Antianemic vitamins. Antianemic drugs
Chemical structure and properties. Pernicious anemia (Addison-Birmer disease) remained a fatal disease until 1926, when raw liver was first used to treat it. The search for the antianemic factor contained in the liver led to success, and in 1955 Dorothy Hodgkin deciphered the structure of this factor and its spatial configuration using the method of X-ray structural analysis.
The structure of vitamin B12 differs from the structure of all other vitamins in its complexity and the presence of a metal ion in its molecule -
Cobalt. Cobalt is coordinated to four nitrogen atoms that make up the porphyrin-like structure (called the corrin core) and to the nitrogen atom of 5,6-dimethylbenzimidazole. The cobalt-containing core of the molecule is a planar structure with a nucleotide located perpendicular to it. The latter, in addition to 5,6-dimethylbenzimidazole, contains ribose and phosphoric acid (the cyanide group associated with cobalt is present only in purified vitamin preparations; in the cell it is replaced by water or a hydroxyl group). Due to the presence of cobalt and amide nitrogen in the vitamin molecule, this compound was named Cobalamin.
Metabolism. Vitamin B|2 contained in food in the gastric juice binds to a protein produced by the lining cells of the gastric mucosa - a glycoprotein called intrinsic factor of Castle. One molecule of this protein selectively binds one molecule of the vitamin; further in the ileum, this complex interacts with specific receptors on enterocyte membranes and is absorbed by endocytosis. The vitamin is then released into the blood of the portal vein. When high doses of cyanocobalamin are administered orally, it can be absorbed in the small intestine by passive diffusion without the participation of intrinsic factor, but this is a slow process. In diseases of the stomach accompanied by impaired synthesis of intrinsic factor, absorption of cobalamin does not occur.
Cyanocobalamin, Used in medical practice, in enterocytes it turns into Oxycobalamin, Being a transport form of the vitamin. Transport of oxycobalamin in the blood is carried out by two specific proteins: Transcobalamin I (p-globulin with molecular weight - 120000) and Transcobalamin I((3-globulin with a molecular weight of 35000). The second of these proteins plays a major role in the transport of the vitamin, and transcobalamin I serves as a kind of circulating depot of the vitamin. In the liver and kidneys, oxycobalamin is converted into its coenzyme forms: Methylcobalamin(methyl-B]2)ideoxyadenosinecobalamin(d-adenosine-B12). Coenzymes are carried through the bloodstream to all tissues of the body
The vitamin is excreted from the body in urine.
Biochemical functions. TO Currently, ~15 different B12-regulated reactions are known, but only two of them occur in mammalian cells - the synthesis of methionine from homocysteine (obviously
Does not satisfy the body's needs) and isomerization of D-methylmalonyl-CoA into succinyl-CoA. Let's consider these reactions.
1. In the first reaction Participates Methyl-B12, Being Coenzyme of methionine synthase (homocysteine methyltransferase). The enzyme transfers a methyl group from 5-methyl-THFA to homocysteine to form methionine:
With a decrease in the content of vitamin B12 in the diet, the synthesis of methionine by methionine synthase decreases, but since methionine is supplied with food during a nutritious diet, protein metabolism is not immediately disrupted. At the same time, a decrease in methionine synthase activity leads to the accumulation of 5-methyl-THFA (see diagram), which is formed during the reduction of 5,10-methylene-THFA, i.e., the pool of other THFA coenzymes is exhausted. Thus, even if the total level of folate is quite sufficient, a functional deficiency is created - the content of formyl and methylene derivatives of THFC decreases. It is these derivatives, or more precisely, the one-carbon radicals they bring, that are necessary for the synthesis of nucleic acid precursors. This phenomenon is called Sequestration Pula TGFC.
The described reaction serves as an example of the close relationship between two vitamins - folic acid and cobalamin. Therefore, the similarity of the symptoms of the disease with a deficiency of any of them is not surprising.
In the mid-1990s, reports emerged of a strong link between folate deficiency and an increased risk of myocardial infarction; However, the individual risk of heart attack is associated with abnormally high levels of serum homocysteine. This is explained by the fact that folate-deficient individuals have increased levels of cofactors TGFC Limits metabolic flux through the methionine synthase reaction with subsequent accumulation of homocysteine, the substrate of this enzyme. Homocysteine is suspected to be the metabolite responsible for cardiac damage, although the mechanism of its toxic action is unknown.
2. Second reaction Requires the participation of another coenzyme form of the vitamin - D-adenosine-B12. Coenzyme Included in Methimalonyl-CoA mutases. Features of the catalysis of this enzyme are the formation of free radical reaction intermediates and a change in the valence of cobalt. The substrate for its action is methylmalonyl-CoA, formed by the carboxylation of propionyl-CoA (the reaction is discussed on p. 50).
This reaction is very important in the metabolism of propionic acid (more precisely, propioniol-SKoA), which is formed during the oxidation of fatty acids with an odd number of carbon atoms, the side chain of cholesterol, and the oxidative breakdown of amino acids: isoleucine, methionine and serine.
Hypovitaminosis. Cobalamin deficiency occurs due to their low content in food during a vegetarian diet, and even more so during fasting. Of particular importance is impaired absorption of the vitamin in gastritis with low acidity (in cases of impaired formation of internal Castle factor), surgical removal of the stomach or ileum.
Hypovitaminosis manifests itself as malignant megaloblastic anemia, or Addison-Birmer anemia. The disease is also called pernicious anemia. Disorders of hematopoietic function are similar to those observed with a lack of folic acid. In addition, the posterior and lateral columns of the spinal cord are affected due to impaired myelin synthesis; degenerative changes are also observed in the peripheral nervous system and brain. Neurological symptoms boil down to parasthesias, a feeling of numbness in the hands and feet, unsteadiness of gait, weakening of memory up to confusion.
