A Textbook of Clinical Pharmacology and Therapeutics

• Stomatitis suggests the possibility of neutropenia.


• Diarrhoea is uncommon, but goldcolitis is life-
  threatening.

Pharmacokinetics

The plasma half-life of goldincreases with repeated adminis-
tration and ranges from one day to several weeks. Goldis
bound to plasma proteins and is concentrated in inflamed
areas. It is excreted in urine and a small amount is lost in the
faeces.Goldcontinues 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 toxi-
city (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

Penicillamineacts by several mechanisms, including metal
ion chelation and dissociation of macroglobulins. It inhibits
release of lysosomal enzymes from cells in inflamed connec-
tive tissue.

Adverse effects

Penicillaminecommonly 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

Penicillamineis contraindicated in patients with systemic
lupus erythematosus, and should be used with caution, if at
all, in individuals with renal or hepatic impairment.

Pharmacokinetics

Penicillamineis well absorbed. A number of hepatic metab-
olites are formed and rapidly excreted renally.

Drug interactions

Penicillamineshould not be used with gold,chloroquineor

immunosuppressive treatment, because of increased toxicity.

It chelates metals and should not be given with iron prepar-

ations for this reason.

HYPERURICAEMIA ANDGOUT 171

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,infliximabandetanercerptare 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

withmethotrexateare 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