Blood

Blood is the largest tissue of the body which is made up of formed elements suspended in plasma. The formed elements include red blood cells (erythrocytes), white blood cells(leucocytes) and platelets (thrombocytes). The plasma has proteins like coagulation factors, albumin, globulin and some elements dissolved there-in.

DRUGS THAT INFLUENCE ON ERYTHROPOIESIS
Agents influencing on erythropoiesis are divided into drugs that stimulate the formation of erythrocytes (red blood cells) and drugs that inhibit erythropoiesis. Drugs stimulating erythropoiesis are used for the treatment of anemias. Anemia is a condition in which the number of red blood cells and the amount of hemoglobin in the blood are less than normal. Nowadays hypochromic and hyperchromic, hypo- and aplastic, hemolytic anemias are known. Hypochromic anemia is characterized by a decrease in the ratio of the weight of hemoglobin to the volume of the erythrocyte. It means that erythrocytes contain less hemoglobin than they could have under optimal conditions. Mostly, hypochromic anemia is accompanied by iron deficiency state that’s why it sometimes is named hypoferric anemia.

Iron forms the nucleus of the heme, which when combined with appropriate globin chains forms hemoglobin. Hemoglobin is a protein whose structure allows for the reversible binding of oxygen, providing the critical mechanism for oxygen transport from the lungs to other tissues. Ionic iron is a component of myoglobin and enzymes necessary for energy transfer (e.g., cytochrome oxidase, xanthine oxidase, and succinic dehydrogenase), however, the vast majority of iron is normally present in hemoglobin. In addition, iron is stored in the form of ferritin and hemosiderin (in liver, spleen).

Iron deficiency is commonly seen in children during rapid growth periods, in menstruating women, and in pregnant or lactating women. The most common cause of iron deficiency in adults, however, is blood loss. These situations are all associated with increased iron requirements. Iron is normally available in the diet from a wide variety of foods but is especially abundant in meat protein. Iron is absorbed only in ionic conditions, especially in the ferrous form (Fe2+). That’s why iron absorption is increased in the presence of hydrochloric acid (convert nonionic iron to ionic) and ascorbic acid (reduce ferric iron [Fe3+] to ferrous). Absorption is decreased by the presence of chelators or complexing agents in the intestinal lumen. Gastric resection decreases iron absorption by decreasing hydrochloric acid production. Iron is transported across the intestinal mucosal cell by active transport. The absorbed iron can combine with the protein apoferritin to yield ferritin and stored in mucosal cells which are exfoliated and excreted in the feces or can be transported to the plasma where it is bound to transferrin (globulin). Thus iron is transported to the developing erythroid cells in bone marrow. Iron can be stored in two forms: ferritin and hemosiderin. Both ferritin and hemosiderin are stored in macrophages in the liver, spleen, and bone marrow. Most of the iron liberated by the destruction of hemoglobin is conserved and reused by the body. Excretion of iron occurs primarily as desquamation of cells of GI mucosa.

The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia. The treatment of iron deficiency anemia consists of administration of oral or parenteral iron preparations. Ferrous lactate and ferrous sulfate are commercially available for oral administration.

Also combine iron preparations such as “Ferroplex” (ferrous sulfate plus ascorbic acid), ferramide (complex compound of iron with nicotinamide) can be used. Oral iron preparations should be taken between meals for maximum absorption but may be taken with or after meals, if necessary, to minimize adverse GI effects.

Common adverse effects of oral iron therapy include teeth darkening, epigastric discomfort, dark stools, and constipation. These effects are usually dose-related and can often be overcome by lowering the daily dose of iron. It is postulated that iron interferes with hydrogen sulfide (H2S) that leads to the iron sulfide (FeS) production. The last one can cause teeth darkening. On the other hand, hydrogen sulfide is known as stimulating of bowel motility, that’s why decreasing of free hydrogen sulfide volume associated with constipation. Parenteral therapy should be reserved for patients that unable to tolerate or absorb oral iron and patients with extensive chronic blood loss. Parenteral iron agents include ferbitol, fercoven, and ferum-lek. Ferbitol is injected intramuscularly, fercoven is for intravenous injection, and ferum-lek can be used by both routes. Chest tightness, shock, hypotension, tachycardia, flushing, and arrhythmias have occurred in patients receiving parenteral iron preparations.

Large amounts of oral iron cause necrotizing gastroenteritis, with vomiting, abdominal pain, and bloody diarrhea followed by shock and dyspnea. Urgent treatment of overdosing includes stomach lavage with sodium bicarbonate solutions to form insoluble iron salts. Deferoxamine (iron chelating compound) should be given by injection to bind iron. Appropriate supportive therapy for shock and dyspnea (heart glycosides, hypertensive agents, and analeptics) must also be provided.

Some agents of cobalt are indicated for the treatment of hypochromic anemia. One of them is coamide. It is a complex compound of cobalt with nicotinamide. Coamide stimulates erythropoiesis and promotes assimilating of iron. It is administered subcutaneously. In addition, copper-containing agent “Hemostimulin” (copper sulfate, ferrous sulfate, and dry dietary blood) is indicated for the treatment of hypochromic anemia as well as nicotinic acid.

Erythropoietin is a glucoprotein that stimulates erythroid proliferation and differentiation. It is produced by the kidney in response to tissue hypoxia. When anemia occurs, more erythropoietin is produced by the kidney. Recombinant human erythropoietin (epoetin alpha) is produced in a mammalian cell expression system using recombinant DNA technology. Erythropoietin is indicated in the treatment of anemia associated with renal failure, chronic inflammation, AIDS, and cancer.

Hyperchromic anemia is characterized by an increase in the ratio of the weight of hemoglobin to the volume of the erythrocyte. It means that the erythrocytes contain more hemoglobin than normal. Usually, hyperchromic anemia is associated with vitamin B12 and/or folic acid deficiency. It leads to impaired DNA synthesis, inhibition of normal mitosis, and abnormal maturation of the cells. These changes are most apparent in tissues where cells undergo rapid cell division, such as the bone marrow and the gastrointestinal epithelium. It is characterized by diminished cell division in the face of continued RNA and protein synthesis. This leads to the production of large (macrocytic) erythrocytes that have a high RNA:DNA ratio and are defective in the sense that they are highly susceptible to destruction. Also, anemias caused by vitamin B12 and folic acid deficiency is called megaloblastic anemia.

Vitamin B12 is a group of cobalt-containing substances (cobalamins), having biologic activity in humans. Vitamin B12 is synthesized by microorganisms and it is present in many foods of animal origin, particularly liver, kidney, fish, and meat; plants contain minimal amounts of the vitamin. Cyanocobalamin is a cobalamin that found in food. In humans, an exogenous source of vitamin B12 is required for nucleoprotein and myelin synthesis, cell reproduction, normal growth, and the maintenance of normal erythropoiesis. Cells characterized by rapid division (e.g., epithelial cells, bone marrow, and myeloid cells) appear to have the greatest requirement for vitamin B12. Сoenzyme B12 is essential for synthesis of methionine. Vitamin B12 also can be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic (pernicious) anemia of Addison-Birmer, GI lesions (glossitis) and neurologic damage (paresthesia, disorder of gait) that begins with an inability to produce myelin.

Vitamin B12 is absorbed from the small intestine following oral administration. In the stomach, free vitamin B12 (extrinsic Castle’s factor) is attached to intrinsic factor (IF or intrinsic Castle’s factor); IF, a glycoprotein secreted by the gastric mucosa, is necessary for active absorption of the vitamin from the GI tract. Absorption of cyanocobalamin following oral administration is decreased by structural or functional damage to the stomach or ileum. In the intestinal mucosal cell, vitamin B12 is released from the vitamin B12-IF complex and becomes rapidly bound to plasma proteins. Vitamin B12 is distributed into the liver, bone marrow, and other tissues.

