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Iron as a Drug and Drug–Drug Interactions
Abstract
• Bioavailabiltiy of oral iron may be enhanced in the presence of reducing agents such as ascorbic acid.
• All commercially available iron salts are effective in the treatment of iron deficiency.
• Administration of oral iron should be separated from other medications by at least 1–2 hours.
• The use of iron dextran is not attractive compared to other IV iron preparations because of its side effect profile.
• Infusion-related side effects such as hypotension can be alleviated by slowing the rate of administration of IV iron preparations.
• Acute iron toxicity should be treated promptly with gastric lavage and supportive care.
• Chronic iron toxicity can result in significant organ damage and is treated with chelation agents such as deferoxamine, deferiprone, and deferasirox.
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To determine if and to what extent the total iron-binding capacity (TIBC) would increase following an iron overload, and to identify specific iron-binding proteins that might be responsible for the increased TIBC.
A prospective laboratory investigation.
A certified regional poison control center.
Six healthy adult male volunteers.
All volunteers ingested 20 mg/kg of elemental iron. Blood samples were drawn at hourly intervals for eight hours and analyzed for serum iron, TIBC, transferrin, ferritin, lactoferrin, glucose, bicarbonate, and WBC. Within two hours of ingestion, subjects developed symptoms of toxicity, including nausea, lightheadedness, vomiting, severe crampy abdominal pain, and voluminous diarrhea. The TIBC was statistically significantly increased at all points measured from one to six hours. Despite rising above 300 micrograms/dL in five of six subjects, the serum iron never exceeded the TIBC in any subject. Transferrin and ferritin did not increase to account for the increased TIBC. The lactoferrin levels did increase, but they did not correlate with significant increases in the TIBC.
Twenty mg/kg of elemental iron caused clinical toxicity in this study, and after iron overload the colorimetric TIBC increased by unknown mechanisms.
Serum ferritin, liver iron stores, and liver histology were studied in 38 children with thalassaemia major who were being treated by regular blood transfusions. There was no correlation between serum ferritin levels and either the number of transfusions or the amount of iron deposited in the liver. However, for a given level of iron stores, ferritin levels were higher in patients with chronic hepatitis (including chronic aggressive and chronic persistent forms) than in those with hepatic siderosis only. We conclude that serum ferritin reflects tissue iron deposits in regularly transfused thalassaemic patients, only in the absence of hepatitis.
Fluoroquinolones are used worldwide in the treatment of severe infections. These drugs, however, can interact with other agents. This paper is a review of drug interactions with different quinolone derivatives at the absorption phase; the review deals mainly with the prototype quinolones, ciprofloxacin and ofloxacin, and also with some of the newer agents. The concomitant agents considered are food, H2-receptor antagonists, anticholinergic drugs and metallic cationcontaining compounds. Food (standard breakfast), H2-receptor antagonists and anticholinergic drugs had no major effect on the bioavailability of the quinolones. However, antacids, ferrous sulfate and other metallic cation-containing compounds impaired the bioavailability of the quinolones. This effect is due to chelation between the functional groups of the quinolone molecule and the metallic cations, resulting in insoluble complexes that can not be absorbed. The degree of impairment varied between different quinolone derivatives.
Nineteen of 135 patients (four with idiopathic hemochromatosis and 131 with chronic anemia) had cardiac iron deposits (CID). The ventricular CID were grossly visible in nine patients and microscopically visible only in ten patients. Atrial CID were extensive in six patients with extensive ventricular CID, but in the other thirteen patients atrial CID were minimal. Iron deposits in cardiac conduction tissue were minimal and always less than in working myocardium. Every patient who had iron in the myocardium also had iron in other organs and tissues. Nine patients had pigmentary cirrhosis which was associated with anemia and exogenously administered iron in six and unassociated with anemia in three (idiopathic hemochromatosis). Each of seven patients with extensive CID without other cardiac disease had clinical evidence of cardiac dysfunction, and five had chronic congestive cardiac failure. In contrast, cardiac failure, usually transient and mild, occurred in one of six patients with minimal CID and in eight of eighty-four patients without CID. Of the nineteen patients with CID, three had idiopathic hemochromatosis; 16 had chronic anemia. Each anemic patient who received more than 100 units of blood had extensive CID unless chronic bleeding diatheses coexisted. Each anemic patient with extensive CID who received less than 100 units of blood had hepatic cirrhosis. In conclusion (1) grossly visible CID are always associated with cardiac dysfunction and usually chronic cardiac failure; (2) CID, usually extensive, occur in patients with idiopathic hemochromatosis; (3) extensive CID occur in patients who receive more than 100 units of blood unless bleeding diatheses coexist; (4) patients with chronic anemia and hepatic cirrhosis who receive less than 100 units of blood also may have extensive CID; (5) CID initially occur in ventricular myocardium, and are usually more extensive in ventricular than in atrial myocardium; (6) CID are always more extensive in working than in conducting myocardium; (7) supraventricular arrhythmias correlate with the extent of CID in atrial myocardium. Thus, the iron heart is not a strong heart but a weak one.
Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease. The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes. Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures, a family history of hemochromatosis, or consistent early signs and symptoms of the disease.
Most discussions of iron therapy include a statement about the ineffectiveness of iron ingested simultaneously with antacids. This study was designed to determine whether or not antacids inhibit iron absorption. A small-dose iron tolerance test was used to compare absorption of iron with and without various antacids. Liquid antacid containing aluminum hydroxide and magnesium hydroxide did not significantly decrease iron absorption. Sodium bicarbonate and calcium carbonate caused the plasma iron increase to be 50% and 67% less than the control values, respectively. However, when calcium carbonate was present in a multivitamin-plus-minerals tablet, the plasma iron change was not significantly different from control trials. Presumably the competitive binding of iron by ascorbic acid in the vitamin pill allowed uninhibited absorption of the iron. Our results suggest that certain antacids may be combined with iron therapy without reducing the efficacy of the iron.
(JAMA 1986;255:1468-1470)
▪ Objective: To determine whether simultaneous ingestion of ferrous sulfate and thyroxine reduces the efficacy of thyroid hormone in patients with primary hypothyroidism.
▪ Design: Uncontrolled clinical trial.
▪ Setting: Outpatient research clinic of a tertiary care center.
▪ Patients: Fourteen patients with established primary hypothyroidism on stable thyroxine replacement.
▪ Intervention: All patients were instructed to ingest simultaneously, a 300-mg ferrous sulfate tablet and their usual thyroxine dose every day for 12 weeks.
▪ Results: After 12 weeks of ferrous sulfate ingestion with thyroxine, the mean level of serum thyrotropin (thyroid stimulating hormone, TSH) rose from 1.6 ± 0.4 to 5.4 ± 2.8 mU/L (P < 0.01), but the free thyroxine index did not change significantly. Subjective evaluation using a clinical score showed that nine patients had an increase in symptoms and signs of hypothyroidism; the mean score for the 14 patients changed from 0 to 1.3 ± 0.4 (P = 0.011). When iron and thyroxine were mixed together in vitro, a poorly soluble purple complex appeared that indicated the binding of iron to thyroxine.
▪ Conclusions: Simultaneous ingestion of ferrous sulfate and thyroxine causes a variable reduction in thyroxine efficacy that is clinically significant in some patients. The interaction is probably caused by the binding of iron to thyroxine.
Transfusion therapy for inherited anemias and acquired refractory anemias both improves the quality of life and prolongs survival. A consequence of chronic transfusion therapy is secondary iron overload, which adversely affects the function of the heart, the liver and other organs. This session will review the use of iron chelating agents in the management of transfusion-induced secondary iron overload.
In Section I Dr. John Porter describes techniques for the administration of deferoxamine that exploit the pharmacokinetic properties of the drug and minimize potential toxic side effects. The experience with chelation therapy in patients with thalassemia and sickle cell disease will be reviewed and guidelines will be suggested for chelation therapy of chronically transfused adults with refractory anemias.
In Section II Dr. Nancy Olivieri examines the clinical consequences of transfusion-induced secondary iron overload and suggests criteria useful in determining the optimal timing of the initiation of chelation therapy. Finally, Dr. Olivieri discusses the clinical trials evaluating orally administered iron chelators.
To determine whether simultaneous ingestion of ferrous sulfate and thyroxine reduces the efficacy of thyroid hormone in patients with primary hypothyroidism.
Uncontrolled clinical trial.
Outpatient research clinic of a tertiary care center.
Fourteen patients with established primary hypothyroidism on stable thyroxine replacement.
