1. Agents Used In Anemias
HAEMATINICS

2. 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

3. 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

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

5. 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)

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

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

8. 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)

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

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

11. 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

12. 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

14. 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

16. 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

17. 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.

18. 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

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

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

21. 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.

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

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

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

25. 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

26. Dose calculation Total iron deficit (TID)
Body wt (Kg) ˟ (Target Hb-Actual Hb g/dl) ˟ 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

27. 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.

28. 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

29. 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

30. 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)

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

32. 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

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

35. 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.

36. Pharmacodynamics

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

38. 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.

39. 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.

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

41. 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

42. 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.

43. 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

44. 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

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

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

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

48. 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

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

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

51. 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)

52. 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

53. 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

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

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

56. Toxicity
Bone pain
Fever, malaise, arthralgia, myalgia