Cyanocobalamin is usually considered the vitamin B12 preparation of choice. It is used in the treatment of pernicious anemia and in patients with malabsorption of vitamin B12, such as those with partial or total gastrectomy, regional enteritis, and ileal resection. The drug has been used for the management of hepatitis, neuralgia and neuropathies, and multiple sclerosis. Vitamin B12 is usually nontoxic even in large doses; however, mild diarrhea, peripheral thrombosis, and itching have been reported.

Folic acid (vitamin Bc, pteroylglutamic acid) is a compound composed of a pteridine heterocycle, p-aminobenzoic acid, and glutamic acid. It is present in a wide variety of foods, particularly liver, kidneys, yeast, and leafy, green vegetables. Also it has been synthesized in bowel by microflora. In man, an exogenous source of folate is required for nucleoprotein synthesis and the maintenance of normal erythropoiesis. Folic acid is the precursor of active tetrahydrofolic acid, which is involved in the biosynthesis of purines and thymidylates of nucleic acids. The folate cofactors are interconvertible by various enzymatic reactions and serve the important biochemical function of donating one-carbon units at various levels of oxidation. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias.

Folic acid is absorbed rapidly from the small intestine following oral administration. Tetrahydrofolic acid and its derivatives are distributed into all body tissues; the liver contains about one-half of total body folate stores. Folic acid is largely metabolized in the liver and is excreted by kidneys.

Folic acid is used for the treatment of megaloblastic and macrocytic anemias, resulting from folate deficiency, megaloblastic anemias of pregnancy and infancy, tropical sprue, megaloblastic anemia associated with liver disease and alcoholism. It is used orally. Folic acid is relatively nontoxic. Allergic reactions to it have been reported rarely.

Drugs that inhibit erythropoiesis are used for the treatment of polycythemia (erythremia). Bone marrow hyperplasia and an increase of erythrocytes in blood characterize this disease. Radioactive phosphorus-32 isotope (32P), which is a β-emitter, is used for polycythemia treatment. Also, it causes leukopenia and thrombocytopenia.

DRUGS FOR PARENTERAL NUTRITIONAL THERAPY
This group includes hydrolysin, aminocrovine, and polyamine. These drugs contain amino acids and are indicated for nutrition during therapy of cachexia, unconscious state, starvation, pre- and postoperative state. They should be used only when the gut cannot be used (operation at gullet or stomach). Hydrolysin is obtained by hydrolysis of serum proteins of cattles; aminocrovine is the hydrolysate of human blood proteins; and polyamine is the complex of 13 amino acids. Lipofundin (intralipid) is fat emulsion that produced from safflower oil. It contains emulsified fat particles, similar to naturally occurring chylomicrons. Intravenous fat emulsion provides the patient requiring parenteral nutrition with a source of calories and the essential fatty acids (polyunsaturated).

PLASMA SUBSTITUTES AND DEINTOXICATION SOLUTION.
Polyglucin (dextran 60) and reopolyglucin (dextran 40) are a glucose polymers (dextrans) with average molecular weights of approximately 60,000 and 40,000 correspondently. The principal effect of dextrans following intravenous administration is plasma volume expansion, resulting from the drugs colloidal osmotic effect in drawing fluid from the interstitial to the intravascular spaces. Plasma volume expansion is accompanied by an increase of cardiac and urinary output, of blood pressure (hemodynamic action). Polyglucin possesses more strong hemodynamic effect than reopolyglucin. However, reopolyglucin improves microcirculation by diminished erythrocyte aggregation and blood viscosity. About 70% of a dose of reopolyglucin are excreted unchanged in urine within 24 hours after administration. Polyglucin is not excreted by the kidneys but is slowly degraded to glucose.

Dextrans, especially polyglucin, are used for fluid replacement and for plasma volume expansion in the treatment of shock resulting from burns, surgery, hemorrhage, or other trauma in which a circulating volume deficit is present. Reopolyglucin is also used for prophylaxis and treatment of thromboembolic complication, during extracorporeal circulation.

Adverse effects of dextrans include allergic reactions such as urticaria, hypotension, and sometimes anaphylactoid reactions. Care must be taken in administering dextrans to patients with impaired renal function, pulmonary edema, or congestive heart failure.

Albumin human is a solution of serum albumin prepared from blood obtained from healthy human donors. Serum albumin is an important factor in the regulation of plasma volume through its contribution to the oncotic pressure of plasma. Intravenous administration of albumin human causes a shift of fluid from the interstitial spaces into the circulation, reducing hemoconcentration and blood viscosity, and raising of blood pressure. Albumin contains amino acids and provides modest nutritive effect. Albumin functions as a carrier of intermediate metabolites (bilirubin), trace metals, and some drugs, thus affecting their transport, and inactivation. Albumin human solutions are used in the treatment of shock resulting from burns, surgery, and hemorrhage; of hypoproteinemia (hepatic cirrhosis, postoperative patients); of cerebral edema. Adverse reactions, which may be caused by allergy or protein overload, include chills, fever, vomiting.

Gelatinol is an agent of splited food gelatin. It is used as a hemostat, plasma substitute, and protein food adjunct in malnutrition. Polyvinylpyrrolidone (povidone) derivative solutions are neohemodes and enterodes. Polyvinylpyrrolidone is a synthetic polymer. All above-mentioned derivatives has low molecular weight (8 000 and 12 000). Also, these agents contain ions of sodium, potassium, calcium, magnesium, and chlorine. Polyvinylpyrrolidone binds with toxins in blood and eliminate them quickly from organism. In addition, these preparations improve the blood circulation in kidneys, enhance the diuresis, and can act as a plasma extender. Neohemodes is injected intravenously for deintoxication that caused by gastrointestinal diseases (e.g., dysentery and salmonellosis), acute liver and kidney insufficiency, burns, etc. Quick infusion of neohemodes can diminish the blood pressure. Enterodes has the same indications as neohemodes but it used orally. Glucose (dextrose) is a monosaccharide. It increases blood glucose concentrations, provides calories, induces diuresis depending on the volume administered. 5% glucose solution is isotonic solution and 40% glucose solution is hypertonic. Glucose injections are used for the treatment of hypoglycemia, and as source of calories and water for hydration/deintoxication during infection diseases, liver disorders, heart insufficient, shock, and collapse. Hypertonic glucose injections are used to provide adequate calories in a minimal volume of water. Hyperglycemia may occur as a result of the rate of administration or metabolic insufficiency.

SALT SOLUTIONS
Solution of sodium chloride provides electrolyte supplementation. Sodium is the major cation of extracellular fluid and functions principally in the control of water distribution, fluid and electrolyte balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of acid-base balance. Chloride, the major extracellular anion, closely follows the physiologic disposition of sodium. 0.9% solution of sodium chloride is an isotonic solution because it has approximately the same osmotic pressure as body fluids. 3% and 5% sodium chloride are the hypertonic solutions. Isotonic sodium chloride is used for extracellular fluid replacement during shock or collapse; irrigation of wounds, eyes, noise, and mucosa; deintoxication during poisoning; and dilution of drugs before their using. Hypertonic sodium chloride is used in the management of purulent wounds (it promotes outflow of pus); uterine and gastrointestinal bleeding; as weak antimicrobe agent. Excessive administration of sodium chloride may result in hypernatremia and lose of bicarbonate with an acidifying effect.

Ringer's solution includes sodium chloride, sodium bicarbonate, potassium chloride, calcium chloride, and water for injection. It has even more “physiologic” content than 0,9% solution of sodium chloride. Ringer’s solution has the same indication as sodium chloride. Such solutions as “Quartasol”, “Trisol”, “Acesol”, etc contain sodium chloride and potassium chloride; “Quartasol” and “Trisol” also include sodium bicarbonate. These solutions decrease hypovolemia and blood viscosity, hinder the development of acidosis, promote microcirculation, increase diuresis, and cause deintoxication. Thus, they are used for the treatment of intoxication and hypohydremia during different diseases (e.g., cholera, dysentery).

