Agents Used In Anemias HAEMATINICS

By the end of lecture students should be able to: Know various types of anemias Know aetiology of anemias Know drugs used for treatment of anemias Explain pharmacokinetics and pharmacodynamics of Iron Know acute and chronic toxicities of iron Know the management of overdose of iron

Haematopoiesis 200 billion new blood cells are produced per day in normal person Process occur in bone marrow in adults Essential nutrients: iron, vitamin B12, folic acid, pyridoxine, ascorbic acid and riboflavin Hematopoietic growth factors

Erythropoiesis is controlled by a feedback system in which a sensor in the kidney detects changes in oxygen delivery to modulate the erythropoietin secretion

Anemia Decrease in haemoglobin level below normal Deficiency in oxygen-carrying erythrocytes Symptoms Features of tissue hypoxia Pallor, fatigue, dizziness, exertional dyspnoea CVS adaptations to anemia (tachycardia, increased cardiac output, vasodilation)

ANEMIAS: Microcytic hypochromic anemia- iron deficiency most Most common cause of chronic anemia is iron deficiency Macrocytic anemias- Vit B12 deficiency Folic acid deficiency

Drugs used for the correction of anemias Include: Iron Folic acid Vit B12 Hematopoietic growth factors

IRON Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms haemoglobin Increased iron requirement Growing children Pregnancy Increased losses of iron (menstruating women)

Iron containing heme is also an essential component of Myoglobin Cytochromes Catalase Peroxidase Metalloflavoprotein enzymes Xanthine oxidase Mitochondrial enzymes

Sources: Natural Meat, green vegetables, grain Synthetic Iron preparations In body catalysis of hemoglobin in senescent or damaged erythrocytes

Pharmacokinetics Average diet contain 10-15 mg of elemental iron daily Total iron absorption can increase to 3-4 mg/day in pregnant woman Iron in meat is absorbed as such (hemoglobin and myoglobin) Nonheme iron in foods is reduced by ferroreductase to ferrous form A peptide hepcidin produced by liver cells-key central regulator of the system

Duodenum and Proximal jejunum as Fe+2 BY: Absorption: Duodenum and Proximal jejunum as Fe+2 BY: Active transport by DMT1 (divalent metal transporter) Iron complexed with heme Iron absorption increases when iron stores are depleted regulated by mucosal iron stores

Absorption….. The absorbed iron is actively transported into the blood across the basolateral membrane by transporter ferroportin and oxidized to ferric iron by ferroxidase hephaestin

DISTRIBUTION Bound to Transferrin (β –globulin) bind two molecules of ferric iron The transferrin-iron complex enters maturing erytthoid cells Transferrin receptors, transferrin iron complex is internalized in erythroid cells by endocytosis

Storage As ferritin in liver, spleen and bone and in parenchymal liver cells Ferroportin is storage protein level is regulated by hepcidin Low hepcidin lead to release of iron from storage sites Ferritin level is checked in serum to estimate total body iron stores.

Small amount lost in faeces by exfoliation of intestinal mucosal cells Elimination Small amount lost in faeces by exfoliation of intestinal mucosal cells Trace amounts in bile, urine and sweat 1 mg of iron is lost from body per day

Therapeutic uses of Iron Iron Deficient Anemia Treatment and prevention Pregnancy Lactation Growing children Premature Babies Patents with chronic kidney disease Blood loss

Inadequate iron absorption Gastrectomy Malabsorption Syndrome GI Bleeding due to: Ulcers Aspirin Excess consumption of coffee Hookworm infestation

Oral preparations of iron Oral Iron Ferrous Sulphate Ferrous Gluconate Ferrous Fumarate Treatment with oral iron should be continued for 3-6 months after correction of cause of iron loss.

Oral Iron Therapy Dosage: 200- 400 mg/ day for 3- 6 months Adverse effects: nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea, black stools

To overcome adverse effects Lower daily dose of iron Take iron with food Change iron preparation.

PARENTRAL IRON THERAPY Indications: Patients unable to tolerate oral iron Patients with extensive blood loss Malabsorptive states Patients with advanced chronic renal diseases.

I/M and I/v use: Iron dextran (ferric oxyhydroxide and dextran polymers) 50 mg /ml I/V only: Iron sucrose complex Sodium ferric gluconate complex

Dose calculation Total iron deficit (TID) Body wt (Kg) ˟ (Target Hb-Actual Hb g/dl) ˟ 2.4 + depot iron (mg) Total amount of venofer to be administered in ml = TID mg 200 mg/ml Ratio of total serum iron concentration and TIBC

Adverse Effects Local pain & tissue staining Headache, giddiness, flushing Fever, Arthralgia, Backache Nausea, Vomiting Urticaria Rarely Anaphylaxis & death. Test dose of iron dextran is given.