All patients were instructed to ingest simultaneously, a 300-mg ferrous sulfate tablet and their usual thyroxine dose every day for 12 weeks.
After 12 weeks of ferrous sulfate ingestion with thyroxine, the mean level of serum thyrotropin (thyroid stimulating hormone, TSH) rose from 1.6 +/- 0.4 to 5.4 +/- 2.8 mU/L (P < 0.01), but the free thyroxine index did not change significantly. Subjective evaluation using a clinical score showed that nine patients had an increase in symptoms and signs of hypothyroidism; the mean score for the 14 patients changed from 0 to 1.3 +/- 0.4 (P = 0.011). When iron and thyroxine were mixed together in vitro, a poorly soluble purple complex appeared that indicated the binding of iron to thyroxine.
Simultaneous ingestion of ferrous sulfate and thyroxine causes a variable reduction in thyroxine efficacy that is clinically significant in some patients. The interaction is probably caused by the binding of iron to thyroxine.
Plasma levels of penicillamine, urinary recovery of penicillamine and its oxidized metabolites, and urinary excretion of copper were examined afier single 500-mg oral doses of penicillamine to six healthy men. Penicillamine was given after an overnight fast, a standard breakfast, and after antacid and ferrous sulfate. Following the fasting dose, the mean peak plasma level of 3.05 g/ml developed at 3.8 hr and the drug was cleared from plasma with a t½ of 2.1 hr. Penicillamine levels were reduced to 52%, 35%, and 66% of those from the fasting dose after food, ferrous sulfate, and antacid. The rates of penicillamine appearance and disappearance from plasma were essentially treatment independent. There were good correlations between urinary recovery of total penicillamine (r = 0.875), between urinary copper excretion (r = 0.758) and the penicillamine plasma concentration AUCs. The availability of oral penicillamine is very susceptible to interactions with other substances. Further studies may be necessary to assess the full clinical significance of these interactions.
Whereas hemoglobin (Hb) E-β thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and β-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-β thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with β-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-β thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-β thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-β thalassemia is similar to that observed in patients with β-thalassemia. These data, in the only cohort of patients with Hb E-β thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with β-thalassemia may be generally applicable to those with Hb E-β thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.
Iron is an ubiquitous metal of vital importance to the normal physiologic processes of many organisms. Recent discoveries of mutations in genes that lead to inherited iron overload diseases have advanced the understanding of iron homeostasis in humans. This article provides an overview of the human iron cycle, regulation of iron homeostasis, how perturbations in this homeostasis lead to iron overload disease in adults and children, and strategies for diagnosis of inherited iron overload.
Iron has the capacity to accept and donate electrons readily, interconverting between ferric (Fe2+) and ferrous (Fe3+) forms. This capability makes it a useful component of cytochromes, oxygen-binding molecules (i.e., hemoglobin and myoglobin), and many enzymes. However, iron can also damage tissues by catalyzing the conversion of hydrogen peroxide to free-radical ions that attack cellular membranes, proteins, and DNA. Proteins sequester iron to reduce this threat. Iron ions circulate bound to plasma transferrin and accumulate within cells in the form of ferritin. Iron protoporphyrin (heme) and iron–sulfur clusters serve as enzyme cofactors. Under normal circumstances, only trace amounts . . .
Severe acute iron poisoning developed in a 1 1/2-year-old child who had eaten an iron preparation that resembles a popular chocolate candy. Tablets containing iron, with and without vitamins, and the sugar-coated candy of similar appearance, were radiographed with human gastric juice in vitro. Times of dissolution of the radiopaque tablets were noted, to assess the value of abdominal radiographs in the diagnosis and management of acute iron poisoning.
seen in other instances of acute intoxication 3 as well as in chronic intoxication?. 9. ~a This pattern is a result of saturation kinetics operative for DPH elimination in children. 19 ..... :~ DPH is metabolized to para-hydroxyphenytoin (about 80% of a dose) and other metabolites, and little is excreted unchanged in the urine. That previous studies have not reported significant amounts of DPH in dialysis fluid is indicative of metabolic clearance occurring concurrently with dialysis. The apparent clinical improvement reported to occur "immediately" during or after dialysis may be fortuitous or due to removal of an active DPH metabolite. Thus, until a series of DPH intoxicated patients are dialysed and compared with nondialysed controls, each group having excretion studies of DPH and para-hydroxyphen ytoin in urine and dialysis fluid, dialysis should be considered only as an investigative procedure.
