Penicillamine

Pharmacokinetics

After oral administration about two-thirds (50–70%) of a dose of penicillamine is absorbed. As much as 33% can be degraded in the gut before absorption can take place. With a half-life of less than 1 hour, penicillamine is rapidly cleared after oral administration, largely by formation of disulfides with plasma albumin and with low-molecular weight thiols, such as cysteine and glutathione. Low-molecular weight disulfides constitute the major urinary metabolites. The penicillamine-albumin disulfide, on the other hand, has a long half-life. The consequence of this is slow accumulation: in healthy volunteers pseudo-steady-state plasma concentrations of penicillamine–albumin disulfide are not reached until the second week of daily administration. Peak plasma concentrations of penicillamine occur at 1.5–4 hours after ingestion and range from 5 μmol/l after 150 mg to 28 μmol/l after 800 mg (when conventional-release oral formulations are used). About 80% of penicillamine is protein-bound; about 7% occurs as l -cysteine- d -penicillamine disulfide, 5% as penicillamine disulfide, and 6% as free penicillamine. A large proportion is rapidly excreted in the urine, mainly as the disulfide or as the disulfide metabolite conjugated with cysteine; formation and excretion of the latter can cause cysteine depletion. Some penicillamine is converted to S-methyl-penicillamine and is either excreted by the kidneys or metabolized in the liver. Although S-methylation is a quantitatively minor elimination pathway, S-methyl-penicillamine is a potential substrate for sulfoxide formation, and patients with rheumatoid arthritis who form the sulfoxide at a reduced rate are at greater risk of adverse reactions [ ]. The concentrations of penicillamine and its metabolites within cells and at the cell surface are largely unknown, but may be relevant to variability in response in regard to cellular sites of action.

Uses

General adverse effects and adverse reactions

In clinical trials about 50% of patients experienced one or more adverse reactions and withdrawal was necessary in about one-third [ ].Long-term follow-up studies have shown that many patients (up to 80%) stop taking penicillamine, either because of lack of efficacy or adverse reactions [ ], most commonly because of mucocutaneous reactions (for example a rash or stomatitis) [ ].

Adverse reactions are less common when small doses are used, when increments are made only slowly, when patients are closely monitored, and when penicillamine has been tolerated for some years. However, in a meta-analysis of a large series of clinical trials, dose was not a strong determinant of the risk of adverse reactions (dose range 500–1250 mg/day) [ ]. With regard to the safe use of penicillamine the words of Huskisson are still true [ ]: “Perhaps the most important aspect of the surveillance of patients receiving penicillamine is the need for the physician and patient to be able to contact each other. The physician must find the patient if his blood count changes. The patient must find the physician if he becomes ill. Disasters have occurred when patients consulted physicians who were unaware of the problems of penicillamine and instituted unwise therapy for them. Penicillamine can only be used by those who know how to use it and skilful management [of adverse reactions] is a most important aspect, perhaps the most important aspect of the treatment.”

In patients with rheumatoid arthritis, delayed disease complications or serious intercurrent disorders can be mistaken for complications of treatment with penicillamine or other drugs [ ]. Anyone responsible for a patient taking penicillamine must bear in mind that serious adverse reactions can occur suddenly and at any time during treatment, even with very small doses (as low as 125 mg/day) and after many years. Penicillamine can be the unexpected cause of serious adverse reactions as an additive to Chinese herbs [ ].

Early effects are gastrointestinal upsets and, more characteristically, loss of taste. Although a fall in the number of platelets is common, serious thrombocytopenia is less frequent. After long-term use of high doses, skin collagen and elastin are impaired, resulting in increased friability and sometimes in disorders such as perforating elastoma or cutis laxa; the latter has also been observed in neonates.

Hypersensitivity reactions are frequent early in a course of penicillamine, with urticarial or maculopapular rashes, fever, and lymphadenopathy. Cross-allergy to penicillin can occur. In addition, the use of penicillamine can be complicated by a unique variety of often serious autoimmune reactions, involving the skin, kidneys, liver, lungs, muscles, or other organs. Proteinuria is found in more than 10% of patients and sometimes develops into the nephrotic syndrome. Pemphigus, myasthenia gravis, polymyositis, or a lupus-like syndrome occur in smaller percentages. Reactions such as aplastic anemia, Goodpasture's syndrome, and thrombotic thrombocytopenic purpura (Moschcowitz’s syndrome) are rare but serious.

