Penicillamine


Article Author:
Stephanie Mejias


Article Editor:
Kamleshun Ramphul


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Barry Liskow
Brian Farah


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Phillip Hynes


Updated:
6/18/2019 4:45:09 AM

Indications

Penicillamine is approved by the FDA as a treatment for Wilson disease and cystinuria. It also is used as an off-label treatment option for lead poisoning in children.[1]

Mechanism of Action

Penicillamine can chelate heavy metals such as lead, copper, and mercury and form a soluble complex that is renally excreted in the urine. It also can combine and form disulfide bonds with cysteine and facilitates the excretion in urine. This helps to prevent the formation of cystine calculi. 

In rheumatoid arthritis, it is known to depress T cell activity.

It has a plasma peak time of 1 to 3 hours and a peak plasma concentration of 1 to 2 mg/L for the 250 mg dose. More than 80% is protein bound, and it is excreted in the urine.[2]

Administration

It usually exists as 250 mg tablets and 125 mg or 250 mg capsules.

  • Wilson Disease:  In Wilson disease in adults, the usual recommended dose is 750 mg to 1,500 mg per day in divided doses. A maximum dose of 2,000 mg per day is allowed, and the most often used dosage is 250 mg, 4 times per day. The dose that gives an initial 24-hour copper excretion of more than 2 mg/day in the urine should be kept constant for 3 months. The maintenance dose should give a free copper level of less than 10 mcg/dL in the serum. The recommended off-label dosing for pediatric cases of Wilson disease is 20 mg/kg/day divided into 2 to 3 doses.
  • Cystinuria: In Cystinuria among adults, an oral daily dose of 1 to 4 g per day in divided doses can be used. The initial dose is usually 250 mg/day, gradually titrated up to reduce the risk of adverse effects. The aim is to limit the excretion rate of cysteine to 100 to 200 mg/day. Children suffering from cystinuria are recommended to have an oral dose of 30 mg/kg/day in 4 divided doses.
  • Juvenile Rheumatoid Arthritis: In juvenile rheumatoid arthritis, the dose for the first 2 months is 5 mg/kg per day, then 10 mg/kg per day for the next 4 months.
  • Rheumatoid Arthritis: In rheumatoid arthritis, an initial dose of 125 to 250 mg/day is used orally. The dose is then increased by 125 to 250 mg/day over the next 1 to 3 months to reach 500 to 750 mg/day, depending on the response.
  • Lead Poisoning: It can be used as a treatment for lead poisoning at a dose of 1 to 1.5 g per day orally.

Penicillamine should be taken at least 1 hour before meals or 2 hours after meals. Some protocols recommend taking the drug at least 2 hours before meals in cases of lead poisoning. It is also advised to take the drug at least 1 hour apart from other drugs or zinc-containing products and if the patient is consuming milk or antacids. It is highly recommended to supplement the patient with pyridoxine. In patients with Wilson disease, 25 to 50 mg/day of pyridoxine is advised. A multivitamin regimen without copper can also be added. In patients with rheumatoid arthritis or cystinuria, it is recommended to take 25 mg of pyridoxine per day. The last dose of the day should be taken at least 3 hours after dinner.

Adverse Effects

Most Common Adverse Effects 

  • Diarrhea
  • Dysgeusia

Less Common Adverse Effects 

  • Skin rash
  • Proteinuria
  • Thrombocytopenia
  • Leukopenia

Rare Adverse Effects

  • Local thrombophlebitis, vasculitis
  • Anxiety, agitation, dystonia, Guillain-Barre syndrome, myasthenia (including extraocular muscles), myasthenia gravis, neuropathy, psychiatric disturbance
  • Agranulocytosis, aplastic anemia, pure red cell aplasia, sideroblastic anemia, positive ANA titer, thrombotic thrombocytopenic purpura
  • Increased serum alkaline phosphatase, hepatic failure, intrahepatic cholestasis
  • Lupus-like syndrome
  • Diplopia, optic neuritis, visual disturbance
  • Tinittus, renal failure, asthma, interstitial pneumonitis, pulmonary fibrosis
  • Breast disease (mammary hyperplasia), Goodpasture syndrome, hematuria, nephrotic syndrome
  • Dermatomyositis, polymyositis[3]
  • Polyarthralgia (migratory, often with objective synovitis)

Contraindications

Penicillamine is contraindicated in the following conditions:

  • Patients with a previous history of penicillamine-related aplastic anemia
  • Penicillin allergy, discontinue if an immune reaction
  • Renal insufficiency and rheumatoid arthritis
  • Pregnancy risk factor  D (It has been associated with multiple birth defects such as congenital cutix laxa)
  • Concurrency with antimalarials, immunosuppressants

Breastfeeding: Presence of the drug in breast milk is unknown and not documented. There is a manufacturers advice against breastfeeding.

Monitoring

Given the adverse effects, it is recommended to monitor and watch out for the following:

  • Allergic Reactions: 33% of patients can present with an allergic reaction to the drug. It often presents with a rash that heals on stopping the drug. The drug should also be stopped if the patient presents with fever, arthralgia, and lymphadenopathy.[4]
  • Pulmonary: Patients presenting with dyspnea should undergo a pulmonary function test. It also is associated with obliterative bronchiolitis.[5]
  • Dermatologic: Patients can present with a drug-induced lupus-like rash and other dermatologic changes. It also has been associated with pemphigus[6], and it is recommended to stop the drug and start treatment on high dose corticosteroids.
  • Gastrointestinal: Patients can present with multiple gastrointestinal side effects such as taste alteration, oral ulceration, and gingivostomatitis. These may require discontinuation of the drug based on severity.
  • Renal: Penicillamine has been associated with multiple renal side effects such as Goodpasture syndrome, proteinuria, and hematuria. Proper renal function tests should be done in patients experiencing such complaints or having risk factors.[7][8][9]
  • Hepatic: Periodic liver function tests also should be done as penicillamine has been associated with intrahepatic cholestasis, hepatitis, and increased alanine aminotransferase and aspartate aminotransferase levels.

