Mechanism of action

Penicillin derivative. Demonstrates chelating properties – creates permanent, water-soluble complex compounds with ions of copper, lead, mercury, cadmium, thallium, zinc, nickel, gold and iron. The mechanism of action in RA is unknown. Penicillamine reduces the concentration of rheumatoid factor (IgM) and immunoglobulin complexes in the serum and synovial fluid with a slight reduction in total serum immunoglobulin levels.In vitroit inhibits the activity of T lymphocytes without affecting B lymphocytes. In Wilson’s disease, it reduces the absorption of copper from the gastrointestinal tract and its removal from the tissues. Penicillamine is effective in the severe form of lead, as well as in poisoning with other heavy metals: iron, mercury, copper. It has anti-neurolytic effects. In patients with cystinuria, it forms complexes with cystine that are more soluble than cystine and more easily excreted by the kidneys.

Pharmacokinetics

The drug is well absorbed from the gastrointestinal tract, reaching the maximum plasma concentration 2 h after administration, aftert_{1 / 2α}is 1 h, t_{1 / 2β}– 5 h. It penetrates into almost all tissues. 80% of the drug is excreted in the faeces and urine within 48 hours after administration.

Indications for use – Penicillamine

RA(including juvenile arthritis).
Wilson’s disease(lento-hepatic degeneration).
Treatment and prevention of cystinuria.
Lead poisoning.
Chronic active hepatitis.

Contraindications for use – Penicillamine

Hypersensitivity to any component of the preparation, a history of aplastic anemia or agranulocytosis during the use of penicillamine, chronic lead poisoning in people who have X-rayed substances containing lead in the gastrointestinal tract, until their removal, parallel use of gold preparations, anti-cold drugs, cytostatics, oxyphenylbutazone, phenylbutazone, rheumatoid arthritis with simultaneous renal impairment in the past.

Hematological disorders, Goodpasture’s syndrome,myasthenia gravisDisorders such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture’s syndrome andmyasthenia gravis
has been reported in some patients using penicillamine . When using the drug, every 2 weeks during the first 6 months of using the preparation, and then monthly urine general tests, completeblood countswith smears, and the number of platelets should be performed. The patient should be informed about the possible symptoms of granulocytopenia and/or thrombocytopenia (fever,sore throat, chills, haemorrhage, bleeding).

Nephrotic syndrome
Treatment with penicillamine may cause proteinuria and/or haematuria during treatment, which may be a warning sign of emerging glomerulonephritis which may lead to nephrotic syndrome ; it is necessary to ensure that these symptoms are related to treatment and to monitor these patients. The symptoms of proteinuria may disappear with the use of the drug, but if this does not occur, treatment with penicillamine should be discontinued. In patients with Wilson’s disease or cystinuriaIn patients treated with penicillamine who experience changes in urine, the risk of continued use of the drug should be weighed against its therapeutic benefit. In patients treated with penicillamine for cystinuria, an X-ray of the urinary tract is recommended annually in order to detect kidney stones as soon as possible.

Liver function control
It is recommended to perform liver function tests every 6 months while using the preparation. Do not use corticosteroids in parallel when treating chronic active hepatitis; liver function tests should be performed periodically.

Obstructive bronchiolitis. Occupational bronchiolitismay
rarely occur when using the preparation ; patients should be warned to notify their physician immediately if they develop symptoms such as: exercise-induceddyspnoea, unexplainedcough,wheezing; lung function tests should be considered.

Myasthenic syndrome
Cases of myasthenic syndrome, sometimes leading to the development ofmyasthenia gravis, have been reported ; symptoms usually disappear after drug discontinuation.

PemphigusPenicillamine treatment should be discontinued
in the event ofpemphigus .

Gold salts
Patients who have been discontinued from gold salt therapy due to serious adverse reactions may be at an increased risk of adverse reactions during penicillamine therapy. If treatment is discontinued for any reason, re-treatment should be started at a low dose, gradually increasing until an effective therapeutic dose is reached.

Early-type allergic reaction
In the 2nd or 3rd week after starting treatment, some patients may develop fever in response to penicillamine administration, sometimes with an accompanying rash. The early-type allergic rash reaction usually resolves within a few days of stopping the drug and rarely occurs after restarting low dose dosing. Antihistamines may be given ifitching and rash occur.

Delayed allergic reaction
Much less frequently, usually after 6 months or later, a rash is observed which is a delayed allergic reaction; in this case, treatment should be discontinued. The occurrence of a rash with fever,joint pain, enlarged lymph nodes, and other allergic symptoms is usually indications for drug discontinuation.

Cross
-sensitivity. Patients who are hypersensitive to penicillin may be allergic to penicillamine (cross-sensitivity).

Penicillin contamination
The risk of adverse effects due to contamination of penicillin with trace amounts of penicillin during production has been eliminated as penicillamine is now produced synthetically and not by penicillin degradation.

Surgery
Before the planned surgery, due to the influence of penicillamine on collagen and elastin, the daily dose of the drug should be reduced to 250 mg. Treatment with a higher dose should be resumed only after the postoperativewounds have healed completely.

Additional ingredients of the preparation
Due to the lactose content, do not use in patients with hereditary galactose intolerance, primary lactase deficiency or malabsorption ofglucose-galactose.

