NSAIDs inhibit the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid

to prostaglandins (PGs) and thromboxane. Two forms of COX have been identified--COX-1, which is
constitutively expressed in most tissues and organs, and the inducible enzyme, COX-2, which has been
localized primarily to inflammatory cells and tissues

What Causes Inflammation and What Are Its Effects?

When inflammation occurs, chemicals from the body's white blood cells are released into
the blood or affected tissues to protect your body from foreign substances. This release of
chemicals increases the blood flow to the area of injury or infection, and may result in
redness and warmth. Some of the chemicals cause a leak of fluid into the tissues, resulting
in swelling. This protective process may stimulate nerves and cause pain.

Signs of an inflammation
:There are five signs that may indicate an acute inflammation

Redness

Heat

Swelling

Pain

Loss of function

https://en.wikipedia.org/wiki/Analgesic

Pain is a distressing feeling often caused by intense or damaging stimuli, such as stubbing a toe,
burning a finger or putting alcohol on a cut. The examples represent respectively the three classes
of nociceptive pain - mechanical, thermal and chemical - and neuropathic pain. Because it is a complex,
subjective phenomenon, defining pain has been a challenge. The International Association for the Study
of Pain's widely used definition states: "Pain is an unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or described in terms of such damage." [1] In medical
diagnosis, pain is asymptom.

In medical parlance, swelling,

is a transient abnormal enlargement of a body part or area not caused by proliferation of cells.[1] It is
caused by accumulation of fluid in tissues.[2] It can occur throughout the body (generalized), or a specific
part or organ can be affected (localized).[2] Swelling is usually not dangerous and is a common reaction to
a inflammation or a bruise.
Traumatic swellings develop immediately after trauma, like a hematoma or dislocation.
Inflammatory swelling may be either acute or chronic. The presentations of acute swellings are redness,
local fever, pain and impairment of function of the affected organ.

An analgesic or painkiller
Is any member of the group of drugs used to achieve analgesia, relief from pain.
Analgesic drugs act in various ways on the peripheral and central nervous systems. They are distinct
from anesthetics, which temporarily affect, and in some instances completely eliminate, sensation.
Analgesics include paracetamol (known in North America as acetaminophen or simply APAP), the
non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, and
opioid drugs such as morphine and oxycodone.

An anesthetic
(anaesthetic or anesthetic in English) is a drug that causes anesthesia, which is a reversible loss of
sensation. Anesthetics contrast with analgesics (painkillers), which relieve pain without eliminating
sensation.

NSAIDs[edit]
Main article: Nonsteroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs (usually abbreviated to NSAIDs), are a drug class that groups
together drugs that provide analgesic (pain-killing) and antipyretic (fever-reducing) effects, and, in higher
doses, anti-inflammatory effects. The most prominent members of this group of
drugs, aspirin, ibuprofen and naproxen, are all available over the counter in most countries.[7] As
analgesics, NSAIDs are unusual in that they are non-narcotic and thus are used as a non-addictive
alternative to narcotics.[citation needed]
Most NSAIDs inhibit the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and
thereby, the synthesis of prostaglandins and thromboxanes. It is thought that inhibiting COX-2 leads to
the anti-inflammatory, analgesic and antipyretic effects and that those NSAIDs also inhibiting COX-1,
particularly aspirin, may cause gastrointestinal bleeding and ulcers. [4]

Mechanism of action[edit]
Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both
the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is
competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism
of aspirin, which is irreversible inhibition.[57] 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. This mechanism of action was elucidated by John
.Vane (19272004), who received a Nobel Prize for his work (see Mechanism of action of aspirin)

COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal
physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective
role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme
facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects
.of NSAIDs
When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach
.prostaglandin levels, ulcers of the stomach or duodenum internal bleedingcan result
NSAIDs have been studied in various assays to understand how they affect each of these enzymes.
While the assays reveal differences, unfortunately different assays provide differing ratios. [58]
The discovery of COX-2 led to research to development of selective COX-2 inhibiting drugs that do not
.cause gastric problems characteristic of older NSAIDs
Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity.
It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of
the body.[3]

