Teaching TY Haematinics

HAEMATINICS
ME 1/11 SEM 3 12/3-17/3/2012

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000
TY CS& SC IMU 2012

Slide 1
HAEMATINICS
These are the substances which are required for the formation of blood (erythropoiesis) and are used for the treatment of anaemia.
These are mainly IRON, FOLIC ACID & VIT B12
Slide 2
Case Scenario
A 26 year old lady with 22 weeks of pregnancy attends the 1st 1ntenatal booking visit. On enquiry she has had 3 normal full term deliveries and one caesarean section for a twin pregnancy at 38 weeks of pregnancy and one abortion at 19 weeks. She feels easily tired too and sleepy She is really tiring to look after the children nowadays this is also during the last week. On Examination She is anaemic. She is otherwise fit and well. Hb level 10.5 gm/dl Microcytic hypochromic (MCV <80 fL) Macrocytic (MCV >100 fL) Treatment- Haematinics
fL = femto-litre = 1015 L = 1 m3
Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000 Slide 3
Normal blood film
Severe iron deficiency anaemia
TY CSU IMU
Red cells Macrocytosis
Slide 5
White cells - Hypersegmented neutrophils
TY CSU IMU
Anaemia
What is anaemia?
Haemoglobin level: The cut-off point for the women by WHO 12 g/dl. Men 13 g/dl Anaemia is a reduction in the number of RBCs or the Haemoglobin content of blood below normal for age and sex of the individual Acute/ Chronic
7
ALL ANAEMIA CASES

34.3
NUTRITION
32.1
DISEASE RELATED
33.6
UNEXPLAINED
Slide 8
ANAEMIA WITH NUTRI. DEFICIENCY

48.3
IRON
18.8
FOLIC ACID
17.2
B12 9.9
IRON FA & B12
5.8
FA & B12
PATHOGENESIS It is a condition in which the balance between production and destruction of RBCs is disturbed by:1. Blood Loss 2. Impaired red cell formation 3. Increased destruction of RBCs
Types (Blood Picture)

Normocytic (MCV 80-100 fL)
Microcytic hypochromic / normochromic (MCV <80 fL) Macrocytic (MCV >100 fL)
11
Diagnosis
Peripheral blood film
Flow cytometry automatic counters
12
Erythropoiesis
Iron Vitamin B12 Folic acid
It is regulated by erythropoietin - secreted by kidneys - stimulates the bone marrow

13
IRON Distribution in the Body: Total body iron in an adult is 2.5-5g. It is more in men 50 mg/kg than in women 38 mg/kg. It is distributed into:-Hemoglobin 66% Iron stores as ferritin, Haemosiderin 25% Myoglobin - 3% Parenchymal Iron (in enzymes) 6%
Slide 14
Daily Requirement :Adult male Adult Female Infants Children Pregnancy 0.5 1 mg 1 2 mg 60 g / kg 25 g / kg 3 5 mg
Slide 15
Dietary Sources Diet contains 10 to 15 mg iron/day

Rich Liver, Egg yolk, Oyster, Dry fruits, Wheat germs, yeast
Medium Meat, Chicken, Fish, Spinach, Banana, Apple Poor Milk and its products, Root vagetables
Slide 16
IRON ABSORPTION
The average daily diet contain 10-15 mg of iron. 5% to 10% absorbs dietary iron = 0.5 to 1 mg/day Adequate for male and postmenopausal
Menstruating/pregnant woman require 1 to 3 mg/day Menstrual loss is 30 mg/period. Absorption occurs all over the intestine, but
magnify in the upper part.
To absorb- iron Ferric to ferrous by acid reducing agent. From gut to Intestinal mucosal cells by 1. Divalent metal transporter. From mucosa to plasma by 2. Ferroportin transporter Absorbed ferrous to plasma by F transporter or oxidised to ferric form and ferric form +apoferritin= ferritin is stored in the mucosal cells.
Slide 18
GUT
MUCOSAL CELLS Ferric PLASMA
Ferrous
Ferrous
Ferroportin
Ferrous
Divalent metal transporter 1
Ferrous Ferric + Apoferritin Ferritin
Ferric + Transferrin
Circulate in the plasma

