Non-Steroidal Anti-inflammatory Drugs

(NSAIDs) and Drugs for the Treatment of

Rheumatoid Disorders

Prof. Erejuwa O. Omotayo

Department of Pharmacology and Therapeutics,
Faculty of Basic Clinical Sciences,
Ebonyi State University

NSAIDs - I
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are also known as non-narcotic or non-opioid analgesics. The
NSAIDs have analgesic, antipyretic and anti-inflammatory actions. Unlike the narcotic analgesics, NSAIDs do
not depress CNS, produce no physical dependence and are not liable to abuse. NSAIDs mostly act on pain
mechanism in the periphery and are mostly over-the-counter (OTC) drugs.

The NSAIDs are classified as follows:

1. NON-SELECTIVE COX INHIBITORS
i. Salicylates: Aspirin.
ii. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
iii. Fenamate: Mephenamic acid.
iv. Enolic acid derivatives: Piroxicam, Tenoxicam
v. Acetic acid derivative: Ketorolac, Indomethacin, Nabumetone
vi. Pyrazolone derivatives : Phenylbutazone, Oxyphenbutazone.

2. COX-2 INHIBITORS

a. PREFERENTIAL COX-2 INHIBITORS

Diclofenac, Meloxicam, Nimesulide, Etodolac, Aceclofenac

b. SELECTIVE COX-2 INHIBITORS

Celecoxib, Etoricoxib, Parecoxib.

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3. COX-3 INHIBITORS (Analgesic-antipyretic with poor anti-inflammatory action)
i. Paraaminophenol derivative: Paracetamol (Acetaminophen)
ii. Pyrazolone derivatives: Metamizol, Propiphenazone.
iii. Benzoxazocine derivative: Nefopam

MECHANISM OF ACTION OF NSAIDs

The NSAIDs inhibit cyclooxygenase (COX) which leads to blockade of prostaglandin synthesis.

BIOSYNTHESIS OF PROSTAGLANDINs
PGs belong to a class of biologically active compounds known as eicosanoids. Other eicosanoids
include thromboxanes (TXs) and leukotrienes (LTs). Most cells are capable of synthesizing one or more of
these eicosanoids. There are no preformed stores of PGs. PGs are synthesized locally from arachidonic acid.
The rate of PG synthesis is dependent on the rate of arachidonic acid release from membrane phospholipids in
response to appropriate chemical and mechanical stimuli which activate phospholipase A2. Following the
releaseof arachidonic acid, it is acted upon by two types of enzymes – COX and lipoxygenase (LOX). The COX
pathway produces PGs, TXs and prostacyclin (PGI2) while the LOX pathway generates LTs. Most tissues have
COX and are capable of generating diverse forms of PGs. PGE2 and PGF2α are the main PGs. While the lung
and spleen can synthesize several of the PGs, the endothelium produces PGI2 which is highly unstable and
converts to 6-keto PGF1α. The platelets synthesize TXA2 (due to its instability) which changes to TXB2.

The COX exists in 3 isoforms: COX-1, COX-2, and COX-3. These isoforms catalyse the same
reactions. COX-1 is constitutive. That is, it is synthesized and active in the basal state and its level does not
change much once the cell is fully grown. The PGs generated by COX-1 plays important physiological ‘house-
keeping’ functions. These include gastric mucosal protection, maintenance of renal function and haemostasis.

On the other hand, COX-2 (usually present in small amounts) is inducible. The COX-2 is induced by
cytokines, growth factors, and other signal molecules or stimuli at the site of inflammation. This leads to
production of PGs which mediate several of the inflammatory responses. It is generally believed that
eicosanoids generated by COX-2 play predominant roles in inflammatory and other pathological changes. It
should be noted that COX-2 is constitutively present in the brain, kidney and foetus where it may serve
physiological role at these sites

COX-3 is predominantly found in canine and human cerebral cortex. Prostaglandins produced by COX-
3 mediate predominantly pain and fever. COX-3 activity is selectively inhibited by paracetamol as well as a few

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other analgesic and antipyretic NSAIDs.

The LOX pathway, which occurs primarily in the lungs, white blood cells and platelets, generates LTs
such as LTB4, LTC4 and LTD4. These LTs constitute the ‘slow reacting substance of anaphylaxis’ (SRS-A)
released during anaphylaxis.

