Haematinics

Dr. D. K. BrahmaAssociate Professor

Department of PharmacologyNEIGRIHMS, Shillong

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)

IRON

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 (Fe3+) – 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 + Fe3+ Ferritin Haemosiderinaggregates

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

Iron – Transport, storage etc.• In plasma immediately converted to Fe3+ 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

Iron –Absorption, Transport, storage etc. - Image

Essentials of Medical pharmacology by KD Tripathi – 6 th Edition, JAYPEE, 2008

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

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

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

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

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

VITAMIN – B12

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)

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

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 – 4/5th 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

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

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

FOLIC ACID

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

Folic acid – Metabolic function

• Conversion of homocysteine to methionine• Generation of thymidylate• Conversion of serine to glycine• Purine synthesis de novo• Histidine metabolism

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)

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

Erythropoietin (EPO)

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

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

Remember ….. Take home !

• Haematinics – The Perfect example of a

Teamwork

Thank you