1. 1
North Maharashtra University
School Of Life Sciences
Assignment On
Cox II Inhibitors
Submitted To
Dr. Arun G. Ingle
Submitted By
Miss. Mugdha P. Padhye
(M. Sc. I)
2. 2
Index-
Sr.
No.
Contents
Page
No.
1 Introduction 3
2 History 3
3 Types of COX Enzymes 4
4 Mechanism of Action of COX enzymes 5
5 COX Enzyme (2) Inhibition Mechanism 6
6 Medical Uses & Side Effects of COX 2 Inhibitors 8
7 COX 2 Inhibitors available in market 9
8 References 10
3. 3
Introduction-
Cyclooxygenase (COX) is an enzyme (EC 1.14.99.1) that is responsible for formation of
important biological mediators called prostanoids (signalling molecules), including
prostaglandins (mediators of inflammatory and anaphylactic reactions), prostacyclin (active in
the resolution phase of inflammation) and thromboxane (mediators of vasoconstriction)
resulting into inflammation and pain.
Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and
pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that reduce
inflammation but are different from steroids, such as aspirin and ibuprofen, exert their effects
through inhibition of COX. The names "prostaglandin synthase (PHS)" and "prostaglandin
endoperoxide synthetase (PES)" are still used to refer to COX.
History-
In the 1990s, researchers discovered that two different COX enzymes existed, now known as
COX-1 and COX-2. The COX-2(which produces PGE2) was discovered in 1991 by Daniel L.
Simmons at Brigham Young University. COX-3 is the most recently discovered cyclooxygenase
(COX) isozyme (in 2002 by Simmons).
This all research began with prostaglandins. The first of these chemicals discovered was isolated
from the prostate gland, thus the name. We are interested in Prostaglandin E-2 (PGE2) which
causes inflammation and is made from a fatty acid called arachidonic acid.
Arachidonic acid is converted into PGE-2 by an enzyme called cyclo-oxygenase, abbreviated as
COX. Blocking the COX enzyme decreases PGE-2 production.
Meat primarily contains Arachidonic acid
Enzyme COX (Cyclo-oxygenase)
Prostaglandins E2 (PGE-2)
Arachidonic acid is found primarily in meats. This is the basis to reduce meat consumption for
people with chronic inflammatory conditions. The less meat consumed the less arachidonic acid
available and the less PGE-2 synthesized to promote inflammation.
4. 4
Types of COX-
Crystallographic Structure of COX-1 Crystallographic Structure of COX-2
Figure 1: Types of COX
At present, three COX isoenzymes are known: COX-1, COX-2, and COX-3.
COX-1 is an enzyme which is normally present in a variety of tissues in the body, including sites
of inflammation and the stomach. Cox-1 is produced throughout the body and regulates blood
flow in the kidneys, supports normal platelet function and maintains the stomach lining. The
body produces a steady supply of COX-1 to these areas which require it to function normally.
COX-2 is activated and made only under certain conditions and is primarily present at sites of
inflammation. When activated, COX-2 produces those hormones like prostaglandins, PGE-2
which is associated with inflammation and tumor development.
COX-3 is not functional in humans but encoded by the same gene as COX-1, with the difference
that COX-3 retains an intron that is not retained in COX-1.
5. 5
Mechanism of action of COX Enzymes-
COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself
derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among
other things) as messenger molecules in the process of inflammation.
Phospholipid Bilayer (Phospholipase A2)
Arachidonic Acid
Enzyme COX
Prostaglandins Prostacyclins Thromboxane
Figure 2: Mechanism of action of COX Enzymes
Figure 3: The Current COX Concept
6. 6
COX Enzyme (2) Inhibition Mechanism-
COX-2 inhibitors are a class of drugs which selectively inhibit COX-2, while sparing COX-1,
thereby reducing gastrointestinal toxicity. COX-2 selective inhibitors are the newest of the NSAIDs
(nonsteroidal anti-inflammatory drugs).
a) Natural COX inhibition
Culinary mushrooms, like Maitake, may be able to partially inhibit COX-1 and COX-2.
