Critically discuss why a nitric oxide containing moiety has been used to

modify COX-2 inhibitors.

Medicinal drugs are derived and formulated with the aim of improving
or curing some sort of ailment or disease. However, majority of the
drugs available on the market and in development today also are
associated with many adverse/side effects. This is because, while
providing its specific benefit, the drug also inadvertently targets other
areas of the body, and brings forth the side-effects associated with the
non-specific targets. For example, paracetamol provides pain relief but
is also associated with hepatotoxicity at high doses. As a result, drug
compounds fail in development, are withdrawn from the market and
patient compliance is severely reduced. Formulation scientists are then
forced to go back to the drawing board to formulate new compounds
that will provide maximum benefits with a very small toxic profile.
Nitric oxide (NO) is one such functional group that has been added to
improve efficacy and safety of drug molecules.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a class of drugs
that are used for the treatment of acute or chronic conditions
where pain and inflammation are present. They are said to have
analgesic, antipyretic, anti-inflammatory and anti-thrombotic
properties. They provide these properties by inhibiting cyclooxygenase,
which normally is responsible for the conversion of Arachidonic acid to
the various prostaglandins, which are key mediators in the
inflammatory response. There are two variants of the cyclooxygenase
enzyme; COX1 and COX2. The COX2 enzyme is mainly responsible for
prostaglandin and prostacyclin synthesis, while COX1 is responsible for
maintaining mucosal blood flow, mucus secretion, and reducing
neutrophil adherence. A NSAID such as aspirin, which is non-specific to
which variant of COX, it inhibits, will provide relief from pain &
inflammation and prevent platelet aggregation, but will also cause side
effects such as gastritis and ulceration because of the COX1 inhibition.
Adverse effects, particularly those caused by erosion of gastric
mucosal protection, frequently limit long-term therapy with nonspecific
NSAIDs.Drug developers looked to solve this problem by developing
drugs, which were specific to supressing only the COX2 enzyme whilst
preserving the gastric protective effects of COX1. Drugs such as vioox
achieved this outcome, however due to an increased risk of
cardiovascular events it was withdrawn from the market. COX2 is
essential as a defensive response to ischemia as it up regulates
Prostacyclin synthesis, which helps to preserve myocardial blood flow
and helps with prevention of thrombosis during ischemia. This is where
the role of NO started to arise.

Nitric Oxide (NO) which is a source of smog in polluted urban air,

actually has many protective roles in human physiology such as: blood
pressure regulation, innate immune response during pathogen
invasion, chronic infection, neurotransmission and cellular apoptosis.
The addition of a NO releasing moiety to NSAIDs would not impair their
ability to supress cyclooxygenase, and therefore prostaglandin
synthesis, so all of the beneficial effects of the NSAIDs are retained.
The NO released from these derivatives is able to counteract some of
the detrimental effects of COX inhibition and in doing so prevents the
development of mucosal injury, gastritis and potentially cardiovascular
events.
NO works by binding to soluble guanyl cyclase in smooth muscle cells
and via cGMP second messenger cascade which reduces Ca
concentration causing smooth muscle relaxation and hence
vasodilation which counteracts reduction in mucosal blood flow due to
COX1. Also, NO releasing COX2 inhibitors do not significantly affect
systemic blood pressure and does not interfere with antihypertensive.
Increase renal blood flow, GFR and urine production.

NO releasing COX2 inhibitors protects the myocardium by releasing NO

which acts like prostacyclin.
Inhibits platelet aggregation, causes vasodilation, relaxes vascular
smooth muscles and reduces BP

Some NO releasing aspirin derivatives are 5000x more effective

than aspirin. NSAIDs have been suggested to significantly delay
neurodegeneration in alzheimers disease but has limitations due to
GI toxicity. NO releasing NSAIDs have produced beneficial effects in
AD in mouse model.
Better option for patients with existing ulcers, hypertension, GI
related conditions