thus, the large dose is uricosuric and smaller doses cause retention of uric acid.


• Hence large doses are effective in treatment of "Gout".

6) Metabolic Effect:-

• Salicylate causes conversion of large part of energy (derived from oxidation) into heat by uncoupling of oxidative phosphorylation.


• This is one of the causes of hyperpyrexia following large dose of salicylates. (Salicylte Poisoning).

ADVERSE EFFECTS:-

1) Gastric acidosis leading to epigastric distress, nausea, vomiting and headache long-term therapy may cause a peptic ulcer and G.I hemorrhage.

2) Hypersensitivity reaction like skin rashes, urticaria, pruritus, bronchospasm etc

3) Kidney failure.

4) Liver damage.

5) In pregnant women: by inhibiting prostaglandin synthesis in the uterus may delay the onset of labor & cause greater blood loss at the time of delivery.

CONTRAINDICATIONs:-

1) Known hypersensitivity to any NSAIDS.

2) Peptic ulcer or gastric acidosis or hyperacidity.

3) Liver failure (liver cirrhosis).

4) Kidney failure (renal impairment/acute nephritis).

5) Bronchial asthma.

6) Pregnant women.

THERAPEUTIC USES OF ASPIRIN:-

1) As an analgesic and antipyretic.

2) As Antirheumatic in acute rheumatic fever.

3) As an antiplatelet agent in coronary thrombosis.

4) As anti-inflammatory and anti-gout agent. (at high dose)

5) Local applications as keratolytic, fungistatic and antiseptic. (Salicylic Acid)

6) As counter-irritant and rubefacient eg.methyl salicylate

DRUG INTERACTIONS OF SALICYLATES:-

1) It displaces warfarin, sulfonylurea and phenytoin from plasma protein binding site thus toxicity of these drugs may occur.

2) It reduces effects of diuretics like furosemide and spironolactone by inhibiting tubular chloride reabsorption.

3) Glucocorticoids may decrease salicylate concentration.