1. Antianemeic drugs
Agents to Tr anemia

2. 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.

3. 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).

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

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

12. 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)

13. 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.

14. 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).

15. 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).

16. 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.

17. 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.

18. 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

19. 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.

21. 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.

23. 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.

24. 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.

25. 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.

26. Initial therapy: 100-1000 mcg of vit B12 IM daily or every other day for 1-2 wks
Maintenance: 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.

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

28. 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.

30. 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.

31. 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).

32. 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.

33. 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.

34. 4- Hematopoietic Growth Factors:
Glycopt hormones regulate ! proliferation & differentiation of hematopoietic progenitor cells in BM.
Produced by recombinant DNA technology.

35. 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.

36. 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.

37. Clinical Pharm/ Uses:
1- Anemia + chronic RF
Erythropoietin 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.

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