Antianemeic drugs Agents to Tr anemia

Hematopoiesis: production of erythrocytes, platelets, & leukocytes from stem cells in ! BM. Require a constant supply of 3 essential nutrients: - Iron - Vitamin B12 - Folic acid + hematopoietic GFs. Anemia: deficiency in O2-carrying erythrocytes.

Anti-anemic drugs In iron deficiency & other hypochromic anemia: Iron Pyridoxine, Riboflavin, Copper In megaloblastic anemia: Vit B12 Folic acid Hematopoietic GFs Erythropoietin (in chronic RF).

Agents used to Tr anemia 1- Iron: Iron deficiency is ! most common cause of chronic anemia. Total Body Iron 4 g in ! adult male 2.5 g in ! adult female Source: meat & green vegetables.

Iron forms ! nucleus of ! iron-porphyrin heme ring, w together e globin chains forms Hg. Hg reversibly binds O2 (delivery). Iron deficiency causes: small erythrocytes e insufficient Hg are formed: microcytic hypochromic anemia. PK: All of ! iron used to support hematopoiesis is reclaimed from catalysis of ! Hg in senescent / damaged erythrocytes.

Dietary requirements are small & easily available in food. Iron absorption: Actively absorbed in duodenum & proximal jejunum. In ! ferric (+++) form & is complexed to other organic & inorganic molecules. ! acid in ! stomach & hydrolytic enzs in small intestine release ! iron from these complexes. It is then reduced to ! ferrous (++) form (more readily absorbed). Abs is increased by: glucose, amino acids & ascorbic acid. & decreased by : phosphate bicarbonate bile acids, antacids & tetracycline. Heme iron in meat Hg & myoglobin can be absorbed intact. Iron in vegetables & grains, tightly bound to organic cpds; < available for abs.

Excess iron: stored in mucosal cell as ferritin, a water-soluble complex. Distribution: Iron is transported in ! plasma bound to transferrin, a β globulin binds 2 molecules of ferrous iron. ! iron is transported to ! marrow for use /storage. ! transferrin-iron complex enters maturing erythroid cells by a specific R mechanism. transferrin conc increased in Iron store depletion & iron deficiency anemia.

Storage: When free iron levels are H, apoferritin is produced to sequester iron & protect organs from toxic effect of excess free iron. Iron is stored in intestinal mucosal cells & as ferritin, in macrophages in liver, spleen, & bone. Elimination: No mechanism for excretion Small amounts in feces & bile.

A- Use of iron: Tr of iron deficiency anemia Prevent anemia in increased iron requirement: - premature infants, - children during rapid growth periods, - pregnant & lactating women, - increased bld losses & iron (heavy menstruation), - patients e chronic kidney D & Tr e GF erythropoietin (parenteral iron is preferred). - Malabs, inadequate iron abs, GIT bleeding, gastrectomy & severe small bowel D.

B- Tr Iron deficiency anemia is Tr e oral/ parenteral iron. po iron if GIT is normal. 1- Po iron: 200 – 400 mg for 3-6 months. Forms: FERROUS sulfate, gluconate, fumarate or succinate. All are effective & inexpensive.

SE: N, epigastric discomfort, abdominal cramps, constipation/ diarrhea & black stools. Rx: lower ! dose/ taking ! tablet immediately after/ e meal.

2- Parenteral iron: (postgasrectomy, small bowel section, inflammatory bowel D, noncompliance of po, malabs syndrome, marked bld loss & advanced chronic renal D). Iron dextran: stable complex of ferric OH & low molecular wt dextran (IM/ IV infusion). Advantage of IV: eliminates local pain & tissue staining (SE: IM). + allow delivery of entire iron dose. Also Iron sorbitol (IM)

SE: headache, light-headness, fever, arthralgia, N, V, back pain, flushing, urticaria, B.spasm. Rare: anaphylactic & death. Also dextran can cause hypersensitivity rxs. Alternative preparations: Iron-sucrose complex & iron Na+ gluconate complex. ONLY (IV) less hypersensitivity than dextran.