PREPARATIONS OF CALCIUM AND POTASSIUM
Calcium is essential to transmission of nerve impulses, contraction of muscles, bone formation, and blood coagulation. Calcium also plays regulatory roles in the release of hormones, in the maintenance of the capillary permeability. Calcium deficiency is characterized by reduced bone mass (osteoporosis) and tetany (twitches, cramps). Calcium is absorbed from the GI tract. Vitamin D and parathyroid hormone increase the capability of the absorptive mechanisms. More than 99% of total body calcium is found in bone and teeth.

Calcium salts are used for the treatment or prevention of calcium depletion. Also, calcium therapy is used for the treatment of heart arrest, allergic reactions, bleeding, hyperpermeability of vessels (vasculitis), skin diseases (psoriasis, itching), hepatitis. For oral and intravenous administration, the gluconate, lactate, and chloride salts of calcium are available.

Calcium salts, especially chloride, by any route of administration can produce irritation. They may cause local necrosis if they will be injected subcutaneous. Rapid injection may cause vasodilation, decreased blood pressure, and arrhythmias.

Potassium is the major cation of intracellular fluid and is essential for maintenance of isotonicity and electrodynamic characteristics of the cell. Potassium is essential to transmission of nerve impulses, contraction of muscles, gastric secretion, and renal function. Potassium supplements are used for treatment of arrhythmias, potassium depletion. Conditions, which may result in potassium deficiency, include vomiting, diarrhea, and administration of certain drugs including diuretics, corticosteroids, and cardiac glycosides. In addition, potassium chloride is a component of several multiple electrolyte intravenous infusion fluids.

For oral and intravenous administration, “Panangin” (potassium asparaginate) and potassium chloride are available. Hyperkalemia is the most common hazard of potassium therapy. It is accompanied by paresthesia, arrhythmias, and vomiting.

ACIDIFYING AND ALKALINIZING AGENTS
Ammonium chloride is an acid-forming salt that result from dissociation of the salt to an ammonium cation and a chloride anion. The chloride anion combines with fixed bases in the extracellular fluid, thereby reducing the alkaline reserve of the body and acidosis results. It increases sodium and water excretion that leads to diuretic effect.

Ammonium chloride is used orally. Also it increases bronchial secretion and facilitates its expulsion. Ammonium chloride is used for the treatment of metabolic alkalosis, edematous conditions, and bronchitis. It may cause metabolic acidosis and irritation of gastric mucosa. Hydrochloric acid (HCl) is the acid of gastric juice. It possesses strong irritant potency. It is used internally as diluted hydrochloric acid for hypo- or achlorhydria.

Sodium bicarbonate is an alkalinizing agent, which dissociates to provide bicarbonate ion. Sodium bicarbonate is used in the treatment of metabolic acidosis, certain intoxications (e.g., phenobarbital, and salicylates), for increasing of the solubility of certain weak acids (e.g., sulfanilamides, uric acid), for bettering of expulsion of the bronchial secretion during bronchial asthma. For the use of sodium bicarbonate as an antacid, see “Antacids”.

DRUGS USED IN DISORDERS OF COAGULATION
Hemostasis is the spontaneous arrest of bleeding from a damaged blood vessel. The immediate hemostatic response of a damaged vessel is vasospasm. Within seconds, platelets stick to the exposed collagen of the damaged endothelium (platelet adhesion) and to each other (platelet aggregation). This localized stasis triggers blood coagulation that is characterized by the transformation of soluble fibrinogen into insoluble fibrin. Blood coagulation and thrombus formation must be confined to the smallest possible area to achieve local hemostasis in response to bleeding from trauma or surgery without impaired blood flow. Fibrinolysis regulates and delimits hemostasis.

Bleeding and thrombosis are altered states of hemostasis. Impaired hemostasis results in spontaneous bleeding; stimulated hemostasis results in thrombus formation. The drugs used to arrest bleeding and to inhibit thrombosis are the subjects of this chapter.

Drugs that used for the prevention or treatment of thrombosis are the next:

1. Anticoagulant drugs

1.1	anticoagulants of direct action (heparin, enoxaparin, sodium citrate, hirudin);

1.2	anticoagulants of indirect action or oral anticoagulants (neodicumarin, syncumar, phenylin).

2. Antiaggregate drugs (acetylsalicylic acid, ticlopidine, and dipyridamole).

3. Fibrinolytic drugs (streptokinase, streptodecase, urokinase, and alteplase).

Heparin is an anionic, sulfated glycosaminoglycan present in mast cells. It average molecular weight is about 12,000. Heparin is strongly acidic and reacts with certain basic compounds resulting in a loss of pharmacologic activity. Commercial heparin is prepared from either porcine intestinal mucosa or bovine lung tissue. Heparin potency is expressed in International Units.

Effects. Heparin acts as a catalyst to markedly accelerate the rate at which antithrombin III (heparin cofactor) neutralizes thrombin and activated coagulation factor IX, X, XI, XII. In low doses heparin prevents the conversion of prothrombin to thrombin and in higher doses it inhibits the conversion of fibrinogen to fibrin. Patients with familial antithrombin III deficiency may appear to be resistant to the effects of heparin, since adequate levels of antithrombin III are necessary for the drug's anticoagulant effect. Heparin therapy produces prolongation of the activated coagulation time, whole blood clotting time, etc. Heparin clears lipemic plasma by stimulating of lipoprotein lipase, which hydrolyze triglycerides to free fatty acids and glycerol. Heparin in high doses has been reported to decrease on platelet aggregation.

Heparin is not absorbed from the GI tract and must be administered parenterally. The onset of anticoagulant activity is immediate following direct intravenous injection and occurs within 30-60 minutes following subcutaneous. The duration of action is about 2-6 hours. The drug is metabolized in vessels endothelium and in the liver.

Indications. Heparin is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, chronic consumptive coagulopathies (disseminated intravascular coagulation). Fixed low-dose subcutaneous heparin therapy is used for prevention of postoperative deep-vein thrombosis and pulmonary embolism in patients undergoing major abdominal or thoracic surgery who are at a risk of thromboembolic disease. Heparin is the anticoagulant of choice when an immediate effect is required. An oral anticoagulant (usually a coumarin derivative) is generally used for follow-up anticoagulant therapy after the heparin therapy has been established and when long-term anticoagulant therapy is indicated. In first case therapy with the two drugs should be overlapped for a short period of time.

Hemorrhage, the major adverse effect of heparin therapy, is an extension of the pharmacologic action of the drug and may range from minor local ecchymosis to major hemorrhagic complications. Nosebleed, hematuria, or tarry stools may be noted as the first sign of bleeding or overdosage; easy bruising or petechiae may precede frank bleeding. That’s why the coagulation time and whole blood clotting time should be determined during heparin therapy in all patients. Discontinuance of heparin will usually correct minor bleeding or overdosage within a few hours. If severe hemorrhage or overdosage occurs, protamine sulfate should be administered immediately. In adequate dosage, protamine sulfate neutralizes the anticoagulant effect of heparin. Deep subcutaneous injection of heparin may rarely cause local irritation, hematoma, or cutaneous necrosis.

Enoxaparin is a depolymerized heparin. The average molecular weight of enoxaparin is approximately one-third that of regular heparin; therefore, enoxaparin is referred to as a low molecular weight heparin. Enoxaparin has less effect on thrombin than does unfractionated heparin. However, enoxaparin has more antiaggregation properties. Compared with unfractionated heparin, enoxaparin has greater bioavailability after subcutaneous administration and a longer half-life, allowing less frequent administration (1-2 times per day). Enoxaparin is used for the prevention of postoperative deep-vein thrombosis. The usual precautions and contraindications associated with heparin anticoagulation therapy should be followed in patients for whom enoxaparin therapy is considered.