All tetracycline derivatives are bacteriostatics and their concentration in serum should not fall during the therapy below the generally accepted minimum therapeutic concentration of 0.5 to 1.5μg/ml.
Tetracyclines have a high affinity to form chelates with polyvalent metallic cations such as Fe+++, Fe++, At+++, Mg++ and Ca++. Many of these tetracyclinemetal complexes are either insoluble or otherwise poorly absorbable from the gastrointestinal tract. Milk and other dairy products, antacids containing polyvalent cations, as well as various iron salts ingested simultaneously with tetracycline derivatives, might interfere with their absorption by 50 to 90% or even more. The severity of interaction depends both on the nature of the tetracycline derivative and of the cation, on the doses used, on pharmaceutical factors, and on time schedules in dosing. An interval of 3 hours between the ingestion of tetracyclines and cations prevents the interaction.
The pharmacokinetic interactions in absorption of tetracyclines are likely to be clinically significant in cases where the infecting pathogens are moderately resistant to tetracyclines and relatively high serum concentrations are needed for proper bacteriostasis.
The drug of choice for the treatment of iron poisoning is desferrioxamine, though the best route of administration, dose, and duration of treatment are unclear. We report fatal lung injury in four patients who were treated with continuous intravenous infusions. The patients, aged 19-26 years, had received desferrioxamine infusions of 15 mg/kg per h for 65-92 h. Respiratory distress developed after 32-72 h. The patients met clinical, physiological, and necropsy criteria for the diagnosis of adult respiratory distress syndrome (ARDS); none had any of the known risk factors for the development of this disorder. We reviewed the records of forty-three iron-poisoned patients treated with desferrioxamine infusions. No patient treated for less than 24 h had pulmonary complications; however, of the fourteen treated for longer than 24 h, four were the patients with ARDS and four others had pulmonary oedema of other causes. We suggest that the pulmonary complications are caused by continuous infusion of desferrioxamine and that the ARDS in these patient was a consequence of free-radical generation. We recommend that desferrioxamine infusion should not be administered for longer than 24 h.
The ability of methyldopa and levodopa to interact with both ferrous and ferric iron under a variety of conditions likely to be encountered physiologically has been examined. Spectrophotometric studies of ferrous sulphate in the presence of methyldopa indicate that no complexation occurs below pH2, whilst between pH 4-9, a variety of iron-methyldopa complexes is formed. The formation of these complexes is fast at high pH (pH 9: t1/2 less than 5 s), whilst the rate slows as the pH is lowered (pH 4: t1/2 greater than 30 min). These complexes are characteristic of iron-catecholate species, indicating that in the presence of methyldopa (and levodopa) ferrous iron undergoes autoxidation to the ferric form. The tight binding of ferric iron to methyldopa is predicted to alter the biodistribution characteristics of the complex with respect to the unchelated components. Furthermore, under the acid conditions of the stomach, redox cycling can occur. This will result in both catechol oxidation and production of the toxic hydroxyl radical. The findings suggest that care should be exercised when simultaneous administration of either methyldopa or levodopa with ferrous sulphate is indicated.
The influence of calcium supplements on the absorption of dietary nonheme iron and of iron supplements was evaluated in 61 normal volunteer subjects by use of a double-radioisotope technique. When taken without food, calcium carbonate did not inhibit the absorption of ferrous sulphate with doses of either 300 mg Ca and 37 mg Fe or 600 mg Ca and 18 mg Fe. However, at the latter levels, calcium citrate and calcium phosphate reduced iron absorption significantly by 49% and 62%, respectively. All calcium supplements inhibited absorption of the iron supplement when taken with food. The absorption of dietary nonheme iron was also inhibited by all three supplements. This inhibition was less pronounced from a meal of high iron availability and low calcium content (28%) than from a breakfast meal of low iron availability and high calcium content (55%). These results suggest that taking regular calcium supplements with meals makes it more difficult for women to meet their daily iron requirement.