Hematopoietic disorders in cobalamin hypovitaminosis are difficult to relate directly to a defect in the coenzyme functions of vitamin B12. However, if we take into account the close “cooperation” of this vitamin with folic acid, the pathogenesis of pernicious anemia becomes more clear. As already noted, with vitamin B12 deficiency, the use of 5-methyl-THFA in the methionine synthesis reaction is disrupted, as a result of which all folic acid gradually falls into a kind of trap (is sequestered), creating a functional deficiency of its coenzyme derivatives. This explains the disruption of nucleic acid biosynthesis and, consequently, the inhibition of bone marrow hematopoiesis.
Congenital disorders of absorption, transport and metabolism of vitamin B12.
Anemia due to a congenital defect in the formation of intrinsic Castle factor. This interferes with the absorption of the vitamin. In the blood, its concentration decreases significantly. Parenteral administration of vitamin preparations is effective.
Megaloblastic anemia due to impaired absorption of vitamin B12 in the intestine. The disorder is caused by a congenital defect in the mechanism for releasing the vitamin into the bloodstream and binding it to transcortin (transcobalamin II). Interestingly, the absorption of lipids and carbohydrates is not impaired. Characterized by persistent proteinuria and increased excretion of amino acids (valine, isoleucine, threonine and methionine).
Anemia caused by a congenital transcobalamin defect. In the absence of transcobalamin II in the blood, severe anemia develops from the first weeks of a child’s life. The therapeutic effect is achieved by introducing megadoses of vitamin B12, 1000 times higher than physiological. Obviously, at such concentrations of cobalamin, other proteins take over the transport function.
Congenital methylmalonate acidemia. With this pathology, there is a high level of methylmalonic acid and increased excretion in the urine. Methylmalonatacidemia can be caused by both insufficient dietary intake of vitamin Bp and a congenital disorder of its metabolism.
Congenital methylmalonatacidemia manifests itself in the first year of a child’s life with persistent vomiting, ketoacidosis, neutropenia and thrombocytopenia, delayed psychomotor development, and reduced resistance to infectious diseases. Megaloblasts in the blood, however, are usually not detected. Diagnosis is made by detecting high concentrations of methylmalonic acid in urine, blood plasma, or cerebrospinal fluid; the level of the vitamin in the blood remains normal, indicating a congenital defect in its utilization (but not absorption). The disease is strongly familial.
Metabolic abnormalities in methylmalonatacidemia may affect different aspects of cobalamin function, namely:
Education may be disrupted Coenzyme Forms Vitamin - deoxyadenosine-cobalamin, as a result of which the conversion of methyl malonyl-CoA into succinyl-CoA is difficult and methylmalonic acid appears in excess in the blood.
Education may be disrupted Apoenzyme Methylmalonyl-CoA mutase, which also blocks the conversion of megylmalonyl-CoA to succinyl-CoA.
Combined defect It can affect both coenzyme forms of the vitamin - methyl-B12 and d-adenosine-B1G. This is accompanied by additional metabolic disorders, i.e., in addition to impaired metabolism of methylmalonic acid, the biosynthesis of methionine from homocysteine is also blocked, resulting in homocystinuria and a decrease in methionine content in the blood and tissues . Megaloblasts are found in the blood, and degenerative changes in the nervous tissue are noted.
Accumulation of methylmalonic acid and Methyl molonyl-Co A Inhibits the synthesis of fatty acids inherent in the cell. The use of acyl synthase methylmalonyl-CoA (instead of Malonil-CoA) Leads to the appearance of fatty acids of an unusual structure with a branched chain; in addition, accumulation in tissues Propyonyl-CoA(precursor of unused methyl malonyl-CoA) leads to an increase in the formation
Vania of fatty acids with an odd number of carbon atoms. All this disrupts the biosynthesis of complex lipids in nervous tissue, leading to its demyelination and the development of corresponding severe neurological syndromes.
Treatment consists of reducing the proportion of dietary protein (or a diet low in isoleucine, threonine and methionine) and supplementing with homocysteine and choline, as well as high doses of cobalamin.
Hypervitaminosis. The administration of the vitamin, even in a thousandfold dose compared to the physiological dose, did not have a toxic effect.
Assessment of the body's supply of vitamin B12. This is done by determining the content of the vitamin in the blood serum, or determining the daily excretion of methylmalonic acid, which increases tens and hundreds of times when the body’s supply of cobalamin is low. Sometimes the loading method is also used using parenteral administration of cobalt-labeled vitamin B12.
Daily requirement - Food sources. The synthesis of cobalamins in nature is carried out exclusively by microorganisms. Animal and plant cells do not have this ability. The main food sources of the vitamin are liver, meat (it contains 20 times less cobalamin than liver), seafood (crabs, salmon, sardines), milk, eggs. Strict vegetarians, who exclude not only meat but also dairy products from their diet, sooner or later develop BP-deficiency anemia.
The daily requirement is 3 mcg.
Sources
Food products contain vitamin only animal products: liver, fish, kidneys, meat. It is also synthesized by the intestinal microflora, however, the possibility of vitamin absorption in the lower gastrointestinal tract has not been proven.
Daily requirement
Structure
Contains 4 pyrrole rings, a cobalt ion (with a valency from Co 3+ to Co 6+), and a CN – group. In the body, during the synthesis of coenzyme forms, the cyanide group CN - is replaced by methyl or 5"-deoxyadenosyl.
Metabolism
Required for absorption in the intestine Castle's intrinsic factor- a glycoprotein synthesized by the parietal cells of the stomach. In the blood, the vitamin is transported in the form of hydroxycobalamin by specific transport proteins (α- and β-globulins).
Biochemical functions
Vitamin B 12 is involved in two types of reactions - reactions isomerization And methylation.
1. Basis isomerizing action Vitamin B 12 is able to promote the transfer of a hydrogen atom to a carbon atom in exchange for any group.