Although lymphatic malignancies have been described in a few patients using penicillamine [ ], a causal relation is considered unlikely.

Observational studies

In an Austrian study, patients with rheumatoid arthritis were followed for a mean of 10 years [ ]. Of 27 courses of penicillamine, 13 were discontinued because of adverse reactions, 12 because of lack of effectiveness, and 2 because of remission. Furthermore, an analysis of the reasons for DMARD withdrawal in patients in the Czech and Slovak Republics has underlined the fact that lack of effectiveness is, in addition to adverse reactions, an important reason for stopping penicillamine [ ].

Long-term follow-up data in 88 children with Wilson's disease, including 43 taking penicillamine, have been reported [ ]. The drug was withdrawn in seven cases because of adverse reactions: bone marrow suppression in three, hematuria in two, a rash in one, and hemolytic anemia in one. Hemolytic anemia is a poorly documented adverse effect of penicillamine, and it is unfortunate that in this case no details were given. In three more children with adverse reactions the drug was continued; two had a rash and one drowsiness.

In a trial in 15 preterm neonates daily enteral penicillamine (in a locally produced formulation, dose not specified) for 2 weeks after birth eliminated stages I and II retinopathy of prematurity but not of laser surgery [ ]. There were no adverse reactions in these babies.

The finding that penicillamine in high doses, as used in Wilson's disease, reduces total skin collagen, has prompted a trial in diffuse cutaneous systemic sclerosis. In a retrospective analysis of 84 patients with recent onset progressive disease penicillamine, median dose 750 mg/day for at least 3 months, caused significant reduction in skin disease and improvement of renal, cardiac, and pulmonary involvement [ ]. At the last follow-up, 20% of the patients were still taking penicillamine, 30% had stopped because of disease improvement, and 21% had stopped because of adverse reactions, showing the familiar pattern of proteinuria (n = 7), rash (n = 4), neutropenia (n = 3), and pemphigus (n = 2). In addition, 23% had died, mainly from complications of the disease. Four patients were lost to follow-up.

Combinations with other drugs used in rheumatoid arthritis

Adding chloroquine or hydroxychloroquine to penicillamine in the management of rheumatoid arthritis probably offers no therapeutic advantages, produces more adverse reactions, and may even be less effective [ ]. A combination of penicillamine and sulfasalazine seems to be more effective, although the extent of the advantage is uncertain, and adverse reactions may be more frequent [ ]. In one study penicillamine and intramuscular gold together produced much earlier improvement, but efficacy and adverse reactions did not differ significantly compared with either drug alone.

In an open, uncontrolled study, the combination of penicillamine and intramuscular gold yielded the highest proportion of remissions in patients with refractory rheumatoid arthritis [ ]. The possible consequences of previous intolerance to gold compounds in association with adverse reactions to penicillamine administration have been reviewed [ , ]; at present no firm conclusions can be made. Penicillamine does not chelate gold stores in the body.

Comparative studies

Penicillamine 600–1800 mg/day (n = 23) and zinc sulfate (n = 12) have been compared in Wilson's disease [ ]. Neuropsychiatric symptoms became worse or remained unchanged in 75% of the patients who received penicillamine, whereas zinc sulfate improved these symptoms in 90% of patients. In six patients penicillamine was withdrawn because of adverse reactions: proteinuria and microhematuria in two, high titers of antinuclear antibodies or a lupus-like syndrome in three, and amenorrhea in one. The drugs were equally effective in improving liver involvement and there were no differences in follow-up hepatic copper contents.