INHIBITION OF SYNTHESIS OF PGs

Majority of the NSAIDs inhibit COX-1 and COX-2 non-selectively. With advances in research,
selective COX-2 inhibitors are now available. The selective COX-2 inhibitors have 2 major advantages over
non-selective COX-1/COX-2 inhibitors. These include lack of antiplatelet aggregatory and gastric mucosal
damaging effects. Most traditional NSAIDs are competitive and reversible inhibitors of COX. The COX
activity is restored following dissociation of NSAID from COX which is influenced by the pharmacokinetic
property of the drug. On the other hand, aspirin exerts an irreversible inhibitory effect on COX. Therefore, the
restoration or return of COX activity depends on the synthesis of new COX. NSAIDs do not inhibit the
generation of LTs and may even increase it since all of the arachidonic acid will be diverted to the LOX
pathway. Glucocorticosteroids inhibit phospholipase A2 leading to inhibition of arachidonic acid release from
membrane lipids. This invariably results in decreased generation of all eicosanoids (PGs, TXs and LTs).
Glucocorticosteroids also inhibit the induction of COX-2 by cytokines at the site of inflammation.

PHARMACOLOGICAL EFFECTS OF NSAIDs

1. ANALGESIC EFFECT
PGs have a highly sensitizing effect on free nerve endings. This leads to hyperalgesia whereby stimuli that
usually should not have elicited pain are able to do so. NSAIDs block the hyperalgesic effect and various pain
sensitizing mechanisms of PGs, bradykinin, interleukins (ILs), tumor necrosis tumor-alpha (TNF-α) and other
algesic substances via inhibition of COX-2. The inhibition of COX-2 is the main mechanism of action leading
to analgesic effect of NSAIDs. They are generally effective in the treatment of pain associated with
inflammation.

2. ANTIPYRETIC EFFECT
Infections and tissue injuries are usually accompanied by fever. Fever results from the generation of pyrogens
such as ILs, interferons and TNF-α which stimulate the formation of PGs E2 in the hypothalamus leading
increased temperature threshold. NSAIDs block the action of pyrogens. It should be noted that fever can also
occur via other mechanisms that are not connected to PG pathway.

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3. ANTI-INFLAMMATORY EFFECT
NSAIDs exerts anti-inflammatory effect through inhibition of COX (primarily COX-2 and to a less extent
COX- 1) which reduces production of PGs at the injury or inflammation site. Generally, inflammation is a
consequence of activity of several mediators, of which PGs are just one of them. Other inflammatory mediators
include leukotrienes, cytokines and platelet activating factor. Therefore, administration of NSAIDs alone may
not be sufficient to ameliorate inflammation completely.

4. ANTI-PLATELET AGGREGATORY EFFECT

NSAIDs inhibit the synthesis of platelet thromboxane A2 through inhibition of COX-1. This leads to inhibition
of platelet aggregation resulting in prolongation of bleeding time. Aspirin is highly active and it irreverisibly
inhibits platelet COX. Small doses of aspirin are therefore able to exert antithrombotic effect for several days.
Risk of anticoagulant-associated bleeding may be enhanced.

5. ANTI-DYSMENORRHOEIC EFFECT

PGs play a predominant role in dysmenorrhoea. Women suffering from dysmenorrhoea have elevated levels of
PGs in menstrual flow, endometrial biopsy and PG metabolites in circulation. Administration of NSAIDs
reduces the levels of uterine PGs and provides relief in many patients.

6. CLOSURE OF DUCTUS ARTERIOSUS

PGE2, which is synthesized via COX-2, plays an important role in the maintenance of patency of ductus
arteriosus during foetal circulation. At birth, through unknown mechanisms, PGE2 synthesis stops and the
ductus closes. However, in some cases, the ductus fails to close and small doses of aspirin or indomethacin are
administered. In many instances, by inhibiting PG production, the ductus closes within few hours.
Administration of NSAIDs should be avoided in late pregnancy or near term in order to avoid premature closure
of ductus or risk of post-partum haemorrhage.

7. PARTURITION

A sudden burst in uterine PG synthesis usually occurs prior to commencement of labour. This is believed to
trigger and enhance the progression of labour. NSAIDs are usually administered to delay labour though labour
can still take place in the absence of PGs.