Hematinics

• Hematinics are the agents used a) Treatment of anemiab) Increase the number of RBC or hemoglobin

content of RBC or both when there is deficiency

Normal erythropoiesisPluripotent stem cell

Erythroid burst forming unit

Erythroid colony forming unit Within BM

Erythroblast

Reticulocyte Peripheral blood

Mature red cell

Normal erythropoiesis

• Erythropoietin production is impaired in conditions such as RA, cancer and Sickle cell anemia

• Normally survive for 120 days

Normal erythropoiesis

• Destroyed by reticuloendothelial system found in spleen and BM

• Iron is removed from haem component of Hb and transported back into bone marrow for reuse

Normal erythropoiesis

• Pyrole ring from globin is excreted as conjugated bilirubin by the liver and the polypeptide portion enters the body’s protein pool

Anemia

Introduction

• Not a single disease• Results from a number of different pathologies• Defined as a reduction from the normal quantity of

Hb in blood• WHO defines anemia as Hb levels less than 13 g/dl

for males and less than 12 g/dl for females• Low Hb levels results in decreased oxygen carrying

capacity of blood

Epidemiology

• Most common condition resulting in significant morbidity and mortality

• Worldwide: Over 50% of pregnant women and 40 % of infants are anemic

Aetiology

Two different mechanisms:1. Reduced Hb synthesis (due to lack of nutrient

or bone marrow failure)

Reduced proliferation of precursors or defective maturation of precursors or both

Aetiology

• Increased Hb loss due to haemorrhage (red cell loss) or hemolysis (red cell destruction)

(More than one cause can be found in a patient)

Classification of anemia:

A) Morphological classification: 1) normocytic normochromic anemia

-acute blood loss -marrow failure ( aplastic anemia)- chronic renal failure - anemia of chronic disease

2) Microcytic hypochromic anemia- iron deficiency anemia - thalessemia

3) Macrocytic Anemia :- Vitamin B-12 deficiency- folic acid deficiency

B) Patho-physiological classification:1) Hemorrhagic or blood loss anemia

- acute blood loss - chronic blood loss

2) Impaired RBC production a) Nutritional deficiency anemia :

- iron deficiency anemia - Vitamin deficiency anemia- Protein – energy malnutrition

b) Aplastic Anemia - leukemia - lymphoma - myeloproliferative diseases

c) Chronic Renal Failure d) Anemia of chronic Disease

3) Hemolytic Anemia

Symptoms and signs of anemia

Symptoms • Fatigue • Faintness• Headache • Palpitations • Angina of effort • Breathlessness

Signs • Pallor • Tachycardia • Systolic flow murmur • Cardiac failure • Koilonychia • Jaundice

Classification of hematinics

1) Drugs used in anemias : a) Drugs used in iron deficiency anemia:

i) iron preparations ii) copper iii) cobaltiv) pyridoxin v) riboflavin

b) drugs used in megaloblastic anemias :

i) Vit B-12 ii) Folic acid iii) Vitamin –C

2) Hematopoietic growth factors

a) erythropoetinb) myeloid growth factors :

- G-CSF ( filgrastim)- GM-CSF

( sargramostim)- pegfilgrastim

c) megakaryocyte growth factors:- interleukin -11 (oprelvekin)- thrombopoetin

IRON

Iron Absorption , transport and strorage of iron

Iron distribution

Pharmacokinetics ABSORPTION• absorbs 5–10% of iron ingested or about 0.5–1 mg daily.• normally absorbed in the duodenum and proximal jejunum.• absorption increases in response to low iron stores or increased iron

requirements.• abundant in meat. heme iron in meat hemoglobin and myoglobin can be

absorbed intact without first dissociated into elemental iron . Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells.

two mechanisms: i) active transport of ferrous iron and ii) absorption of iron complexed with heme • divalent metal transporter, DMT1,. • actively transported into the blood across the basolateral membrane,

probably by the transporter IREG1, also known as ferroportin1.• Excess iron can be stored in the mucosal cell as ferritin, a water-soluble

complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin.

TRANSPORT• transported in the plasma bound to transferrin, a -globulin that

specifically binds two molecules of ferrous iron The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptors internalize the transferrin-iron complex through the process of receptor-mediated endocytosis.

• Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells. Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin.

STORAGE• primarily 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 is detectable in serum. Since the 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.

ELIMINATION• Small amounts are lost in the feces by exfoliation of intestinal mucosal

cells, and trace amounts are excreted in bile, urine, and sweat.

