Clinical pharmacology of modern iron preparations and their place in the treatment of iron deficiency anemia

October 10, 2021

Anemia is a decrease in hemoglobin content and/or a decrease in the number of red blood cells per unit volume of blood, leading to a decrease in oxygen supply to tissues

What is anemia?

Anemia is a decrease in hemoglobin content and/or a decrease in the number of red blood cells per unit volume of blood, leading to a decrease in the supply of oxygen to tissues. The diagnosis of anemia is made when hemoglobin decreases below 130 g/l in men and below 115 g/l in women.

In children, the age of the child is taken into account when diagnosing anemia. Anemia is classified depending on the cause and mechanisms of occurrence, as well as by color index. The severity depends on the decrease in hemoglobin levels in the blood and is divided into: mild, moderate and severe.

In the initial stages of the disease, a person feels constant fatigue and decreased performance. If you perform a laboratory blood test with these symptoms, it will determine a decrease in the level of hemoglobin and red blood cells. low hemoglobin is a very common ailment that occurs in both adults and children. This phenomenon can develop for a number of reasons and is a serious disease that must be treated. Otherwise, anemia can cause significant damage to health.

Symptoms of low hemoglobin

Although different types of anemia have different causes, their symptoms are very similar. Here are the frequent complaints of patients with low hemoglobin, that is, with iron deficiency anemia: fatigue, weakness, fatigue, dizziness, pallor, headache, feeling of cold, numbness of the limbs, shortness of breath, feeling of lack of air, increased heart rate, chest pain.

Most often, anemia manifests itself as pale skin, often with moderate yellowness, weakness and fatigue, and sometimes with decreased concentration. Shortness of breath and rapid heartbeat appear. You can also notice external signs of anemia: a person looks pale and lethargic, he exhibits some “oddities” in behavior: a desire arises to eat chalk, he begins to like unpleasant odors.

In older people, angina attacks may occur and become more frequent, and in young women, menstrual irregularities may occur. The usual explanations for this are: “tired”, “stress in the family and at work”, “lack of sleep”, “overworked”. Meanwhile, quite often these are signs of anemia.

Why does the body need hemoglobin?

Hemoglobin provides oxygen transport. In the capillaries of the lungs, a maximum of four oxygen molecules bind to one oxygen molecule and form oxyhemoglobin. Then, in the blood stream, red blood cells deliver this ligament to organs and tissues. Here, the oxygen necessary for oxidative processes is freed from bonding with hemoglobin.

Iron is necessary for the normal functioning of the human immune system. A lack of this microelement can lead to problems with potency in men and disrupt the menstrual cycle in women. Low hemoglobin levels can also warn of other serious diseases.

Signs of iron deficiency in the body may include loss of energy, depression, hair loss and dry skin, drowsiness and irritability. However, to determine true anemia and replenish iron deficiency, it is necessary to conduct a detailed blood test.

At risk are vegetarians and fans of strict diets, teenagers during hormonal changes in the body, and child athletes who do not take additional vitamin and mineral complexes. If pregnant women do not take special multivitamins, they are also at risk of developing anemia.

The doctor reminds you that you should not buy drugs to replenish hemoglobin and ferritin reserves at the pharmacy yourself. They are prescribed only by doctors. In addition, the effect of the drugs begins only after six months and therefore the course of treatment cannot be interrupted.

results

• The study included 440 patients. 97% of patients were women. The average age of the patients was 38 years.
• According to the analysis, the mean change in hemoglobin level after 2 weeks of therapy was 2 g/dL in the oral iron + vitamin C group and 1.84 g/dL during iron monotherapy (difference between groups 0.16 g/dL; 95% CI , −0.03-0.35 g/dl).
• The mean change in serum ferritin levels after 8 weeks of therapy was 35.75 ng/ml during iron + vitamin C therapy and 34.48 ng/ml during iron alone (difference between groups, 1.27 ng/ml; 95% CI, −0.70–3.24 ng/mL; P = 0.21).
• There were no significant differences between the groups in the frequency of side effects (20.9% in the combination therapy group and 20.5% in the iron monotherapy group).
• Not a single patient refused therapy due to the development of adverse events.

Treatment and medications for low hemoglobin

Of course, treatment of anemia always includes the prescription of medications. It is impossible to eliminate iron deficiency anemia without iron supplements, only with a diet that includes a lot of iron. The absorption of iron from food is limited, its maximum is 2.5 mg/day. From medicinal preparations, iron is absorbed 15-20 times more.