Clinical Toxicity Acute Iron Toxicity Seen in young children, who accidently ingest Iron tablets. 10 tablets in children Symptoms: vomiting, necrotizing gastroenteritis causing abdominal pain, bloody diarrhea followed by metabolic acidosis, dyspnea, coma & death

Rx i) Gastric Aspiration Gastric lavage, with carbonate solution to form insoluble Iron. whole bowel irrigation ii) Deferoxamine - potent iron chelating compound given intravenously iii) Supportive Therapy

Chronic Iron Toxicity Hemochromatosis (excess iron is deposited in the heart, liver, pancreas, and other organs) Cause is inherited hemochromatosis and patient receiving many blood transfusions Rx Intermittent Phlebotomy (1 unit of blood is removed every week) Iron. Chelation therapy (Deferoxamine, deferasirox is oral iron chelator)

Vit B 12 Cofactor for several essential biochemical reactions in humans Deficiency lead to megaloblastic anemia, GIT symptoms and neurologic abnormalities Cyanocobalamine Hydroxocobalamine

Source: microbial synthesis from meat, eggs and dairy products (microorganisms grow in soil, sewage, water or in intestinal lumen of animals) Chemistry: porphyrin like ring with a central cobalt atom attached to nucleotide

Structure……. Various organic groups may be covalently bound to cobalt atom forming different cobalamines Deoxyadenosylcobalamine Methylcobalamine active form of vitamins in humans

Pharmacokinetics Vitamin B12 is absorbed only after it complexes with intrinsic factor (glycoprotein) This complex of vit B12 and intrinsic factor is absorbed in distal ileum Transported to various cells by binding with transcobalamin I, II and III Excess is transported to liver for storage.

Pharmacodynamics

Deficiency of vit B 12 also cause ‘folate trap’ Methyltetrahydrofolate is not converted into other intracellular forms of folic acid

Clinical uses Treat or prevent deficiency Megaloblastic, macrocytic anemia mild or moderate leukopenia or thrombocytopenia. Neurologic syndrome (paresthesias in peripheral nerves, weakness. Progresses to spasticity, ataxia and CNS dysfunction.

Mechanism for Peripheral Neuropathy Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoA. Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin. If no Vitamin B12, methylmalonyl-CoA goes on to form abnormal fatty acids and causes subacute degeneration of the nerves. Only B12 can correct this problem.

Diagnosis Serum levels of vitamins (Vit B12 and Folic acid) Schilling test (measures absorption and urinary excretion of radioactively labelled vitamin B12)

Common causes of vit B12 deficiency Pernicious anemia Defective secretion of intrinsic factor Partial and total gastrectomy Malabsorption syndrome Inflammatory bowel disease Small bowel resection

Treatment If the cause is malabsorption, Parenteral injections of vit B12 cyanocobalamine or hydroxocobalamine. vitamin B12 can be administered intranasally as a spray or gel.

Parenteral therapy Inj Cyanocobalamin or hydroxcobalamin Initial therapy 100 – 1000 µg – I/M-D or on alternate days for 1-2 weeks Maintenance therapy 100 – 1000 µg – I/M- once a month

Folic Acid Source Plant and animal (liver, kidney & green vegetables. Essential for normal DNA synthesis Source Plant and animal (liver, kidney & green vegetables. Chemistry Pteroylglutamic acid p-aminobenzoic acid and glutamic acid

Pharmacokinetics of Folic Acid Site of absorption: Proximal jejunum Polyglutamates monoglutamate α- 1 glutamyl transferase (conjugase)

PHARMACODYNAMICS: Tetrahydrofolate cofactor participate in one-carbon transfer reactions dTMP DNA synthesis Required for the synthesis of : Amino acids purines DNA

dTMP synthesis cycle dTMP synthase, dihydrofolate reductase and serine transhydroxymethylase Synthesis of methionine from homocystine Donate one carbon for synthesis of essential purines

Folic Acid Deficiency Seen in Inadequate dietary intake of folates Prolong cooking In alcholics & in pt with liver diseases Pregnancy Hemolytic Anemias Malabsorption Syndrome Drugs Methotrxate , trimethoprim and pyrimethamine

Treatment of Folic Acid Deficiency parentral administ rarely needed. Oral therapy: Dose 1mg/d – continued until cause is corrected or removed.

Hematopoietic Growth Factors Glycoproteins hormones Erythropoietin G-CSF GM-CSF Interlukin-II Romiplostim

Erythropoietin Source: Recombinant DNA technology I/V administration Dose calculated in IU. Epoetin alfa and epoetin beta Half life is 4-13 hrs Darbepoetin alfa is heavily glycosylated (longer half life)

Pharmacodynamics Erythropoietin receptors on red cell progenitors (JAK/STAT) Increased production of RBCs in bone marrow if No nutritional deficiency is present No primary bone marrow disorder No bone marrow suppression from drugs

Clinical uses Anemia due to chronic renal disease After treatment increase in reticulocyte count is observed in 10 days Increase in Hb in 2-6 weeks Anemia due to zidovudine treatment in HIV patients Reduce the need of transfusions in high risk patients

Toxicity Hypertension Thrombotic complications Allergic reactions are rare Erythropoieitin is banned by International Olympic Committee

Myeloid Growth factors Filgrastrim Sargramostim Pegfilgrastim Leograstim used for cancer chemotherapy induced Neutropenia Congenital neutropenia Cyclic neutropenia Myelodysplasia Aplastic anemia

Toxicity Bone pain Fever, malaise, arthralgia, myalgia