Even though ingestion of chewable iron preparations is much more common, treatment recommendations for iron overdose are usually based on experience with nonchewable preparations. To determine the optimal time to measure serum iron concentrations, five volunteers were given chewable iron in 5 mg/kg and 10 mg/kg doses and their serum iron concentrations monitored. Peak levels occurred at 4.2 and 4.5 hours, respectively, after ingestion, and levels drawn at 3 hours were within 90% of the peak. Nausea and headache were experienced by all volunteers, and serum iron exceeded baseline total iron binding capacity in two subjects at the 10 mg/kg dose. In minor iron overdose resulting from the ingestion of chewable vitamins, serum iron concentrations measured between 3 and 7 hours (95% confidence level of peak concentrations) may be adequate in assessing the peak serum iron concentration.
Since gastric acid is an important luminal factor in the absorption of non-heme iron, the effect of omeprazole on the absorption of iron in a rat model was studied. Iron absorption studies were performed on rats on a normal diet (N = 42) and rats fed an iron-deficient diet (N = 43) for three weeks. Rats were orally dosed with 40 mumol/kg of omeprazole or placebo daily for two days prior to iron absorption studies. Rats were orally dosed with 1 mmol of ferrous chloride, ferric chloride or food iron (dietary suspension) containing 11 micrograms of iron and labeled with 1 microCi of 59Fe. Omeprazole-treated rats on the normal diet had no significant reduction in the absorption of ferric, ferrous, or food iron. In the rats on the iron-deficient diet, the absorption of ferrous iron decreased from 76 +/- 7.5% (mean +/- SE) in control rats to 38 +/- 8.5% in the omeprazole-treated rats (P less than 0.003) and the absorption of food iron decreased from 65 +/- 7.5% in control rats to 37 +/- 6.5% in the omeprazole-treated rats (P less than 0.016). There was no significant reduction in the absorption of ferric iron. Omeprazole therapy is unlikely to be associated with significant iron malabsorption in normal patients but may reduce iron absorption in pathological states associated with increased iron absorption such as iron deficiency.
Although the acute ingestion of iron-containing preparations can produce very serious consequences, the majority of reported exposures are not associated with significant morbidity or mortality. We present 3 cases of acute iron ingestion and review the aspects of general management, with an emphasis on the appropriate choice of a gastrointestinal decontamination procedure.
The gastrointestinal effects of iron overdose have been described in children. They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation. They typically occur in the stomach or proximal small bowel. We describe an adult example of both, each occurring in the distal portion of the small intestine. Both patients had ingested enteric-coated iron preparations and both experienced significant, protracted abdominal pain. Thus adults as well as children are at risk for severe gastrointestinal complications after iron overdose. Significant protracted abdominal pain should alert the clinician of its possibility. Damage to distal areas of the bowel can occur with complete sparing of proximal portions particularly if the iron is an enteric-coated preparation.
The hemodynamic effects of severe iron poisoning were studied in five mongrel dogs. Anesthetized animals were instrumented with arterial, venous, and pulmonary artery thermodilution catheters. Iron intoxication was induced by orogastric administration of ferrous sulfate (600 mg/kg elemental iron). Pulmonary artery wedge pressure values were maintained near preintoxication values by saline infusion, and sodium bicarbonate (1.5 mEq/kg/dose) was given for pH less than 7.25. Hourly hemodynamic measurements were obtained for five hours. Cardiac output, mean arterial pressure, pH, and heart rate decreased significantly (P less than .05), whereas systemic vascular resistance, left ventricular stroke work, and oxygen consumption did not change. All animals developed metabolic acidosis despite saline (3.6 +/- 0.9 L, mean +/- SD) and bicarbonate administration (4.2 +/- 0.8 mEq/kg). These findings suggest that decreased cardiac output was partially due to decreased heart rate but not to decreased preload or abnormal left ventricular afterload. Alkali therapy and maintenance of oxygen consumption did not prevent development of metabolic acidosis.
The principle of iron conservation is the basis of iron metabolism; the normal basal loss of iron from the body is about 1 mg daily in a 70 kg man and 0.8 mg in a 55 kg woman. Iron is lost mainly by the menstrual and gastrointestinal routes. The total iron requirement during pregnancy is 800 mg; in the last month the requirement may amount to 7 to 8 mg/day. Supplementary iron is recommended for many menstruating women, and during the latter part of pregnancy. Correct fetal iron metabolism is ensured by proper maternal iron status, although there are contradictory opinions and findings about the relationship between maternal and fetal iron metabolism. Preterm infants fed on breast milk have a negative iron balance, and require an iron intake of about 0.6 mg/kg/day, and 3.4 mg/1 g haemoglobin, to compensate for intestinal and venesection iron losses, respectively. The absorption of supplementary iron by the preterm infant is a linear function of intake. Preterm infants do not require iron supplements when given repeated blood transfusions.