General scheme of the isomerization reaction
This function is important in the process of oxidation of residues fatty acids with an odd number of carbon atoms, on the last reactions of utilization of the carbon skeleton valina, leucine, isoleucine, threonine, methionine, side chain cholesterol. As a result of these reactions, methylmalonyl-SCoA, which, with the participation of vitamin B12, is converted into succinyl-SCoA and subsequently burns in the tricarboxylic acid cycle.
An example of an isomerization reaction involving vitamin B 12
Methylmalonyl-SKoA is formed from propionyl-SKoA in a carboxylation reaction with the participation of vitamin H (biotin). Propionyl-SKoA, in turn, is formed in the oxidation reactions of the above amino acids.
Accumulation of methyl malonate is an absolute diagnostic sign of vitamin B12 deficiency.
An example of a methylation reaction involving vitamin B 12
This reaction ensures the retention of free folic acid in the cell. If there is a lack of cobalamin, methyl-THFA is not used in this reaction and easily penetrates the plasma membrane and leaves the cell. Intracellular folic acid deficiency occurs, although there may be a lot of it in the blood.
The role and place of vitamin B12 and folic acid in metabolism
Hypovitaminosis B12
Cause
Nutritional deficiency - usually observed in vegetarians. At the same time, if a person ate meat for some time in his life, then the reserves of the vitamin in the liver are so large that they last for several years.
However, more often the cause of hypovitaminosis B 12 is not the lack of vitamin in food, but poor absorption in diseases stomach(atrophic and hypoacid gastritis) and the absence of internal Castle factor, and diseases intestines.
Also sometimes found autoimmune disorders, in which antibodies are formed against the parietal cells of the stomach and against the intrinsic factor of Castle, which interferes with the absorption of the vitamin. In this case, anemia develops, called pernicious.
Clinical picture
1. Macrocytic anemia, in which the number of red blood cells is reduced by 3-4 times. It occurs more often in the elderly, but can also occur in children. The immediate cause of anemia is loss of folic acid cells with vitamin B12 deficiency and, as a consequence, a slowdown in cell division due to a decrease in the synthesis of inosine monophosphate and, accordingly, purine nucleotides, and a decrease in the synthesis of thymidyl monophosphate, and therefore DNA.
Vitamin B12 deficiency without hematological disorders is surprisingly widespread, especially among the elderly.
2. Neurological violations:
- slowing down the oxidation of fatty acids with an odd number of carbon atoms and the accumulation of toxic methyl malonate causes fatty degeneration neurons and demyelination nerve fibers. This manifests itself in numbness of the hands and feet, memory impairment, gait disturbance, decreased skin sensitivity, impaired tendon reflexes (Achilles, knee),
- insufficient resynthesis of methionine (from homocysteine) leads to a decrease in the volume of methylation reactions, in particular, the synthesis of the neurotransmitter decreases acetylcholine.
Dosage forms
Cyanocobalamin, cobamide, oxycobalamin, methylcobalamin.
In medicine, cyanocobalamin is used to treat various chronic anemias and normalize hematopoiesis, for polyneuritis, multiple sclerosis, radiculitis, and to normalize lipid metabolism in fatty liver.
The vitamin exhibits anabolic properties and is used in pediatrics to treat underweight newborns.
DRUGS AFFECTING BLOODOOSIS
MEDICINES INTERPENDING RED CYTE AGGREGATION
PENTOXYPHYLLINE or trental (Pentoxyphillinum; in tablets of 0, 1 and in amps of 5 ml of 2% solution) is a derivative of dimethylxanthine, similar to theobromine. The main effect of the drug is to improve the rheological properties of blood. It promotes the bendability of red blood cells, which improves their passage through the capillaries (the diameter of red blood cells is 7 microns, and the diameter of capillaries is 5 microns).
Since trental increases the bendability of red blood cells, limits the aggregation of blood cells, and reduces the level of fibrinogen, it ultimately reduces the viscosity of the blood and makes it more fluid, reducing resistance to blood flow. Improvement in the rheological properties of blood occurs slowly. The effect occurs after 2-4 weeks.
Indications for use:
1) for peripheral circulatory disorders:
Raynaud's disease;
Diabetic angiopathy;
Vascular pathology of the eye;
2) for disorders of cerebral and coronary circulation;
3) with circulatory shock.
Trental is contraindicated during pregnancy, in patients with hemorrhages and myocardial infarction. Undesirable effects: nausea, anorexia, diarrhea, dizziness, facial flushing.
ANTIANEMIC DRUGS
Antianemic drugs are used to enhance hematopoiesis and eliminate qualitative disorders of erythropoiesis.
Anemia can develop as a result of insufficiency of various hematopoietic factors:
Iron (iron deficiency anemia);
Some vitamins (B12-deficient, folate-deficient, E-deficient);
Protein (protein deficiency).
In addition, the role of hereditary disorders of erythropoiesis, copper and magnesium deficiency is very significant. There are hypochromic and hyperchromic anemias. Hyperchromic anemia occurs due to a deficiency of B vitamins (folic acid - Bc and cyanocobalamin - B12). All other anemias are hypochromic. The incidence of anemia is high, especially among pregnant women.
Most often, hypochromic anemia is of iron deficiency origin. Iron deficiency may result from:
Insufficient intake of iron into the body of the fetus and child;
Poor absorption from the intestine (malabsorption syndrome, inflammatory bowel disease, taking tetracyclines and other antibiotics);
Excessive blood loss (helminthic infestation, nosebleeds and hemorrhoids);
Increased iron consumption (intensive growth, infections).
Iron is an essential component of a number of enzymes of both hemin and non-hemin structures. Hemin enzymes: - hemo- and myoglobin;
Cytochromes (P-450);
Peroxidases;
Catalase.
Non-heme enzymes: - succinate dehydrogenase;
Acetyl-CoA dehydrogenase;
NADH dehydrogenase etc.