Comparisons with other drugs used in rheumatoid arthritis

In an outpatient study in New Zealand, the changing patterns were studied in the use of “slow-acting” antirheumatic drugs [ ]. There were increases in the use of methotrexate and of drugs in combination, whereas there was a marked reduction in the use of auranofin. Penicillamine had the highest “average toxicity” score. However, despite the increased popularity of sulfasalazine and immunosuppressive drugs, drugs such as penicillamine continue to be used worldwide. In a long-term follow-up study, the proportion of patients who continued to take their first DMARD or who were in remission at 5 years was 53% for penicillamine, compared with 34% for aurothiomalate, 31% for auranofin, and 30% for hydroxychloroquine [ ]. Of the 179 patients who used penicillamine, 36 stopped taking it because of adverse reactions (see Table 1 ). In an open, randomized, follow-up study of patients with rheumatoid arthritis, 98 were allocated to penicillamine (median daily dose 750 mg, range 375–1000 mg) and 102 to sulfasalazine [ ]. Over follow-up for 12 years as many as 95 patients (48%) died, four from peptic ulcer disease complications, illustrating the prevalence of premature mortality in patients with rheumatoid arthritis. Only 4 of the 98 patients continued to take penicillamine. Major reasons for withdrawal of penicillamine, other than death, were adverse effects (n = 47) and lack or loss of effect (n = 36) (see Table 1 ). In neither study was any of the deaths thought to have been related to penicillamine.

A diagnostic and monitoring database program called DIAMOND runs across a network of personal computers throughout the Staffordshire Rheumatology Centre [ ]. For about 10 years, drug histories, blood test results, and clinical correspondence files for about 2000 patients have been accessible, and the system is linked to the main hospital pathology database. The DIAMOND system has been used to study adverse reactions and durations of treatment for commonly prescribed DMARDs, including penicillamine (combination treatments excluded). With a median survival time of 34 months, penicillamine held an intermediate position, between methotrexate (< 96 months) and azathioprine (13 months) at the extremes; 38% of the patients continued to take penicillamine after 5 years. There were strong associations between penicillamine and both proteinuria and thrombocytopenia, both well-established adverse effects of penicillamine. Myasthenia gravis occurred in eight of 582 penicillamine users (1.4%) and not in patients using other DMARDs.

Systematic reviews

The Cochrane Hepato-Biliary Group in Copenhagen have reported a meta-analysis of the benefit to harm balance of penicillamine in primary biliary cirrhosis, encompassing 7 clinical trials and 706 patients [ ]. In the penicillamine group there was a four-fold increase in adverse events, often serious adverse reactions characteristic of penicillamine, while there was no beneficial effect on hard end-points. Although the treatment group had significantly reduced serum alanine aminotransferase activity, there were no differences in other liver tests, nor in pruritus, fatigue, liver complications, progression of liver histological stage, liver transplantation, or mortality.

Cardiovascular

Penicillamine has no direct effect on the cardiovascular system. However, penicillamine-associated polymyositis can involve cardiac muscle and cause dysrhythmias, Adams–Stokes attacks, and death. Necrotizing vasculitis can occur as an immunological reaction to penicillamine [ ]. The effect of penicillamine on collagen and elastin fibers, which causes characteristic skin lesions, also includes the vascular wall, but effects of vascular insufficiency have not been reported.

Respiratory

Although penicillamine has no direct pharmacological effects on the lungs [ ], its use is associated with a spectrum of pulmonary adverse reactions: interstitial and alveolar reactions, pulmonary fibrosis, bronchiolitis obliterans, and pulmonary/renal syndromes [ ]. However, the differentiation between drug reactions and pulmonary disorders secondary to rheumatic or other underlying diseases is often difficult. The clinical presentation of bronchiolitis obliterans is acute, with cough, shortness of breath, and other non-specific respiratory complaints. The prognosis is often poor. Two separable but overlapping groups have been described: acute and chronic cellular bronchiolitis with less conspicuous scarring, and constrictive bronchiolitis, with histology varying from fibrotic and inflammatory lesions to complete small airway obliteration [ ].

In addition, several autoimmune reactions to penicillamine can secondarily affect pulmonary function. Penicillamine-induced polymyositis [ ] or myasthenia gravis can cause respiratory failure, even requiring ventilatory support [ ]. The diagnosis and management of lupus-induced pleurisy have been reviewed [ ].