The bioavailability of iron in five ferrous sulfate preparations was studied in 10 healthy male volunteers. The preparations were an oral solution, two types of film-coated tablets and two types of enteric-coated tablets. Blood samples were drawn hourly from 8 am to 6 pm on the day before each study day to assess baseline serum iron concentrations and on the study day. Spectrophotometry was used to measure the serum iron concentrations. The area under the curve (AUC), the maximum concentration and the time to achieve the maximum concentration were compared by analysis of variance. The enteric-coated preparations resulted in AUCs less than 30% of the AUC for the oral solution. The two film-coated products produced AUCs essentially equivalent to that of the oral solution. We conclude that the bioavailability of iron in the enteric-coated preparations was low, relative to that of the film-coated products and the oral solution, and that these products should not be considered interchangeable.
Iron poisoning continues to be a major toxicologic problem, with major impact on the gastrointestinal and circulatory systems. Failure to recognize the severity of iron intoxication may result in an inappropriate level of intervention. By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine. In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume. Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage. Under rare circumstances in which large numbers of iron tablets are present in the gastrointestinal tract, surgical removal may be indicated. In addition, measures such as hemodialysis and exchange transfusion should be reserved for those unusual poisonings in which more conservative therapy is unsuccessful. In rare cases of iron intoxication, late sequelae such as hepatic necrosis and gastrointestinal scarring with obstruction may occur. The prompt recognition and initiation of management of children with acute iron poisoning is the single most critical element in decreasing the morbidity and mortality associated with these products.
This study examined the effect of ferrous sulfate, a widely used iron treatment, on levodopa bioavailability in normal subjects. A 250 mg tablet of levodopa was taken with and without a 325 mg tablet of ferrous sulfate by eight normal subjects in a randomized crossover trial. When levodopa was taken with ferrous sulfate there was a 55% decrease in peak levodopa levels (3.6 +/- 2.6 vs 1.6 +/- 0.82 nmol/ml; p less than 0.05) and a 51% decrease in AUC (257 +/- 133 vs 125 +/- 51 nmol.min/ml; p less than 0.01). Persons with the highest peak levodopa levels and AUC after levodopa alone had the greatest reduction in peak levodopa levels and AUC after levodopa ingestion with ferrous sulfate. Iron in its ferrous state is oxidized rapidly to the ferric state in the presence of levodopa at pHs found in the small intestine. In the ferric state, iron binds very strongly to levodopa. Chelation of iron by levodopa is the likely mechanism for this drug interaction. The clinical significance of this interaction is yet to be established.
Most discussions of iron therapy include a statement about the ineffectiveness of iron ingested simultaneously with antacids. This study was designed to determine whether or not antacids inhibit iron absorption. A small-dose iron tolerance test was used to compare absorption of iron with and without various antacids. Liquid antacid containing aluminum hydroxide and magnesium hydroxide did not significantly decrease iron absorption. Sodium bicarbonate and calcium carbonate caused the plasma iron increase to be 50% and 67% less than the control values, respectively. However, when calcium carbonate was present in a multivitamin-plus-minerals tablet, the plasma iron change was not significantly different from control trials. Presumably the competitive binding of iron by ascorbic acid in the vitamin pill allowed uninhibited absorption of the iron. Our results suggest that certain antacids may be combined with iron therapy without reducing the efficacy of the iron.
This study examined the effect of two widely used iron treatments on methyldopa absorption, metabolism, and blood pressure control. A 500 mg tablet of methyldopa (2.37 mmol) was taken with and without ferrous sulfate (325 mg) by 12 normal subjects in a randomized crossover trial. When ferrous sulfate was taken with methyldopa there was a decrease in the proportion of methyldopa excreted as "free" methyldopa (49.5% +/- 12.4% vs 21.1% +/- 4.77%; p less than 0.01), a significant increase in the proportion excreted as methyldopa sulfate (37.8% +/- 12.3% vs 65.8% +/- 10.5%; p less than 0.01), and a decrease in the percentage of methyldopa absorbed (29.1% +/- 12.5% vs 7.88% +/- 4.14%; p less than 0.01). These factors resulted in an 88% reduction in the quantity of "free" methyldopa excreted. To determine if an iron preparation without sulfate produced the same effect, the study was repeated with ferrous gluconate (600 mg) with similar results. The clinical consequences of the methyldopa-ferrous sulfate interaction was determined in five hypertensive subjects receiving chronic methyldopa therapy. The subjects took ferrous sulfate for 2 weeks. There was an increase in both systolic and diastolic blood pressure in four patients and a decrease in blood pressure in all patients after ferrous sulfate was discontinued. The increases in blood pressure were substantial in three of the patients.
