Intramuscular iron. Iron sorbitol inj. (50 mg of iron/ml) is an iron-sorbitol-citric-acid complex of MW < 5000 that is rapidly absorbed into the blood from the site of i.m. injection. Iron sorbitol is bound to plasma globulin, transferrin, and is stored in the marrow and liver. It is not substantially taken up in the reticuloendothelial system. Excess unbound iron is excreted in the urine (about 30% of the dose) which may turn black transiently at the time of peak iron excretion or only on standing for some hours.
Intravenous iron. Iron dextran inj. (ferric hydroxide complexed with dextrans; 50 mg/ml) and iron sucrose inj. (ferric hydroxide complexed with sucrose; 20 mg/ml) are administered by slow i.v. injection or infusion (not recommended for children).
Oral iron therapy should not be given 24 h before i.m. injections begin and for 5 days after the last i.v. injection; not only is continuation unnecessary, but it may promote adverse reactions by saturating the plasma protein (transferrin) binding capacity so that the injected iron gives a higher unbound plasma iron concentration than is safe.
Doses. The approximate total requirement is ascertained from manufacturers' dosage schedules which relate body weight to the haemoglobin deficit. Iron sorbitol is normally given daily or on alternate days where tolerance is low. It is given by deep i.m. injection, which can be painful. It stains the skin (for up to 2 years) but this can be minimised by inserting the needle through the skin and then moving the skin and subcutaneous tissue laterally before entering the muscle so that the needle track becomes angulated when the needle is withdrawn (the Z-technique).
Adverse effects. General reactions include headache, dizziness, nausea, vomiting, disorientation, pressure sensations in the chest, myalgia, hypotension, a metallic taste, urticaria and hypersensitivity. Intravenous iron may rarely cause anaphylactoid reactions and facilities for cardiopulmonary resuscitation should be available.
Folic acid deficiency may be unmasked by effective iron therapy. Where there is a deficiency of both iron and folic acid, the lack of the latter may not be obvious because haematopoiesis is impaired by insufficiency of iron. If iron is supplied increased erythropoiesis reveals the folic acid deficiency. This is most likely to happen in pregnancy due to high fetal requirements for both haematinics and so folic acid is commonly given to all pregnant patients with anaemia (see below); it also occurs in malabsorption syndromes where both may be malabsorbed.
Acute overdose: poisoning
High doses of iron salts by mouth can cause severe gastrointestinal irritation and even necrosis of the mucous membrane. Autopsy shows severe damage to brain and liver. Iron poisoning is particularly dangerous in children. Sustained-release forms are safer in homes where heedless parents live with small children. Ferrous sulphate is the most toxic.
Typically acute oral iron poisoning has the following phases:
1. 0.5-1 h after ingestion there is abdominal pain, grey/black vomit, diarrhoea, leucocytosis and hyperglycaemia. Severe cases are indicated by acidosis and cardiovascular collapse which may proceed to coma and death.
2. There follows a period of improvement lasting 6-12 h, which may be sustained or which may deteriorate to the next stage.
3. Jaundice, hypoglycaemia, bleeding, encephalopathy, metabolic acidosis and convulsions are followed by cardiovascular collapse, coma and sometimes death 48-60 h after ingestion.
4. 1-2 months later, upper gastrointestinal obstruction may result from scarring and stricture.
Treatment of acute iron poisoning is urgent and immediate efforts must be made to chelate iron in the blood and in the stomach and intestine. Raw egg and milk help to bind iron until a chelating agent is available.
The first step should be to give desferrioxamine 1-2 g i.m.; the dose is the same in adults and children. Only after this should gastric aspiration or emesis be performed. If lavage is used, the water should contain desferrioxamine 2 g/1. After empty ing the stomach, desferrioxamine 10 g in 50-100 ml water should be left in the stomach to chelate any remaining iron in the intestinal lumen; it is not absorbed.
