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Haematinics
1. Haematinics
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong
2. Background
โข These are the substances required in the formation of
blood, and are used in the treatment of anaemias
โข Anaemia: a condition in which there is a deficiency of
red cells or of haemoglobin in the blood, resulting in
pallor and weariness
โข Balance between production and destruction of RBCs
are disturbed:
โ Blood Loss (acute or chronic)
โ Impaired cell formation due to
โข Deficiency of essential factors โ Iron, Vit. B12 and Folic acid
โข Bone marrow depression (hypoplastic), erythropoietin deficiency
โ Increased cell destruction (haemolytic)
4. Iron โ Basics
โข Total Body Iron content โ 3.5 gm (average): Male โ 50 mg/kg and Female
โ 38 mg/kg
โข Hemoglobin โ 66% - Protoporphyrin โ 4 Iron containing haeme residues
โข Loss of 100 ml of blood โ 50 mg elemental Iron
โข To raise 1 gm/dl โ 200 mg elemental Iron required
โข Stored only in Ferric form (Fe3+
) โ in combination with apoferritin โ mainly
in RE Cells
โข Many cellular enzymes โ cytochromes, peroxidases, catalases, xanthine
oxidases and some mitochondrial enzymes
โข Severe Iron deficiency affects all cells
โข Daily requirement: Male: 0.5 to 1 mg/day; Female: 1.5 to 2 mg/day (more
in pregnancy) โฆโฆโฆโฆ Sources ???
Apoferritn + Fe3+
๏ Ferritin Haemosiderinaggregates
5. Iron Absorption
โข Diet โ 10 to 20 mg โ absorbed from all over the Intestine (more
from upper part)
โข 2 forms โ haeme and Inorganic
โ Haeme โ minor form of dietary Iron but absorbed better without any
transporter
โ Inorganic โ in ferric form but absorbs lesser โ converted to ferrous
form in Intestine for absorption โ needs transporter
โ Divalent metal transporter (DMT1) and Ferroportin (FP)
โข Factors increasing absorption โ acid, reducing substances โ ascorbic
acid, amino acid etc. and meat
โข Factors impending absorption โ alkali (antacids), Phosphates,
phytates, tetracycline and presence of other food
โข Mucosal block: from mucosal cell โ transported to plasma or
remains stored in mucosal cell by forming ferritin - Ferritin curtain
โ Balance between those two โ detremines how much Iron to enter
body - by haematopoietic transcription factor
6. Iron โ Transport, storage etc.
โข In plasma immediately converted to Fe3+
form โ complexed
with transferrin (Tf) โ Total Plasma Iron โ 3 mg - recycled
โข Transported to RBCs by transferrin receptors (TfRs) โ
endocytosis โ Iron dissociates from TfR in acidic pH of
vesicles
โข Iron utilized for Hb synthesis โ TfRs return to surface
โข In Iron deficiency โ TfRs increase
โข Storage โ RE cells in Liver, spleen, bone and muscles as
ferritin and haemsiderin
โข Apoferritin โ determines how much Iron storage needed -
synthesis regulated by Iron status and Iron regulating
element on mRNA โ blocked in low Iron โ no apoferritin
synthesis โ in high Iron state โ more apoferritin synthesis
โข Excretion โ 0.5 to 1 mg/day โ exfoliation in GI mecosal
cells, RBCs and in Bile โฆ. Also in skin, urine and sweat
7. Iron โAbsorption, Transport, storage
etc. - Image
Essentials of Medical pharmacology by KD Tripathi โ 6th
Edition, JAYPEE, 2008
8. Iron Preparations - Oral
โข Preferred route โ ferrous salts โ high Iron content, inexpensive,
better absorbed than ferric salts โฆ. Gastric irritation and