Plasma
Ferric + Transferrin
Cells
Membrane + Transferrin Receptors Endocytosis
Released iron
Slide 20
STORAGE
RE cells Liver, Spleen, Bone-marrow, hepatocytes, myocytes as ferritin and haemosiderin
Slide 21
Plasma Iron
from Old RBC 120 days Iron Store Intestinal absorption
An Iron common pool
Erythrpoiesis, Other cells, Restorage
Slide 22
Iron Excertion:Iron is tenaciously conserved by the body. Daily excretion in adult male is 0.5 1mg. Mainly as exfoliated G.I mucosal cell, some RBC in bile. Other routes are desquamated skin, sweat and urine. In menstruating women, monthly menstrual loss may be averaged to 0.5 1 mg/day
Causes of Iron Deficiency Anaemia

Bleeding heavy menstruation gastric (PU, cancer occult bleeding) or piles hookworm infestation use of NSAIDs for pain / inflammation
24
Increased Physiological Demand for Iron Pregnancy and Lactation Infancy, children and adolescents (rapid growth)
25
Inadequate Absorption post-gastrectomy generalized malabsorption (severe small bowel disease, Crohns disease / celiac disease) Inadequate Intake -- Rare for adult, but extreme poverty
26
Normal blood film
Severe iron deficiency anaemia
TY CSU IMU
Blood reports
Hb is low MCV is low ( <80fL) microcytes MCHC is low hypochromic Ferritin is low Total iron binding capacity (TIBC) is increased Serum iron is low Transferrin saturation is < 19%
28
Indications for Iron therapy

Used for therapy and prophylaxis
1. Iron deficiency anaemia due to dietary lack or to chronic blood loss 2. Pregnancy total 1000 mg (50 to 100mg elemental iron = 200 to 500 ug folic acid) 3. Absorption is reduced. Mal absorption syndrome. 4. Premature babies 5. Severe pernicious anaemia with hydroxycobalamine 6. 3.As an Astringent:- Ferric chloride is used in throat paint.
Excess Iron Required 1. In pregnancy Expansion of RBC mass Foetus Loss during delivery 2. Lactating mother
Slide 30
Preparation and Doses 1. The preferred type of iron is ferrous salts. Ferrous form is inexpensive, high iron content and are better absorbed than ferric salts. Sustained release preparations are more expensive but used for patient who cannot tolerate the standard forms. The preferred route is the Oral Route.
Slide 31
2. Liquid formulation stain teeth. Less satisfactory.

200 mg elemental iron daily in 3 divided doses gives maximum haemopoietic response. Infant and children 3 to 5 mg/kg
30 mg/day is for prophylaxsis Absorption is better taken in empty stomach. May have side-effects more.
Slide 32
Adverse Effect:- Oral Route Are common at the therapeutic level. Related to elemental iron dose. Mainly Gastrointestinal symptoms Constipation are common. Blackens the face
Slide 33
Preparations & Doses 100 to 200 mg elemental iron/day Oral Route

1-Ferrous sulphate dried-200_300mg daily (60 to 100 mg Eiron) 2-Ferrous gluconate 1.2-1.8 g in divided daily doses (140 mg E iron) 3. Ferrous Fumerate 200 400 mg is divided daily dose. (140 mg E iron) 4. Ferrous succinate and Ferrous glycine sulphate 5. Colloidal ferric hydroxide 200 400 mg daily
Slide 34
Parental Iron Therapy

Indications Not tolerated. Failure to absorb. No- compliance In presence of severe deficiency Along with erythropoietin
Total Iron requirement = 4.4 x body wt kg x Hb deficit g/dl

Parental Iron Therapy
1. Iron dextran injection : Dose 1 ml 2. Iron sorbitol injection : 50 mg of iron/ml Dose 1.5 mg of iron / kg
Slide 36
Adverse Effect:Local -* Pain at site of in injection. * Pigmentation of skin * Sterile abscess
Slide 37
Systemic
* Fever, headache, joint pains, flushing, palpitation, chest pain, dyspnoea, lymph node enlargement * A metallic taste in mouth lasting for few hrs. * An anaphylactoid reaction resulting in vascular collapse & death. * Iron sorbital causes more immediate reaction than iron dextran, should be avoided in patients with kidney disease
ACUTE IRON POISIONING