Indications of oral iron therapy

Prophylactic use :1) pregnancy- from 4th month

to lactation.2) Menstruation3) Infancy and childhood4) Premature babies and

babies weaned late 5) Professional blood donors

Therapeutic use :1) Iron deficiency anemia2) Iron deficiency anemia due to:

- menorrhagia- peptic ulcer - piles - hook worm infestation

3) Malabsorption syndrome 4) Anemia of pregnancy 5) Treatment of severe pernicious

anemia

Adverse effects of oral iron therapy

1) Gastrointestinal upset- nausea - heart burn - upper abdominal discomfort - constipation or diarrhoea - abdominal cramps

2) Hemochromatosis 3) Obscure the diagnosis of git bleeding due to

balckening of stools ( melena )

Parenteral iron preparations: • Iron dextran is a stable complex of ferric hydroxide and low-

molecular-weight dextran containing 50 mg of elemental iron per milliliter of solution. It can be given by deep intramuscular injection or by intravenous infusion, although the intravenous route is used most commonly– headache, light-headedness, fever, arthralgias, nausea and vomiting,

back pain, flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death.

– hypersensitivity reaction to the dextran component. Hypersensitivity reactions may be delayed for 48–72 hours after administration.

– Anaphylactic reactions• Iron-sucrose complex and iron sodium gluconate complex only

by the intravenous route.

Indications of parenteral iron therapy

• unable to tolerate ( GIT upset)• unable to absorb oral iron ( malabsorption syndrome,

ulcerative colitis , achlorhydria, surgical resection of gut)• patients unreliable in taking drug( extreme old age and

mentally ill patients ) • patients with extensive chronic blood loss who cannot

be maintained with oral iron alone. • Immediate iron therapy need :premature birth,

pregnancy , infancy• Blood loss from hemorrhoids , worm infection

• Total iron requirement (mg) = 4.4* body weight (kg)* Hb deficit ( g/dL)

Adverse effects of parenteral iron• Local discomfort• Discoloration of skin• Headache ,fever , arthralgia• Anaphylactic reaction• Respiratory distress• Circulatory collapse • Severe chest pain • Hemolysis • tachycardia • Bronchospasm

Contraindications :• History of asthma • Acute phase of kidney

disease • History of allergy

Acute iron poisoning Fatal dose : 2-10 grams ( 10 tablets

for children)Clinical course of acute iron

poisoning :1) First phase: 0.5-1 hrs after

ingestion• Abdominal pain , nausea , vomiting ,

diarrhoea , with black or bloody stool ( children)

• Constipation with black stool ( adults )

• Drowsiness , cardiovascular collapse • Coma

2) Second phase :8-16 hrs after ingestion

• Period of improvement or pass onto third phase

3) Third phase : 24 hrs after ingestion

• Cardiovascular collapse • Convulsion, coma • Liver damage 4) Fourth phase : 1-2 months

after ingestion• Recovery with pyloric

stenosis due to scarring

Treatment 1) Prevent further absorption: • induce vomiting or gastric lavage by 1% NaHCO3

• give egg yolk or milk orally • Desferroxamine (5-10g in 100 ml saline )2) Specific antidote : • Desferroxamine : 1-2 g i/v or i/m 3) Supportive measures : • maintenance of fluid , electrolytes and acid base balance • Diazepam or phenobarbitone i/v• Cardiopulmonary support

Chronic iron poisoning– Excess iron deposited in heart ,

liver , pancreas and other organs leading to organ failure and death.

Results from:– Excessive parenteral therapy– Repeated blood transfusion to

treat hemolytic anemia– Inherited disorder

• Hemosiderosis– Excess accumulation of

hemosiderin in liver

• Hemochromatosis :– Inherited disorder , excessive iron

absorption – Brown pigmentation of skin– Pancreatic damage leading to

diabetes– Cirrhosis of liver with ascites – Hepatic coma – Gonadal atrophy

Treatment: 1) Intermittent

phlebotomy (Removal of one unit of blood per week )

2) Iron chelation therapy – desferoxamine, deferasirox (oral)

3) High intake of tea

Desferroxamine • Isolated from Streptomyces pilosus• Has high affinity for ferric iron.

Competes with iron of ferritin and hemosiderin .

• Iron+desferroxamine = ferrioxamine( nonabsorbable) and is excreted in bile and faeces

• Oral absorption poor , so given parenterally.

• Therapeutically used in acute iron poisoning and diagnosis and treatment of chronic iron poisoning.

• 100 mg chelates 8.5 mg of iron

• Adverse effects:– Hypotension– Pruritus – Wheals – Rash – Anaphylaxis – Dysuria– Abdominal discomfort – Fever – Leg cramps – Tachycardia – Neurotoxicity – Visual and auditory changes

Folic acid

• Structure 3 building blocks a) pteridine groupb) para – amino benzoic acid ( PABA)c) glutamic acid

• Not present in nature but parent compound of folates

• Sources : yeast , liver , green vegetables Fruits , nuts and cereals

Daily requirements :Adult: 50 mcg / dayPregnant women : 100-200 mcg / dayLactating women : 100-200 mcg / day

Pharmacokinetics :