However, the food must be complete and contain a sufficient amount of well-absorbed iron and protein. It is better to take iron supplements together with ascorbic acid. The latter improves the absorption of iron in the intestines. Since food significantly reduces the absorption of inorganic iron, taking the tablets before meals is more effective.

There are a wide variety of iron supplements. Experience has shown that organic salts of ferric iron and iron compounds with various organic radicals are most easily absorbed by the body and do not cause side effects. Such drugs are safer, they have less risk of overdose and poisoning than coarser inorganic salts. The gums and teeth do not darken, there is no heaviness in the stomach, and quite rarely there is a need to discontinue the drug.

Iron supplements

Now there are many medicines on the market that can be taken orally: coated tablets, for example Sorbifer Durules, chewable tablets Maltofer and Ferrum Lek, Actiferrin drops, Ferrum Lek and Actiferrin syrups for children, Actiferrin and Maltofer drops for infants, there are also injectable forms : Ferrum Lek, at the moment they are used strictly under the control of blood tests.

During pregnancy, it is especially necessary to carefully monitor the hemoglobin level in the blood. For pregnant and lactating women, there are special forms: chewable tablets Maltofer Fol, long-acting tablets coated with Tardiferon, which contain not only iron salts, but also folic acid, which is necessary during pregnancy in higher doses. Depending on the age of the child, a drop form or syrup (Aktiferrin, Maltofer, Ferrum lek) is selected and treatment is carried out.

Iron deficiency anemia in children

Why are iron supplements necessary for IDA? What are the advantages of the latest generation drugs? Why should iron supplements be taken for a long time?

Anemia is a pathological condition characterized by a decrease in red blood cell mass, often in combination with a decrease in the number of red blood cells per unit volume of blood.
There are many causes of anemia; For children, iron deficiency anemia (IDA) is most typical. IDA is characterized by the presence of small hypochromic red blood cells and depletion of iron stores in the body. The prevalence of iron deficiency in children at an early age, according to WHO, ranges from 17.5 to 30%.

The following reasons for the development of iron deficiency in children can be identified.

• Insufficient iron stores at birth. Premature babies, as well as children from mothers who suffered from anemia during pregnancy, are at risk for developing IDA. The condition of the placenta is also of great importance, since the positive balance of iron in the fetus is due to the perfect transport mechanisms of the placenta.
• Insufficient intake of iron from food and impaired absorption in the gastrointestinal tract. What matters is not so much the iron content in the product, but the efficiency of its absorption and assimilation. Iron is absorbed in the duodenum and jejunum, therefore, with various diseases of the digestive tract (chronic enteritis, malabsorption syndrome), iron deficiency can also develop due to impaired absorption.
• Increased need for iron due to growth, intensive processes of tissue differentiation, maturation of various organs and systems, and an increase in circulating blood volume. The need for iron is especially high during traction, puberty and during the formation of menstrual function in teenage girls.
• Excessive loss of iron by the body. This is primarily blood loss: bleeding of various locations (for diseases of the digestive tract - ulcerative processes, polyps, vascular anomalies, nasal), helminthic infestation, menstruation in teenage girls. Excessive loss of iron can occur with severe allergic manifestations on the skin due to the loss of a microelement with exfoliating epithelium, with frequent acute respiratory viral infections in children, since viruses and bacteria use the child’s iron for their metabolic processes.

It is important to note that in young children the causes of iron deficiency are, as a rule, insufficient iron stores and poor nutrition, and in older children - blood loss and sudden traction.

Pathophysiological aspects

Since iron absorption is limited, most people's dietary intake barely meets the body's current needs; iron deficiency can easily develop as a result of illness or poor nutrition. This process consists of several stages.

Stage 1. Iron loss exceeds iron intake. Against the background of a negative iron balance, its reserves in the bone marrow are gradually depleted. Although serum iron and hemoglobin levels remain normal, serum ferritin levels decrease (below 20 ng/mL). As iron stores are depleted, a compensatory increase in transferrin concentration occurs (as evidenced by an increase in iron-binding capacity).

Stage 2: Depleted iron stores no longer provide erythropoietic function to the bone marrow. While plasma transferrin levels rise, serum iron levels decrease, resulting in an increasing deficiency in red blood cell production. Erythropoiesis is impaired when iron levels are below 50 mcg% and transferrin saturation is below 16%. The concentration of ferritin receptors in the serum increases (more than 8.5 mg/l).