High doses of iron salts by mouth can cause severe GI irritation and necrosis of mucous membrane. It occurs mostly in infants& children. It is very rare in adults. Manifestation are vomiting, abdominal pain, haematemesis, diarrhoea, lethargy, cyanosis, dehydration, acidosis, convulsions & finally shock , cardiovascular collapse & death.
Slide 39
TREATMENT:1. Chelate iron in the blood, stomach and intestine. 2. To prevent further absorption of iron from gut. A. Desferrioxamine 1 to 2 G I/M give urgently B. Induce vomiting or perform gastric lavage with sodium bicarbonate solution to render iron insoluble. C. Give egg yolk & milk orally compete iron.
Slide 40
D. Deferrioxamine 5-10 mg in 100 ml saline may be left in the stomach after lavage to prevent further iron absorption.
E. IV infusion desferrioxamine 80 mg/kg/24h or IM 2 g in sterile water every 12 hourly.
Slide 41
Vitamin B12(Cyanocobalamine)
TY CSU IMU
Vitamin B12(Cyanocobalamine) Cobalamins - Active cellular co enzyme. Necessary for DNA synthesis. Formed from Cyanocobalamin and hydroxocobalamin.
Vitamin B12(Cyanocobalamine) is Extrinsic factor in the food. Principal sources - Meat (particularly liver), eggs and dairy products.
Slide 43
Absorption Vitamin B12 absorption needs Intrinsic factor, glycoprotein secreted by parietal cells in the stomach, binds to vitamin B12 in the duodenum. This vitamin B12intrinsic factor complex subsequently aids in the absorption of vitamin B12 in the terminal ileum. Then transported bound to plasma glycoprotein - transcobalamin II. Excess B12 is stored in the liver (80%) and the rest in the kidney, adrenal, pancreas and other organs.
Vit B12 and folic acid are essential vitamins for normal DNA synthesis Deficiency leads to impaired DNA synthesis; reduced cell division, but RNA and protein synthesis continue large (macrocytic) and fragile RBCs. Daily requirement- 2.4 ug. 2.6 ug for pregnant mother Average adult stores ~ 3000 - 5000g
Red cells Macrocytosis
Slide 46
White cells - Hypersegmented neutrophils
TY CSU IMU
Causes of B12 deficiency

Partial or total gastrectomy Diseases of distal ileum Nutritional deficiency: very rare but possible in strict vegetarians after many years without meat, egg or dairy products Fish tapeworm (sequestration of B12 by the worms) Prolonged exposure to N2O anaesthesia (N2O inactivates the vitamin)
48
Therapy
Since almost all cases of B12 deficiency are due to malabsorption, parenteral treatment is needed, and for life.
Hydroxycobalamin (produces higher and more sustained blood level) or cyanocobalamin.
Slide 49
Toxicity
Vit. B12 and folic acid have no known toxic effects even in high doses which are excreted in the urine and faeces Rare (allergic) effects: itching, fever, nausea, dizziness, anaphylaxis (especially hydroxycobalamin)
50
Folic acid (Pteroyl glutamic acid)
Slide 51
Folic acid (Pteroyl glutamic acid)

Folates are co-factors in the synthesis of purines and pyrimidines which are essential for DNA synthesis To be effective folates must be in the tetrahydro (FH4) form. The enzyme dihydrofolate reductase reduces dietary folic acid to FH4 (tetrahydrofolate) Folates are found in the green vegetables (heat labile), liver (more heat stable), yeast, nuts, cereals, fruits
Slide 52
Folic acid is readily and completely absorbed in the duodenum and proximal jejunum Is subsequently transported into the blood stream by active and passive transport. Since body stores are relatively low and daily requirement high, deficiency (and anaemia) can occur within 1-6 months Excreted in urine and stool and destroyed by catabolism
Slide 53
The average daily diet contains 500 700g of folate of which 50 - 200g is absorbed. Daily requirement 400 ug. per day Pregnancy- 600 to 800 ug. per day
Slide 54
Causes of folate deficiency

Often by dietary insufficiency (poverty, elderly) For alcoholics and liver disease, poor diet and very low liver storage Pregnancy (deficiency associated with neural tube defect) Haemolytic anaemia Dialysis Patients
55
Mal- absorption (e.g. coeliac disease or tropical sprue) Drugs that interfere with folate absorption e.g. Phenytoin, Oral contraceptives and Isoniazid Methotrexate, Pyrimethamine, Trimethoprim can interfere with metabolism
56
Therapy
Parenteral administration is rarely needed because folic acid is well absorbed even in mal-absorption syndromes Dont use in undiagnosed megaloblastic anaemia. 600 to 800 micrograms of folate for pregnant mothers
57
ERYTHROPOINTIN
In 1906, Paul Carnot, a professor of medicine in Paris, France, and his assistant, DeFlandres, proposed the idea that hormones regulate the production of red blood cells.
Erythropoietin is produced in the kidney and liver, and is involved in the production and differentiation of erythrocytes.
Slide 59
Erythropoietin
Slide 60
Clinical use
Anaemia of chronic renal failure (epoietin is given i.v., s.c., or i.p.) Anaemia in AIDS patients Cancer (chemotherapy) related anaemia Surgery and autologous blood transfusion (orthopaemic, cardiac procedures) Myelodysplasia
61
Abuse: sportsman to enhance performance

