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Cu2+
D-Penicillamine
Renally excreted Binds copper via free sulphahydryl group Action
Trientine
Hypersensitivity reactions and pancytopoenia are rare.
Haemorrhagic gastritis, Sideroblastic anemia can occur.
Trientine chelates iron; coadministration of iron should
be avoided since the trientine iron complex is toxic.
It is safe in pregnancy
but reduce the dose.
Monitoring
is done as per penicillamine.
Also monitor iron as it chelates it.
5 % can’t tolerate penicillamine so use it as a second line.
Caution with a history of renal disease, severe
thrombocytopenia, or autoimmune
tendency.Crossreactivity to penicillin may occur so use
cautiously in those with a penicillin allery.
Written by Dr Sebastian Zeki
Adverse effects — Liver Transplantation It is used if fulminant or not responding to medical therapy. Contraversially it is used with predominant neurological problems. Use Intolerant of penicillamin/ trientes Non-responsive neuropsych disease Pts who have been decoppered Adverse effects —GI upset (best with acetate), also increase amylase and lipase without pancreatitis; Safe in pregnancy Dosing
Presence of D-penicillamine in urine by amino acid analysis (stoichiometric binding so accurate copper excretion surrogate) 30% have raised ALT despite adequate treatment Wilson’s Disease Treatment Fulminant Hepatic Failure This is an indication for emergency liver transplantation. Remove copper quickly by plasma exchange with FFP (removes 12mg per session). Haemofiltration and albumin dialysis have also been described as temporizing measures. Prognosis The prognosis in patients with Wilson's disease is excellent in all but those with advanced disease and those who present with rapidly progressive liver failure and haemolysis. The neurologic, psychiatric, and hepatic abnormalities gradually improve with treatment, and liver biochemical tests results usually return to normal. There is no increased HCC risk. Ammonium tetrathiomolybdate This interferes with copper absorption and binds to plasma copper. It is proposed as a more effective treatment for patients with neurologic disease. Treatment
Monitoring FBC/Urinalysis/U&E’s monthly for 3/12 then 3/12 for 1 year, then 6 monthly. Measure 24-hour urinary copper excretion (aim for 2000 mcg/day, falling to <500mcg/day at 6 months). Oral zinc This interferes with copper absorption by inducing enterocyte metallothionein (endogenous metal chelator), which has a greater affinity for copper than for zinc; the bound copper is excreted faecally during enterocyte turnover. Dosing comes in several forms: Zinc acetate (50mg tds)/ gluconate/sulfate. Dose: 750-1500mcg/day
NH2......NH......NH......NH2
Action
Renally excreted Binds copper via free nitrogen group D-Penicillamine
Cu2+
Lifetime therapy is required: 2 phases a)Removing copper ie chelators such as D-penicillamine/ triamterene for the 30% that do not tolerate treatment b) Preventing reaccumulation. Low dose chelators or zinc (stops copper absorption). Avoid copper containing foods- liver, kidney, shellfish, nuts, dried fruits or beans, peas, unprocessed wheat, chocolate, cocoa, and mushrooms. — Start with incremental doses of 250 to 500 mg/day inc. by 250 mg increments every 4-7d to max 1g-1.5g/d daily in 2-4 divided doses. This regimen may reduce early adverse side effects but doesn’t reduce the incidence of late-onset toxicity eg.nephrotic syndrome. Lower dose (750 to 1000 mg daily in 2 divided doses) sufficient in maintenance phase (usually after 4-6m). Therapeutic response to dose changes takes 6-8w. Paed dose: is 20 mg/kg per day (rounded to the nearest 250 mg) given in 2/3 divided doses. Penicillamine
Withold penicillamine if: -WBC< 3000 per cu mm -Neutrophils < 2000 -Platelets < 120,000, -or if a steady decline over three successive tests is observed, even though the counts remain within the normal range. -Proteinuria > 2+ on a dipstick -Red cell or white casts are observed at microscopic examination of the urine, or if more than 10 red cells are seen per hpf Use other treatments if inc toxicity risk eg history of renal disease, severe thrombocytopenia, or an autoimmune tendency. Pharmocakinetics
Crossreactivity to penicillin may occur Early sensitivity reactions (1-3 wks) are characterized by fever, cutaneous eruptions, lymphadenopathy, neutropenia, thrombocytopenia, and proteinuria- discontinue immediately and use alternative. Proteinuria/ renal problems >2g proteinuria may herald nephrotic syndrome so the drug has to be stopper Once stopped, proteinuria may take 1-2 years to resolve Can also get crescentic glomerulonephritis. Goodpasture syndrome Miscellaneous Problems Bone marrow toxicity including severe thrombocytopenia or total aplasia(may not be reversible) Myasthenia gravis, Polymyositis, Hepatotoxicity, Loss of taste Lupus-like syndrome characterized by hematuria, proteinuria, a +e antinuclear antibody. Dermatological : Elastosis perforans serpiginosa pemphigus, lichen planus, and aphthous stomatitis. GI Problems Nausea, vomiting, and anorexia are dose-related signs of gastric irritation and improve if the dose is reduced. Neurological problems: Neurology worsens in 10% and can also get new neurology in some necessitating switch to trientine Can also add zinc acetate- but watch Hb as increased risk of sideroblastic anaemia with combination tx. Pyridoxine: Penicillamine inactivates pyridoxine. Thus, small doses of pyridoxine, 25 mg per day, should be given to patients treated with penicillamine to prevent pyridoxal phosphate deficiency. 750-1000mg/day
Maintenance Phase- When normal stnthetic function, and near normal ALT, and 24 hour urinary copper is 200-500mcg/day- takes about 5 years to achieve these goals Treatment Phase (4-6 months)
max 1000-1500mg/ day
5 days
5 days
5 days
5 days
250mg
250mg
t 1/2= 5 hours Absorption reduced by 50% by food Asymptomatic patients — Prefer triamterene as relatively side effect free Symptomatic patients —Use chelator until stable (penicillamine or trientine). Trientine may be preferred, especially in patients with neurologic symptoms, since it appears to be less likely to exacerbate them. Patients presenting with fulminant hepatic failure require liver transplantation.Plasmapheresis, exchange transfusion, hemofiltration, or dialysis may be performed while transplant is being awaited. Special cases Prior to surgery — Reduce dose to 50% of presurgery dose prior to surgery, as penicillamine can impair wound healing. Do not stop altogether. Pregnancy — Reduce to 50% in third trimester as impaired wound healing in C-section No problems with breast feeding on treatment. Wilson’s dose penicillamine causes no teratogenicity, whereas higher doses (for cystinuria) does. Interruption of therapy is associated with a high risk of hemolytic episodes with hepatic insufficiency including maternal fatality.
