.

1

Overview Hematinic Agents

▪ Iron

▪ Folic Acid and Vitamine B12 – collectively known as Maturation factors

Haemopoetic Growth Factors

http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood.html

http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood.html

4 globin + 1 haem. Haem

▪ consists of a tetrapyrrole porphyrin ring containing ferrous (Fe2+) iron.

▪ Each haem group can carry 1oxygen molecule▪ bound reversibly to Fe2+ and to a

histidine residue in the globin chain→ basis of oxygen transport.

.

2

Definition: ↓ [Hb] in blood &/ RBC per age, sex and geographical location.

Normal Hb:

▪ 14 - 16 g/dl in Male

▪ 13 - 15 g/dl in Female

Acute: fatigue → chronic: asymptomatic.

Classification based on indices of red cell are:

▪ hypochromic, microcytic anaemia

▪ macrocytic anaemia

▪ normochromic normocytic anaemia

▪ mixed pictures.

<<<< INPUT:Nutritional deficiency

IMBALANCE

BROKEN MACHINE- - Synthesis <<- - Chronic disease

>>>OUTPUT: Bleeding Haemolysis

<<<< INPUT:Nutritional deficiency

IMBALANCE

BROKEN MACHINE- - Synthesis <<- - Chronic disease

>>>OUTPUT: Bleeding Haemolysis

FIX THE UNDERLYING

CAUSES!!

↓↓↓↓ FORMATION

1. Nutritional▪ Iron Deficiency

▪ Folic Acid/ Vit B12 Deficiency

▪ Protein Deficiency

2. Decreased Synthesis▪ Aplastic Anaemia

▪ Replacement of BM (e.g. Leukaemia)

▪ Thalassemia

3. Chronic Disorder▪ Kidney Disease

▪ Advanced Malignancy

▪ Chronic Liver Disease

↑↑ ↑↑DESTRUCTION

1. Post Haemorrhage▪ Acute & chronic blood Loss

2. Excessive Haemolysis▪ Intracellular Defect

(Defective RBC)

▪ Thalassemia

▪ Haemoglobinopathies

▪ Sickle cell anaemia

▪ Extracellular Defect

▪ Rh Incompatibility

▪ Auto Immune Haemolytic Anaemia

▪ Certain Snake Venom

Hematinics are drugs used to stimulate theformation of red blood cells.

Used primarily in the treatment of anemia

Example:

▪ Iron

▪ Folic Acid

▪ Vitamin B12

.

3

Basic Pharmacology Pharmacokinetics

▪ Absorption

Pharmacodynamics Indications Drug Interactions Side Effects

Important properties :

▪ Absorbed in ferrous form in duodenum

▪ Stored in ferric form

▪ Ferritin & haemosiderin

▪ Transferrin

Fe + protoporphyrin →Heme Heme + globin →Hemoglobin Hemoglobin binds O2 & provides O2 delivery Fe deficiency →microcytic hypochromic anemia Body content of iron:

▪ Essential: myoglobin, Hb, enzyme, transferrin → not available for hemoglobin synthesis

Liver Egg yolk Beans Dry fruits

Poor sources – milk & its products Ascorbic acid & HCl ↑ absorption Alkalies, phosphates, phytates & tetracyclines ↓

absorption

http://izzrawda.wordpress.com/2009/03/16/do-you-have-anemia/

.

4

Iron deficiency anemia can occur under the following four conditions:

1. Less Intake of Fe, Vitamins and Protein

2. Diminished absorption

3. Increased Loss

4. Excessive Demand

1. Iron deficiency due to dietary lack or to chronicblood loss.

2. Pregnancy

3. GIT abnormality: malabsorption

4. Premature baby

5. Early treatment of pernicious anemia

Oral: ferrous sulfate, ferrous succinate, ferrous gluconate and ferrous

fumarate. S/E: GIT upset, blackened stool, teeth stain, metallic taste Form: tablet, liquid, sustained-release

Parenteral iron Indication: when oral iron is not absorbed, not tolerated or with

Erythropoietin (EPO) Deep IM: iron-dextran or iron-sorbitol citrate precaution: local reaction, anaphylaxis

Slow IV: iron dextran , sodium ferric gluconate complex, iron sucrose Precaution: risk of anaphylaxis!!!

Iron - dextran Iron-sorbitol-citrate

Can be given IV or IM Only IM

Not excreted About 30% excreted in urine

Absorbed through lymphatics Absorbed directly in circulation

Not bound to transferrin Not bound to transferrin

.

5

Therapeutic dose:▪ 1000 mg ferrous sulphate tds provides around 60 mg elemental

iron per dose

Adequate response: ▪ ↑ Hb of 0.5 - 1 g/dl per week

Failure of response ▪ after 2 weeks of oral iron requires re-evaluation for ongoing blood

losses, infection, poor compliance or other causes of microcytic anaemia.

Priority: oral preparation

1. Iron chelates in the gut with tetracyclines, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, norfloxacin and ofloxacin;

2. It also forms stable complexes with thyroxine, captopril and bisphosphonates. Ingestion should be separated by 3 hours.

3. ↑absorption: vit C4. ↓absorption: desferrioxamine, tea (tannins) , Ca, Zn, and

bran

Dose related include nausea, abdominal cramps and diarrhea.▪ overcome : ↓dose or by taking the tablets after or with meals

Acute iron toxicity

▪ Ingestion of large quantities of iron salts.

▪ Result: severe necrotising gastritis with vomiting, haemorrhageand diarrhoea→ collapse

▪ Treatment : gastric lavage with NaHCO3, iron chelating agent, and treatment of causes.