Side effects: Flu-like symptoms, Hypertension, Encephalopathy with headache, Disorientation convulsion blood viscosity (due to RBC mass)
Slide 62
Colony Stimulating Factors (CSF)

Cytokinase stimulate growth, differentiation and functional activitty of colonies of myeloid cells Some have been developed for clinical use. Filgrastim Lenograstim Molgramostim
Slide 63
G-CSF Filgrastim (NEUPOGEM)
Recombinant human G-CSF Produced in E.coli

64
Clinical Uses
severe neutropenia after autologous hematopoietic stem cell transplantation and high-dose cancer chemotherapy reduces morbidity secondary to bacterial and fungal infections neutropenia of AIDS patients receiving zidovudine
65
Filgrastim is administered by subcutaneous injection or intravenous infusion over at least 30 minutes half-life of 3.5 hours Adverse reactions mild to moderate bone pain skin reactions following subcutaneous injection rare cutaneous necrotizing vasculitis
66
Lesson Outcomes 1. Discuss the iron metabolism and pharmacokinetics of iron 2. Explain the indications of use for different types of iron preparation in the treatment of iron deficiency anaemia 3. Discuss different types of iron therapy, indications & adverse effects (contraindications) 4. Discuss the iron toxicity & its treatment 5. Discuss the pharmacokinetics, indications of use, therapy and adverse effects for Vitamin B12 & Folic acid 6. Describe the outline of erythropoietin & G-CSF therapy
67
Contents Treatment of Iron deficiency (oral and parental preparations of iron) Management of iron overload Treatment of B12 deficiency (oral and parental preparations of B12) Treatment of Folic acid deficiency Erythropoietin & G-CSF therapy
68
THANK YOU
TY CS & SC IMU

Teaching TY Haematinics

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HAEMATINICS

ME 1/11 SEM 3 12/3-17/3/2012

TY CS& SC IMU 2012

These are mainly IRON, FOLIC ACID & VIT B12

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Normal blood film

Severe iron deficiency anaemia

Red cells Macrocytosis

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

White cells - Hypersegmented neutrophils

ALL ANAEMIA CASES

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

ANAEMIA WITH NUTRI. DEFICIENCY

Types (Blood Picture)

It is regulated by erythropoietin - secreted by kidneys - stimulates the bone marrow

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Dietary Sources Diet contains 10 to 15 mg iron/day

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Divalent metal transporter 1

Ferrous Ferric + Apoferritin Ferritin

Circulate in the plasma

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

RE cells Liver, Spleen, Bone-marrow, hepatocytes, myocytes as ferritin and haemosiderin

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

from Old RBC 120 days Iron Store Intestinal absorption

An Iron common pool

Erythrpoiesis, Other cells, Restorage

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Causes of Iron Deficiency Anaemia

Normal blood film

Severe iron deficiency anaemia

Indications for Iron therapy

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

2. Liquid formulation stain teeth. Less satisfactory.

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Preparations & Doses 100 to 200 mg elemental iron/day Oral Route

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Parental Iron Therapy

Total Iron requirement = 4.4 x body wt kg x Hb deficit g/dl

Parental Iron Therapy

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Adverse Effect:Local -* Pain at site of in injection. * Pigmentation of skin * Sterile abscess

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

ACUTE IRON POISIONING

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

E. IV infusion desferrioxamine 80 mg/kg/24h or IM 2 g in sterile water every 12 hourly.

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Red cells Macrocytosis

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

White cells - Hypersegmented neutrophils

Causes of B12 deficiency

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Folic acid (Pteroyl glutamic acid)

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Folic acid (Pteroyl glutamic acid)

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000

Operational Obstetrics & Gynecology Bureau of Medicine and Surgery 2000