Stage 3. Anemia with apparently normal red blood cells and red blood cell indices.

Stage 4. Development of microcytosis and then hypochromia.

Stage 5: Iron deficiency is accompanied by symptoms of tissue disorders.

Clinical manifestations

The idea of ​​the clinical status of a patient with anemia depends on the underlying disease and the form of anemia (acute or chronic). IDA is a chronic condition. The manifestation of anemia per se is explained using pathophysiological mechanisms. Most symptoms of IDA are a reflection of cardiovascular and gas exchange changes that compensate for the decrease in red blood cell mass. The severity of symptoms depends on the speed of development of anemia (with the slow development of anemia, characteristic of iron deficiency conditions, there is enough time for the full development of compensatory mechanisms) and its duration. Even moderate anemia is often asymptomatic. The child may complain of fatigue, shortness of breath and palpitations, especially after physical activity. In severe anemia, symptoms persist even at rest, and the patient cannot tolerate physical activity. If the hemoglobin level is less than 75 g/L, resting cardiac output increases markedly as both heart rate and stroke volume increase. Symptoms of heart failure develop when myocardial reserve is depleted. Consequently, the severity of the patient’s condition is determined primarily by the severity of cardiovascular disorders.

Symptoms of moderate to severe anemia extend to other organ systems. The patient often complains of dizziness and headaches, tinnitus, and even fainting is possible. The person becomes irritable, sleep is disturbed, and concentration decreases. Because blood flow to the skin is reduced, hypersensitivity to cold may develop. Symptoms also arise from the gastrointestinal tract - a sharp decrease in appetite, dyspeptic disorders (nausea, changes in the nature and frequency of stool), primarily due to the shunting of blood bypassing the vascular bed of the internal organs. In teenage girls, the menstrual cycle is disrupted, which manifests itself in the form of amenorrhea or heavy bleeding.

The main sign of anemia is pale skin. However, its information content is limited by other factors that determine skin color.

Therefore, the most informative sign of anemia is the pallor of visible mucous membranes - the mucous membrane of the oral cavity, the nail bed and the conjunctiva of the eyelids. The color of the skin on the folds of the palmar surface is also considered informative - if they do not differ in color from the surrounding skin, then the patient’s hemoglobin level is usually less than 80 g/l.

The development of pallor of the skin during anemia is explained by two factors: the first is, undoubtedly, a decrease in the level of hemoglobin in the blood, the second is the shunting of blood bypassing the vessels of the skin and other peripheral tissues, which promotes increased blood supply to vital organs. Redistribution of blood flow is one of the important mechanisms for compensating for anemia.

Other clinical symptoms of anemia include the already mentioned tachycardia, significant fluctuations in pulse pressure, systolic ejection murmur over the atria, decreased mental and physical activity, children become irritable, quickly get tired, their sleep is restless, and their appetite is reduced.

With IDA, the usual symptoms of anemia are accompanied by signs specific to iron deficiency. With prolonged iron deficiency, perverted appetite (eating chalk, dirt, paints) and sense of smell appear (like the strong smells of gasoline, paints, varnishes, eating ice (pagophagia), glossitis, cheilitis, koilonychia (thinned, striated, brittle nails) develop. With deficiency iron, the activity of the immune system decreases due to a decrease in the synthesis of IL-2 and T-killers; children are more likely to get ARVI, which, in turn, aggravates the existing iron deficiency.

The diagnosis is confirmed by laboratory data. The criterion for diagnosing IDA is microcytic, hypochromic, normoregenerative anemia. IDA is characterized by anisocytosis, thrombocytosis, decreased serum iron levels (less than 13 mmol/l), total iron-binding capacity of serum is unchanged or increased, serum ferritin level is less than 15 ng/ml, transferrin saturation is less than 16%, erythrocyte protoporphyrin level is increased, Hb level A2 is reduced, irritation of the red line is noted in the bone marrow (erythrocytes: granulocytes = 1:1 - 1:2), a typical lack of iron reserves and ring-shaped sideroblasts in the bone marrow.

The differential diagnostic search includes thalassemia, lead poisoning, anemia in chronic diseases, congenital disorders of iron metabolism (transferrin deficiency, impaired iron utilization, impaired iron reutilization), hemosiderosis, including Goodpasture's syndrome, copper deficiency.

