Penicillamine adverse effects

Several studies have shown an increased frequency of penicillamine adverse effects in patients with low sulfoxidation activity, especially with regard to proteinuria and probably thrombocytopenia and myasthenia gravis (SED-12, 547) (3,196,387,388). The sulfoxidation capacity is expressed as the sulfoxidation index, calculated as the percentage of administered 5-carboxymethyl-L-cysteine (750 mg), excreted as sulfoxides in the urine in 8 hours. A sulfoxidation index above 6% is taken as indicative of relative impairment of sulfoxidation capacity. 

A number of review articles (la—7) accentuate both the efficacy and the toxicity of penicillamine, adverse effects leading to drug withdrawal in approximately one third of the patients. Helmke et al. (20 ) conclude that adverse reactions to penicillamine — especially renal complications — are particularly likely to occur in patients with a positive ANF test (either before or during penicillamine treatment). 

Penicillamine (29) can be effective in patients with refractory RA and may delay progression of erosions, but adverse effects limit its useflilness. The most common adverse side effects for penicillamine are similar to those of parenteral gold therapy, ie, pmritic rash, protein uria, leukopenia, and thrombocytopenia. Decreased or altered taste sensation is a relatively common adverse effect for penicillamine. A monthly blood count, platelet count, and urinalysis are recommended, and also hepatic and renal function should be periodically monitored. Penicillamine is teratogenic and should not be used during pregnancy. 

Penicillamine onset may be seen in 1 to 3 months, and most responses occur within 6 months. Early adverse effects include skin rash, metallic taste, hypogeusia, stomatitis, anorexia, nausea, vomiting, and dyspepsia. Glomerulonephritis may occur, which manifests as proteinuria and hematuria. Penicillamine is usually reserved for patients who are resistant to other therapies because of the rare but potentially serious induction of autoimmune diseases (e.g., Goodpasture s syndrome, myasthenia gravis). 

Netter, P. et al., Adverse effects of D-penicillamine. A cooperative study by the French regional drug surveillance centers, J. Rheumatol., 15, 1730, 1988. 

With the combination of traditional DMARDs complete remissions are obtained in 30% of early RA over a period of 5 years. These remissions last on average less than 10 months. After 5 years only half of the patients continue with MTX and less than 25% stay on other DMARDs. After 5 years non-compliance is mostly due to adverse effects and lack of efficacy of NSAIDs, hydroxychloroquine, sulfasalazine, prednisone, d-penicillamine, azafhio-prine, and gold salts. Only MTX retains some efficacy. With these therapeutic modalities joint erosions progress to permanent joint destruction, deformities and disability. 

For patients who are unable to tolerate penicillamine, trientine, another chelating agent, may be used in a daily dose of 1-1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Zinc acetate administered orally increases the fecal excretion of copper and is sometimes used for maintenance therapy. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. 

Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (see Chapter 36). Its ability to increase urinary excretion of lead and mercury had occasioned its use in outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower adverse-effect profile, has generally replaced penicillamine for these purposes. 

Adverse Side Effects. Penicillamine is considered to be fairly toxic when compared with other DMARDs.68 Side effects that have been reported as occurring more frequently include fever, joint pain, skin rashes and itching, and swelling of lymph glands. Other adverse effects that may occur less frequently... 

Adverse effects are frequent. Patients may experience gastrointestinal upset, and dose-related impairment of taste is common. Thrombocytopenia is frequent but resolves when the drug is withdrawn unless it indicates the more serious aplastic anaemia which may also occur. Allergic reactions (rashes, fever) tend to occur during the early stages of treatment. Proteinuria, if it is heavy, is a reason for stopping penicillamine for it may herald the development of the nephrotic syndrome. 

This effect, attributed here to bucillamine, is a rare but well-established adverse effect of penicillamine. Although the patient had also taken isoniazid for pulmonary tuberculosis, that was unlikely to have played a part, since the breast enlargement started earlier and progressed after the isoniazid had been withdrawn. 

Patients with rheumatoid arthritis and poor sulfoxidation state are six times more susceptible than others to the adverse effects of sodium aurothiomalate (80). This parallels an earlier similar finding with penicillamine, which has the same sulfhydryl group in its structure. 

