NSAIDs and prostaglandin (PG) synthesis inhibition

In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs

blocked PG generation. This is now considered to be the major mechanism of action of NSAIDs.

Prostaglandins, prostacyclin (PG I2) and  Thromboxane A2 (TXA2) are produced from arachidonic acid by the enzyme cyclooxygenase which exists in a 

• constitutive (COX-1 ) and  
• an inducible (COX-2) isoforms;

 the former [constitutive (COX-1 )] à serves physiological 'house keeping' functions, while

the latter [inducible (COX-2)]           ànormally present in minute quantities,

is induced by cytokines and other signal molecules at the site of inflammation à generation of

PGs locally which mediate many of the inflammatory changes. However, COX-2 is constitutively

present at some sites in brain and in juxtaglomerular cells: may serve physiological role at

these sites.
Most NSAIDs inhibit COX-1 and COX-2 nonselectively,
but now some selective COX-2 inhibitors have been produced.

Aspirin inhibits COX irreversibly by acetylating one of its serine residues; return of COX

activity depends on synthesis of fresh enzyme.

Beneficial action due to PG synthesis Inhibition::-

• Analgesia: prevention of pain nerve ending sensitization

• Antipyresis

• Antiinflammatory

• Antithrombotic

• Closure of ductus arteriosus in newborn ' " ...

Other NSAIDs are competitive and reversible

inhibitors of COX, return of activity depends on

their dissociation from the enzyme which in turn

is governed by the pharmacokinetic characteristics of the compound.

History and Classification of NSAID’s/Pain Killer Medicine

( Aspirin / Paracetamol / Brufen / Diclo / Nimesulide )

History:-
Willow bark (Salix alba) had been used for many centuries.Sillicylic acid was prepared by hydrolysis of the bitter glycoside obtained from this plant.Sodium Salicylate was used for fever and pain in 1875; its great success led to the introduction of acetylsalicylic acid (aspirin) in 1899.

Phenacetin and antipyrine were also produced at that time. The next major advance was the development of phenylbutazone in 1949 having antiinflammatory activity almost comparable to corticosteroids. The term Nonsteroidal Antiinflammatory Drug (NSAlD) was coined to designate such drugs. Indomethacin was  introduced in 1963. A host of compounds heralded by the propionic acid derivative ibuprofen  have been added since

then and cyclooxygenase (COX) inhibition is recognised to be their most important mechanism of action. Recently some selective COX-2  inhibitors (celecoxib, etc ) have

been added.

All drugs grouped in this class NSAID’s (Non Steroidal Anti Inflammatory Drugs) have
Analgesic (Relieves pain) Antipyretic (Relieves Fever) and Anti-inflammatory (Relieves Inflammation/Swelling) actions in different measures. In contrast to morphine they do not depress CNS, do not produce physical dependence, have no abuse liability and are weaker analgesics (except for inflammatory pain).

They (NSAID’s) are also called
Nonnarcotic, Nonopioid or Aspirin like analgesics.

They act primarily on peripheral pain mechanisms, but also in the CNS to raise pain threshold. They are more commonly employed and many are over the counter

drugs.

CLASSIFICATION

A. Nonselective COX Inhibitors (Traditional NSAID’s)

1. Salicylates: Aspirin
2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
3. Anthranilic acid derivative: Mephenamic acid.
4. Aryl-acetic acid derivatives: Diclofenac ,Aceclofenac.
5. Oxicam derivatives: Piroxicam, Tenoxicam.
6. Pyrrolo-pyrrole derivative: Ketorolac.
7. Indole derivative: Indomethacin.
8. Pyrazolone derivatives : Phenylbutazon, Oxyphenbutazone.

B. Preferential  COX-2 inhibitors

1. Nimesulide, Meloxicam, Nabumetone.

C. Selective  COX-2  Inhibitors

1. Celecoxib, Etoricoxib, Parecoxib.

D. Analgesic- antipyretics with poor antiinflammatory action

1. Paraaminophenol derivative: Paracetamol (Acetaminophen).
2. Pyrazolone darivatives: Metamizol , Propiphenazone.
3. Benzoxazocine derivative: Nefopam