Subsequently, desferrioxamine should be administered by i.v. infusion not exceeding 15 mg/kg/h (maximum 80 mg/kg/24 h) or further i.m. injections (2 g in sterile water 10 ml) should be given 12-hourly. Poisoning is severe if the plasma iron concentration exceeds the total iron binding capacity (upper limit 75 mmol/1) or the plasma becomes pink due to the large formation of ferrioxamine (see below). If severe poisoning is suspected i.v. rather than i.m. administration of desferrioxamine is indicated without waiting for the result of the plasma concentration.
Desferrioxamine (deferoxamine) (Desferal) (t]/2 6 h) is an iron-chelating agent (see Chelating agents, p. 154). During a systematic investigation of actino-mycete metabolites, iron-containing substances (sideramines) were discovered. One of these substances was ferrioxamine. The iron in this can be removed chemically, leaving desferrioxamine.
When desferrioxamine comes into contact with ferric iron, its straight-chain molecule twines around it and forms a nontoxic complex of great stability (ferrioxamine), which is excreted in the urine giving it a red/orange colour, and in the bile. It is not absorbed from the gut and must be injected for systemic effect. In acute poisoning, as opposed to chronic overload, desferrioxamine 5 g chelates the iron contained in about 10 tablets of ferrous sulphate or gluconate. It has a negligible affinity for other metals in the presence of iron excess.
Desferrioxamine has been shown to be effective in the therapy of acute iron poisoning and in the treatment and perhaps in the diagnosis of diseases associated with chronic iron accumulation. A topical formulation is available for ocular siderosis.
Serious adverse effects are uncommon but include rashes and anaphylactic reactions; with chronic use cataract, retinal damage and deafness can occur. Hypotension occurs if desferrioxamine is infused too rapidly and there is danger of (potentially fatal) adult respiratory distress syndrome if infusion proceeds beyond 24 h.1
Humans are uniquely unable to excrete excess iron so that, if there is uncontrolled iron intake, it progressively accumulates. Grossly excessive parenteral iron therapy or a hundred or more blood transfusions (as in treatment of thalassaemia2) can lead to haemosiderosis. Oral iron therapy over many years has also been reported to cause haemosiderosis.
Treatment of chronic iron overload, e.g. haemochro-matosis, patients who are transfusion-dependent due to chronic haemolytic anaemias, thalassaemia and refractory anaemias with transfusional iron overload (siderosis). The goal of therapy is the reduction and maintenance of body iron stores at normal or near-normal levels to avoid the tissue damage associated with iron overload.
Iron may be removed by repeated venesection in haemochromatosis where there is no anaemia. A single vensection of 450 ml of blood, in the absence of anaemia, removes 200-250 mg of iron and can be repeated weekly in individuals with haemochromatosis until the ferritin reaches the normal range. After complete removal of the iron load, maintenance therapy in the form of venesection every 3-4 months is required. A small number of patients with haemosiderosis and cardiac failure may require chelator therapy.
Patients with transfusion siderosis require a long-term programme of chelation therapy. In patients who are transfusion-dependent from infancy (thalassaemia major, congenital refractory anaemia) chelation therapy is commenced after 10-20 transfusions at about 3 years of age. In older patients with acquired transfusion-dependent anaemias chelation is commenced after 20 transfusions or when the serum ferritin is 2-3 times the upper limit of normal.
Chelation can be effectively carried out only by slow parenteral administration of desferrioxamine s.c. or i.v. through an indwelling catheter with a small portable syringe pump e.g. over 9-12 h
1 Tenenbein M et al 1992 Lancet 339: 699.
2 A 26-year-old subject with beta-thalassaemia major had been transfused 404 units of blood over his lifetime. His iron stores were so high (estimated at above 100 g) that he triggered a metal detector at an airport security checkpoint (Jim R T S 1979 Lancet 2: 1028).
VITAMIN B 3
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