Principles of treatment of IDA in children

• Elimination of the causes underlying the development of iron deficiency.
• Therapy for IDA should be carried out with iron supplements, since it is impossible to compensate for iron deficiency in this condition with diet therapy alone; true iron deficiency is not accompanied by a deficiency of vitamins B12, B6, and folic acid.
• The goal of therapy with iron supplements is to eliminate iron deficiency in the body, and not just to normalize hemoglobin levels, so the treatment period is long (at least 3 months).
• IDA therapy is carried out mainly with oral iron supplements.
• Blood transfusions for IDA are carried out only for health reasons.

Diet therapy for IDA in children

It is now generally accepted that it is impossible to eliminate iron deficiency in the body through diet therapy alone. This is due to the fact that the absorption of iron from food is limited - 1.8-2 mg (no more than 2.5 mg) of iron per day - even with a balanced diet appropriate for age and consumption of sufficient amounts of foods high in iron. (For comparison: a healthy child, depending on age, loses from 0.15 to 0.6 mg of iron per day, a girl during menstruation - 15-50 mg) When taking modern iron supplements, it is absorbed 20 times better. Diet therapy should be one of the components of IDA therapy in children.

On the other hand, it is very important to focus not on the iron content in food, but on its form. It is the form of iron that determines the percentage of its absorption and assimilation and, consequently, the effectiveness of therapy. Of the various forms of iron, the easiest to absorb is heme iron, a complex organic compound in which iron is found in hemoglobin; inorganic compounds - iron salts - are absorbed by the body much worse. Iron in heme is actively captured by the cells of the intestinal mucosa and absorbed unchanged. The processes of heme absorption in the intestine do not depend on the acidity of the environment and the activity of food enzymes. Iron from cereals, vegetables, and fruits is absorbed much less well due to the presence of ferroabsorption inhibitors in them, such as oxalates, phosphates, tannin and others. Compare: the absorption coefficient of iron from beef (heme iron) is 17-22%, from fruit - no more than 3%. The degree of absorption of iron from animal products also depends on the form of iron-containing compounds. Thus, from the liver, where iron compounds are presented in the form of ferritin and transferrin, iron is absorbed in significantly smaller quantities than from meat products, although the total iron content in the liver is 3 times higher than in meat. Therefore, including liver in the diet to eliminate iron deficiency or for preventive purposes does not make any sense. Thus, the diet should be as rich as possible in foods that contain iron in the form of heme (beef tongue, rabbit meat, beef).

It should also be noted that meat, liver and fish improve the absorption of iron from fruits and vegetables when consumed simultaneously.

The absorption of iron from cereals, legumes, tubers, vegetables, and fruits is much lower, since they contain iron in non-heme form, and largely depends on the content in the diet of substances that inhibit or potentiate the absorption of iron. Ascorbic acid, meat, poultry, fish products, as well as substances that reduce the acidity of food (for example, lactic acid) enhance the absorption of non-heme iron. Soy protein and polyphenols found in tea, coffee, nuts and legumes reduce the absorption of non-heme iron. Despite the high iron content in some products of plant origin, they cannot meet the high iron requirement characteristic of a growing organism, since iron from them is absorbed much less well than from animal products. Recommendations to consume large quantities of fruit juices, apples, pomegranates, buckwheat and other products in order to replenish iron depots in IDA also cannot be considered justified. A diet balanced in terms of the main ingredients allows you to “cover” only the physiological need of the child’s body for iron, but does not eliminate iron deficiency in any way and should be used in combination with iron supplements in the treatment of IDA. However, a complete and balanced diet plays an important role in preventing the development of iron deficiency in a child’s body during all periods of childhood.

Drug therapy for IDA

The main goal of IDA therapy is to eliminate iron deficiency in the child’s body. This is achieved by taking iron-containing medications. The main requirements for iron preparations are a sufficient content of elemental iron and the absence of side effects and complications. Currently, there is a sufficient selection of iron preparations on the Russian pharmaceutical market, which expands the physician’s capabilities and allows taking into account the individual characteristics of patients when prescribing treatment (Table 1). In particular, convenient forms for young children have appeared - drops and syrup (ferrum lek, maltofer, actiferrin, hemofer).

All drugs are registered and approved for use in the Russian Federation.

Modern iron supplements are divided into two groups:

• ionic iron-containing preparations (salts, polysaccharide iron compounds);
• non-ionic compounds, i.e. preparations represented by the hydroxide-polymaltose complex of ferric iron (ferrum lek, maltofer).