A- Acute iron tox: Causes: Signs & symptoms: Necrotizing gastroenteritis, V, abdominal pain, bloody diarrhea, followed by shock, lethargy, & dyspnea. + severe metabolic acidosis, coma & death. Tr: Whole bowel irrigation/ gastric lavage: 1% NaHCO3. Antidote: Deferoxamine (Desferroxamine), potent iron-chelating agent, bind absorbed iron & promote its excretion in urine & feces (intragastric, IM, SC, IV infusion).

Chronic iron tox: Overload / hemochromatosis, result when excess iron is deposited in ! hrt, liver, pancreas, & other organs. It can lead to organ failure & death. Causes: patients e inherited hemochromatosis (excessive iron abs;; tissue damage), & in patients who receive many RCs transfusions over a long period of time as chronic hemolytic anemia (thalassemia).

Tr: intermittent phlebotomy: Removing one unit of bld every wk until all excess iron is removed. Or parenteral deferoxamine (less efficient, more complicated, expensive, & hazardous). Recent oral iron chelator: deferasirox. Effective as deferoxamine at reducing liver iron conc & more convenient.

2- Cyanocobalamin = Vitamin B 12 (extrinsic F) CoF for several essential biochemical rxs. Deficiency;; anemia, GI symptoms, & neurologic abnormalities. Chemistry: porphyrin-like ring e a central cobalt atom attached to nucleotide. Source: Meat (liver), eggs, & dairy products. For therap use: Cyanocobalamin & hydroxycobolamin.

PK: Stored mainly in liver Normal daily requirement: 2 -3 mcg. For its abs, it makes a complex e intrinsic F, a glycopt secreted by ! parietal cells of ! gastric mucosa. + R mediated transport system in ! lumen. Must be converted to active forms b4 abs: Deoxyadenosyl-cobalamin & methyl-cobalamin. Vit B12 deficiency results from malabs of Vit B12 due to lack/loss/ malfunction of intrinsic F. This intrinsic F may be absent in gastrectomy & pernicious anemia. Nutritional deficiency (rare). Route of administration: mainly: parenteral,, IM Or po/ aerosol. Excretion: kidney

Pharmacodynamics: 2 essential enzymatic rxs require Vit B12: 1- Methylcobalamin: as intermediate in ! transfer of methyl gp from N-methylTHF to homocysterine, forming methionine. ! depletion of THF prevents synthesis of adequate supply of deoxythymidylate (dTMP) & purines required for DNA synthesis. Tr by Vit B12 & folic acid.

2- Isomerization of methylmalonyl-CoA to succinyl CoA by methylmalonyl-CoA mutase. In vit B12 deficiency: methylmalonyl-CoA accumulate. Neurologic manifestations due to disruption of methionine synthesis. Tr by Vit B12 only.

Clinical pharm: Deficiency of vit B12: Megaloblastic anemia (macrocytic anemia + leukopenia &/ thrombocytopenia) Hematologic abnormalities Hypercellular BM e accumulation of megaloblastic erythroid. Neurologic syndrome: paresthesia & weakness in peripheral nerves, spasticity, & ataxia.

Causes of vit B12 deficiency: Pernicious anemia (Defective secretion of intrinsic F by ! gastric mucosal cells). Partial/ total gastrectomy Malabs syndrome, inflammatory bowel syndrome or small bowel resection. Damage of distal ileum that absorb vitB12-intrinsic F complex, Surgical resection of ! ileum. TR: Vit B12.

Tr: parenteral inj of vit B12. Available as: 1-Cyanocobalamin 2-Hydroxycobolamin is preferred (more highly pt bound: longer DOA). Uses: 1- Pernicious anemia 2- Neurologic abnormalities 3- Gastrectomy 4- Cyanide poisoning.