In clinical trials about 50% of patients experienced one or more adverse effects and withdrawal was necessary in about one-third (22-26). A mucocutaneous reaction (for example a rash or stomatitis) is the most frequent reason for discontinuing the drug (27). Long-term follow-up studies have shown that many patients (up to 80%) stop taking penicillamine, either because of adverse effects or lack of efficacy (27-31). 

Table 1 Adverse effects leading to the withdrawal of penicillamine in two studies...

Stomatitis is a troublesome adverse effect of DMARDs. Ulcers of the oral mucosa are not uncommon in patients taking penicillamine (188,173) and lead to withdrawal in 3.1% of patients (174). However, stomatitis may be a consequence of multiple factors, including hematinic deficiency, virus or Candida infection, recurrent aphthous ulceration, or Sjogren s syndrome. Moreover, aphthous stomatitis often occurs in users of non-steroidal antiinflammatory drugs (175). 

In one study in children with low-level lead poisoning, urinary incontinence was mentioned as a suspected adverse effect of penicillamine (239). 

Monosymptomatic nail changes, with longitudinal ridging, transverse or longitudinal defects of the nail plate, absence of lunulae, and a tendency toward onychoschizia, can also occur as adverse effects of penicillamine (326). 

In a long-term prospective study of 69 patients taking penicillamine (750 mg/day) for progressive systemic sclerosis, 27 had adverse effects requiring either temporary reduction or complete withdrawal of therapy. Five of these had two, or, in one case, three different reactions (115). 

Although published experience in children is limited, penicillamine has the same pattern of adverse effects as in adults. However, an interesting difference is that taste dysfunction has so far not been reported in children (SED-10, 221) (SEDA-14, 198). In two children with Wilson s disease, penicillamine was thought to have caused persistence of a pre-existing increase in amintran-sase activity (187). 

Iron compounds reduce the systemic availability of penicillamine to about 35% and copper excretion to about 28%, probably as a result of catalysis of the oxidation of penicillamine to its disulfide (2,398,400). Even the iron present in certain multivitamin formulations can be sufficient to cause interference, and when a patient who has regularly taken iron stops taking it, increased absorption of penicillamine and adverse effects can ensue (401,402). 

Shannon MW, Townsend MK. Adverse effects of reduced-dose d-penicillamine in children with mild-to-moderate lead poisoning. Ann Pharmacother 2000 34(1) 15-18. 

Stein HB, Patterson AC, Offer RC, Atkins CJ, Teufel A, Robinson HS. Adverse effects of D-penicillamine in rheumatoid arthritis. Ann Intern Med 1980 92(l) 24-9. 

Cross-aUergy with D-penicillamine has been hypothesized to explain the apparently higher frequency of adverse effects of pyritinol in patients with rheumatoid arthritis (1). 

The adverse effects of stepronin, a sulfhydryl compound, which is used in rheumatoid arthritis, are similar to those of penicillamine. In a long-term open study, treatment had to be interrupted in 30% of 36 patients because of severe adverse effects (1). Seven patients had mucocutaneous reactions (dermatitis, pruritus, stomatitis, glossitis, ageusia), three proteinuria, and one thrombocytopenia and leukopenia. 

In 69 patients with rheumatoid arthritis, tiopronin 1500 mg/day was as effective as penicillamine (2). The adverse effects of the two drugs were similar. Tiopronin was associated with obstructive bronchiolitis in one case. There was little cross-intolerance the same unwanted effect was only observed in four cases one of pemphigus, one of toxic dermatitis, and two instances of proteinuria. 

In 66 patients with cystinuria, adverse reactions to tiopronin (mean dose 1193 mg/day) were common, and occurred in 76% of the patients with a history of D-penicillamine treatment and 65% of those without a history of D-penicillamine treatment, compared with 84% who had adverse effects with D-penicillamine (3). Serious adverse reactions requiring drug withdrawal were less common with tiopronin. Among the patients who took both drugs 31% had to stop taking tiopronin, whereas 69% could not tolerate D-penicillamine. 

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