What are NSAIDs and how do they work?

• Drug with analgesic( without impairing

consciousness ), antipyretic, and anti-
inflamammatory effects
• weak acids, PH 3-5, well absorbed
from stomach and intestinal mucosa
• protein-bound in plasma ( albumin),
• metabolised in the liver
 Prostaglandins
• Prostaglandins : produced by the cells,
promote inflammation, pain, and fever; blood
clotting function of platelets; protect the
lining of the stomach from damaging effects
of acid.
• two COX enzymes, COX-1 and COX-2. produce
prostaglandins that promote inflammation,
pain, and fever
Classification of NSAID
 Acetic acid derivatives
• Arthrotec (diclofenac/misoprostol)
• Diclofenac (Voltaren® Meitifen,Formax ®)
• Ketorolac (Toradol Keto, Painoff,Keto Inj,
Kop Inj )
• Tolmetin (Tolectin ®)
• Etodolac (Lodine ® Lonine )
• Indomethacin (Indocin® Acemet )
• Sulindac (Clinoril Unidac ®)
Carboxylic acid derivatives

• Diflunisal (Dolobid ®)
• Salsalate (Disalcid ®)
 Enolic acid (oxicam) derivatives

• Meloxicam ( Mobic ® Subic )

• Piroxicam (Feldene Tonmax inj, Foglugen)
• Tenoxicam ( Tencam, Sutondin )
 Napthylkanone derivatives

• Nabumetone (Relafen ® Relifex, No-ton )

 Proprionic acid derivatives
• Flurbiprofen (Ansaid ® Flufen,Lefenine, Flur
Di Fen )
• Ketoprofen (Orudis ®) Ketoprofen inj
• Oxaprozin (Daypro ® )
• Ibuprofen (Motrin ® Purfen ,Mac Safe syr,
Arfen inj )
• Naproxen (Naprosyn ® Napton)
 COX-2 inhibitors

• Celecoxib (Celebrex ® )
• Rofecoxib (Vioxx ® )
• Valdecoxib (Bextra ® )
 Indomethacin
Indomethacin (sometimes also called indometacin) is a widely used nonsteroidal anti-
inflammatory drug (NSAID). Like other members of this family, it works by inhibiting the
cyclooxygenase enzymes (COX-1 and 2), thereby decreasing prostaglandin levels. This is
medically useful for decreasing inflammation, fever, and pain.
Its pharmacological effect is thought to be mediated through inhibition of the enzyme
cyclooxygenase (COX), the enzyme responsible for catalyzes the rate-limiting step in
prostaglandin synthesis via the arachidonic acid pathway.

Chemical Formula C19H16ClNO4

IUPAC Name
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid
"Traditional" synthesis of
indomethacin
 Pharmacology
of Indomethacin
•For moderate to severe rheumatoid arthritis including acute flares of
chronic disease,
• ankylosing spondylitis,
•osteoarthritis, acute painful shoulder (bursitis and/or tendinitis)
• acute gouty arthritis.
 Pharmacodynamics
1. Indomethacin inhibits the catalytic activity of the COX enzymes,
the enzymes responsible for catalyzing the rate-limiting step
in prostaglandin synthesis via the arachidonic acid pathway.

2. Indomethacin is known to inhibit two well-characterized isoforms

of COX, COX-1 and COX-2, with greater selectivity for COX-1.
COX-1 is a constitutively expressed enzyme that is involved in
gastric mucosal protection, platelet and kidney function.

3. It catalyzes the conversion of arachidonic acid to prostaglandin

(PG) G2 and PGG2 to PGH2. It also catalyzes the conversion of
arachidonic acid to PGG2 and PGG2 to PGH2.

4. In the COX-2-mediated pathway, PGH2 is subsequently converted

to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved
in mediating inflammation, pain and fever. Decreasing levels of PGE2
leads to decreased inflammation.
 Mechanism of action
Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase
or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1
and -2).
Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a
number of prostaglandins involved in fever, pain, swelling, inflammation, and
platelet aggregation.
Indomethacin antagonizes COX by binding to the upper portion of the active site,
preventing its substrate, arachidonic acid, from entering the active site.
Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2,
the enzyme responsible for releasing arachidonic acid from phospholipids.
Indomethacin is more selective for COX-1 than COX-2, which accounts
for its increased adverse gastric effects relative to other NSAIDs. COX-1
is required for maintaining the protective gastric mucosal layer. The analgesic,
antipyretic and anti-inflammatory effects of indomethacin occur as a result of
decreased prostaglandin synthesis. Its antipyretic effects may be due
to action on the hypothalamus, resulting in an increased peripheral
blood flow, vasodilation, and subsequent heat dissipation.
Protein binding 97%

Absorption Bioavailability is approximately 100% following oral administration

and 80–90% following rectal administration.
Metabolism Hepatic.

Route of Indomethacin is eliminated via renal excretion, metabolism, and

elimination biliary excretion.

Half life 4.5 hours

 Toxicity
The following symptoms may be observed
following overdosage: nausea, vomiting,
intense headache, dizziness, mental
confusion, disorientation, or lethargy. There
have been reports of paresthesias, numbness,
and convulsions. The oral LD50 of
indomethacin in mice and rats (based on 14
day mortality response) was 50 and 12 mg/kg,
respectively.