The absorption of iron from a medicinal product depends on the content of elemental (active) iron in it. The largest amount of elemental iron is contained in preparations in which iron is presented in the form of fumarate (ferretab, ferronate) or ferrous sulfate (actiferrin, ferro-foil, hemofer prolangatum, ferro-gradumet). Currently, a new generation of iron preparations has appeared, which include drugs represented by the hydroxide-polymaltose complex of ferric iron (maltofer, ferrum lek). The peculiarity of these drugs is that the entry of iron from the intestine into the blood occurs through active absorption, in contrast to iron salt compounds, the absorption of which occurs along a concentration gradient. This is important because it eliminates the possibility of an overdose of iron preparations containing ferric iron hydroxide-polymaltose complex.

Iron salt preparations in the intestinal lumen interact with food components and other medications, which complicates the absorption of iron. Therefore, this group of iron supplements is prescribed one hour before meals. However, against the background of pronounced free radical stress that occurs when iron interacts with the intestinal mucosa during its diffusion, the damaging effect of iron compounds on the intestinal mucosa increases, which is manifested by dyspeptic disorders, including necrosis of the mucosa. If iron salt preparations are poorly tolerated, they can be taken with food, which will reduce side effects, but iron absorption, in turn, will worsen. Iron salt preparations should not be taken with tea, milk or combined with certain medications (tetracyclines, chloramphenicol, calcium supplements, antacids, penicillamine), since this reduces the absorption of iron.

Nonionic iron preparations, as studies have shown, do not interact with food components and medications, which allows the use of these preparations without disturbing the diet of children (the preparations can be added to food, juices) and treatment regimens for concomitant pathologies (if there is a need for such treatment ).

The daily therapeutic dose of iron preparations should be sufficient to normalize hemoglobin levels and replenish iron reserves in the bone marrow, which for iron salt preparations is 3-6 mg/kg/day of elemental iron in two or three doses. Iron hydroxide-polymaltose complex (ferrum lek) is prescribed at a dose of 3-6 mg/kg/day in one or more (at the patient’s request) doses.

Adverse reactions when taking iron supplements

The most common side effects observed during treatment with ferrodrugs (Table 2): metallic taste in the mouth, darkening of tooth enamel, allergic skin rashes, dyspeptic disorders as a result of irritation to the mucous membrane of the digestive tract, especially the intestines (loose stools, nausea, vomiting ). Therefore, the initial doses of drugs should be 1/2-1/3 of the therapeutic dose, followed by increasing them to the full dose over several days in order to avoid the occurrence of severe side effects. If you are intolerant to the salt preparation, it can be replaced with an iron hydroxide-polymaltose complex, the use of which does not result in the above-described effects. Iron hydroxide-polymaltose complex can be used immediately in full dose. Non-ionic iron preparations do not cause the side effects listed above, and a feeling of stomach fullness is also rare.

Parenteral administration of iron supplements

Parenteral administration of iron supplements is carried out only under strict indications due to the development of pronounced local and systemic side effects. Indications are as follows: pathology of the digestive tract (impaired intestinal absorption syndrome, ulcerative colitis, chronic enterocolitis, gastrointestinal bleeding) and intolerance to iron-containing drugs when taken orally.

Contraindications to the prescription of iron supplements are anemia not caused by iron deficiency (hemolytic, aplastic), hemosiderosis, hemochromatosis.

Duration of treatment

The clinical and therapeutic effects of oral ferrotherapy develop gradually. After some time, clinical improvement appears: weakness decreases, dizziness disappears, the child becomes more active, appetite increases, and the skin and visible mucous membranes gradually turn pink. On the 8-10th day of therapy, a reticulocyte crisis is observed - up to 5%, which confirms the effectiveness of treatment. Later, an increase in hemoglobin levels is observed; most often, normalization of hemoglobin occurs in the 3-6th week from the start of therapy and depends on the severity of anemia. On average, Hb levels increase by 10 g/l in 10 days. However, normalization of hemoglobin levels is not a sign of elimination of iron deficiency. To completely replenish the iron depot in the body, the course of ferrotherapy should be at least 3 months.

Reasons for the ineffectiveness of ferrotherapy

The ineffectiveness of therapy while taking iron supplements, if they are well tolerated, may be due to the following factors:

• wrong diagnosis,
• ongoing blood loss
• intercurrent diseases (ARVI, exacerbation of chronic foci of infection).

IDA is a disease that, with proper treatment, can lead to complete recovery!