A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS 169
Chapter 33). All NSAIDs cause wheezing in aspirin-sensitive
individuals.
COX-2 inhibitors increase cardiovascular events, limiting
their usefulness. Unfortunately, they were aggressively marketed
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, cardiovascular
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 withdrawal
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
Indometacin has 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 toxicities
occur, as with other NSAIDs (see above). Headache is also
common; less often light-headedness, confusion or hallucinations
arise.
Pharmacokinetics
Indometacin is readily absorbed by mouth or from suppositories.
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
Naproxen is used rheumatic and musculoskeletal diseases,
acute gout and dysmenorrhoea.
Mechanism of action
Naproxen is approximately 20 times as potent an inhibitor of
COX as aspirin. An additional property is inhibition of leukocyte
migration, with a potency similar to colchicine.
Adverse effects
Naproxen causes all of the adverse effects common to
NSAIDs.
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.
Prednisolone is generally preferred for systemic use when a
glucocorticoid is specifically indicated (e.g. for giant-cell arteritis,
where steroid treatment prevents blindness). A brief course
of high-dose prednisolone is usually given to suppress the disease,
followed if possible by dose reduction to a maintenance
dose, given first thing in the morning when endogenous glucocorticoids
are at their peak. A marker of disease activity, such as
C-reactive protein (CRP), is followed as a guide to dose reduction.
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 destruction
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