Sodium citrate binds calcium-ions in blood that prevents blood clotting. It is used as stabilizator of blood during its conserving. Hirudin is a powerful and specific thrombin inhibitor from the leech, which is now being prepared by recombinant DNA technology.

Oral anticoagulants

Coumarin anticoagulants (neodicumarin, syncumar) are the derivatives of 4-oxycoumarin. Indandione anticoagulant (phenylin) is a derivative of indandione. Coumarin and indandione derivatives are indirect-acting anticoagulants.

Effects. Coumarin and indandione derivatives alter the synthesis of blood coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor), and X (Stuart-Prower factor) in the liver by interfering with the action of vitamin K, which is necessary for the gamma-carboxylation of several glutamic acid residues in the precursor proteins of these coagulation factors. In adequate dosage, phytonadione (vitamin K1) reverses the effect of coumarin and indandione derivatives on the hepatic synthesis of vitamin K-dependent coagulation factors. In contrast to heparin, coumarin and indandione derivatives have no anticoagulant effect in vitro.

Because coumarin and indandione derivatives do not alter catabolism of blood coagulation factors, depletion of circulating functional vitamin K-dependent coagulation factors must occur before effects of the drugs become apparent. An anticoagulant effect generally occurs within 24 hours following administration of neodicumarin, but peak anticoagulant and antithrombogenic effects may be delayed for 72-96 hours. Similarly, there is a period of latency following discontinuance of the drugs until blood concentrations of functional vitamin K-dependent coagulation factors return to pretreatment levels. Coumarin- or indandione-derivative therapy inhibits thrombus formation and may prevent extension of existing thrombi. The drugs have no direct effect on established thrombi. Neodicumarin, syncumar, and phenylin are well absorbed from the GI tract. Coumarin and indandione derivatives are usually detectable in plasma within 1 hour following oral administration, and peak plasma concentrations of the drugs are usually attained within 1-12 hours. They are 97% or more bound to plasma proteins, primarily albumin. Coumarin and indandione derivatives are hydroxylated by hepatic microsomal enzymes to inactive metabolites. In general, coumarin and indandione derivatives are excreted in bile as inactive metabolites, then they are reabsorbed, and excreted in urine. Indications. The most widely accepted indications for anticoagulant therapy include the treatment of venous thrombosis and pulmonary embolism and prevention of these conditions in high-risk patients. A coumarin derivative is generally used for follow-up anticoagulant therapy after the effects of full-dose heparin therapy have been established and when long-term anticoagulant therapy is indicated.

The efficiency of indirect-acting anticoagulants is measured by prothrombin ration: it must be not less than 40-50% (normal is 80-100%). Hemorrhage is the most common adverse effect of indirect-acting anticoagulants. If moderate or severe hemorrhage occurs or if the prothrombine time is excessively prolonged, the drug should be discontinued immediately and phytonadione administered. Coumarin and indandione derivatives should be used with caution in any condition where added risk of hemorrhage is present. Concurrent administration of numerous drugs has been reported to affect patient response to indirect-acting anticoagulants. Nonsteroidal anti-inflammatory agents (aspirin, butadione) can inhibit platelet aggregation and displace of albumin-bound indirect-acting anticoagulants, increasing their free fraction. These changes can cause GI bleeding and peptic ulceration. Barbiturates and rifampin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes that transform neodicumarin. Cumarin derivatives potentiate the action of the hypoglycemic agents and diphenine, because cumarins inhibit hepatic metabolism of these drugs.

Fibrinolytic agents

Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin (fibrinolysin) from its precursor zymogen, plasminogen (profibrinolysin). These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down.

Streptokinase is a nonenzymatic protein produced by group C β-hemolytic streptococci. The activity of streptokinase is expressed in International Units (IU). Streptokinase promotes thrombolysis. Streptokinase converts plasminogen into the proteolytic enzyme plasmin. Plasmin degrades fibrin, fibrinogen, and other plasma procoagulant proteins. Plasmin is inactivated by circulating inhibitors, including α2-antiplasmin. Plasmin generated in the circulation is bound to antiplasmin and is released at the thrombus site resulting in external lysis. The effects of streptokinase on coagulation usually disappear within a few hours but may persist for up to 12 hours after discontinuance of intravenous infusion. Laboratory control during fibrinolytic therapy includes assure of thrombin time and fibrinogen amount. During the first few hours of streptokinase therapy, the drug may rapidly activate plasminogen and cause hyperplasminemia that may lead to coagulation defects.

Streptokinase has been shown to decrease the viscosity of blood and plasma, and to decrease the erythrocyte and platelet aggregation tendency, thus increasing blood flow and perfusion of collateral blood vessels.

Following intravenous infusion, streptokinase is rapidly cleared from the circulation. The serum half-life is about 80 minutes. Streptokinase is used as a thrombolytic agent in selected cases of myocardial infarction, pulmonary embolism, acute vein or arterial thrombosis. The drug is generally most effective in lysing recently formed thrombi. For example, streptokinase therapy should be initiated as soon as possible after myocardial infarction, preferably within 3-6 hours, since potential clinical benefit diminishes as the time period to initiation of therapy increases. Streptokinase therapy should be initiated no later than 3 days, after onset of the thromboembolic episode.

The most frequent and severe adverse effects of streptokinase therapy are hemorrhage, fever, and allergy. Severe spontaneous bleeding has occurred during streptokinase therapy. If serious spontaneous bleeding occurs, streptokinase therapy should be terminated immediately. Plasma volume expanders and aminocaproic acid may be used. Streptokinase is strongly antigenic; repeated administration elicits antibodies that diminish the effect of the drug and may cause allergic reactions, including anaphylaxis.

Streptodecase – is an agent of streptokinase that binds with polysaccharide water-soluble molecule. It ensures prolong releasing of streptokinase. One infusion of streptodecase provides fibrinolytic effect during subsequent 3 days.

Urokinase is an enzyme produced by the kidneys and excreted in urine. Commercially available urokinase is isolated from human kidney tissue cultures. The activity of urokinase is expressed in International Units (IU). Urokinase has the same mechanism action as streptokinase. The fibrinolytic effect of urokinase usually disappears within a few hours but increased thrombin time, decreased plasma levels of fibrinogen and plasminogen may persist for up to 12-24 hours following discontinuance of the infusion.

Agent reportedly is not absorbed from the GI tract. Following intravenous infusion, the drug is rapidly cleared from the circulation. Urokinase is estimated to have a plasma half-life of 10-20 minutes. Urokinase has the similar indications with streptokinase. The most frequent and severe adverse effect of urokinase therapy is hemorrhage. In contrast to streptokinase, urokinase is reportedly nonantigenic. Alteplase, a biosynthetic (recombinant DNA origin) form of the enzyme human tissue-type plasminogen activator (t-PA), is a thrombolytic agent. Endogenous human t-PA is a serine protease secreted principally by vascular endothelial cells. It may be activated by several endogenous proteases, including plasmin, tissue kallikrein, and trypsin.

Alteplase is a thrombolytic agent. t-PA as well as streptokinase and urokinase promote conversion of plasminogen into form of plasmin. During physiologic fibrinolysis, the activity of circulating plasmin is inhibited rapidly (half-life approximately 100 msec) by α2-antiplasmin. The fibrinolytic activity of plasmin is maintained within the thrombus because the active sites of plasminogen (and thus plasmin) at which fibrin binds are the same sites at which α2-antiplasmin binds. Fibrin-bound plasmin within the thrombus, therefore, is relatively protected from inactivation. Thrombolytic agents such as streptokinase and urokinase activate both fibrin-bound and circulating plasminogen indiscriminately; systemic activation of plasminogen results in the release of large amounts of plasmin into the circulation that leads to degradation of plasma procoagulant proteins. Predominantly, alteplase activates fibrin-bound plasminogen.

