Hematinics - The Merck Veterinary Manual

Hematinics

Anemia can be treated pharmacologically by providing components needed for RBC production, including Hgb synthesis, and by stimulating bone marrow formation of RBC.

Vitamin B₁₂ is essential for DNA synthesis. Deficiency causes inhibited nuclear maturation and division. RBC maturation arrest in the bone marrow leads to megaloblastic or pernicious anemia. Vitamin B₁₂, a porphyrin-like compound consisting of a ring structure that contains a centrally located cobalt, is derived from the diet and microbial synthesis in the GI tract. However, except for ruminants, microbial production occurs in the large intestine, from which vitamin B₁₂ is not readily absorbed. Dietary deficiency of B₁₂ is rare; deficiency usually results from poor absorption from the GI tract.

Vitamin B₁₂ absorption is complex and depends on gastric acid, pepsin, and intrinsic factor secreted from gastric parietal cells or pancreatic duct cells. Intrinsic factor binds to and protects vitamin B₁₂ from digestion. In this form, B₁₂ binds to highly specific receptor sites in the brush border of the ileum, where it enters enterocytes by pinocytosis. Interference with its absorption in the ileum results in continuous depletion, although many months of defective absorption are necessary before deficiency develops. Vitamin B₁₂ is bound in the plasma to transcobalamin. It is stored in large quantities in the liver and slowly released as needed. It is excreted into the bile but undergoes enterohepatic cycling.

Vitamin B₁₂ (dogs: 100-200 µg, PO, SC, sid; cats: 50-100 µg, PO, SC, sid) is available in oral and parenteral preparations of cyanocobalamin. There are no significant toxicities associated with therapy. Indications for therapy are limited to cases of vitamin B₁₂ malabsorption, such as ileectomy, gastrectomy, or deficiency malabsorption syndromes (eg, exocrine pancreatic insufficiency). Chronic administration of H₂ -receptor blockers (cimetidine, ranitidine, famotidine) can also lead to vitamin B₁₂ deficiency because an acid environment is necessary for its absorption.

Folic acid is needed for DNA and RNA synthesis. Anemia associated with folic acid deficiency is characterized as megaloblastic. Sources of folic acid in the diet include yeast, liver, kidney, and green vegetables, although it can also be formed by microbes. Folic acid is stored in the liver but not as avidly as vitamin B₁₂. Because folic acid is destroyed by catabolic processes every day, serum levels decrease rapidly in the presence of deficient diets. Absorption of folic acid is not as sensitive as that of vitamin B₁₂, although jejunal pathology can result in folate deficiency.

Folic acid (dogs: 5 mg, PO, sid; cats: 2.5 mg, PO, sid) is available in both oral and parenteral formulations. Significant toxicity is not associated with therapy. Indications for therapy include inadequate intake due to administration of selected drugs (eg, methotrexate, potentiated sulfa drugs, some anticonvulsants [eg, primidone and phenytoin]), liver disease, malabsorption, or other chronic debilitating diseases.