• Route : oral , parenteral • Absorption: from proximal jejunum• Distribution: widely distributed • Folates are excreted in the urine and stool and are also

destroyed by catabolism• folic acid deficiency and megaloblastic anemia can develop

within 1–6 months after the intake of folic acid stops• Dietary folates consist primarily of polyglutamate forms of N5-

methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase")

Pharmacodynamics

• Functions : Tetrahydrofolate cofactors participate in one-carbon

transfer reactions1) DNA synthesis : cofactors for the synthesis of

purines and pyrimidines 2) Synthesis of thymidylic acid :

enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N5,N10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP

Causes of folate deficiency

A) Nutritional ( major causes) 1) poor intake due to

• old age • Starvation • Anorexia

2) gastrointestinal disease • Partial gastrectomy • Coeliac disease • Crohn’s disease

B) Poor Utilisation:

1) Physiological • pregnancy • starvation • prematurity 2) Pathological • hemolytic disease with

excess RBC formation• malignant disease with

increased cell turnover • inflammatory disease

C) Malabsorption syndrome D) Antifolate drugs :– anticonvulsants ( phenytoin , primidone )– methotrexate – Pyrimethamine – Trimethoprim– Sulfonamides

Effects of folate deficiency

• Megaloblastic anemia • Neural tube defect ( spina bifida ) in the foetus

High-risk patients:• pregnant women • patients with alcohol dependence,• hemolytic anemia• liver disease • certain skin diseases • patients on renal dialysis

Indications of folic acid

1) Treat magaloblastic anemia due to folate deficiency

2) Pregnant women3) Premature infants 4) Patients with hemolytic anemia 5) Liver disease 6) Chronic skin disease 7) Renal dialysis8) With anti convulsant drugs

• Folinic acid (leucovorin calcium, citrovorum factor) is the 5-formyl derivative of tetrahydrofolic acid used in methotrexate therapy

• Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone, and increase the frequency of seizures in susceptible children

Preparations and doses of folic acid :Liquid oral preparations and injectables in

combination form Given im Dose Therapeutic : 2-5 mg / day Prophylactic : 0.5 mg / day

Vit B12

• consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide.

• Deoxyadenosylcobalamin and methylcobalamin are the active forms

• The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products

• extrinsic factor

Pharmacokinetics • stored, primarily in the liver, with an average adult having a total vitamin

B12 storage pool of 3000–5000 mcg

• normal daily requirements of vitamin B12 are only about 2 mcg• is absorbed only after it complexes with intrinsic factor, a glycoprotein

secreted by the parietal cells of the gastric mucosa• the intrinsic factor-vitamin B12 complex is subsequently absorbed in the

distal ileum by a highly specific receptor-mediated transport system.• Nutritional deficiency is rare but may be seen in strict vegetarians after

many years without meat, eggs, or dairy products.• vitamin B12 is transported to the various cells of the body bound to a

plasma glycoprotein, transcobalamin II• Stored in liver • Excreted through urine

Pharmacodynamics

1) transfer of a methyl group from N5-methyltetrahydrofolate to homocysteine, forming methionine

• conversion of the major dietary and storage folate, N5-methyltetrahydrofolate, to tetrahydrofolate necessary for transfer of one-carbon groups.

2) isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase

Indications of Vit B12a) Megaloblastic anemia b) Neurologic syndrome associated with cobalamin deficiency c) Pernicious anemia

• Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin

• Administered im • Initial therapy should consist of 100–1000 mcg of vitamin B12

• Maintenance therapy consists of 100–1000 mcg intramuscularly once a month for life

• neurologic abnormalities are present, maintenance therapy injections should be given every 1–2 weeks for 6 months before switching to monthly injections

• oral doses of 1000 mcg of vitamin B12 daily are usually sufficient to treat patients with pernicious anemia

Erythropoetin

• most important regulator of the proliferation of committed progenitors (CFU-E) and their immediate progeny

• cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function

• induces release of reticulocytes from the bone marrow• Hypoxia-inducible factor (HIF-1)--a sensor in the

kidney detects changes in oxygen delivery to modulate the erythropoietin secretion

• Recombinant human erythropoietin (epoetin alfa), produced using engineered Chinese hamster ovary cells

• supplied in single-use vials of from 2000 to 40,000 units/ml for intravenous or subcutaneous administration, three times a week

• epoetin alfa is cleared from plasma with a half-life of 4 to 8 hours.• erythropoiesis-stimulating protein or darbapoetin alfa • Epoetin alfa is effective in the treatment of anemias associated

with surgery, AIDS, cancer chemotherapy, prematurity, and certain chronic inflammatory conditions

• rapid increase in hematocrit and hemoglobin and include hypertension and thrombotic complications

• absolute or functional iron deficiency may develop• Serious thromboembolic events have been reported, including

migratory thrombophlebitis, microvascular thrombosis, pulmonary embolism, and thrombosis of the retinal artery