Alteplase is not absorbed after oral administration and must be administered parenterally. It has the resemble uses to streptokinase. The most frequent and severe adverse effect of alteplase therapy is hemorrhage.

Antiaggregate agents

Platelet function is regulated by two categories of substances. The first group consists of agents that induce the platelet aggregation, e.g., and thromboxane A2, collagen, thrombin, ADP, calcium ions, prostaglandin E2, serotonin, and catecholamines. The second category contains agents that inhibit platelet aggregation, e.g., prostacyclin I2, AMP, adenosine, methylxanthines, and heparin. The prostaglandin thromboxane A2 is an arachidonate product that causes platelets to aggregate. It is synthesized in platelets. Prostacyclin I2 is an arachidonate product also, but it inhibits aggregation and adhesion of platelets. Prostacyclin I2 is formed in endothelium of vessels wall. Acetylsalicylic acid (aspirin) inhibits the synthesis both of thromboxane A2 and prostacyclin I2 by inactivation of the enzyme cyclooxygenase. However, inhibition of cyclooxygenase in platelets is irreversible, because the anuclear platelet cannot synthesize new proteins, it cannot manufacture new enzyme during its 10-day lifetime. That’s why diminish of thromboxane A2 is more evident. Other salicylates and other nonsteroidal anti-inflammatory drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because their action is reversible. Daily dose 325 mg of aspirin is approved for prophylaxis of myocardial infarction. The risk-versus-benefit measure of aspirin as a prophylactic drug is questionable for patients with peptic ulcer disease.

Ticlopidine reduces platelet aggregation by inhibiting the ADP pathway of platelets. Unlike aspirin, the drug has no effect on prostaglandin metabolism. It is used in the prevention of vascular events among patients with transient ischemic attacks, completed strokes, and unstable angina pectoris. Adverse effects include nausea, diarrhea, hemorrhage, and, most seriously, leukopenia. It is particularly useful in patients who cannot tolerate aspirin.

Dipyridamole (curantyl) increases endogenous concentrations of adenosine and cyclic adenosine monophosphate (cAMP) by inhibiting their destruction. It is postulated that adenosine and cAMP are the platelet aggregation inhibitors. Also adenosine is a coronary vasodilator. Dipyridamole is indicated to prevent thromboembolic complications, in the treatment of occlusive vascular diseases as well as to reduce the recurrence of transient ischemic attacks and risk of reinfarction.

Dipyridamole may preferentially dilate, and increase blood flow through, nondiseased coronary blood vessels, leading to a redistribution of blood flow away from significantly stenotic coronary vessels. This "coronary steal" effect may leads to angina pectoris. Dipyridamole dilates the blood vessels and its using can be accompanied by hypotension, tachycardia, and flushing.

Drugs used in bleeding disorders are divided into:

1. Coagulant drugs

1.1. drugs for topical using (thrombin, gelatin sponge);

1.2. drugs for general using (fibrinogen, cryoprecipitate).

2. Antagonists of anticoagulant drugs (protamine sulfate, vitamin K).

3. Inhibitors of fibrinolysis (aminocaproic acid, contrycal, aprotinin, etc).

4. Coagulating substances of plant nature (leaf of nettle, water pepper, etc.).

Thrombin is a hemostatic agent. It is commercially available as a powder containing the protein substance prepared from prothrombin of human serum. Thrombin affects hemostasis principally by converting fibrinogen to fibrin. Agent is used topically as an aid in hemostasis when oozing blood and minor bleeding from capillaries and small venules is accessible. Thrombin solutions may be used in conjunction with absorbable gelatin sponge for hemostasis. Gelatin increases blood stickness.

Fibrinogen is prepared from normal human plasma. It is a coagulant (clotting factor II) and used as an adjunct in the management of acute, congenital, or acquired chronic hypofibrinogenemia. It is injected intravenously. Cryoprecipitate is a plasma protein fraction and is obtainable from whole blood. It is used to treat deficiencies of factor VIII in patients with hemophilia A and occasionally to provide fibrinogen.

Calcium-ions stimulate forming of thromboplastine, transforming of prothrombine to thrombine and polymerization of fibrin. Calcium drugs are administered during hypocalcemia (transfusion of citrate blood), during increased permeability of capillaries (hemorrhagical vasculitis), before operations.

Protamine is a cationic protein that occurs in the sperm of certain species of fish. Commercially available protamine sulfate is prepared from the sperm of salmon. Protamine sulfate, which is strongly basic, acts as a heparin antagonist in vitro and in vivo by complexing with strongly acidic heparin to form a stable nonactive salt. Protamine sulfate is used in the treatment of severe heparin calcium or heparin sodium overdosage. Hypersensitivity reactions including urticaria, angioedema, and anaphylactoid reactions have occurred occasionally after administration of protamine sulfate.

Vitamin K (antihemorrhagic vitamin) is a fat-soluble substance. Two natural forms exist: vitamins K1 and K2. Vitamin K1 (phyloquinone) is found primarily in leafy green vegetables. Vitamin K2 (menaquinone) is found in animal liver, and is synthesized by intestinal bacteria in human organism. Vitamin K is required for the synthesis of blood coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor), and X (Stuart-Prower factor) in the liver. In adequate doses, vitamin K reverses the inhibitory effect of coumarin and indandione derivatives on the synthesis of these factors. Vitamin K deficiency, which occur in the presence of malabsorption syndromes (colitis, enteritis, and jaundice), is associated with low blood level of prothrombin and others coagulation factors that is exhibited by bleeding.

Phytomenadione (phytonadione) is identical to naturally occurring vitamin K1. Like another lipid-soluble vitamins, vitamin K1 is absorbed from the GI tract only in the presence of bile salts. Vicasol (menadione) is the water-soluble salt of vitamin K3.. Vicasol is available both for oral using and for injection. Vitamin K is used in the treatment of bleeding that associated with hypoprothrombinemia, hemorrhagic disease of the newborn. The hemostatic effect of vitamin K is delayed for 6 hours. Vitamin K is relatively nontoxic; however, allergic reactions and thrombosis may appear.

Aminocaproic acid is an inhibitor of fibrinolysis. It inhibits the activation of profibrinolysin (plasminogen) and it also inhibits the action of fibrinolysin (plasmin). Aminocaproic acid is rapidly and completely absorbed from the GI tract. It is excreted in urine as unchanged drug within 12 hours following the dose. Aminocaproic acid is used intravenously as well as orally in the treatment of excessive bleeding resulting from systemic hyperfibrinolysis. Use of the drug should be accompanied by laboratory tests to determine the degree of fibrinolysis present. Adverse effects of aminocaproic acid are mild. They include vomiting, abdominal pain, diarrhea, dizziness, and fever. Contrycal, aprotinin, an animal origin drugs, are the serine protease (trypsin, kinins, plasmin, etc) inhibitors that inhibits fibrinolysis by free plasmin. Aprotinin will reduce bleeding from many types of surgery, especially that involving extracorporeal circulation for open-heart procedures. It is currently approved for use in patients undergoing coronary artery bypass grafting who are at high risk of excessive blood loss. Contrycal inhibits trypsin, kinins, and fibrinolysin. It is used for the treatment of acute pancreatitis because it is associated with excessive serum level of proteases. The most serious adverse effects of these agents are allergic reactions.

Coagulating substances of plant nature (leaf of nettle, water pepper, etc.) include tanning substances, vitamins K, C, P, etc. They cause stabilizing action on vascular wall and increase firmness of capillaries. They are used in form of decocts, tinctures, extracts during chronic bleeding (uterine, intestinal, etc.).