Acute iron poisoning is most common in children below the age of 5 years. While there is no doubt that it may be fatal, recent surveys show that death occurs in only a very small percentage of cases and that iron salts are responsible for a small minority of fatalities due to overdosage with drugs. Similarly, the proportion of severe cases seems to have fallen over the last thirty years, possibly due to earlier and more aggressive treatment but more probably due to an increase in the number of minor exposures reported.
Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss. They also cause metabolic acidosis by interfering with intermediary metabolism and producing shock and reduced tissue perfusion.
The clinical course of acute iron poisoning is divided into 4 phases. Features of acute gastrointestinal irritation dominate the period up to 6 hours after ingestion and most patients do not develop other features or progress beyond this stage. Rarely, blood loss may be sufficient to cause hypotension. Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis. The second phase, 6 to 12 hours after ingestion, is one of remission of features. Phase 3 comprises the period 12 to 48 hours from ingestion and is reached only by a small minority of patients. Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop. The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers.
Acute iron poisoning in humans has not been adequately studied and is unlikely to be so now because of the infrequent and sporadic occurrence of cases. The evidence for many conventional aspects of management is therefore unsatisfactory. Assessment of severity of poisoning is an essential prerequisite to optimum management but is difficult. The amount of elemental iron ingested is unacceptable since it is seldom known with accuracy and absorption is unpredictable because of vomiting and diarrhoea. The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning. Measurement of the serum iron concentration is the most satisfactory method with levels above the predicted serum iron binding capacity (i.e. > 70 μmol/L or 375 μg/dl) indicating circulating free iron and the risk of serious toxicity. Emergency serum iron measurements should be available round-the-clock to obviate the need to use indirect methods based upon urine colour change in response to intramuscular desferrioxamine (deferoxamine) [the desferrioxamine challenge test].
Treatment of the majority of patients poisoned with iron salts requires no more than decisions about gastric emptying and the need for administration of the specific chelating agent, desferrioxamine. Immediately the patient presents, blood should be taken for urgent measurement of the serum iron concentration and gastric emptying carried out, if indicated, while waiting for the result. An important exception to this guideline are patients who are in shock, coma or who have metabolic acidosis who should be started on intravenous desferrioxamine at a rate of 15 mg/kg/hour without waiting for the result of the serum iron concentration.
The stomach should be emptied if >10 mg/kg bodyweight of elemental iron has been ingested within the preceding 4 hours. Gastric lavage is preferable to induced emesis and tepid tap water is probably as adequate as any other solution for the purpose and is safer than some. Desferrioxamine (10g) should be left in the stomach at the end of lavage, although its efficacy in preventing iron absorption is uncertain.
Patients whose serum iron concentrations are greater than their expected iron binding capacity should be given desferrioxamine 15 mg/kg/hour intravenously and observed for adverse effects such as rashes, hypotension and, rarely, anaphylaxis. The rate of administration should be reduced to 5 mg/kg/hour as soon as clinical improvement has occurred (which will usually be within 4 hours) and stopped when the serum iron has fallen below the expected total iron binding capacity. The total dose of desferrioxamine should not exceed 80 mg/kg per 24 hours.
Iron overdosage in pregnancy should be managed in the same manner. The limited evidence available indicates that desferrioxamine protects the mother and appears to have no adverse effects on the fetus.
In addition to these measures, severe poisoning may require blood transfusion, correction of metabolic acidosis with intravenous sodium bicarbonate, supportive treatment for hypotension and maintenance of a clear airway and adequate ventilation. Renal and hepatic function must be monitored in symptomatic patients and failure treated conventionally.