Interactions – Penicillamine

Vitamin B₆, iron
Penicillamine increases the need for vitamin. B₆. During treatment with penicillamine, simultaneous administration of vit. B₆. Iron supplementation may also be necessary.

Heavy metals
Forms complex compounds with many heavy metals; in the case of using iron preparations, there should be a two-hour interval between taking both drugs.

Drugs that inhibit the bone marrow function
Do not use concurrently with drugs that inhibit the function of the bone marrow, such as: gold preparations, anti-cold drugs, cytostatics, oxyphenylbutazone or phenylbutazone.

Pyridoxine
Penicillamine is a pyridoxine antagonist and also increases the excretion of pyridoxine in the urine, which may contribute to anemia or peripheral neuritis.

Side effects – Penicillamine

Common: thrombocytopenia, lymphadenopathy, hypersensitivity reactions, stomatitis, urticaria, erythema, pruritus, arthralgia, glomerular damage, urinary tract infection, pyrexia.

Uncommon: agranulocytosis, aplastic anemia, haemolytic anemia, leukopenia.

Rare: chronic bronchitis, optic neuritis, tinnitus, pancreatitis, relapse of gastric ulcer, cholestatic jaundice, exfoliative dermatitis, Lyell’s syndrome, pemphigus,myasthenia gravis, lupus-like syndrome, Goodpasteure’s syndrome.

Penicillamine can cause acute hypersensitivity reactions, especially at the beginning of treatment. Cross-sensitivity with penicillamine may occur. In the event of allergic reactions, the use of penicillamine should be discontinued and corticosteroids administered, then the administration of penicillamine should be started, starting with the lowest doses of the drug, gradually reaching the effective therapeutic dose. In the event of a taste disturbance (except for people with Wilson’s disease), 5–10 mg of copper / d in 2 doses should be administered. division (5-10 drops of 4% copper sulphate solution in fruit juice).

Pregnancy and lactation – Penicillamine

The safety of penicillamine in pregnant women has not been established. Animal studies have shown that administering doses to rats 6 times the maximum recommended human dose causes fetal malformations in the skeletal system and cleft palate. It is not recommended for use during pregnancy (with the exception of Wilson’s disease – the dose should be reduced to 1 g / day, and if a caesarean section is to be performed, during the last 6 weeks of pregnancy and until the postoperative wounds heal – to 250 mg / day).

It is not known if the drug passes into the food; not recommended for use during breastfeeding.

Dosage – Penicillamine

After, at least 30 minutes before a meal.

RA (including juvenile arthritis).
Adults. 125–250 mg / d for a month, then the dose should be increased every 4–12 weeks by 125–250 mg until disease remission is achieved, then use the minimum effective dose. Discontinue treatment if efficacy is not achieved after 12 months of use. The maintenance dose is usually 500–750 mg / day. Dose max. 1.5 g / day. After achieving remission lasting 6 months, it is recommended to gradually reduce the dose by 125–250 mg every 12 weeks. In the elderly, do not use the initial dose> 125 mg / d in the first month of treatment. Thereafter, the dose may be increased every 4-12 weeks by 125 mg until disease remission is achieved. Do not use doses> 1 g / day.
Kids. The starting dose is 2.5–5 mg / kg / day, it can be increased gradually every 4 weeks for 3–6 months. The maintenance dose is usually 15–20 mg / kg / day.

Wilson’s disease.
Adults. 1.5–2 g / d in dose division After disease remission is achieved, the dose may be reduced to 0.75–1 g / day. In patients with a negative copper balance, the lowest effective dose should be used. The dose of 2 g / d should not be used for more than a year. In the elderly, 20 mg / kg bw / dw. division; the dose should be titrated to achieve remission of disease symptoms and maintain a negative copper balance.
Kids. Usually 20 mg / kg b.w./d in 2-3 doses. 1 hour before a meal. In children after the age of 12, usually 0.75–1 g / d.

Cystinuria. It is best to find the lowest effective dose after quantifying the amino acid concentration in urine by chromatography.
Dissolution of cystine stones in adults: 1-3 g / d per dose. division; urine cystine concentration should be kept <200 mg / l.
Prevention of cystine stones in adults: 0.5–1 g / d until the urinary cystine concentration is <300 mg / l. In elderly patients, the minimum dose required to achieve urinary cystine concentration <200 mg / l should be used.
Kids. 20–30 mg / kg bw / d in 2–3 doses division 1 hour before a meal; adjust the dose to obtain urinary cystine levels <200 mg / l. During treatment, consume large amounts of fluids (at least 3 liters a day, including 500 ml at bedtime and 500 ml at night) and follow a diet low in methionine (this diet should not be used in growing children and pregnant women).

Lead poisoning.
Adults. 1–1.5 g / d in dose division until lead is excreted in the urine of about 0.5 mg / d. In the elderly, 20 mg / kg bw / dw. division until lead excretion in urine is achieved 0.5 mg / d.
Kids. Only to be used when blood lead concentration is <45 µg / dL; the total dose should be 15-20 mg / kg / day in 2-3 doses. division

Chronic active hepatitis. Adults. Initially, 500 mg / d at a dose. Subsequently, the dose may be gradually increased every 3 months to 1.25 g / d.

Notes for Penicillamine

Penicillamine does not impair psychophysical fitness.