IMMUNOTROPIC AGENTS
The immune system is designed to protect the host from invading pathogens and to eliminate disease. It is provided by two major components: the innate and the adaptive (acquired) immune systems. The innate immune system is the first line of defense against an antigenic insult and includes physical (e.g., skin), biochemical (e.g., complement, lysozyme), and cellular (macrophages, neutrophils) components. The adaptive immune system include production of antibodies, which are the effectors of humoral immunity; and the activation of lymphocytes, which are the effectors of cell-mediated immunity. The generation of specific immunity requires the participation of antigen-presenting cells (macrophages, Langerhans cells) and B-lymphocytes. Cell-mediated immunity is ensured mainly by T-lymphocytes that able to discriminate between foreign ("nonself") antigens and "self" antigens of the host and to respond to a previously encountered antigen in a learned way by initiating a vigorous memory response.

Immunostimulating agents. Such drugs can be used to increase the immune responsiveness of patients who have immunodeficiency. The major potential uses are in immunodeficiency disorders, chronic infectious diseases, and cancer.

Classification of immunostimulating agents.

1.	Agents that stimulates nonspecific immunity (methyluracil, pentoxyl).

2.	Agents that mostly stimulate macrophages and T-lymphocytes (sodium nucleate, BCG, prodigiosane, pyrogenal, thymus agents, levamisole, interferon).

3.	Agents that hasten macrophages and granulocytes formation (filgrastim, molgramostim)

4.	Agents that predominantly stimulate B-lymphocytes (myelopid). Methyluracil and pentoxyl are the derivatives of pyrimidine. These drugs hasten cell regeneration, wounds healing; stimulate cellular and humoral immunity. They indicated in the cure of mild leukopenia, badly closed wounds, burns, bone crash, and ulcer disease of duodenum. Methyluracil and pentoxyl are well absorbed from intestine. These drugs are good tolerated. However, pentoxyl may cause gastrointestinal disorders.

Sodium nucleate, a sodium salt of nucleic acid, is formed by hydrolysis of yeast. It promotes the acceleration of restoring processes; stimulates leukopoiesis, cooperation of T- and B-lymphocytes, and phagocytic properties of macrophages. Sodium nucleate is indicated for different diseases that accompanied with leukopenia. BCG is a viable strain of Mycobacterium bovis that has been used for immunization against tuberculosis. It has also been employed as a nonspecific adjuvant immunostimulant in cancer therapy (leukemia, cancer of intestine, bladder, and breast). BCG appears to act at least in part via activation of macrophages to make them more effective killer cells.

Prodigiosane is a microbial polysaccharide that is extracted from Bac. prodigiosum. It stimulates cellular immunity (T-lymphocytes) and adrenal cortex. It postulates that prodigiosane augments the interferon synthesis. Prodigiosane is prescribed as adjuvant drug in the treatment of diseases that characterized by depressed immunity. For instance, chronic inflammation processes, postoperative period, during antibiotic therapy, badly closed wounds, etc. Agent is injected intramuscularly once per 3-7 days. Fever, headache, arthralgia, and fatigue sometimes are observed after prodigiosane administration.

Pyrogenal (Grecian: pyr- fire, gen- producing) is a microbial polysaccharide that is synthesized by Pseudomonas aeruginosa. It is a fever-inducing agent. Pyrogenal is similar in action to prodigiosane. In addition, pyrogenal stimulates the restoring of central and peripheral nervous system; activates the disappearance of scars. Pyrogenal is indicated in the treatment of chronic prostatitis, chronic inflammation of women reproductive system, inflammation and damages of peripheral and central nervous system, and postburn scars. Agent is prohibited during fever and pregnancy.

Levamisole was first synthesized for the treatment of parasitic infections. Later studies suggested that it appears to act as an immunorestorative agent in the presence of immunosuppression, but does not stimulate the immune response to above normal levels. Thus, it modulates the immune response or acts like immunomodulating agent. Mechanism of action is related to T-cell activation and proliferation, augmentation of monocyte and macrophage activity, and an increase in neutrophil mobility, adherence, and chemotaxis. Levamisole is used for the treatment of both primary and secondary immunodeficiency, autoimmune disease, chronic and relapse infections, cancer, etc. It has also been widely tested in rheumatoid arthritis and found to have efficacy. Agent is taken orally. However, it can induce severe agranulocytosis, which required discontinuation of its use. Thus, levamisole therapy must be under regular leukocyte measurement. Thymalin consists of a group of protein hormones synthesized by the thymus. These proteins have been isolated and purified from bovine thymus glands. Thymalin regulates the amount of T- and B-lymphocytes and activates cell immunity. Thymalin is used for the treatment of different states that are associated with immunodeficiency and depression of hemopoiesis. For example, acute or chronic purulent processes, burns, chemotherapy of patients with cancer, etc. Tactivin is an agent of protein structure, which is obtained from bovine thymus gland. It appears to convey T-cell specificity to uncommitted lymphoid stem cells and to induce the maturation of pre-T cells. Tactivin increases the number of T-lymphocytes. It induces enhanced production of interleukins. This agent is indicated for the treatment of T-lymphocyte deficiency states including psoriasis, leukosis, etc. Thymalin and tactivin are prohibited during pregnancy and in case of hypersensitiveness to these drugs. Vilosen as well as previous drugs are an extract of cattle thymus. It is used locally in drops or inhalation for the treatment of allergic disorders of the upper respiratory ways (allergic rhinitis and sinusitis).

Interferons are belong to cytokines. They have antiproliferative, antimicrobial, and antitumor effects (see chapter “Antiviral agents”). The production of highly purified interferons has been greatly facilitated by the pharmaceutical application of gene cloning techniques. Three major classes of interferons are now recognized: - (leukocyte), - (fibroblast), and -(immune, T-lymphocyte). Each type can function as a potent cytokine with complex antiviral and immunomodulatory activity. -interferon has the stronger action on the immunity than other interferons. Interferons activate macrophages, T-lymphocytes, and natural killer cells. Natural -interferon has been used for prophylaxis and treatment of the common cold virus’s infections and herpes keratitis. Recombinant -interferon (reaferon, itron A) is approved for the treatment of hepatitis B and C, leukemia, bladder and renal carcinoma, and malignant melanoma. Poludan, amixin stimulates the synthesis of endogenous interferon and thus possess antiviral activity. Poludan is a topical agent for the treatment of virial eyes diseases. Amixin is active in case of virus’s hepatitis B and C.

Three cytokines with colony-stimulating properties have been studied extensively and are now being used in humans. They are erythropoietin (see chapter “Drugs that influence on erythropoiesis”), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). G-CSF stimulates mainly the forming of granulocytes. GM-CSF promotes the forming of macrophages or activates combine granulocyte-macrophage colonies. Filgrastim (G-CSF) and molgramostim (GM-CSF) are produced by recombinant techniques. These drugs hasten recovery from neutropenia in patients with malignancies who are receiving chemotherapy and accelerate marrow recovery after autologous bone marrow transplantation.

Myelopid is an immunomodulating agent of peptide structure, which is received from cattle or porcine bone marrow tissue cultures. At immunodeficient patients it restores the indicators of T- and B-lymphocytes, restores the formation of antibodies, and promotes the restoring of another indicators of humoral immunity. Myelopid is used in the cure of acquired immunodeficiency states with predominant confound of humoral immunity, including postoperative aggravations, osteomyelitis, etc. Agent is injected subcutaneously. Adverse effects include vertigo, fatigue, nausea, and fever.

Immunosuppressive agents. Agents that suppress the immune system play an important role in the retention of organ or tissue grafts and in the treatment of certain diseases that arise from dysregulation of the immune response. There is definite overlap between the drugs used for immunosuppression and those used in cancer chemotherapy (cytotoxic drugs). Classification of immunosuppressive agents.

