Clinical Pharmacology and Therapeutics

CHAPTER 26
ANTI-INFLAMMATORY DRUGS AND
THE TREATMENT OF ARTHRITIS
● Introduction: inflammation 167
● Non-steroidal anti-inflammatory drugs 167
● Glucocorticoids 169
● Disease-modifying antirheumatic drugs 169
● Cytokine (TNF) inhibitors 171
● Hyperuricaemia and gout 171
INTRODUCTION: INFLAMMATION
Inflammation plays a major role in the pathophysiology of a
wide spectrum of diseases. It is primarily a protective
response, but if excessive or inappropriately prolonged can
contribute adversely to the disease process. Consequently
anti-inflammatory drugs are very widely used. Some are safe
enough to be available over the counter, but they are a twoedged
sword and potent anti-inflammatory drugs can have
severe adverse effects.
Inflammatory cells: many different cells are involved in different
stages of different kinds of inflammatory response, including
neutrophils (e.g. in acute bacterial infections), eosinophils,
mast cells and lymphocytes (e.g. in asthma, see Chapter 33),
monocytes, macrophages and lymphocytes (for example, in
autoimmune vasculitic disease, including chronic joint diseases,
such as rheumatoid arthritis and atherothrombosis, where
platelets are also important, see Chapter 27).
Inflammatory mediators: include prostaglandins, complementand
coagulation-cascade-derived peptides, and cytokines (for
example, interleukins, especially IL-2 and IL-6, and tumour
necrosis factor (TNF)). The mediators orchestrate and amplify
the inflammatory cell responses. Anti-inflammatory drugs
work on different aspects of the inflammatory cascade including
the synthesis and action of mediators, and in the case of
immunosuppressants on the amplification of the response (see
Chapter 50).
NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit
prostaglandin biosynthesis by inhibiting cyclo-oxygenase
(COX), see Figure 26.1. This is the basis of most of their therapeutic,
as well as their undesired actions. COX is a key enzyme
in the synthesis of prostaglandins and thromboxanes (see also
Chapters 25 and 30), important medi-ators of the erythema,
oedema, pain and fever of inflammation. There are two main
isoforms of the enzyme, namely a constitutive form (COX-1)
that is present in platelets, stomach, kidneys and other tissues,
and an inducible form, (COX-2), that is expressed in inflamed
tissues as a result of stimulation by cytokines and is also present
to a lesser extent in healthy organs, including the kidneys.
(A third form, COX-3, is a variant of COX-1 of uncertain
importance in humans.) Selective inhibitors of COX-2 were
developed with the potential of reduced gastric toxicity. This
was at least partly realized, but several of these drugs
increased atherothrombotic events, probably as a class effect
related to inhibition of basal prostacyclin biosynthesis.
Use
NSAIDs provide symptomatic relief in acute and chronic
inflammation, but do not improve the course of chronic
inflammatory conditions, such as rheumatoid arthritis as
regards disability and deformity. There is considerable variation
in clinical response. Other types of pain, both mild (e.g.
headaches, dysmenorrhoea, muscular sprains and other soft
tissue injuries) and severe (e.g. pain from metastatic deposits
in bone) may respond to NSAID treatment (Chapter 25).
Aspirin is a special case in that it irreversibly inhibits COX-1
and has a unique role as an antiplatelet drug (Chapters 29 and
30), as well as retaining a place as a mild analgesic in adults.
Adverse effects and interactions common to NSAIDs
The main adverse effects of NSAIDs are predominantly in the
following tissues:
• gastro-intestinal tract: gastritis and gastric mucosal
ulceration and bleeding;
• kidneys: vasoregulatory renal impairment, hyperkalaemia,
nephritis, interstitial nephritis and nephrotic syndrome;
• airways: bronchospasm;
• heart: cardiac failure with fluid retention and myocardial
infarction (COX-2);
• liver: biochemical hepatitis.