COX-2 inhibitors[edit]
Main article: COX-2 inhibitor
These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was
discovered to have at least 2 different versions: COX1 and COX2. Research suggested most of the
adverse effects of NSAIDs to be mediated by blocking the COX1 (constitutive) enzyme, with the
analgesic effects being mediated by the COX2 (inducible) enzyme. Thus, the COX2 inhibitors were
developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These
drugs (such as rofecoxib,celecoxib, and etoricoxib) are equally effective analgesics when compared with
NSAIDs, but cause less gastrointestinal hemorrhage in particular.[8]
After widespread adoption of the COX-2 inhibitors, it was discovered that most of the drugs in this class
increase the risk of cardiovascular events by 40% on average. This led to the withdrawal of rofecoxib
and valdecoxib, and warnings on others. Etoricoxib seems relatively safe, with the risk of thrombotic
events similar to that of non-coxib NSAID diclofenac.[8]

Antipyretic activity[edit]
NSAIDS have antipyretic activity and can be used to treat fever.[60][61] Fever is caused by elevated levels
of prostaglandin E2, which alters the firing rate of neurons within thehypothalamus that control
thermoregulation.[60][62] Antipyretics work by inhibiting the enzyme COX, which causes the general

inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.[60][61] PGE2 signals to the
hypothalamus to increase the body's thermal set point. [61][63] Ibuprofen has been shown more effective as
an antipyretic thanparacetamol (acetaminophen).[62][64] Arachidonic acid is the precursor substrate for
.cyclooxygenase leading to the production of prostaglandins F, D & E

Classification[edit]
NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were
known long before their mechanism of action was elucidated and were for this reason classified by
.chemical structure or origin. Newer substances are more often classified by mechanism of action

Salicylates[edit]

Aspirin (acetylsalicylic acid)

Diflunisal (Dolobid)

Salicylic acid and other salicylates

Salsalate (Disalcid)

Propionic acid derivatives[edit]

Ibuprofen[65]

Dexibuprofen

Naproxen

Fenoprofen

Ketoprofen

Dexketoprofen

Flurbiprofen

Oxaprozin

Loxoprofen

Acetic acid derivatives[edit]

indomethacin

Tolmetin

Sulindac

Etodolac

Ketorolac

Diclofenac

Aceclofenac

Nabumetone (drug itself is non-acidic but the active, principal metabolite has a carboxylic acid
group)

Enolic acid (Oxicam) derivatives[edit]

Piroxicam

Meloxicam

Tenoxicam

Droxicam

Lornoxicam

Isoxicam (withdrawn from market 1985[66][67])

Phenylbutazone (Bute)

Anthranilic acid derivatives (Fenamates)[edit]

The following NSAIDs are derived from fenamic acid. which is a derivative of anthranilic acid,[68]:235 which
in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin.[68]:235[69]:17

Mefenamic acid

Meclofenamic acid

Flufenamic acid

Tolfenamic acid

Selective COX-2 inhibitors (Coxibs)[edit]

Celecoxib (FDA alert[70])

Rofecoxib (withdrawn from market[71])

Valdecoxib (withdrawn from market[72])

Parecoxib FDA withdrawn, licensed in the EU

Lumiracoxib TGA cancelled registration

Etoricoxib not FDA approved, licensed in the EU

Firocoxib used in dogs and horses

Sulfonanilides[edit]

Nimesulide (systemic preparations are banned by several countries for the potential risk of
hepatotoxicity)

Others[edit]

Clonixin

Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX
inhibitor

H-harpagide in Figwort[73] or Devil's Claw[74]

Chirality[edit]
Most NSAIDs are chiral molecules (diclofenac is a notable exception). However, the majority are
prepared in a racemic mixture. Typically, only a single enantiomer is pharmacologically active. For some
drugs (typically profens), an isomerase enzyme in vivo converts the inactive enantiomer into the active
form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor
correlation between NSAID efficacy and plasma concentration observed in older studies, when specific
.analysis of the active enantiomer was not performed

Ibuprofen and ketoprofen are now available in single, active enantiomer preparations (dexibuprofen and
dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has
.always been marketed as the single active enantiomer

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160790/

Carrageenan-induced edema is a standard prostaglandindependent

model of inflammation, in which S-ketoprofen
shows very good inhibitory action
https://www.wikigenes.org/e/chem/e/667550.html