Aditia Retno FitriDepartment of PharmacologyFaculty of Medicine Diponegoro UniversityIndonesia

OverviewHematinic Agents

Iron Folic Acid and Vitamine B12

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 1 oxygen molecule bound reversibly to Fe2+

and to a histidine residue in the globin chain basis of oxygen transport.

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

Normal Hb: 14g to 16g /dl in Male 13g to 15g /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.

BALANCE

OUTPUT

MACHINE

INPUT

<<<< INPUT:Nutritional deficiency

IMBALANCE

BROKEN MACHINE

- - Synthesis <<- - Chronic

disease

>>>OUTPUT:

Bleeding Haemolysi

s

<<<< INPUT:Nutritional deficiency

IMBALANCE

BROKEN MACHINE

- - Synthesis <<- - Chronic

disease

>>>OUTPUT:

Bleeding Haemolysi

s

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) Thalassaemia

3.      Chronic Disorder Kidney Disease Advanced Malignancy Chronic Liver Disease

↑↑ ↑↑DESTRUCTION

1.      Post Haemorrhage Acute & chronicBlood

Loss 2.      Excessive

Haemolysis Intracellular Defect

(Defective RBC)▪ Thalassaemia▪ Haemoglobinopathies▪ Sickle Cell Anaemia

Extracellular Defect▪ Rh Incompatibility▪ Auto Immune

Haemolytic Anaemia▪ Certain Snake Venom

Hematinics are drugs used to stimulate the  formation of red blood cells. 

Used primarily in the treatment of anemia

 Example: Iron Folic Acid Vitamin B12

Basic PharmacologyPharmacokinetic

AbsorptionPharmacodynamic IndicationDrug InteractionSide Effect

Important properties : several oxidation states form stable coordination complexes

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

Essential: myoglobin, Hb, enzym, transferrin not available for haemoglobin synthesis

Storage: Ferritin, hemosiderin Hb synthesis

PHARMACOKINETICS

Daily diet : 10–15 mg absorbption 5–10% Location : duodenum and proximal jejunum Heme iron directly absorbed Nonheme iron reduced to ferrous (Fe2+)

absorbed Iron crosses the luminal membrane by active transport

of ferrous iron and absorption of iron complexed with heme

DMT1 transporter absorbed iron can be actively transported into the

blood by ferroportin and oxidized to ferric iron (Fe3+) Excess iron can be stored in intestinal epithelial cells as

ferritin

Iron is transported in the plasma bound to transferrin

Transferrin-iron complex receptor-mediated endocytosis enters maturing erythroid cells

Endosomes: ferric ferrous transported by DMT1 hemoglobin synthesis or stored as ferritin.

The transferrin-transferrin receptor complex is recycled to the plasma membrane, where the transferrin dissociates and returns to the plasma.

Storage : in intestinal mucosal cells: as ferritin in macrophages in the liver, spleen, and

bone, and in parenchymal liver cells. Apoferritin synthesis is regulated by the

levels of free iron. Ferritin present in serum is in

equilibrium with storage ferritin in reticuloendothelial tissues the serum ferritin level can be used to estimate total body iron stores.

no mechanism for excretion Small amounts are lost in the feces

by : exfoliation of intestinal mucosal cells trace amounts are excreted in bile,

urine, and sweat no more than 1 mg of iron per day.

regulation of iron balance : absorption and storage

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

The daily requirement of iron Male : 1mg / day Female

▪ 2mg / day▪ 3mg / day (during pregnancy and lactation)

Iron deficiency anaemia can occur under the following four conditions: Less Intake of Fe, Vitamins and Protein Diminished Absorption Increased Loss Excessive Demand

Basically: Iron deficiencyApplication:

Iron deficiency due to dietary lack or to chronic blood loss.

Pregnancy: TM2 GIT abnormality: malabsorption Premature baby Early treatment of pernicious anemia

Oral: ferrous sulfate, ferrous succinate, ferrous

gluconate and ferrous fumarate. SE: GIT upset, blackened stool, teeth stain Form: tablet, liquid, sustained-release

Parenteral iron Indication: not able to absorb oral iron Prep

Deep IM: iron-dextran (50 mg Fe/mL) or iron-sorbitol precaution: local reaction, anaphylaxis

Slow IV: iron dextran, sodium ferric gluconate complex, iron sucrose

Precaution: risk of anaphylacsis!!! Oral iron should not be given 24 h before i.m.

begin and for 5 days after the last i.v. injection;

Therapeutic dose: 3-6 mg/Kg/day of elemental ironInduces an ↑Hb of 0.25-0.4 g/dl per day or 1%/day rise in hematocrit.

Adequate response: ↑ Hb of 2 g/dl after 3 weeks of tx

Failure of response after 2 weeks of oral iron requires reevaluation

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

Priority: oral preparation.

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

it also forms stable complexes with thyroxine, captopril and biphosphonates.

Ingestion should be separated by 3 hours. ↑absorption: vit C ↓absorption: desferrioxamine, tea

(tannins) , Ca, Zn, and bran

chronic infection in haemolytic anaemias unless there

is also haemoglobinuria increased erythropoiesis associated with

chronic haemolytic states stimulates increased iron absorption and adding to the iron load may cause haemosiderosis.

Dose related, include nausea, abdominal cramps and diarrhoea.

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,

haemorrhage and 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 and leading to diabetes.

Used for treatment of iron toxicity 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

▪ In severe poisoning: slow IV too fast: hypotension▪ forms a complex with ferric iron, excreted in the

urine. Deferiprone

▪ orally absorbed ▪ to treat iron overload in patients with thalassaemia major, in

whom desferrioxamine is CI. ▪ careful monitoring : Agranulocytosis and other blood

dsyscrasias

Present as haemoglobin; myoglobin, cytochromes and other enzymes.

Absorption: Ferric iron (Fe3+) ferrous iron (Fe2+) active transport into mucosal cells in jejunum and upper

ileum transported into plasma and/or stored intracellularly as ferritin.

Iron loss occurs mainly by sloughing of ferritin-containing mucosal cells; iron is not excreted in the urine.

Iron in plasma is bound to transferrin, and most is used for erythropoiesis. Some is stored as ferritin in other tissues. Iron from time-expired erythrocytes enters the plasma for re-use.

The main therapeutic preparation is ferrous sulfate. Unwanted effects include gastrointestinal disturbances. Severe

toxic effects occur if large doses are ingested; these can be countered by desferrioxamine, an iron chelator.

Basic and Clinical Pharmacology 11th Ed, Katzung

Pharmacology Rang et al 5th Edition Goodman & Gilman’s The Pharmacological

Basis of Therapeutics, 11th ed. Color atlas of pharmacology Clinical Pharmacology, 9th Ed USMLE Pharmacology Recall Pharmacology for the health care

profession