With a lack of iron, the hemoglobin content decreases (the color index is less than one), as well as the activity of respiratory enzymes in tissues (hypotrophy).
Iron is absorbed in the duodenum, as well as in other parts of the small intestine. Ferrous iron is well absorbed. Trivalent iron received from food is converted into divalent iron under the influence of hydrochloric acid of the stomach. Calcium, phosphates contained in milk, especially cow's milk, phytic acid, tetracyclines interfere with the absorption of iron. The maximum amount of iron (ferrous that can enter the body per day is 100 mg).
Iron is absorbed in two stages:
Stage I: iron is captured by mucosal cells.
This process is supported by folic acid.
Stage II: transport of iron through the mucosal cell and its release into the blood. Iron in the blood
oxidized to trivalent, binds to transferrin.
The more severe the iron deficiency anemia, the less saturated this protein is and the greater its capacity and ability to bind iron. Transferrin transports iron to hematopoietic organs (bone marrow) or storage organs (liver, spleen).
To treat patients with hypochromic anemia, drugs prescribed both orally and by injection are used.
Preferably ferrous iron preparations are used internally, as it is better absorbed and less irritating to the mucous membrane.
In turn, drugs prescribed orally are divided into:
1. Organic iron preparations:
Iron lactate; - ferrocal;
Gemostimulin; - ferroplex;
Conferon; - ferrocerone;
Aloe syrup with iron; - ferramide.
2. Inorganic iron preparations:
Ferrous sulfate;
Ferric chloride;
Iron carbonate.
The most accessible and cheapest drug is ferrous iron sulfate (Ferrosi sulfas; tablets of 0.2 (60 mg iron)) and powders in gelatin capsules of 0.5 (200 mg iron)). This preparation contains a high concentration of pure iron.
In addition to this drug, there are many others. IRON LACTATE (Ferri lactas; in gelatin capsules 0.1-0.5 (1.0-190 mg iron)).
ALOE SYRUP WITH IRON (in 100 ml bottles) contains a 20% solution of ferrous chloride, citric acid, aloe juice. Use one teaspoon per dose in a quarter glass of water. Among the undesirable effects when taking this drug, dyspepsia is common.
FERROCAL (Ferrocallum; combined official preparation containing 0.2 ferrous iron, 0.1 calcium fructose diphosphate and cerebrolecithin in one tablet). The drug is prescribed three times a day.
FERROPLEX is a dragee containing ferrous sulfate and ascorbic acid. The latter sharply increases iron absorption.
The drug FEFOL is a combination of iron and folic acid.
Long-acting preparations (TARDIFERON, FERRO - GRADUMET), manufactured using a special technology on an inert plastic sponge-like substance, from which iron is gradually released, are considered more modern.
There are many drugs, you can use any, but you must remember that the therapeutic effect does not develop immediately, but after 3-4 weeks of taking the medicine. Repeated courses are often required. This means that side effects are primarily associated with the irritating effect of iron ions on the gastrointestinal mucosa (diarrhea, nausea). 10% of patients develop constipation because ferrous iron binds hydrogen sulfide, which is a natural irritant of the gastrointestinal tract. There is staining of the teeth. Poisoning is possible, especially in children (sweet, colored capsules).
Iron Poisoning Clinic:
1) vomiting, diarrhea (stool becomes black);
2) blood pressure drops, tachycardia appears;
3) acidosis, shock, hypoxia, and gastroenterocolitis develop.
The fight against acidosis is gastric lavage (3% soda solution). There is an antidote, which is a complexone. This is DEFEROXAMINE (desferal), which is also used for chronic aluminum poisoning. It is prescribed orally, intramuscularly or intravenously at a dose of 60 mg/kg per day. 5-10 grams are prescribed orally. If this drug is not available, then you can prescribe TETACIN-CALCIUM intravenously.
Only in the most severe cases of hypochromic anemia, when iron absorption is impaired, do they resort to drugs for parenteral administration.
FERKOVEN (Fercovenum) is administered intravenously, contains divalent iron and cobalt. When administered, the drug causes pain along the vein, thrombosis and thrombophlebitis are possible, chest pain and facial hyperemia may appear. the drug is very toxic.
FERRUM-LEK (Ferrum-lec; in amp. 2 and 5 ml) is a foreign drug for intramuscular and intravenous administration containing 100 mg of ferric iron in combination with maltose. The ampoules for intravenous administration contain 100 mg of iron sucrose. The drug for intramuscular injection cannot be used for intravenous administration. When prescribing the drug into a vein, the drug should be administered slowly; the contents of the ampoule must first be diluted in 10 ml of an isotonic solution.
When treating patients with hyperchromic anemia, vitamin preparations are used:
Vitamin B12 (cyanocobalamin);
Vitamin BC (folic acid).
Cyanocobalamin is synthesized in the body by intestinal microflora and is also supplied with meat and dairy foods. In the liver, vitamin B12 is converted into the coenzyme cobamide, which is part of various reducing enzymes, in particular reductase, which converts inactive folic acid into biologically active folinic acid.
Thus, vitamin B12:
1) activates hematopoietic processes;
2) activates tissue regeneration;
Cobamamide, in turn, is necessary for the formation of deoxyribose and promotes:
3) DNA synthesis;
4) completion of red blood cell synthesis;
5) maintaining the activity of sulfhydryl groups in
glutathione, which protects red blood cells from hemolysis;
6) improvement of myelin synthesis.
To absorb vitamin B12 from food, intrinsic Castle factor is needed in the stomach. In its absence, immature red blood cells appear in the blood - megaloblasts.
Vitamin B12 preparation CYANOCOBALAMIN (Cianocobalaminum; dispensed in 1 ml amps of 0.003%, 0.01%, 0.02% and 0.05% solution) is a means of replacement therapy, administered parenterally. In its structure, the drug has cyanide and cobalt groups.
