A Textbook of Clinical Pharmacology and Therapeutics

Chapter 33). All NSAIDs cause wheezing in aspirin-sensitive
individuals.
COX-2 inhibitors increase cardiovascular events, limiting
their usefulness. Unfortunately, they were aggressively mar-
keted to elderly people many of whom were not at high risk
for gastro-toxicity and this has led to the withdrawal of agents
that would have been valuable for a more carefully targeted
patient population. It is unclear how much, if any, cardiovas-
cular risk is associated with conventional NSAIDs, but it is
possible that this is, at a maximum, similar to certain COX-2-
selective drugs.
NSAIDs cause hepatitis in some patients. The mechanism
is not understood, but the elderly are particularly susceptible.
Different NSAIDs vary in how commonly they cause this
problem. (Hepatotoxicity was one of the reasons for the with-
drawal of one such drug, benoxaprofen, from the market.)
Aspirin is a recognized cause of hepatitis, particularly in
patients with systemic lupus erythematosus.
Aspirin and ibuprofen are covered in Chapter 25). Other
important NSAIDs are covered below.

INDOMETACIN

Use

Indometacinhas a powerful anti-inflammatory action, but
only a weak analgesic action. It is used to treat rheumatoid
arthritis and associated disorders, ankylosing spondylitis and
acute gout. Adverse effects are common (approximately 25%
of patients).

Adverse effects

Gastric intolerance and toxicity, renal and pulmonary toxici-
ties occur, as with other NSAIDs (see above). Headache is also
common; less often light-headedness, confusion or hallucina-
tions arise.

Pharmacokinetics

Indometacinis readily absorbed by mouth or from supposito-
ries. It undergoes extensive hepatic metabolism. Both the parent
drug and inactive metabolites are excreted in the urine.

Drug interactions

The actions of antihypertensive drugs and diuretics are
opposed by indometacin.Triamterene, in particular, should
be avoided, because of hyperkalaemia.

NAPROXEN

Use

Naproxenis used rheumatic and musculoskeletal diseases,
acute gout and dysmenorrhoea.

Mechanism of action

Naproxenis approximately 20 times as potent an inhibitor of
COX as aspirin. An additional property is inhibition of leuko-
cyte migration, with a potency similar to colchicine.

Adverse effects

Naproxen causes all of the adverse effects common to

NSAIDs.

DISEASE-MODIFYINGANTIRHEUMATICDRUGS 169

Key points

NSAIDs

• Inhibit cyclo-oxygenase (COX).


• Examples include indometacin, naproxen and
  ibuprofen.


• Uses:
  
  
  • short term: analgesia/anti-inflammatory;
  
  
  • chronic: symptomatic relief in arthritis.
  
  
  
  


• Adverse effects:
  
  
  • gastritis and other gastrointestinal
    inflammation/bleeding;
  
  
  • reversible renal impairment (haemodynamic effect);
  
  
  • interstitial nephritis (idiosyncratic);
  
  
  • asthma in ‘aspirin-sensitive’ patients;
  
  
  • hepatitis (idiosyncratic).
  
  
  
  


• Interactions:
  
  
  • antihypertensive drugs (reduced effectiveness);
  
  
  • diuretics: reduced effectiveness
  
  
  
  


• COX-2-selective drugs may have reduced gastric toxicity,
  but increase cardiovascular thrombotic events.

GLUCOCORTICOIDS

Glucocorticoids are discussed in Chapters 40 and 50. Despite

their profound effects on inflammation (they were the original

‘wonder drugs’ of the 1950s), they have such severe long-term

effects that their use is now much more circumscribed.

Prednisoloneis generally preferred for systemic use when a

glucocorticoid is specifically indicated (e.g. for giant-cell arteri-

tis, where steroid treatment prevents blindness). A brief course

of high-dose prednisoloneis usually given to suppress the dis-

ease, followed if possible by dose reduction to a maintenance

dose, given first thing in the morning when endogenous gluco-

corticoids are at their peak. A marker of disease activity, such as

C-reactive protein (CRP), is followed as a guide to dose reduc-

tion. Intra-articular steroid injections are important to reduce

pain and deformity. It is essential to rule out infection before

injecting steroids into a joint, and meticulous aseptic technique

is needed to avoid introducing infection. A suspension of a

poorly soluble drug, such as triamcinolone, is used to give a

long-lasting effect. The patient is warned to avoid over-use of

the joint should the desired improvement materialize, to avoid

joint destruction. Repeated injections can cause joint destruc-

tion and bone necrosis.

DISEASE-MODIFYING ANTIRHEUMATIC

DRUGS

Disease-modifying antirheumatic drugs (DMARDs) are not

analgesic and do not inhibit COX, but they do suppress the