Initial therapy: 100-1000 mcg of vit B12 IM daily or every other day for 1-2 wks Maintenance: 100-1000 mcg IM once a month for life. Oral dose of 1000 mcg of vit B12 in pernicious anemia who refuse or cannot tolerate ! inj. After parenteral, ! vit can also administered as a spray/ gel.

Adverse effect of Vit B12 1- Allergic hypersensitivity rxs 2- Arrhythmia secondary to hypoK.

3- Folic acid (FA): Reduced form of FA: THFA is essential for ! synthesis of amino acids, purines, & DNA. Its deficiency is uncommon. deficiency of THFA causes anemia, congenital malformations in newborns & occlusive vascular D. Chemistry: FA is pteroglutamic acid, composed of a heterocycle (pteridine), P-aminobenzoic acid + glutamic acid.

FA can undergo reduction, catalyzed by DHFRase… dihydroFA … THFA. Vit B12 is required for activation of FA (demethylation). PK: Source: yeast, liver, kidney, & green vegetables. 5-20 mg of folates are stored in liver. Route: po Converted to mono-glutamyl form then absorbed in ! proximal jejunum . Excreted in urine & stool.

Pharmacodynamics: THFA CoF participate in one-C transfer rx. Produce dTMP needed for DNA synthesis. N-methyleneTHF is required for ! vit B12-dependent rx that generate methionine from hemocysteine. THF COF: donate 1 C unit during synthesis of purine. Preparations: 1- Synthetic FA (tablets/ parenteral) 2- Folinic acid (active form).

FA Deficiency is caused by Malabs & inadequate dietary intake of folate. Alcohol dependence Liver D Clinical Pharm: Folate deficiency; megaloblastic anemia. (1 mg po daily): reverse megaloblastic anemia, restore normal serum folate, & replenish body store of folate. Prophylactically: Pregnant women & patients e hemolytic anemia have increase folate requirements & may become FA-deficient, esp if their diets are marginal. Maternal FA deficiency: fetal neural tube defect as spina bifida.

Patients who require renal dialysis. Drugs: Methotrexate, trimethoprim & pyrimethamine inh DHFRase: deficiency of folate CoFs;; megaloblastic anemia. Long term use of phenytoin H risk patients (FA supplementation): pregnancy, premature infants, hemolytic anemia, liver D, & renal dialysis.

4- Hematopoietic Growth Factors: Glycopt hormones regulate ! proliferation & differentiation of hematopoietic progenitor cells in BM. Produced by recombinant DNA technology.

Erythropietin (epotein): PK: IV/ SC T1/2: 4-13 hr in patient e chronic RF. Produced in ! Kidney Not cleared by dialysis. Given 2-3 times weekly. Darbepoetin α: glycosylate form, longer t1/2.

Pharmacodynamics: 1- Stimulate erythroid proliferation & differentiation by interacting e specific erythropoietin Rs on RC progenitors. 2- Induces release of reticulocytes from BM 3- Tissue hypoxia stimulate erythropoietin synthesis.

Clinical Pharm/ Uses: 1- Anemia + chronic RF Erythropoietin 50-150 IU/kg, IV/SC: improve ! hematocrit (in 10 days) & Hg level (in 2-6 wk) & eliminate ! need for transfusion + Iron & FA. 2- Anemia in HIV patients & zidovudine (anti HIV). 3- Anemia in cancer patients. 4- Anemia due to BM disorders. As in patients e aplastic anemia & other BM failure states, & multiple myeloma. 5- Anemias associated e chronic inflammation (RA) 7- Anemia of prematurity 8- Accelerate erythropoiesis after phlebotomies. 9- Misused by athletes to increase O2 delivery & performance.

Adverse effects &Toxicity: 1- Rapid increase of hematocrit & Hg: HTN & thrombosis. 2- Seizure, headache 3- Transient influenza-like syndrome 4- Mild allergic rxs.