The drug is indicated:
For malignant megaloblastic anemia of Addison-Birmer and after resection of the stomach and intestines;
With diphylbothriasis in children;
With terminal ileitis;
For diverticulosis, sprue, celiac disease;
For long-term intestinal infections;
In the treatment of malnutrition in premature infants;
For radiculitis (improves myelin synthesis);
For hepatitis, intoxication (promotes the formation of choline, which prevents the formation of fat in hepatocytes);
For neuritis, paralysis.
Folic acid (vitamin Bc) is also used for hyperchromic anemia. Its main source is intestinal microflora. It also comes from food (beans, spinach, asparagus, lettuce; egg whites, yeast, liver). In the body, it is converted into tetrahydrofolic (folinic) acid, necessary for the synthesis of nucleic acids and proteins. This transformation occurs under the influence of reductases activated by vitamin B12, ascorbic acid and biotin.
The influence of folinic acid on the division of cells of rapidly proliferating tissues - hematopoietic and blood cells - is especially important.
zestous membrane of the gastrointestinal tract. Folinic acid is necessary for the synthesis of hemoproteins, in particular hemoglobin. It stimulates erythro-, leuko- and thrombocytopoiesis. In chronic folic acid deficiency, macrocytic anemia develops; in acute deficiency, agranulocytosis and aleukia develop.
Indications for use:
Mandatory together with cyanocobalamin for megaloblastic Addison-Birmer anemia;
During pregnancy and lactation;
When treating patients with iron deficiency anemia, since folic acid is necessary for normal absorption of iron and its inclusion in hemoglobin;
For non-hereditary leukopenia, agranulocytosis, some thrombocytopenia;
When prescribing to patients drugs that inhibit the intestinal flora that synthesizes this vitamin (antibiotics, sulfonamides), as well as drugs that stimulate the neutralizing function of the liver (antiepileptic drugs: diphenin, phenobarbital);
For children in the treatment of malnutrition (protein synthesizing function);
In the treatment of patients with peptic ulcer (regenerative function).
Antianemic drugs include iron preparations, vitamin B12 group, folic acid, erythropoietins.
Iron supplements – the basis of replacement therapy for iron deficiency in the treatment of anemic syndrome (pallor, fatigue, shortness of breath, tachycardia, headache).
Two groups of these drugs are used - those containing divalent and trivalent iron.
Due to the fact that most ferrous iron preparations are well absorbed in the intestine, they are usually prescribed orally.
In this case, no more than 10–12% of the iron contained in them is absorbed. With iron deficiency, the absorption rate increases 3 times. Increased bioavailability of iron is facilitated by the presence of ascorbic and succinic acids, fructose, cysteine, etc., as well as the use of special matrices in a number of preparations that slow down the release of iron in the intestines.
Iron absorption may decrease under the influence of certain substances contained in food (tea tannin, phosphoric acid, phytin, calcium salts, etc.), as well as with the simultaneous use of a number of drugs (tetracyclines, Almagel®, Phosphalugel, calcium preparations, Levomycetin, penicillamine, etc. .). They do not affect the absorption of ferric iron.
The optimal daily dose for iron supplements should correspond to the required daily dose of ferrous iron, which is 5–8 mg/kg per day for children under 3 years of age, 100–120 mg per day for children over 3 years of age, 200 mg per day for adults. The use of smaller doses of drugs does not provide an adequate clinical effect.
Ferrous iron is often included in complex vitamin preparations. However, the dose of iron in this case is insignificant, so they cannot be used to treat iron deficiency conditions.
Iron sulfate is part of the drug Sorbifer Durules (table, coating volume): it contains 320 mg of iron sulfate, which corresponds to 100 mg of Fe2+. Tardiferon (gable retard, coating vol.) contains 256.3 mg of iron sulfate, which corresponds to 80 mg of Fe2+. Hemofer prolongatum: tablets contain 325 mg of iron sulfate, which corresponds to 105 mg of Fe2+. Fsrrogradumet: tab., cover. vol., 105 mg (contains 105 mg of iron sulfate). Fenyuls: cape, (contains 150 mg of iron sulfate).
Iron sulfate in combination with ascorbic acid is part of the drug Ferroplex; dragee (contains 50 mg of iron sulfate, which corresponds to 10 mg of Fc2+). The drug is used in children. The composition of the drug Fenyuls 100 is the same.
Iron (III) hydroxide polymaltosate is part of the drug Fsrrum lek; tab., 100 mg (contains 100 mg Fe3+); syrup for oral administration (vial), 50 mg/5 ml, 100 ml (5 ml contain 50 mg Fe3+). Fenyuls complex contains iron (III) hydroxide polymaltosate 50 mg/ml.
Indications for oral iron supplements are iron deficiency anemia, prevention of iron deficiency.
Contraindications: hypersensitivity, hemosiderosis, hemolytic anemia, thalassemia, sideroachrestic anemia, gastric and duodenal ulcers, ulcerative colitis.
Side effects of iron supplements when taken orally: anorexia, metallic taste in the mouth, feeling of fullness in the stomach, pressure in the epigastrium, nausea, vomiting, constipation, brownish staining of teeth, dark staining of khat.
Iron preparations are incompatible with drugs containing the 5R group; lead to decreased absorption of ciprofloxacin and tetracyclines (the interval between taking iron sulfate and these drugs should be at least 2 hours). Salts and oxides of magnesium, aluminum and calcium interfere with the absorption of iron preparations.
Parenteral iron supplements are prescribed only for special indications: intestinal pathology with malabsorption (severe enteritis, malabsorption syndrome, resection of the small intestine, etc.); absolute intolerance to iron supplements when taken orally (nausea, vomiting), which does not allow further treatment to be continued; the need to quickly saturate the body with iron when surgical interventions are planned for patients with iron deficiency anemia; treatment with erythropoietin, when the need for iron sharply, but for a short time (2-3 hours after administration of erythropoietin) increases due to its active consumption by erythrocytes.