Serum concentrations of tetracycline hydrochloride and minocycline hydrochloride were compared when administered with water, milk, a meal, and 300 mg ferrous sulfate in two groups of eight volunteers. Absorption of both antibiotics was significantly decreased by administration with iron (77% inhibition with minocycline and 81% with tetracycline), milk (27% inhibition with minocycline, 65% with tetracycline), and food (13% inhibition with minocycline and 46% with tetracycline). The inhibitory effect on absorption with food and milk was significantly greater for tetracycline than for minocycline.
Nineteen of 135 patients (four with idiopathic hemochromatosis and 131 with chronic anemia) had cardiac iron deposits (CID). The ventricular CID were grossly visible in nine patients and microscopically visible only in ten patients. Atrial CID were extensive in six patients with extensive ventricular CID, but in the other thirteen patients atrial CID were minimal. Iron deposits in cardiac conduction tissue were minimal and always less than in working myocardium. Every patient who had iron in the myocardium also had iron in other organs and tissues. Nine patients had pigmentary cirrhosis which was associated with anemia and exogenously administered iron in six and unassociated with anemia in three (idiopathic hemochromatosis). Each of seven patients with extensive CID without other cardiac disease had clinical evidence of cardiac dysfunction, and five had chronic congestive cardiac failure. In contrast, cardiac failure, usually transient and mild, occurred in one of six patients with minimal CID and in eight of eighty-four patients without CID.Of the nineteen patients with CID, three had idiopathic hemochromatosis; 16 had chronic anemia. Each anemic patient who received more than 100 units of blood had extensive CID unless chronic bleeding diatheses coexisted. Each anemic patient with extensive CID who received less than 100 units of blood had hepatic cirrhosis.In conclusion (1) grossly visible CID are always associated with cardiac dysfunction and usually chronic cardiac failure; (2) CID, usually extensive, occur in patients with idiopathic hemochromatosis; (3) extensive CID occur in patients who receive more than 100 units of blood unless bleeding diatheses coexist; (4) patients with chronic anemia and hepatic cirrhosis who receive less than 100 units of blood also may have extensive CID; (5) CID initially occur in ventricular myocardium, and are usually more extensive in ventricular than in atrial myocardium; (6) CID are always more extensive in working than in conducting myocardium; (7) supraventricular arrhythmias correlate with the extent of CID in atrial myocardium. Thus, the iron heart is not a strong heart but a weak one.
ACCIDENTAL poisoning by iron compounds continues to be a common pediatric problem.1 2 3 This brief review includes the current thoughts on the pathophysiology of iron poisoning, the results of treatment with a new chelating agent, deferoxamine, in 6 previously published cases and 5 new cases treated by us, including a detailed case report. Information is given regarding availability of the drug for clinical use in the treatment of acute iron poisoning. Clinical Features The clinical features of iron intoxication are summarized in Table 1. The patient ingesting an overdose of iron may proceed through four stages.4 Stage 1 occurs from immediately to . . .
contributes to the rapid amelioration of clinical symptomatology observed when it is used for the therapy of acute iron toxicity. 7' s SUMMARY 1. Several of the widely used analytic procedures for plasma iron do not measure total plasma iron when deferoxamine is present. A modification which consists of adding a strong reducing agent, sodium hydrosulfite, at the end of the usual iron analytic method is necessary. 2. The significance of plasma iron concentration as directly measured (without hydrosulfite addition) for evaluating the course of acute iron toxicity is discussed. REFERENCES
Summary1.Several of the widely used analytic procedures for plasma iron do not measure total plasma iron when deferoxamine is present. A modification which consists of adding a strong reducing agent, sodium hydrosulfite, at the end of the usual iron analytic method is necessary.2.The significance of plasma iron concentration as directly measured (without hydrosulfic addition) for evaluating the course of acute iron toxicity is discussed.
In mild to moderate iron deficiency anemia (IDA) where the hemoglobin concentration is above 7 g/dL, the RBC life span is normal.1 The production of RBCs is normal in number, or, in line with the anemia, is somewhat less than normal: production is limited by the availability of iron. In a normal adult, the amount of iron required each day for new RBCs is about 20 mg, all of it recycled from internal sources, most of it from degraded hemoglobin. When the RBC mass in iron deficiency is half the normal size, the recycled iron is about 10 mg/day, almost all going into new hemoglobin. The size of the erythropoietic organ is appropriate to the metabolic state; it is not a seething, hypercellular organ—as in pernicous anemia—held in check by nutritional deficiency. It is important to appreciate the diminished condition of the marrow to understand the basis of appropriate