A variety of flavonoids have been found to inhibit COX-2.
b) COX II Inhibition by NSAIDs & COX Inhibitors
Any of a class of nonsteroidal anti-inflammatory drugs that selectively block prostaglandin
formation so as to cause minimal gastrointestinal side effects is known as COX Inhibitors.
Newly developed drugs that selectively block the COX-2 enzyme are called COX-2 inhibitors.
The basic difference between NSAIDs and COX Inhibitors is that Common NSAIDs such as
aspirin blocks both COX-1 and COX-2, whereas, COX Inhibitors are selective in their action.
All NSAIDs variably inhibit COX-1 and COX-2 and the mechanisms of inhibition fall into three
broad categories, although there are exceptions. For example, nimesulide is a weak competitive
inhibitor of COX-1 but a potent time-dependent inhibitor of COX-2, whereas celecoxib exhibits
slow competitive binding and, at higher concentrations, binds irreversibly.
The three categories are:
Category 1: rapid competitive reversible binding of COX-1 and COX-2 (e.g., ibuprofen,
piroxicam, mefenamic acid);
Category 2: rapid, lower-affinity reversible binding followed by time-dependent, higher-
affinity, slowly reversible binding of COX-1 and COX-2 (e.g., diclofenac, flurbiprofen,
indomethacin);
Category 3: rapid reversible binding followed by covalent modification of COX-1 and
COX-2 (e.g., aspirin).
8. 8
Medical Uses of COX II Inhibitors-
NSAIDs and COX 2 Inhibitors are generally indicated for the symptomatic relief of the
following conditions-
Rheumatoid arthritis and Osteoarthritis
Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's
syndrome)
Dysmenorrhoea (menstrual pain)
Metastatic bone pain
Headache and migraine
Post operative pain
Mild-to-moderate pain due to inflammation and tissue injury
Pyrexia (fever)
Ileus (Blockage of intestine)
Renal colic (Pain associated with the passage of Renal Calculus)
They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours
of birth
Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of
platelet aggregation. This is useful in the management of arterial thrombosis and prevention of
adverse cardiovascular events. Aspirin inhibits platelet aggregation by inhibiting the action of
thromboxane A2.
Side Effects of COX II Inhibitors-
Common side effects of COX-2 inhibitors include-
Insomnia, Abdominal pain, Flatulence (gas), Headache, Nausea, Diarrhea.
COX-2 inhibitors may increase the risk of serious, even fatal stomach and intestinal adverse
reactions, such as ulcers, bleeding, and perforation of the stomach or intestines but to a lesser
extent than other nonselective NSAIDs that block both COX-1 and COX-2. These events can
occur at any time during treatment and without warning symptoms.
People allergic to sulfonamides, for example, trimethoprim (Trimpex, Proloprim, Primsol) and
sulfamethoxazole (Bactrim), aspirin or other NSAIDs may experience allergic reactions to COX-
2 inhibitors and should not take them.
NSAIDs, including COX-2 inhibitors, may increase the risk of heart attacks, stroke, and related
conditions. This risk may increase in patients with risk factors for heart disease and related
conditions and with longer duration of use. NSAIDs should not be used after coronary artery
bypass graft (CABG) surgery.
9. 9
COX II Inhibitors available in market-
Celecoxib (Celebrex) is the only COX-2 inhibitor available in the United States. It is
indicated for treatment of rheumatoid and osteoarthritis, acute pain and the pain
associated with primary dysmenorrhea.
Rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market in 2004
and 2005, respectively, because they excessively increased the risk of heart attacks and
strokes with long term use.
Meloxicam has been released in South Africa, and is one of several so called
"preferential" COX 2 inhibitors but sometimes shows more effect on COX 1.
COX-2 Selective NSAIDs
Chemical Name Brand Name
Celecoxib Celebrex
Valdecoxib Bextra
Rofecoxib Vioxx
Non-selective NSAIDs
Chemical Name Brand Name
Diclofenac
Cataflam, Voltaren, Arthrotec (combination with
misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbiprofen Ansaid