Iron (III) hydroxide sucrose complex contains Venofer® (solution for intravenous administration (amp.), 100 mg/5 ml). The drug is administered intravenously very slowly; The dosage regimen is determined individually, and it depends on the degree of iron deficiency, the average single dose on the first day is 50 mg, the maximum daily dose for adults is 200 mg, for children weighing up to 5 kg - 25 mg per day, 5–10 kg – 50 mg per day. Iron hydroxide oligoisomaltose (Monofer), iron hydroxide dextran (CosmoFer), iron carboxymaltose (Ferinject®).
Adults should not administer more than 100 mg of iron per day parenterally; in children, depending on age, the highest daily dose is 25–50 mg. Parenteral iron preparations require careful adherence to the rules of their administration. The drug is first dissolved in an isotonic NaCl solution. The frequency of use of the drug is usually 1–3 times per week.
With parenteral administration of iron preparations, reactions may occur:
- local (phlebitis, venous spasm, darkening of the skin at the injection site, post-injection abscesses);
- general (arterial hypotension, chest pain, paresthesia, muscle pain, arthralgia, fever, etc.).
Gradually, with continued treatment, hemosiderosis may develop.
Monitoring the effectiveness of therapy is an essential component of the rational use of iron-containing drugs.
In the first days of treatment, an assessment of subjective sensations is carried out; on the 5th–8th day, it is necessary to determine the reticulocyte crisis (2–10-fold increase in the number of reticulocytes compared to the initial value). The absence of reticulocyte crisis indicates either an erroneous prescription of the drug or an inadequate dose. In the 3rd week - determination of the increase in Hb and the number of red blood cells. Normalization of Hb levels and disappearance of hypochromia usually occur by the end of the first month of treatment (with adequate doses of drugs). However, in order to saturate the iron depot, it is recommended to use half the dose of iron-containing preparations (about 100 mg Fe2+ per day) for another 4–8 weeks.
Precipitation may form if stored improperly; ampoules must be checked before injection. Use with caution in chronic liver and kidney diseases; Can be used during pregnancy.
Pharmaceutically incompatible with other drugs.
Contraindications: hypersensitivity, hemosiderosis, anemia not associated with iron deficiency, coronary insufficiency, hypertension, acute glomerulonephritis, pyelonephritis, hepatitis, liver and (or) kidney failure.
Cyanocobalamin (vitamin B12) solution for injection, has high biological activity, is necessary for normal hematopoiesis and the function of the immune system. Vitamin B12, in close interaction with vitamin C and folic acid, is involved in protein, fat and carbohydrate metabolism. Biochemical reactions occurring in the body with the participation of vitamin B12 and folic acid are presented in Fig. 5.2.
Rice. 5.2. Biochemical reactions occurring in the body with the participation of vitamin B 12and folic acid
Cyanocobalamin is prescribed for B12 deficiency anemia. Contraindications: hypersensitivity, acute thromboembolism, erythremia, erythrocytosis. Side effects: mental agitation, pain in the heart, tachycardia, allergic reactions; when used in high doses - hypercoagulation, disruption of purine metabolism.
For angina pectoris, use with caution and in smaller doses.
Incompatible (in one syringe) with thiamine bromide, riboflavin.
Folic acid (Folic acid tab., 0.001 g (Russia); tab., 1 mg). Indications: macrocytic hyperchromic anemia caused by folic acid deficiency. Contraindications: hypersensitivity. Side effects: allergic reactions. Cautions: the administration of folates for B12-deficiency anemia can cause a reticulocyte crisis and sharply worsen the patient’s condition, but never leads to the correction of anemia and the elimination of neurological disorders, therefore treatment for unclear megaloblastic anemia and the lack of sufficient information begins with the administration of vitamin B12.
When taking folic acid simultaneously with antiepileptic drugs (Difenin, Primidon, Phenobarbital), a mutual decrease in the clinical effectiveness of the drugs is possible. For therapeutic purposes, adults are prescribed 5 mg per day, children - in smaller doses depending on age, the duration of treatment is 20-30 days; to prevent folic acid deficiency in the body, the daily dose is 20–50 mcg, during pregnancy and lactation – 300 mcg.
Epoetin beta (Recormon®) is a recombinant drug identical to human erythropoietin. After intravenous or subcutaneous administration, it increases the number of red blood cells, hemoglobin level, and stimulates erythropoiesis. Indications: anemia of chronic diseases (renal in patients on hemodialysis, in cancer patients). Contraindications: hypersensitivity, childhood (up to 2 years), pregnancy, breastfeeding. Side effects: increased LD, hypertensive crisis with symptoms of encephalopathy (headache, dizziness, weakness, confusion, tonic-clonic seizures, thrombosis, progression of vascular atherosclerosis). It is necessary to monitor blood pressure weekly and conduct a general blood test, monitor liver function, potassium and phosphate levels in the blood. The effect is enhanced by iron supplements, folic acid and cyanocobalamin.
Combined drugs. The combination of iron preparations with folic acid: iron fumarate + folic acid (Ferretab® comp., Gyno-Tardifsron®) or iron sulfate + serine + folic acid (Actiferrin compositum) is used to treat iron deficiency anemia with concomitant folic acid deficiency and in conditions , accompanied by an increased need for these substances in the body, including during pregnancy. This also applies to the combination of iron hydroxide polymaltosate + folic acid (Maltofer foul).
The combination of iron sulfate + folic acid + cyanocobalamin (Ferro-Folgamma®) is used for combined iron-folic-B, 2 - deficiency anemia caused by chronic blood loss (stomach, intestinal bleeding, bleeding from the bladder, hemorrhoids, menometrorrhagia), as well as chronic alcoholism, infections, taking anticonvulsants and oral contraceptives, anemia during pregnancy and breastfeeding.