Alveolar hemorrhage can occur with penicillamine, usually as part of a life-threatening pulmonary-renal syndrome resembling Goodpasture's syndrome [ , ].

Rhinitis, bronchospasm, and asthma can occur as a manifestation of hypersensitivity to penicillamine [ ] and rarely of the Churg–Strauss syndrome [ ]. Rhinitis can also be a symptom of penicillamine-induced pemphigus [ ]. In one patient a large pulmonary cyst developed concomitantly with skin lesions characteristic of the use of large doses of penicillamine [ ]. Microscopic derangement of the elastic fibers predominated. Although the frequency is uncertain, penicillamine can be associated with recurrent respiratory tract infections, that is secondary to IgA deficiency [ , ] or as part of the “yellow nail syndrome” [ , ].

Nervous system

Penicillamine, both l -penicillamine and racemic penicillamine, strongly inhibit pyridoxal-dependent enzymes, cause pyridoxine deficiency in animal experiments, and are neurotoxic. Although this effect is much weaker with d -penicillamine, a few case reports have shown that d -penicillamine can also occasionally cause a polyneuropathy, as either a toxic or an allergic reaction [ ]. Rarely, an optic neuropathy [ ] or a polyradiculoneuropathy (Guillain–Barré syndrome) [ , ] can occur. When penicillamine is started in patients with Wilson's disease, pre-existing neurological involvement can acutely worsen; convulsions, muscle spasms, and coma can occur and death can follow [ ]. Worsening of neurological symptoms after starting therapy with penicillamine can occur in up to 50% of neurologically affected patients with Wilson's disease [ , ] and penicillamine can precipitate serious neurological injury in previously asymptomatic patients [ , ]. It is uncertain if this results from alterations of copper distribution at submolecular, subcellular, transcellular, or transorganic levels, or whether it results from some other property of penicillamine (for example its capacity to donate sulfhydryl groups). Since the initial damage may be caused by copper decompartmentalization, it has been suggested that pretreatment with lipid-soluble antioxidants, such as vitamin E, may be useful [ ], whereas at least some of these effects may reflect secondary pyridoxine deficiency. Supplementary oral pyridoxine may be advisable [ ].

Two patients have been described with the internuclear ophthalmoplegia syndrome, probably induced by penicillamine. In one it was secondary to serious progressive intracerebral necrotizing vasculitis [ ], in the other the underlying condition was a myasthenic reaction [ ]. Isolated cases have been described of neuromyotonia [ ] and diffuse fasciculations [ ], attributed to penicillamine.

In 18 patients with Wilson's disease penicillamine 600–3000 mg/day was gradually introduced over a period of 2–3 weeks, adjusted to urinary copper excretion, and after clinical improvement a maintenance dose of 600–900 mg/day was given [ ]. There was initial neurological deterioration, in particular of tremor and dysarthria, in 10 of the patients, but it reversed within 2–4 months. One patient had a hypersensitivity reaction (rash with leukopenia) and another developed cutaneous elastosis of the neck, characteristic of high doses of penicillamine.

In one case acute neurological deterioration in a young child after high doses of penicillamine had a fatal outcome [ ].

• A seriously ill 8-year-old girl, weight 22 kg, with progressive jaundice, hepatomegaly, bilious vomiting, abdominal distension, coagulopathy, swelling of the feet, low-grade fever, drowsiness, and Kayser–Fleischer rings, was given fresh frozen plasma. After a challenge test with penicillamine 1 g plus pyridoxine 25 mg she developed jerky movements of the limbs, titubation of the head, and dysarthria. Since these symptoms were suspected to be due to penicillamine, oral zinc sulfate was begun and 3 days later penicillamine was resumed in a dose of 62.5 mg/day, increasing the dose by doubling every 2 days. When a dose of 500 mg/day (22.7 mg/kg/day) was reached there was recurrence of the neurological symptoms and penicillamine was withdrawn. Subsequently there was worsening of liver failure, gastrointestinal bleeding, peritonitis, and hepatic encephalopathy, and the child died.

Sensory systems

Endocrine

A few patients are on record with suspected penicillamine-induced thyroiditis, in one case associated with a myasthenic reaction [ , ].