Haematinics

A Power point presentation on Pharmacokinetics suitable for teaching UG MBBS Students,.

1. Haematinics
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Background
•These are the substances required in the formation of
blood, and are used in the treatment of anaemias
•Anaemia: a condition in which there is a deficiency of
red cells or of haemoglobin in the blood, resulting in
pallor and weariness
•Balance between production and destruction of RBCs
are disturbed:
–Blood Loss (acute or chronic)
–Impaired cell formation due to
•Deficiency of essential factors – Iron, Vit. B12 and Folic acid
•Bone marrow depression (hypoplastic), erythropoietin deficiency
–Increased cell destruction (haemolytic)

3. IRON

4. Iron – Basics
•Total Body Iron content – 3.5 gm (average): Male – 50 mg/kg and Female
– 38 mg/kg
•Hemoglobin – 66% - Protoporphyrin – 4 Iron containing haeme residues
•Loss of 100 ml of blood – 50 mg elemental Iron
•To raise 1 gm/dl – 200 mg elemental Iron required
•Stored only in Ferric form (Fe
3+
) – in combination with apoferritin – mainly
in RE Cells
•Many cellular enzymes – cytochromes, peroxidases, catalases, xanthine
oxidases and some mitochondrial enzymes
•Severe Iron deficiency affects all cells
•Daily requirement: Male: 0.5 to 1 mg/day; Female: 1.5 to 2 mg/day (more
in pregnancy) ………… Sources ???
Apoferritn + Fe
3+
 Ferritin Haemosiderin
aggregates

5. Iron Absorption
•Diet – 10 to 20 mg – absorbed from all over the Intestine (more
from upper part)
•2 forms – haeme and Inorganic
–Haeme – minor form of dietary Iron but absorbed better without any
transporter
–Inorganic – in ferric form but absorbs lesser – converted to ferrous
form in Intestine for absorption – needs transporter
–Divalent metal transporter (DMT1) and Ferroportin (FP)
•Factors increasing absorption – acid, reducing substances – ascorbic
acid, amino acid etc. and meat
•Factors impending absorption – alkali (antacids), Phosphates,
phytates, tetracycline and presence of other food
•Mucosal block: from mucosal cell – transported to plasma or
remains stored in mucosal cell by forming ferritin - Ferritin curtain
–Balance between those two – detremines how much Iron to enter
body - by haematopoietic transcription factor

6. Iron – Transport, storage etc.
•In plasma immediately converted to Fe
3+
form – complexed
with transferrin (Tf) – Total Plasma Iron – 3 mg - recycled
•Transported to RBCs by transferrin receptors (TfRs) –
endocytosis – Iron dissociates from TfR in acidic pH of
vesicles
•Iron utilized for Hb synthesis – TfRs return to surface
•In Iron deficiency – TfRs increase
•Storage – RE cells in Liver, spleen, bone and muscles as
ferritin and haemsiderin
•Apoferritin – determines how much Iron storage needed -
synthesis regulated by Iron status and Iron regulating
element on mRNA – blocked in low Iron – no apoferritin
synthesis – in high Iron state – more apoferritin synthesis
•Excretion – 0.5 to 1 mg/day – exfoliation in GI mecosal
cells, RBCs and in Bile …. Also in skin, urine and sweat

7. Iron –Absorption, Transport, storage
etc. - Image
Essentials of Medical pharmacology by KD Tripathi – 6
th
Edition, JAYPEE, 2008

8. Iron Preparations - Oral
•Preferred route – ferrous salts – high Iron content, inexpensive,
better absorbed than ferric salts …. Gastric irritation and
constipation limits use
–Ferrous sulfate (20% hydrated salt and dried salt 32% or 65 mg)
–Ferrous gluconate (12% Iron or 28-36 mg)
–Ferrous fumerate (33% or 106 mg)
–Colloidal ferric hydroxide (50%) ……… 150 to 200 mg per day
•Other preparations: Ferrous succinate, Iron choline citrate, Iron
calcium complex, Ferric ammonium citrate, Iron hydroxy
polymaltose … low Iron content (less GI upset) and expensive
•No to Vit. B –complex combination (GOI) with Iron and Folic acid
preparations and also no to sustained release preparations
•Dosage: 200 mg daily in 3 divided doses (3 – 5 mg/kg for children)
•ADRs: Differ in susceptibility – individuals …. Epigastric pain, heart
burn, nausea, vomiting, staining of teeth, metallic taste, bloating,
colic -- CONSTIPATION