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B03. ANTIANEMIC DRUGS
B03A. IRON PREPARATIONS
The physiological role of iron in the human body
The main function of iron in the body is the transport of oxygen and participation in redox processes (with the help of dozens of iron-containing enzymes). Iron is part of hemoglobin, myoglobin, and cytochromes. In addition to red blood cells, a lot of iron is found in brain cells. Iron plays an important role in energy release processes, enzymatic reactions, immune functions, and cholesterol metabolism.
IN The human body receives iron through the nutritional route. Food products of animal origin contain iron in an easily digestible form. Some plant foods are also rich in iron, but it is more difficult for the body to absorb. It is believed that the body absorbs up to 35% of “animal” iron. Most of it is found in beef, beef liver, fish (tuna), pumpkin, oysters, oatmeal, cocoa, peas, leafy greens, brewer's yeast, figs and raisins.
IN The adult human body contains about 3–5 g iron; 2/3 of it is part of hemoglobin. The optimal rate of iron intake into the human body is 10–20 mg/day. Iron deficiency can develop if intake is less than 1 mg/day. The toxicity threshold for iron for humans is
200 mg/day.
Classifications of iron preparations
ATS classification
B: DRUGS AFFECTING THE BLOOD SYSTEM AND HEMOPOIESIS B03 Antianemic drugs B03A Iron preparations
B02AA Iron 2 + preparations for oral administration B03AA02 Iron fumarate B03AA03 Iron gluconate B03AA07 Iron sulfate
В03АВ Iron 3 + preparations for oral administration В03АВ05 Iron polyisomaltose В03АВ09 Iron protein succinylate
B03AC Iron 3 + preparations for parenteral administration B03AC01 Dextriferon B03AC02 Iron oxide saccharin
B03AC06 Iron 3 + dextran hydroxide B03AD Iron preparations in combination with folic acid
216 N. I. Yabluchansky, V. N. Savchenko
Classification by chemical structure
Also used in clinical practice classification of iron preparations by chemical structure:
– Iron salts (ferrous - more often, and trivalent - very rarely):
sulfate (ferroplex, ferrocal, ferrogradumet, tardiferon, sorbifer);
gluconate (ferronal);
chloride (hemofer);
fumarate (heferol);
ascorbate;
lactate.
– Complexes of trivalent iron with proteins and sugars (polymaltose complex with iron hydroxide - maltofer, ferlatum, ferrum lek).
– Combined drugs:
with salts of copper and manganese - totem;
with folic acid – gyno-tardiferon, ferro-foil;
with ascorbic acid – sorbifer-durules, ferroplex.
Classification according to the method of administration of iron supplements
– Iron preparations for oral administration.
– Iron preparations for parenteral administration (dextran complex with iron (III) hydroxide.
Pharmacokinetics
Iron metabolism in the human body includes the following processes:
1. Absorption in the intestine
Iron is absorbed primarily in the duodenum and proximal jejunum. In the human intestine, approximately 1–2 mg of iron per day is absorbed from food. The extent of iron absorption depends on both its amount in the food consumed and its bioavailability.
2. Transport to tissues (transferrin)
The exchange of iron between tissue depots is carried out by a specific carrier - the plasma protein transferrin, which is a J3-globulin synthesized in the liver. Normal plasma transferrin concentration is 250 mg/dL, which allows plasma to bind 250–400 mg of iron per 100 ml. It's true
Private therapeutic pharmacology 217
called total serum iron binding capacity (TSIC). Normally, transferrin is saturated with iron by 20–45%.
3. Tissue utilization (myoglobin, heme, non-heme enzymes)
The higher the saturation of transferrin with iron, the higher the utilization of iron by tissues.
4. Deposition (ferritin, hemosiderin)
In the ferritin molecule, iron is localized inside a protein shell (apoferritin), which can absorb Fe2+ and oxidize it to Fe3+. Apoferritin synthesis is stimulated by iron. Normally, serum ferritin concentration closely correlates with its stores in the depot, with a ferritin concentration of 1 μg/L corresponding to 10 μg of iron in the depot. Hemosiderin is a degraded form of ferritin in which the molecule loses part of its protein coat and becomes denatured. Most of the stored iron is in the form of ferritin, however, as its amount increases, some of it in the form of hemosiderin increases.
5. Excretion and loss
Physiological losses of iron in urine, sweat, feces, skin, hair, nails do not depend on gender and amount to 1–2 mg/day; in women with metrorrhagia – 2–3 mg/day. The daily requirement for iron for men is 10 mg, for women – 20 mg; during pregnancy, childbirth, and lactation, the daily requirement increases to 30 mg.
Effects of using iron supplements
The effects of using iron supplements are assessed by hemogram indicators:
– reticulocytosis (maximum in the first week) – an indicator of stimulation by iron of the erythroid sprout of the red bone marrow;
– increase in the number of red blood cells;
– increased blood hemoglobin levels;
– increase in blood color index.
Indications for use
– Iron deficiency anemia (IDA):
decrease in serum iron less than 14.3 µmol/l;
decrease in hemoglobin less than 100 g/l;
red blood cells less than 4.0×10 12 /l.
– Acute and chronic severe infectious diseases (high consumption of iron to neutralize toxins, fixation of iron in the area of inflammation, phagocytosis of iron).
218 N. I. Yabluchansky, V. N. Savchenko
Features of application
There are two indicators when choosing a dose (Table 1) of the drug: the total content of iron salts and the content of free iron. For example, hemostimulin contains 240 mg of iron salt, and free iron - only 50 mg; ferroplex – 50 mg of salt, free iron – 10 mg. When prescribing iron supplements, the dose is calculated not according to the salt composition, but according to the content of free iron.