1.	Alkylating agents (cyclophosphane, embichine, chlorbutine, and myelosan).

2.	Antimetabolites (mercaptopurine, azathioprine, methotrexate, and ftoruracil).

3.	Anticancer antibiotics (dactinomycin, rubomycin, doxorubicin, and bruneomycin).

4.	Alkaloids (vinblastine, vincristine).

5.	Steroid hormones and their antagonists (tamoxifen, leuprolide).

6.	Enzymes (aspsaraginase). The major clinically useful alkylating agents are cyclophosphane, embichine (mechlorethamine), chlorbutine, and myelosan (busulfan) are the most useful. As a class, the alkylating agents exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylations of DNA within the nucleus probably represent the major interactions that lead to cell death. Cyclophosphane, chlorbutine are used in the treatment of lymphocytic leukemia, lympholeukosis, Hodgkin’s disease, multiple myelosis, neuroblastoma, ovarian carcinoma, breast cancer, etc. Myelosan used for specialized purposes for chronic myeloid leukemia.

One of the major and dose-limiting adverse effects of alkylating drugs is hematological toxicity. Hematopoietic adverse effects include leukopenia, thrombocytopenia, and anemia. Repeated blood counts are essential during administration of these agents because the development of severe leukopenia or thrombocytopenia necessitates interruption of therapy. Anorexia, nausea, and vomiting occur commonly with alkylating drugs, especially at high doses. It is reported that these effects respond to treatment with antiemetics.

Mercaptopurine and azathioprine are the chemical analogs of the physiologic purines. They are the purine antagonist antimetabolites. Ultimately, the synthesis of RNA and DNA is inhibited. Absorption of mercaptopurine from the GI tract is variable and incomplete, but about 50% of a dose is usually absorbed. It is rapidly and extensively oxidized in the liver by the enzyme xanthine oxidase. Mercaptopurine is used mainly for the treatment of acute leukemia. Adverse hematopoietic effects include leukopenia, anemia, and thrombocytopenia. Adverse GI effects include nausea, vomiting, diarrhea, anorexia, abdominal pain, and ulceration of the intestinal epithelium. Also it is hepatotoxic.

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Although azathioprine action is presumably mediated by mercaptopurine as the active form, it has been more widely used than mercaptopurine for immunosuppression in humans. Immunosuppression with azathioprine therapy seems to result from interference with nucleic acid metabolism at steps that are required for the lymphoid cell proliferation. Azathioprine to be of definite benefits in maintaining renal allografts and may be of value also in transplantation of other tissues. It has proved useful as well in cases of autoimmune diseases (rheumatoid arthritis, acute glomerulonephritis, and Crohn's disease).

Methotrexate is a folic acid antagonist. Methotrexate inhibits dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the synthesis of purines, DNA and cell reproduction. Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. It is completely absorbed from the GI tract. Methotrexate is retained for several weeks in the kidneys and liver. It is used orally, intravenously, and intramuscularly. Methotrexate has the similar uses and adverse effects with mercaptopurine.

Ftoruracil (fluorouracil) is a fluorinated pyrimidine antagonist. It acts as an antimetabolite that inhibits DNA and RNA synthesis. Ftoruracil is used for the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas that is not amenable to surgery or irradiation. The major toxic effects of ftoruracil are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the GI tract. Anorexia, nausea, leukopenia, thrombocytopenia, and anemia occur commonly with ftoruracil therapy. Screening of microbial products has led to the discovery of a number of growth inhibitors that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of new RNA or DNA (or both), cause DNA strand scission, and interfere with cell replication. These agents possess also immunosuppressive properties. Anticancer antibiotics include dactinomycin, rubomycin (daunorubicin), doxorubicin, bruneomycin and others. In clinical use, all mentioned above drugs are administered by the intravenous route.

Doxorubicin is one of the most important anticancer drugs, with major clinical application in carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung. The major use of rubomycin is in acute leukemia. Dactinomycin is used in the complex treatment of Wilms' tumor, chorioepithelioma, etc. Bruneomycin is indicated for lymphogranulematosis, chronic lympholeukosis, Wilm’s tumor, etc.

In common with many other cytotoxic drugs, anticancer antibiotics cause bone marrow depression. All blood elements are affected, but platelets and leukocytes are affected most profoundly, and severe leuko- and thrombocytopenia sometimes occurs. Nausea and vomiting, diarrhea, and oral ulcers may also be noted. Alopecia and various skin abnormalities occur occasionally.

Vinblastine and vincristine are the alkaloids derived from Vinca rosea, the periwinkle plant. Their mechanism of action involves depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle. This results in mitotic arrest at metaphase. Vinblastine has value in the treatment of systemic Hodgkin's disease and other lymphomas. Vincristine has been used with considerable success for acute leukemia. These drugs produce nausea and vomiting and marrow depression as well as alopecia. In addition, vincristine causes a significant incidence of neurotoxicity, which limits its use to short courses.

Steroid hormones (glucocorticoids, androgens, estrogens and their antagonists) bind to receptor proteins in cancer cells, and high levels of receptor proteins are predictive for responsiveness of endocrine therapy. As in normal cells, steroid hormones form a steroid-receptor complex that ultimately binds directly to nuclear nonhistone protein of DNA to activate transcription of associated clusters of genes. Glucocorticoids have immunosuppressive and anti-inflammatory properties. Administration of a glucocorticoid (e.g., prednisolone, dexamethasone) reduces the size and lymphoid content of the lymph nodes and spleen, though it has essentially no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow. Their immunology effects are probably due to their ability to modify cellular functions rather than direct cytotoxicity.

Indications for glucocorticoids include autoimmune disorders such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, and lupus erythematosus. Corticosteroids are also used liberally in organ transplant recipients. The glucocorticoid analogs have been useful in the treatment of acute leukemia, lymphomas, myeloma, and other hematologic cancers. The estrogen inhibitor tamoxifen has proved to be extremely useful for the treatment of breast cancer and endometrial cancer. An antiandrogen, flutamide, has been approved for use in the treatment of prostate cancer. Finasteride, a nonsteroidal inhibitor of 5-testosterone reductase, the enzyme that converts testosterone to dihydrotestosterone, is approved only for the therapy of benign prostatic hyperplasia.

Leuprolide is a synthetic peptide analog of naturally occurring gonadotropin-releasing hormone. It inhibits the releasing of follicle-stimulating hormone and luteinizing hormone. This results in reduced testicular androgen synthesis. The latter effect underlies the efficacy of this agent in the treatment of carcinoma of the prostate.

Aminoglutethimide is an inhibitor of adrenal steroid synthesis. It also inhibits the extra-adrenal synthesis of estradiol. Aminoglutethimide is effective in the treatment of metastatic breast cancer in women whose tumors contain significant levels of estrogen or progesterone receptors. Aminoglutethimide is normally administered with adrenal replacement doses of hydrocortisone to avoid symptoms of adrenal insufficiency.

Androgens, estrogens, and adrenocortical hormones all can produce fluid retention through their sodium-retaining effect. Prolonged use of androgens and estrogens will cause masculinization and feminization, respectively. Extended use of the adrenocortical steroids may result in hypertension, diabetes, increased susceptibility to infection, and cushingoid appearance.

Asparaginase catalyzes the conversion of the amino acid asparagine to aspartic acid and ammonia. Some leukemic cells are unable to synthesize asparagine, which is required for the synthesis of DNA and essential proteins. Because normal cells are able to synthesize asparagine, they are less affected by asparaginase-induced depletion of the amino acid. Resistance to the cytotoxic effects of asparaginase develops rapidly. Agent is used for the treatment of acute lymphocytic leukemia.