The drug should be used with caution in the elderly as they are more at risk to develop a skin rash and gastrointestinal side effects.

Penicillamine also interacts with the following drugs:

Major Interactions

  • Aluminum hydroxide
  • Calcium carbonate
  • Carbonyl iron
  • Copper
  • Ferrous fumarate
  • Digoxin
  • Ferrous gluconate
  • Ferrous sulfate
  • Iron dextran
  • Magnesium citrate
  • Magnesium hydroxide
  • Magnesium oxide
  • Magnesium sulfate
  • Pyridoxine
  • Peramivir
  • Polysaccharide iron
  • Promazine
  • Sodium bicarbonate
  • Sodium citrate/citric acid
  • Tenofovir

The following drugs decrease the levels of penicillamine:

  • Aluminum hydroxide
  • Calcium carbonate 
  • Carbonyl iron copper
  • Ferrous fumarate
  • Iron dextran complex
  • Magnesium chloride
  • Magnesium citrate
  • Magnesium hydroxide
  • Magnesium oxide
  • Sodium bicarbonate
  • Digoxin

The following drugs increase levels of penicillamine:

  • Peramivir
  • Promazine

During the first month of therapy, it is advised to check the blood cell levels with a complete blood count, platelet count, and urinalysis as well as to properly monitor for any changes in the skin, lymph nodes, and body temperature twice weekly. From the second month until the fifth month, the laboratory and physical findings should be investigated every 2 weeks, and from sixth month onwards it should be tested on a monthly basis.

Toxicity

Patients should be advised to report any symptoms suggesting toxicity such as fever, bleeding, bruising, and chills. Gold sodium thiomalate can cause toxicity of penicillamine and should be avoided.

Enhancing Healthcare Team Outcomes

Healthcare workers including the nurse practitioner who prescribe penicillamine should be familiar with its pharmacology. Because the agent can bind many drugs and minerals, regular monitoring of the patient is necessary.  The pharmacist should educate the patient not to take the other medications at the same time as penicillamine.  Finally, before prescribing this agent, always ask if the patient has any allergies. Nearly 30% of patients do develop some type of allergic reaction to penicillamine.[10][11]


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Penicillamine - Questions

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Which of the following drugs is used to treat Wilson disease?



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What are the two most common adverse effects of penicillamine use?



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A 20-year-old man comes to the office with impaired balance, tremor, and difficulty speaking. His symptoms have developed slowly over the last seven months. His serum transaminases are elevated. Viral hepatitis serologies are negative. His brother was diagnosed at a young age with a progressive neurologic disease. Kayser-Fleischer rings are seen on examination. What drug can help his condition?



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A 30-year-old male presents to the clinic complaining of a wing-beating tremor, changes in behavior, depression, and psychosis. Further testing shows the presence of copper in the Descemet membrane and mutations in the ATP7B gene on chromosome 13, producing a defective protein. Treatment involving a chelator is initiated. Which of the following changes are this patient's kidneys at the highest risk for with long term therapy?



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Penicillamine - References

References

D-Penicillamine-induced ANCA-associated crescentic glomerulonephritis in Wilson disease., Bienaimé F,Clerbaux G,Plaisier E,Mougenot B,Ronco P,Rougier JP,, American journal of kidney diseases : the official journal of the National Kidney Foundation, 2007 Nov     [PubMed]
Rapidly progressive glomerulonephritis with D-penicillamine., Nanke Y,Akama H,Terai C,Kamatani N,, The American journal of the medical sciences, 2000 Dec     [PubMed]
D-penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature., Karpinski J,Jothy S,Radoux V,Levy M,Baran D,, American journal of nephrology, 1997     [PubMed]
Treatment guidelines for lead exposure in children. American Academy of Pediatrics Committee on Drugs.,, Pediatrics, 1995 Jul     [PubMed]
Perrett D, The metabolism and pharmacology of D-penicillamine in man. The Journal of rheumatology. Supplement. 1981 Jan-Feb     [PubMed]
Levy RS,Fisher M,Alter JN, Penicillamine: review and cutaneous manifestations. Journal of the American Academy of Dermatology. 1983 Apr     [PubMed]
Hsu HL,Huang FC,Ni YH,Chang MH, Steroids used to desensitize penicillamine allergy in Wilson disease. Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi. 1999 Nov-Dec     [PubMed]
Bruguera-Àvila N,Sánchez-Martínez E,Garcia-Olivé I,Pérez-Ochoa JF,Martínez-Barenys C,Ruiz-Manzano J, Obliterating bronchiolitis in a patient treated with (D)-penicillamine. Archivos de bronconeumologia. 2013 Sep     [PubMed]
Khashoggi M,Machet L,Perrinaud A,Brive D,Machet MC,Maruani A,Vaillant L, [D-penicillamine-induced pemphigus: changes in anti-32-2B immunostaining patterns]. Annales de dermatologie et de venereologie. 2013 Aug-Sep     [PubMed]
Vajdi T,Lee WW,Paravar T, Penicillamine-associated cutis laxa and milia en plaque - case report and review of cutaneous changes associated with penicillamine. Dermatology online journal. 2016 May 15;     [PubMed]
Xu SQ,Li XF,Zhu HY,Liu Y,Fang F,Chen L, Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. 2013 Oct;     [PubMed]

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