The minimum daily dose of free iron should be at least 100 mg. The optimal daily dose is 150–200 mg. The optimal dose is well tolerated and can be increased to 300–400 mg (maximum oral dose). Further increase in dose does not lead to a positive effect, since absorption does not increase. The therapeutic dose range for iron is 100–400 mg. The choice depends on individual iron tolerance and the severity of anemia. Usually the daily dose is divided into 3-4 doses. When prescribing high doses (more than 200 mg), it is advisable to divide them into 6-8 doses, since it is believed that the tolerability of high doses improves with divided doses. To improve the tolerability and absorption of iron supplements, it is recommended to take Pancreatin, Festal and other enzyme preparations an hour before taking iron supplements. If dyspepsia occurs when taking iron before meals, it can be prescribed 2 hours after meals.
Treatment of iron deficiency anemia always begins with iron supplementation. Only for special indications is it transferred to parenteral administration. The results of treatment are assessed by changes in the content of reticulocytes. It is believed that reticulocyte crisis appears 3–7 days after the start of treatment with iron supplements. The content of reticulocytes can increase to 10–20 ‰. The maximum reticulocyte reaction occurs 7–10 days from the start of treatment. With proper treatment, the increase in hemoglobin begins from 5 days. Lack of growth during this period does not indicate poor absorption. A normal increase in hemoglobin is 1% per day, or 0.15 g/day. With proper treatment, restoration of normal hemoglobin levels should occur within 3–6 weeks from the start, and complete normalization occurs after 2–3 months. Restoration of iron reserves occurs 4–6 months from the start of treatment, and the course of treatment for iron deficiency anemia should be at least 4–6 months.
If within a month hemoglobin does not tend to recover, it is necessary to analyze all treatment tactics and draw conclusions.
After a course of treatment with iron preparations, it is recommended to repeat courses 2-3 times every six months to consolidate the effect. In general, the treatment process for anemia lasts about 2 years.
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Table 1 |
||||||
Iron supplements for enteral use | ||||||
Complex drugs | ||||||
drugs | Name | |||||
Ferroplex | ||||||
gradumet | ||||||
Vitamin C | ||||||
Sorbifer | ||||||
prolongatum | ||||||
Aktiferin | ||||||
(capsules, drops, | ||||||
Ferumaksin | ||||||
Tardiferon | Vitamin C | |||||
Mucoprotease | ||||||
Vitamin C | ||||||
Gynotardiferon | Mucoprotease | |||||
Folic acid | ||||||
Vitamin C | ||||||
Nicotinamide | ||||||
Vitamins of group B | ||||||
FeSO4 | ||||||
Pantothenic | ||||||
Vitamin C | ||||||
Nicotinamide | ||||||
Vitamins of group B | ||||||
Folic acid | ||||||
Carbonate | Globigen | B12, tocopherol | ||||
(capsules) | Sodium selenite | |||||
Zinc sulfate | ||||||
Hemoferon | Folic acid | |||||
B12 | ||||||
ammonium | ||||||
Ranferon-12 | Folic acid | |||||
(elixir) | B12, ethyl alcohol | |||||
Ranferon-12 | Vitamin C, B12 | |||||
Folic acid | ||||||
(capsules) | ||||||
Zinc sulfate | ||||||
Gemsineral TD | B12 | |||||
Folic acid | ||||||
Globiron N | Folic acid | |||||
B12, +B6 | ||||||
(capsules) | ||||||
Docusate sodium | ||||||
Gluconate | Totem (ampoules, | Copper gluconate | ||||
Manganese gluconate | ||||||
Hydroxide | Globiron | |||||
Globigen | Folic acid | |||||
Maltofer-foul | ||||||
polymal- | Maltofer – Increased iron content in the body (hemolytic anemia, hemochromatosis). – Impaired absorption of iron - pseudoiron deficiency (aplastic anemia due to lead poisoning, hypothyroidism, congenital constitutional anomaly, etc.). – Anemia caused by vitamin B deficiency 12 (Addisson-Biermer anemia). – Hemoblastoses. Relative contraindications: – Gastrointestinal diseases (peptic ulcer of the stomach and duodenum, ulcerative colitis, enteritis). – Chronic liver and kidney diseases. – Chronic inflammatory diseases. Possible side effects and symptoms of overdose Allergic reactions. Complications caused by taking iron supplements are often associated with overdose and are divided into: – Spicy: Related to enteral administration: dyspeptic disorders (nausea, vomiting, constipation); collaptoid state (change in tissue permeability with the introduction of large doses of iron); coma and death (especially in children); necrosis of the intestinal mucosa with a single dose of large doses of iron orally; liver damage. Associated with parenteral administration: allergic reactions: often fever, phlebitis, lymphadenitis, generalized reactions are possible, up to anaphylactic shock; observed mainly when using iron dextran; Iron sucrose does not cause anaphylactic reactions (DIAR - dextran-induced anaphylactic reactions) because it does not contain dextran; pain behind the sternum (massive intake of iron into the hematopoietic organs). Private therapeutic pharmacology 221 redness of the neck and face; skin depigmentation with long-term use; AV block. – Chronic: occur with prolonged excessive administration of iron – hemochromatosis (deposition of iron in organs and tissues, primarily in the liver and pancreas (fibrosis, diabetes)). At the first signs of acute or chronic poisoning with iron preparations, it is necessary to stop administering the drug, and also prescribe drugs that remove iron - calcium catacin, disferal, deferoxamine. Interaction with other substances and medications Iron absorption is inhibited by: tannins contained in tea, carbonates, oxalates, phosphates, ethylenediaminetetraacetic acid (used as a preservative). The same effect when taken is caused by drugs: magnesium, calcium, aluminum hydroxide (antacid - reduces the secretion of gastric juice, which is necessary for the absorption of iron), as well as antibiotics of some groups: tetracycline, chloramphenicol and D-penicillamine (form complex compounds that reduce absorption of both antibiotics and iron). Ascorbic, citric, succinic, malic acids, fructose, cysteine, sorbitol, nicotinamide enhance iron absorption. | |||||
