A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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CHAPTER 26<br />
ANTI-INFLAMMATORY DRUGS AND<br />
THE TREATMENT OF ARTHRITIS<br />
● Introduction: inflammation 167<br />
● Non-steroidal anti-inflammatory drugs 167<br />
● Glucocorticoids 169<br />
● Disease-modifying antirheumatic drugs 169<br />
● Cytokine (TNF) inhibitors 171<br />
● Hyperuricaemia <strong>and</strong> gout 171<br />
INTRODUCTION: INFLAMMATION<br />
Inflammation plays a major role in the pathophysiology <strong>of</strong> a<br />
wide spectrum <strong>of</strong> diseases. It is primarily a protective<br />
response, but if excessive or inappropriately prolonged can<br />
contribute adversely to the disease process. Consequently<br />
anti-inflammatory drugs are very widely used. Some are safe<br />
enough to be available over the counter, but they are a twoedged<br />
sword <strong>and</strong> potent anti-inflammatory drugs can have<br />
severe adverse effects.<br />
Inflammatory cells: many different cells are involved in different<br />
stages <strong>of</strong> different kinds <strong>of</strong> inflammatory response, including<br />
neutrophils (e.g. in acute bacterial infections), eosinophils,<br />
mast cells <strong>and</strong> lymphocytes (e.g. in asthma, see Chapter 33),<br />
monocytes, macrophages <strong>and</strong> lymphocytes (for example, in<br />
autoimmune vasculitic disease, including chronic joint diseases,<br />
such as rheumatoid arthritis <strong>and</strong> atherothrombosis, where<br />
platelets are also important, see Chapter 27).<br />
Inflammatory mediators: include prostagl<strong>and</strong>ins, complement<strong>and</strong><br />
coagulation-cascade-derived peptides, <strong>and</strong> cytokines (for<br />
example, interleukins, especially IL-2 <strong>and</strong> IL-6, <strong>and</strong> tumour<br />
necrosis factor (TNF)). The mediators orchestrate <strong>and</strong> amplify<br />
the inflammatory cell responses. Anti-inflammatory drugs<br />
work on different aspects <strong>of</strong> the inflammatory cascade including<br />
the synthesis <strong>and</strong> action <strong>of</strong> mediators, <strong>and</strong> in the case <strong>of</strong><br />
immunosuppressants on the amplification <strong>of</strong> the response (see<br />
Chapter 50).<br />
NON-STEROIDAL ANTI-INFLAMMATORY<br />
DRUGS<br />
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit<br />
prostagl<strong>and</strong>in biosynthesis by inhibiting cyclo-oxygenase<br />
(COX), see Figure 26.1. This is the basis <strong>of</strong> most <strong>of</strong> their therapeutic,<br />
as well as their undesired actions. COX is a key enzyme<br />
in the synthesis <strong>of</strong> prostagl<strong>and</strong>ins <strong>and</strong> thromboxanes (see also<br />
Chapters 25 <strong>and</strong> 30), important medi-ators <strong>of</strong> the erythema,<br />
oedema, pain <strong>and</strong> fever <strong>of</strong> inflammation. There are two main<br />
is<strong>of</strong>orms <strong>of</strong> the enzyme, namely a constitutive form (COX-1)<br />
that is present in platelets, stomach, kidneys <strong>and</strong> other tissues,<br />
<strong>and</strong> an inducible form, (COX-2), that is expressed in inflamed<br />
tissues as a result <strong>of</strong> stimulation by cytokines <strong>and</strong> is also present<br />
to a lesser extent in healthy organs, including the kidneys.<br />
(A third form, COX-3, is a variant <strong>of</strong> COX-1 <strong>of</strong> uncertain<br />
importance in humans.) Selective inhibitors <strong>of</strong> COX-2 were<br />
developed with the potential <strong>of</strong> reduced gastric toxicity. This<br />
was at least partly realized, but several <strong>of</strong> these drugs<br />
increased atherothrombotic events, probably as a class effect<br />
related to inhibition <strong>of</strong> basal prostacyclin biosynthesis.<br />
Use<br />
NSAIDs provide symptomatic relief in acute <strong>and</strong> chronic<br />
inflammation, but do not improve the course <strong>of</strong> chronic<br />
inflammatory conditions, such as rheumatoid arthritis as<br />
regards disability <strong>and</strong> deformity. There is considerable variation<br />
in clinical response. Other types <strong>of</strong> pain, both mild (e.g.<br />
headaches, dysmenorrhoea, muscular sprains <strong>and</strong> other s<strong>of</strong>t<br />
tissue injuries) <strong>and</strong> severe (e.g. pain from metastatic deposits<br />
in bone) may respond to NSAID treatment (Chapter 25).<br />
Aspirin is a special case in that it irreversibly inhibits COX-1<br />
<strong>and</strong> has a unique role as an antiplatelet drug (Chapters 29 <strong>and</strong><br />
30), as well as retaining a place as a mild analgesic in adults.<br />
Adverse effects <strong>and</strong> interactions common to NSAIDs<br />
The main adverse effects <strong>of</strong> NSAIDs are predominantly in the<br />
following tissues:<br />
• gastro-intestinal tract: gastritis <strong>and</strong> gastric mucosal<br />
ulceration <strong>and</strong> bleeding;<br />
• kidneys: vasoregulatory renal impairment, hyperkalaemia,<br />
nephritis, interstitial nephritis <strong>and</strong> nephrotic syndrome;<br />
• airways: bronchospasm;<br />
• heart: cardiac failure with fluid retention <strong>and</strong> myocardial<br />
infarction (COX-2);<br />
• liver: biochemical hepatitis.