Clinical Pharmacology and Therapeutics

HYPERURICAEMIA AND GOUT 171
• Stomatitis suggests the possibility of neutropenia.
• Diarrhoea is uncommon, but gold colitis is lifethreatening.
Pharmacokinetics
The plasma half-life of gold increases with repeated administration
and ranges from one day to several weeks. Gold is
bound to plasma proteins and is concentrated in inflamed
areas. It is excreted in urine and a small amount is lost in the
faeces. Gold continues to be excreted in the urine for up to one
year after a course of treatment.
PENCILLAMINE
Use
Penicillamine is a breakdown product of penicillin.
Penicillamine should only be used by clinicians with experience
of the drug and with meticulous monitoring, because of its toxicity
(see below). Its effect in rheumatoid arthritis is similar to
gold. Clinical improvement is anticipated only after 6–12 weeks.
Treatment is discontinued if there is no improvement within one
year. If improvement occurs, the dose is gradually reduced to
the minimum effective maintenance dose. Full blood count and
urine protein determination are performed regularly, initially
weekly and then monthly during maintenance treatment.
Mechanism of action
Penicillamine acts by several mechanisms, including metal
ion chelation and dissociation of macroglobulins. It inhibits
release of lysosomal enzymes from cells in inflamed connective
tissue.
Adverse effects
Penicillamine commonly causes taste disturbance, anorexia
and weight loss. Other effects are more serious, and are more
common in patients with poor sulphoxidation.
• Bone marrow hypoplasia, thrombocytopenia and
leukopenia can be fatal. They are indications to stop
treatment.
• Immune-complex glomerulonephritis causes mild
proteinuria in 30% of patients. The drug should be
stopped until proteinuria resolves and treatment then
resumed at a lower dose. Heavy proteinuria is an
indication to stop treatment permanently.
• Other symptoms include hypersensitivity reactions with
urticaria.
• Systemic lupus erythematosus-like and myasthenia
gravis-like syndromes can also be involved.
Contraindications
Penicillamine is contraindicated in patients with systemic
lupus erythematosus, and should be used with caution, if at
all, in individuals with renal or hepatic impairment.
Pharmacokinetics
Penicillamine is well absorbed. A number of hepatic metabolites
are formed and rapidly excreted renally.
Drug interactions
Penicillamine should not be used with gold, chloroquine or
immunosuppressive treatment, because of increased toxicity.
It chelates metals and should not be given with iron preparations
for this reason.
Key points
Disease-modifying antirheumatic drugs (DMARDs)
• Mechanisms are poorly understood; these drugs are
often licensed for indications other than arthritis.
Examples include:
– methotrexate;
– sulfasalazine;
– gold;
– D-penicillamine;
– hydroxychloroquine;
– cytokine (TNF) inhibitors.
• Uses: these drugs are used by rheumatologists to treat
patients with progressive rheumatoid or psoriatic
arthritis. A trial should be considered before a patient
becomes disabled.
• All of these drugs can have severe adverse effects, and
informed consent should be obtained before they are
prescribed (especially those that are unlicensed for this
indication).
• Their action is slow in onset.
• In contrast to NSAIDs, these drugs:
– reduce erythrocyte sedimentation rate (ESR);
– retard progression of bony erosions on x-ray.
• Close monitoring for toxicity (blood counts,
urinalysis and serum chemistry) is essential.
CYTOKINE (TNF) INHIBITORS
Adalimumab, infliximab and etanercerpt are all engineered
proteins which directly or indirectly inhibit tumour necrosis
factor (TNF) signaling, by various mechanisms (blockade of
TNF receptors or binding to, and hence inactivating, circulating
TNF). They are a major advance in treating various immune
diseases (see Chapter 50), including rheumatoid arthritis, but
have serious adverse effects, including infusion reactions and
reactivation of tuberculosis. Increased risk of malignancy is a
theoretical concern. They are currently used by rheumatologists
for adults with active disease which has not responded to two
standard DMARD drugs, usually including methotrexate
(Chapter 48). They are not continued if a response has not
occurred within three months. Combinations of these proteins
with methotrexate are being investigated for refractory disease,
with encouraging results.
HYPERURICAEMIA AND GOUT
Uric acid is the end-product of purine metabolism in humans
and gives rise to problems because of its limited solubility.
Crystals of uric acid evoke a severe inflammatory response