AGENTS FOR THE TREATMENT OF HYPERSENSITIVITY
Whereas the normally functioning immune response can successfully neutralize toxins and eliminate pathogens, clinical instances occur in which an inappropriate response leads to extensive tissue damage (hypersensitivity). Hypersensitivity can be classified, as immediate or delayed depending on the time required for clinical symptoms to become manifest following exposure of the host to the sensitizing antigen. Three categories of immediate hypersensitivity are recognized. Type I hypersensitivity (anaphylaxis) results from cross-linking of membrane-bound IgE on blood basophils or tissue mast cells by antigen. This interaction causes cells to degranulate, releasing substances (histamine, leukotrienes, etc) that induce bronchospasm, collapse, or hay fever. Type II hypersensitivity (cytotoxic reaction) results from the formation of antigen-antibody complexes between foreign antigen and immunoglobulins. It results in lysis of cells that keep antigen. This type of hypersensitivity occurs during blood transfusion reactions and in hemolytic disease of the newborn. In both cases, antibodies are formed against foreign red blood cell membrane antigens to which they bind. It can also be drug-induced and occurs during the administration of levomycetin to allergic patients. In these patients, levomycetin binds to red blood cells or other host tissue to form a neoantigen that evokes production of antibodies capable of inducing complement-mediated cell lysis.

Type III hypersensitivity (immune complex reactions) is due to the presence of elevated levels of antigen-antibody complexes. The formation of these complexes activates complement to produce components that increase vascular permeability and recruit neutrophils to the site of complex deposition. It can cause skin rashes, glomerulonephritis, serum sickness, and arthritis. Delayed-type hypersensitivity is cell-mediated. Delayed-type hypersensitivity is characterized by the influx of the activated macrophages and neutrophils. The activated macrophages display increased phagocytic and antigen-presenting functions; and release copious amounts of enzymes that contribute to the extensive tissue damage and local inflammation (parasitic granuloma, nodular leprosy).

Classification of agents used for the treatment of hypersensitivity:

1. Classification of agents used for the treatment of immediate type hypersensitivity:

1.1	agents that decrease the releasing of histamine and other active substances -cromolyn, ketotifen, glucocorticoids;

1.2	antihistamines - dimedrole, diprazin, diazolin, phencarole, loratidine;

1.3	agents that bind with histamine – histaglobulin;

1.4	agents that inhibit efferent limb of the allergic response – adrenomimetics, euphylline.

1.5	agents that decrease the tissue damage – steroid and non-steroid anti-inflammation drugs.

2. Classification of agents used for the treatment of delayed type hypersensitivity:

2.1	 immunodepressive agents - cyclosporine, azathioprine;

2.2	 agents that decrease the tissue damage – steroid and non-steroid anti-inflammation drugs. Histamine is a physiologically active, endogenous substance that binds to and activates histamine H1- and H2-receptors at various sites in the body causing characteristic allergic signs and symptoms. The principal pharmacologic effects of histamine involve the stimulation of gastric and bronchial secretions; microvascular dilation, hypotension (involving H1-, H2-receptors) and increased vascular permeability (H1-receptors); stimulation of the bronchial and gastrointestinal tract muscles. The term antihistamine has historically been used to describe drugs that act as H1-receptor antagonists. Drugs that antagonize H2-receptors (e.g., cimetidine, famotidine) are used for the lowering of gastric acid secretion. Antihistamines competitively antagonize most of the smooth muscle stimulating actions of histamine on the H1-receptors of the GI tract, uterus, large blood vessels, and bronchial muscle. Antihistamines appear to act by blocking H1-receptor sites, thereby preventing the action of histamine on the cell.

Antihistamines include following drugs: dimedrole (diphenhydramine), diprazin (promethazine), diazolin, phencarole, loratidine, etc. Diprazin, dimedrole are possess m-cholinolytic, ganglioblocking and sedative effects. The antiemetic, antimotion-sickness, and antiparkinsonic actions of these antihistamines appear to result, at least in part, from their central anticholinergic and CNS depressant properties. Diprazin probably is the most potent antihistamines. Also it has α-adrenolytic activity (hypotensive action). Diazolin, phencarole, and loratidine are poorly distributed into the CNS at usual dosages. That’s why they do not cause sedative effect.

Antihistamines generally are well absorbed following oral or parenteral administration. The duration of action is variable but allergic symptoms usually are relieved for 3-6 hours after oral administration of most antihistamines. Some antihistamines (e.g., loratidine) exhibit prolonged duration of effect that lasts in excess of 24 hours.

Indications. Antihistamines are used for the treatment of nasal allergies, allergic dermatosis, and allergic conjunctivitis. Antihistamines are useful in the ancillary treatment of pruritus, urticaria, angioedema, and bronchospasm associated with anaphylactic reactions. Some antihistamines (e.g., dimedrole, diprazin) are useful for the prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness. They are used for their sedative effects as nighttime sleep aids. Adverse effects include sedation, ranging from mild drowsiness to deep sleep, anticholinergic effects (e.g., dryness of mouth, urinary retention, and visual disturbances), and gastrointestinal disorders (e.g., anorexia, nausea, and vomiting). Also they potentiate the depression of the CNS that caused by alcohol, neuroleptics, narcosis agents.

Cromolyn is an antiallergic drug. Cromolyn inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity reactions. It does not possess any intrinsic antihistamine, anti-inflammatory, glucocorticoid, or vasoconstrictive activity. Cromolyn administered orally is indicated in the treatment of ulcerative colitis. Its inhalation is indicated as first-line medication for the prevention of acute bronchospasm. Cromolyn inhalation is not indicated for the relief of acute asthma attacks, especially in status asthmaticus, because it has no immediate bronchodilating activity. Ketotifen has antihistamine and antiallergic activities. It is postulated, that ketotifen inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity. On the other hand, ketotifen blocks H1-receptors. Agent is well absorbed from gastrointestinal tract. The serum half-life is about 20 hours. Ketotifen is used for the prevention of acute bronchospasm, for the treatment of allergic bronchitis, hay fever, and allergic dermatitis. Adverse effects include drowsiness and thrombocytopenia. Histaglobulin is a preparation of the human gamma globulin, containing the antibodies of normal adults, and histamine. It is obtained from pooled liquid human plasma from a number of donors. Histaglobulin increases the production of antihistamine antibodies those results in higher ability of serum to inactivate the histamine. It is used subcutaneously for the treatment of different allergic diseases including bronchial asthma, dermatitis, etc. Drugs that modify allergic responses act at several links in this chain of events. Glucocorticoids (prednisolone) that are often used in severe allergic reactions including anaphylactic reaction, and probably blocks proliferation of the IgE-producing clones. In addition, glucocorticoids increase the sensitiveness of adrenoreceptors to noradrenaline, thus they potentiate the action of adrenomimetics. In the efferent limb of the allergic response adrenomimetics (e.g., adrenaline, isadrin, salbutamol) and direct spasmolytic euphylline produce bronchodilation (see chapter “Adrenergic agents”).

For the treatment of delayed-type hypersensitivity immunosuppressive agent’s glucocorticoids are used also. They have anti-inflammation activity (see chapter “Steroid hormones”). Glucocorticoids reduce the concentration of T-lymphocytes, monocytes, and eosinophils. They also decrease binding of immunoglobulin to cell surface receptors and inhibit the synthesis, and release of interleukins, thereby decreasing T-lymphocyte blastogenesis and reducing expansion of the primary immune response. Glucocorticoids may also decrease concentrations of complement components and immunoglobulins.

Cyclosporine is an antibiotic that appears to act at an early stage in the antigen receptor-induced differentiation of T-cells and blocks their activation. Recent in vitro studies have indicated that cyclosporine inhibits the gene transcription of interleukins and other factors produced by antigen-stimulated T-cells. Cyclosporine is an immunosuppressive agent in human organ transplantation, after bone marrow transplantation, and in the treatment of selected autoimmune disorders. Agent is given orally and intravenously. Toxicities include nephrotoxicity and transient liver dysfunction.