Iron is necessary for Hgb formation. It is available in the diet either as a heme form, which is a small percent of the total but readily absorbed, or a nonheme form. Absorption of the nonheme form is profoundly affected by diet. Iron is absorbed from the proximal jejunum, where it immediately combines in the enterocyte to the globulin transferrin. It is transported in the plasma in this form, but the binding is loose and iron can be easily transferred to tissues. Iron enters cells via specific receptors that interact with transferrin. In the cell, iron combines with the protein apoferritin to become ferritin, the soluble form of iron storage. Smaller quantities are also stored as the insoluble hemosiderin; the amount of this storage form increases when the total amount of iron in the body is much more than apoferritin can accommodate. There is no mechanism for the excretion of iron other than via the GI tract. GI elimination occurs by exfoliation of enterocytes containing iron, biliary elimination, and elimination of dietary iron that has not been absorbed. Indications for iron therapy are limited to treatment or prevention of iron deficiency (eg, blood loss, pregnancy). Iron is available in both oral and parenteral preparations. Oral preparations should be ferrous salts, such as sulfate (dogs: 100-300 mg, sid; cats: 50-100 mg, sid), gluconate, and fumarate. Therapy can be continued for several months to replenish body iron stores. Response to iron therapy can be assessed by monitoring circulating Hgb concentrations. Side effects are dose-related. Parenteral preparations are indicated for initial treatment of iron deficiency or if oral preparations cannot be tolerated or are not feasible (ie, neonatal pigs). Iron dextrans can be given as a single IM injection (100 mg) at 2-3 days of age in newborn piglets. Toxicity may be seen and is manifest as pale skin, bloody diarrhea, and shock (see Iron Toxicity in Newborn Pigs: Introduction). When efficacy of parenteral preparations is compared, dextran complexes and hydrogenated dextrans are more efficient than dextrins. Hgb formation requires pyridoxine and the trace elements copper and cobalt (necessary for B₁₂ synthesis by ruminal microflora). “Shotgun” preparations contain a combination of hematinic agents; the efficacy of such products is questionable. As with any hematinic preparation, provision of these compounds will be ineffective if the nutritional status of the animal is poor.

Epoetin alfa is the synthetic form of the human glycoprotein erythropoietin (ERP). Epoetin alfa is indicated in the treatment of anemia associated with chronic renal failure in dogs and cats. The initial dosage is 100 U/kg, SC, 3 times/wk for 4 mo, while monitoring PCV, followed by a maintenance dosage of 75-100 U/kg, SC, 2-3 times/wk. The most significant adverse effects in dogs and cats are the development of antibodies to ERP, resistance to treatment, and worsening of anemia. Other potential adverse effects include iron deficiency, hypertension, fever, local cellulitis, arthralgia, mucocutaneous ulcers, polycythemia, and CNS disturbances (seizures).

Anabolic steroids are compounds structurally related to testosterone that have similar protein-anabolic activity but minimal androgenic effects, such as masculinization. As part of their anabolic activity, these compounds increase the circulating RBC mass and possibly granulocytic mass. Clinical indications for use of anabolic steroids include chronic, nonregenerative anemias. Response to therapy is variable, and the time to clinical improvement is long, frequently ≥3 mo. The proposed mechanisms of action include increased ERP production via ERP-stimulating factor, differentiation of stem cells into ERP-stimulating factor-sensitive cells (eg, hemocytoblasts), and direct stimulation of erythroid-progenitor cells. The effect of anabolic steroids requires adequate ERP levels and sufficient cells in the bone marrow. Thus, the effectiveness of anabolic steroids in treating anemia may be limited, depending on the cause.

Anabolic steroids can be divided into 2 categories depending on the presence or absence of an alkyl group at the 17-carbon position. They are available as oral and parenteral preparations, including oil-based products intended for slow release. The absorption and disposition of anabolic steroids depend on the type of preparation and the animal species. Most are eliminated after hepatic metabolism. The alkylated products are more effectively absorbed when given PO and are more effective stimulants of bone marrow. Alkylated anabolic steroids include oxymetholone (dogs and cats: 1-5 mg/kg, PO, every 18-24 hr) and stanozolol (dogs: 1-4 mg, PO, bid; 25-50 mg, IM/wk; cats: 1 mg, PO, bid; 25 mg, IM/wk; horses: 0.55 mg/kg, IM, weekly for up to 4 wk). Nonalkylated anabolic steroids include nandrolone decanoate (dogs: 1-1.5 mg/kg, IM/wk; cats: 1 mg/kg, IM/wk; horse: 1 mg/kg, IM, once every 4 wk). Boldenone undecylenate is approved for horses at 1.1 mg/kg, IM, every 3 wk. Side effects of anabolic steroids include sodium and water retention, virilization, and hepatotoxicity. The alkylated products are more hepatotoxic than the nonalkylated products, particularly in cats. Cholestatic liver damage develops early and can be significant but frequently is reversible.