Chronic iron toxicity

▪ Caused by conditions other than ingestion of iron salts

▪ Cause pancreatic damage leading to diabetes.

▪ Desferrioxamine(Desferal) (t1/2 6 h).

▪ not absorbed from the gut but is nonetheless given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as IM and IV

▪ forms a complex with ferric iron, excreted in the urine. Indicated in Acute iron poisoning

▪ Deferiprone

▪ Indicated in Chronic Iron overload

▪ orally absorbed

▪ to treat iron overload in patients with thalassaemia major, in whom desferrioxamine is contraindicated.

▪ careful monitoring : Agranulocytosis and other blood dsyscrasias

.

6

Cyanocobalamin Hydroxocobalamin

Vitamin containing cobalt Cyanocobalamin & Hydrocobalamin are 2 forms present in

diet Present in animal foods & legume is the only vegetable

source Ultimate source: microbial synthesis Also called as Extrinsic factor Active forms are deoxyadenosyl-cobalamin & methyl-

cobalamin Role: conversion of homocysteine to methionine (folic acid

is also req.), methylmalonyl CoA to succinyl CoA & methionine to s-adenosyl methionine

Methyl-FH4 donates the methyl group to B12, the cofactor.

The methyl group is then transferred to homocysteine to form methionine

Deficiency: “methylfolate trap”

Synthesis of DNA

Vit B12 deficiency : accumulation of methyl malonate-CoA → basis of neuropathy in vit B12 deficiency

Vit B12 binds to IF & the IF-vit b12 complex is absorbed in distal ileum

Released into plasma bound to transcobalamines TC I, II, or III

In circulation, cobalamin binds to transcobalamin II

Vit B12 deficiency mostly results from malabsorption, chemotherapy or fish tapeworm infestation

Nutritional deficiency is rare

.

7

1. Pernicious anemia

2. Dietary deficiency: vegetarian

3. Malabsorption syndrome : stagnant loop syndrome ,Crohn’s disease, Fish tape worm infestation, gastrectomy

4. ↑ requirements: pregnancy, hemolytic anemia, hepatic disease

5. Neurological abnormalities (diabetes, alcohol or drug intake) –Methylcobalamin

6. Tobacco amblyopia - Hydroxocobalamin

Prime – PhenytoinPrimidone

B - B12 & Folic acid deficiencyA - AlcoholT - TrimethoprimS - SulfasalazineM - MetforminA - Antifolates (Methotrexate, Pyrimethamine, Proguanil) N - N2O

Contraindication

▪ Inconclusively diagnosed anemia

▪ Allergic to cobalt

Interaction

▪ Alcohol, aminosalicylic acid, neomycin and colchicine may decrease the absorption of oral vit B12

Hydroxocobalamin is preferred to cyanocobalamin:First choice : injection

.

8

Folate: Pharmacodynamics

Etiology :▪ Causes : inadequate diet, alcoholism, pregnancy, drug therapy,

malabsorption syndrome

▪ Other causes : increased requirement, enhanced metabolism, interference in the metabolism

Gastrointestinal manifestations ▪ More widespread and more severe, diarrhea is often present

▪ Cheilosis

▪ Glossitis Neurologic abnormalities do not occur !!! THFA involved in conversion of homocysteine to

methionine (B12 is also req) & generation of thymidylate

Management : Folic acid should not be given until B12 def. and pernicious

anemia have been excluded Oral dose: 1 mg/day Absorption is normal : 50-100 mcg/d Malabsorption : 250-500 mcg/d To replenish depleted folate stores, a daily dose of 1-2

mg/d for 2-3 weeks Duration of therapy depend on underlying causes : 3-4

months to clear folate-deficient erythrocytes from the blood

1. Megaloblastic Anemia

2. Anemia associated with dihydrofolate reductase inhibitors. ▪ Administration of citrovorum factor (methylated folic acid)

alleviates the anemia. 3. Ingestion of drugs that interfere with intestinal

absorption and storage of folic acid.

4. Malabsorption – Sprue, Celiac disease, partial gastrectomy.

5. Rheumatoid arthritis – increased folic acid demand or utilization.

It is a sialo-glycoprotein hormone (MW 34000) produced by kidney.

Anaemia & hypoxia act as stimulus.❖ Proliferation of colony forming cells of erythroid series.❖ Hb formation & erythroblast maturation❖ Releases reticulocytes in circulation

EPO receptor is JAK-STAT binding receptor

It has no effect on RBC life span.

Preparations- Epoetin α,β IV/SC

.

9

1. Anemia of chronic renal failure2. Anemia in AIDS patients on Zidovudine3. Cancer chemotherapy induced anemia4. Pre-operative increased blood production for autologous

transfusion during surgery

Darbopoietin alpha is long acting derivative given weekly

Peginesatide (erythropoiesis stimulating agent) – given in anemia due to CRF in dialysis patients

ADRs – polycythemia & hypertension

Blood cell

Growth factor Drug Indication

RBC Erythropoietin EpoietinDarbopoietinPeginesatide

Anemia in CRF, myelosuppressive

drug use (Zidovudine & cancer

chemotherapy)

WBC G-CSF

GM-CSF

FilgrastimPeg-filgrastimLenograstim

SargramograstimMolgramograstim

Neutropenia due to anticancer drugs,

severe chronic neutropenia, stem

cell transplantation

Platelets IL-11Thrombopoietin

OprelvekinRomiplastimEltrombopag

Thrombocytopenia due to anticancer

drugs, ITP