9. Iron Preparations - Parenteral
•Indications:
–Failure to absorb oral Iron – malabsorption, inflammatory bowel
disease (proximal small bowel)
–Post gastrectomy conditions
–Severe deficiency with chronic bleeding
–Either intolerance and non-compliance to oral Iron
–With erythropoietin
•Calculation: 4.4 X body weight (kg) X Hb deficit (g/dl)
•Not faster absorption than oral but stores replenish faster
•Preparations: Iron-dextran (colloidal solution) 50 mg/ml
Iron and Iron-sorbitol-citric acid complex and Sodium ferric
gluconate complex in sucrose

10. Parenteral Iron
•IM: Z technique – deep in
gluteal region – 2 ml daily or
on alternate days or 5 ml each
side on same day – Iron
sorbitol – 1.5 to 2.00 ml per
day
•IV: Iron dextran - 0.5 ml test
dose –for 5 to 10 minutes … 2
ml for 10 minutes
•Or in 500 ml glucose/saline
slow infusion – constant
observation
•Terminate if – giddiness,
paresthesia or chest
constriction
Essentials of Medical pharmacology by KD Tripathi – 6
th

Edition, JAYPEE, 2008

11. Iron – contd.
•ADRs:
–Local: Pain in IM injection, pigmentation of skin, sterile abscess
–Systemic: Fever, headache, joint pain, flushing, palpitation, chest pain,
dyspnoea, lymph node enlargement
•Metallic taste with sorbitol
•Anaphylactoid reaction – Kidney diseases (no sorbitol)
•Uses:
–Iron deficiency anaemia: Nutritional deficiency, chronic blood loss (GIT
ulcers and hook worm)
•Oral Iron preferred : Target – 0.5 to 1 g/dl per week – 1 to 3 months therapy
plus 2 to 3 months afterwards
•Prophylaxis: Ceiling on Iron absorption - = 3 mg/day ….. Pregnancy and
infancy to be taken care of well in advance
–Megaloblastic anaemia
–As astringent: Ferric chloride

12. Acute Iron Poisoning
•Infants and children – 10 to 20 tablets (60 mg/kg Iron)
•Symptoms: Vomiting, abdominal pain, haematemesis, diarrhoea,
lethargy, cyanosis, dehydration, acidosis, convulsion, CVS collapse
and death (12 – 36 Hours)
–Haemorrhage and inflammation of gut, hepatic necrosis and brain
damage
•Treatment:
–Prevent further absorption: Induce vomitingor gastric lavage with
NaHCO3 – to render Iron insoluble …… and also Egg yolk and Milk orally
–Antidote: Desferrioxamine: 0.5 to 1.00 gm IM repeated 4 – 12 Hourly
or IV 10 – 15 mg/kg/Hour (max 75 mg/day) till serum levels fall
–DTPA and Calcium edetate
–Supportive: Fluid and electrolyte, correction of acidosis and Diazepam

13. VITAMIN – B12

14. Introduction
•Complex cobalt containing compounds
Cyanocobalamin and hydroxocobalamin
•Physical: Water soluble, red crystals
synthesized only by microorganisms
•Sources: Liver, Kidney, sea fish, egg yolk ….
Streptomyces geireus
•Daily Requirement: 1 – 3 mcg (Pregnancy and
Lactation3 – 5 mcg)

15. Vit. B12 - Metabolic functions
•Linked with folic acid metabolism – megaloblastic anaemia
indistinguishable
•Two active forms - Deoxy-adenosyl-cobalamin (DAB12) and methyl-
cobalamin (methyl-B12)
1)Vit. B12 needed for conversion of homocysteine to methionine – methionine
is methyl group donor in metabolic reactions – also critical for making THFA
available
2)Purine and pyrymidine synthesis is affected – folate trap – non availability
of thymidylate for DNA synthesis
3)Malonic acid Succinic acid - important for propionic acid
metabolism (Carbohydrate and lipid metabolism) – linked to demyelination
in Vit. B12 deficiency
4)Methionine S-adenosyl methionine – neurological
damage
5)Vit. B12 is needed for cell growth and multiplications

16. Vit. B12 - Kinetics
•Absorption: Present in food as protein conjugates – released
by cooking/proteolysis
–IF forms a complex with Vit. B12 – attaches to specific receptor in
mucosa – absorbed by active transport
•Transport: In combination with transcobalamin II (TCII) –
congenital absence/abnormal protein (liver disease and BM
disease) – defective supply to tissues
•Storage: In liver – 4/5
th
of Body`s Vit.B12
•Degradation: Not degraded in body – excreted mainly in Bile –
enterohepatic circulation ….. absence of IF and malabsorption
Vs Nutritional deficiency
•Parenteral – completely absorbed -IM and SC administration
– excreted via urine