constipation limits use
โ Ferrous sulfate (20% hydrated salt and dried salt 32% or 65 mg)
โ Ferrous gluconate (12% Iron or 28-36 mg)
โ Ferrous fumerate (33% or 106 mg)
โ Colloidal ferric hydroxide (50%) โฆโฆโฆ 150 to 200 mg per day
โข Other preparations: Ferrous succinate, Iron choline citrate, Iron
calcium complex, Ferric ammonium citrate, Iron hydroxy
polymaltose โฆ low Iron content (less GI upset) and expensive
โข No to Vit. B โcomplex combination (GOI) with Iron and Folic acid
preparations and also no to sustained release preparations
โข Dosage: 200 mg daily in 3 divided doses (3 โ 5 mg/kg for children)
โข ADRs: Differ in susceptibility โ individuals โฆ. Epigastric pain, heart
burn, nausea, vomiting, staining of teeth, metallic taste, bloating,
colic -- CONSTIPATION
9. Iron Preparations - Parenteral
โข Indications:
โ Failure to absorb oral Iron โ malabsorption, inflammatory bowel
disease (proximal small bowel)
โ Post gastrectomy conditions
โ Severe deficiency with chronic bleeding
โ Either intolerance and non-compliance to oral Iron
โ With erythropoietin
โข Calculation: 4.4 X body weight (kg) X Hb deficit (g/dl)
โข Not faster absorption than oral but stores replenish faster
โข 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
โข IM: Z technique โ deep in
gluteal region โ 2 ml daily or
on alternate days or 5 ml each
side on same day โ Iron
sorbitol โ 1.5 to 2.00 ml per
day
โข IV: Iron dextran - 0.5 ml test
dose โfor 5 to 10 minutes โฆ 2
ml for 10 minutes
โข Or in 500 ml glucose/saline
slow infusion โ constant
observation
โข Terminate if โ giddiness,
paresthesia or chest
constrictionEssentials of Medical pharmacology by KD Tripathi โ 6th
Edition, JAYPEE, 2008
11. Iron โ contd.
โข ADRs:
โ Local: Pain in IM injection, pigmentation of skin, sterile abscess
โ Systemic: Fever, headache, joint pain, flushing, palpitation, chest pain,
dyspnoea, lymph node enlargement
โข Metallic taste with sorbitol
โข Anaphylactoid reaction โ Kidney diseases (no sorbitol)
โข Uses:
โ Iron deficiency anaemia: Nutritional deficiency, chronic blood loss (GIT
ulcers and hook worm)
โข Oral Iron preferred : Target โ 0.5 to 1 g/dl per week โ 1 to 3 months therapy
plus 2 to 3 months afterwards
โข Prophylaxis: Ceiling on Iron absorption - = 3 mg/day โฆ.. Pregnancy and
infancy to be taken care of well in advance
โ Megaloblastic anaemia
โ As astringent: Ferric chloride
12. Acute Iron Poisoning
โข Infants and children โ 10 to 20 tablets (60 mg/kg Iron)
โข Symptoms: Vomiting, abdominal pain, haematemesis, diarrhoea,
lethargy, cyanosis, dehydration, acidosis, convulsion, CVS collapse
and death (12 โ 36 Hours)
โ Haemorrhage and inflammation of gut, hepatic necrosis and brain
damage
โข Treatment:
โ Prevent further absorption: Induce vomitingor gastric lavage with
NaHCO3 โ to render Iron insoluble โฆโฆ and also Egg yolk and Milk orally
โ Antidote: Desferrioxamine: 0.5 to 1.00 gm IM repeated 4 โ 12 Hourly
or IV 10 โ 15 mg/kg/Hour (max 75 mg/day) till serum levels fall
โ DTPA and Calcium edetate
โ Supportive: Fluid and electrolyte, correction of acidosis and Diazepam
14. Introduction
โข Complex cobalt containing compounds
Cyanocobalamin and hydroxocobalamin
โข Physical: Water soluble, red crystals
synthesized only by microorganisms
โข Sources: Liver, Kidney, sea fish, egg yolk โฆ.