17. Deficiency - Vit. B12
•Deficiency: Addisonian pernicious anaemia (destruction of
parietal cells – IF absent), gastric mucosal damage, damaged
intestinal mucosa, consumption by abnormal flora (blind loop
syndrome & fish tape worm), nutritional deficiency, increased
demand
•Manifestations: Megaloblastic anaemia, glossitis, GI
disturbance, degeneration of spinal chord and peripheral
neuritis – diminished vibration and position sense,
paresthesia, depressed reflexes and mental changes
•Preparations: Cyanocobalamin Injection, Hydroxocobalamin
Injection and Methylcobalamin Tablets

18. Vit. B12 – Uses and ADRs
•Prophylactically in diabetics and alcoholics – to prevent
peripheral neuritis – 1.5 mg/day
•Treatment of deficiency states: Add Folic acid and Iron
–Very quick response – appetite increases, patient feel better, mucosal
lesions heal, neurological parameters improve
–If due to IF factor lacking – IM or SC (not IV) – necessary to by pass
defective absor scheduleption – daily-weekly-monthly
•Mega doses: in neuropathies, psychiatric disorders,
cutaneous sarcoid
•Tobacco amblyopia – cyanide to cyanocobalamin
•ADRs: Safe – allergic reactions due to contaminants

19. FOLIC ACID

20. Introduction
•Physical: Yellow crystals, insoluble in water, Pteroyl glutamic acid
(PGA) – pteridine + paraminobenzoic acids + glutamic acid
•Daily requirement: 0.2 mg per day (0.8 mg in pregnancy and
lactation)
•Kinetics:
–Absorption: As polyglutamates in food – glutamates split off and
absorbed in upper intestine ….. Reduction to DHFA and methylation
also occurs at same site
–Transport: as methyl-THFA – partly bound to plasma protein
–Store: tissues extract FA rapidly and store as polyglutamates in cells.
Liver takes up major portion – releases methyl-THFA – enterohepatic
circulation (alcohol interferes)
–Excretion: Pharmacological doses – excreted in Urine

21. Folic acid – Metabolic function
•Conversion of homocysteine to methionine
•Generation of thymidylate
•Conversion of serine to glycine
•Purine synthesis de novo
•Histidine metabolism

22. Deficiency - Folic acid
•Deficiency: Inadequate dietary intake, Malabsorption (upper
GIT – coeliac disease, tropical sprue etc.), biliary fistula,
chronic alcoholism, increased demand (pregnancy), drug
induced (phenytoin, phenobarbitone etc.)
•Manifestations: Megaloblastic anaemia (body store lasts for
2-3 months), epithelial damage (glossitis, enteritis, diarrhoea),
neural tube defects (spina bifida), general debility (weakness,
loss weight, sterility)
•Preparations: Folic acid tablets and Folinic acid Injections
(Calcium leucovorin)

23. Folic acid – Uses and ADRs
•Megaloblastic anaemia: due to nutritional deficiency,
pregnancy, pernicious anaemia (adjuvant role with
Vit. B12), malabsorption syndromes, antiepileptic
therapy
•Prophylaxis: 1 mg per day routinly in pregnancy
•Methotrexate toxicity: Folinic acid, citrovorum factor
•Citrovorum rescue: within 3 hours
•ADRs: Non toxic orally, sensitivity by injections rarely

24. Erythropoietin (EPO)

25. Introduction
•Sialoglycoprotein hormone – produced by peritubular cells of Kidney
•Recombinant human erythropoietin (Epoetin α, β) – administerd IV or SC
•Half life: 6 – 10 Hours
•Required for erythropoiesis: anaemia and hypoxia sensed by kidney cells –
EPO secretes and acts on marrow:
–Stimulates proliferation of colony forming cells of erythroid series
–Induces Hb formation and erythroblast maturation
–Release of reticulocytes
•MOA: Binds to specific EPO receptor (JAK-STAT-kinase) – alters
phosphorylation of intracellular proteins and activates transcription
factors to regulate gene expression – erythropoiesis

26. Erythropoietin – Uses and ADRs
•Anaemia of chronic renal failure – 25 – 100 U/kg SC or IV 3
times a day – concomitant Iron therapy
•Anaemia with AIDS patients treated with zidovudine
•Cancer chemotherapy induced anaemia
•Preoperative increased blood production – autologous
transfusion
•ADRs: Nonimmunogenic, ----- ADRs occur due to increase in
haematocrit, viscosity and peripheral resistance – increased
clot formation in AV- shunts, hypertensive episodes, seizure,
flu like symptoms

27. Remember ….. Take home !
•Haematinics – The Perfect example of a
Teamwork

28. Thank you