Streptomyces geireus
โข Daily Requirement: 1 โ 3 mcg (Pregnancy and
Lactation3 โ 5 mcg)
15. Vit. B12 - Metabolic functions
โข Linked with folic acid metabolism โ megaloblastic anaemia
indistinguishable
โข Two active forms - Deoxy-adenosyl-cobalamin (DAB12) and methyl-
cobalamin (methyl-B12)
1) Vit. B12 needed for conversion of homocysteine to methionine โ methionine
is methyl group donor in metabolic reactions โ also critical for making THFA
available
2) Purine and pyrymidine synthesis is affected โ folate trap โ non availability
of thymidylate for DNA synthesis
3) Malonic acid Succinic acid - important for propionic acid
metabolism (Carbohydrate and lipid metabolism) โ linked to demyelination
in Vit. B12 deficiency
4) Methionine S-adenosyl methionine โ neurological
damage
5) Vit. B12 is needed for cell growth and multiplications
16. Vit. B12 - Kinetics
โข Absorption: Present in food as protein conjugates โ released
by cooking/proteolysis
โ IF forms a complex with Vit. B12 โ attaches to specific receptor in
mucosa โ absorbed by active transport
โข Transport: In combination with transcobalamin II (TCII) โ
congenital absence/abnormal protein (liver disease and BM
disease) โ defective supply to tissues
โข Storage: In liver โ 4/5th
of Body`s Vit.B12
โข Degradation: Not degraded in body โ excreted mainly in Bile โ
enterohepatic circulation โฆ.. absence of IF and malabsorption
Vs Nutritional deficiency
โข Parenteral โ completely absorbed -IM and SC administration
โ excreted via urine
17. Deficiency - Vit. B12
โข Deficiency: Addisonian pernicious anaemia (destruction of
parietal cells โ IF absent), gastric mucosal damage, damaged
intestinal mucosa, consumption by abnormal flora (blind loop
syndrome & fish tape worm), nutritional deficiency, increased
demand
โข Manifestations: Megaloblastic anaemia, glossitis, GI
disturbance, degeneration of spinal chord and peripheral
neuritis โ diminished vibration and position sense,
paresthesia, depressed reflexes and mental changes
โข Preparations: Cyanocobalamin Injection, Hydroxocobalamin
Injection and Methylcobalamin Tablets
18. Vit. B12 โ Uses and ADRs
โข Prophylactically in diabetics and alcoholics โ to prevent
peripheral neuritis โ 1.5 mg/day
โข Treatment of deficiency states: Add Folic acid and Iron
โ Very quick response โ appetite increases, patient feel better, mucosal
lesions heal, neurological parameters improve
โ If due to IF factor lacking โ IM or SC (not IV) โ necessary to by pass
defective absor scheduleption โ daily-weekly-monthly
โข Mega doses: in neuropathies, psychiatric disorders,
cutaneous sarcoid
โข Tobacco amblyopia โ cyanide to cyanocobalamin
โข ADRs: Safe โ allergic reactions due to contaminants
20. Introduction
โข Physical: Yellow crystals, insoluble in water, Pteroyl glutamic acid
(PGA) โ pteridine + paraminobenzoic acids + glutamic acid
โข Daily requirement: 0.2 mg per day (0.8 mg in pregnancy and
lactation)
โข Kinetics:
โ Absorption: As polyglutamates in food โ glutamates split off and
absorbed in upper intestine โฆ.. Reduction to DHFA and methylation
also occurs at same site
โ Transport: as methyl-THFA โ partly bound to plasma protein
โ Store: tissues extract FA rapidly and store as polyglutamates in cells.
Liver takes up major portion โ releases methyl-THFA โ enterohepatic
circulation (alcohol interferes)
โ Excretion: Pharmacological doses โ excreted in Urine
21. Folic acid โ Metabolic function
โข Conversion of homocysteine to methionine
โข Generation of thymidylate
โข Conversion of serine to glycine
โข Purine synthesis de novo
โข Histidine metabolism
25. Introduction
โข Sialoglycoprotein hormone โ produced by peritubular cells of Kidney
โข Recombinant human erythropoietin (Epoetin ฮฑ, ฮฒ) โ administerd IV or SC
โข Half life: 6 โ 10 Hours
โข Required for erythropoiesis: anaemia and hypoxia sensed by kidney cells โ
EPO secretes and acts on marrow:
โ Stimulates proliferation of colony forming cells of erythroid series
โ Induces Hb formation and erythroblast maturation
โ Release of reticulocytes
โข MOA: Binds to specific EPO receptor (JAK-STAT-kinase) โ alters
phosphorylation of intracellular proteins and activates transcription
factors to regulate gene expression โ erythropoiesis
26. Erythropoietin โ Uses and ADRs
โข Anaemia of chronic renal failure โ 25 โ 100 U/kg SC or IV 3
times a day โ concomitant Iron therapy
โข Anaemia with AIDS patients treated with zidovudine
โข Cancer chemotherapy induced anaemia
โข Preoperative increased blood production โ autologous
transfusion
โข ADRs: Nonimmunogenic, ----- ADRs occur due to increase in
haematocrit, viscosity and peripheral resistance โ increased
clot formation in AV- shunts, hypertensive episodes, seizure,
flu like symptoms
27. Remember โฆ.. Take home !
โข Haematinics โ The Perfect example of a
Teamwork