AGEN HEMATINIKM. Fadhol RomdhoniLaboratorium FarmakologiFakultas KedokteranUniversitas Muhammadiyah Malang

Pokok BahasanOverviewBesiVitamin B12Asam FolatFaktor Pertumbuhan Hematopoietik

http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood.htmlOVERVIEW

umped by the heart, blood reaches every part of our bodies and 'feeds' each cell with everything it needs; from oxygen and sugar for energy, to the building blocks for new cells to be built.

It also carries the waste products to be cleared away and transports the cells which patrol our bodies and make sure we do not get sick.

It is made up of several important parts: a fluid called 'plasma', white blood cells, red blood cells, and platelets.

The plasma contains all the nutrients from the things we eat.

The platelets make the blood clot if you cut yourself.

The white blood cells stop bugs getting into the body and fight infections, such as a cold or sore throat.

The red blood cells are what give your blood its colour. They pick up oxygen from your lungs and carry it around your body. These are the cells that are important in your sickle cell anaemia. Red blood cells are able to do this because they carry lots of copies of a special protein called 'haemoglobin'.Blood :Formed elements (red and white blood cells and platelets) plasma. Components of the haemopoietic systemMain: blood, bone marrow, lymph nodes and thymusAccessory : spleen, liver and kidneys*

http://www.theironfiles.co.uk/Sickle-cell/General/SCDBlood.html

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Haemoglobin4 globin + 1 haem. Haem consists of a tetrapyrrole porphyrin ring containing ferrous (Fe2+) iron. Each haem group can carry 1 oxygen molecule

bound reversibly to Fe2+ and to a histidine residue in the globin chain basis of oxygen transport.

A schematic visual model of oxygen binding process, showing all four monomers and hemes, and protein chains only as diagramatic coils, to facilitate visualization into the molecule. Oxygen is not shown in this model, but for each of the iron atoms it binds to the iron (red sphere) in the flat heme. For example, in the upper left of the four hemes shown, oxygen binds at the left of the iron atom shown in the upper left of diagram. This causes the iron atom to move backward into the heme, which holds it, tugging the histidine residue (modeled as a red pentagon on the right of the iron) closer, as it does. This, in turn, pulls on the protein chain holding the histidine.*

AnaemiaDefinition: [Hb] in blood &/ RBC per age, sex and geographical location.Normal Hb: 14g to 16g /dl in Male 13g to 15g /dl in FemaleAcute: fatigue chronic: asymptomatic.Classification based on indices of red cell are:hypochromic, microcytic anaemiamacrocytic anaemianormochromic normocytic anaemiamixed pictures.

Classification: hypochromic, microcytic anaemia (small red cells with low haemoglobin; caused by iron deficiency) macrocytic anaemia (large red cells, few in number) normochromic normocytic anaemia (fewer normal-sized red cells, each with a normal haemoglobin content) mixed pictures.

Morphological (according to the size and Hb content of the RBCs)Basically, all anaemias can be classified into three groups as per morphology of the RBCs.1.Microcytic Hypochromic (RBCs are small in size andless haemoglobinised)(a)Iron Deficiency Anaemia(b)Thalassaemia2.Macrocytic normochromic (RBCs are large in size and normally haemoglobinised)(a) Megaloblastic Anaemia due to Folate/B12deficiency3.Normocytic Normochromic (RBCs are normal in size and normally haemoglobinised)(a)Haemolytic Anaemia(b)Post Haemorrhagic AnaemiaInternal BleedingMalaena (black tarry stool)HaemoptysisStreet AccidentBleeding during OperationPost Partum Bleeding (c)Aplastic Anaemia (d)Leukaemia (e)Anaemia due to Renal Failure

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BALANCEOUTPUTMACHINEINPUT

Causes of Anaemia Formation 1.NutritionalIron DeficiencyFolic Acid/ Vit B12DeficiencyProtein Deficiency2.Decreased SynthesisAplastic AnaemiaReplacement of BM (e.g. Leukaemia)Thalassaemia3.Chronic DisorderKidney DiseaseAdvanced MalignancyChronic Liver Disease

Destruction1.Post HaemorrhageAcute & chronicBlood Loss2.Excessive HaemolysisIntracellular Defect (Defective RBC)ThalassaemiaHaemoglobinopathiesSickle Cell AnaemiaExtracellular DefectRh IncompatibilityAuto Immune Haemolytic AnaemiaCertain Snake Venom

CAUSES OF ANAEMIA (ETIOLOGY):It is not difficult to understand that anaemiacan occur either by diminished formation or excessive destruction of RBCS.A.Diminished Formation (Dyshaemopoietic) 1.Nutritional(a)Iron Deficiency (b)Folic Acid/ Vit B12Deficiency(c)Protein Deficiency 2.Decreased Synthesis(a)Aplastic Anaemia(b)Replacement of BM (e.g. Leukaemia)(c)Thalassaemia 3.Chronic Disorder(a)Kidney Disease(b)Advanced Malignancy(c)Chronic Liver DiseaseB.Excessive Destruction1.Post Haemorrhage(a)Acute Blood Loss(b)Ghronic Blood Loss2.Excessive Haemolysis(a)Intracellular Defect (Defective RBC)ThalassaemiaHaemoglobinopathies (Hb C/ E)Sickle Cell AnaemiaHereditary Spherocytosis (b)Extracellular Defect Rh Incompatibility Incompatible Blood Transfusion Auto Immune Haemolytic Anaemia Certain Snake Venom*

BESIFarmakologi dasarFarmakokinetikFarmakodinamik Farmakologi KlinisToksisitas Klinis

Farmakologi dasarImportant properties : several oxidation states form stable coordination complexesFe + protoporfirin HemeHeme + globin HemoglobinHemoglobin binds O2 & provides O2 deliveryFe deficiency microcytic hypochromic anemiaBody content of iron:Essential: myoglobin, Hb, enzym, transferrin not available for haemoglobin synthesisStorage: Ferritin, hemosiderin Hb synthesis

The body of a 70 kg man contains about 4 g of iron, 65% of which circulates in the blood as haemoglobin. About one half of the remainder is stored in the liver, spleen and bone marrow, chiefly as ferritin and haemosiderin. The iron in these molecules is available for fresh haemoglobin synthesis. The rest, which is not available for haemoglobin synthesis, is present in myoglobin, cytochromes and various enzymes*

PHARMACOKINETICS

Humans are adapted to absorb iron in the form of haem. Non-haem iron in food is mainly in the ferric state and this needs to be converted to ferrous iron for absorption. Ferric iron, and to a lesser extent ferrous iron, has low solubility at the neutral pH of the intestine; however, in the stomach, iron dissolves and binds to mucoprotein. In the presence of ascorbic acid, fructose and various amino acids, iron is detached from the carrier, forming soluble low-molecular-weight complexes that enable it to remain in soluble form in the intestine. Ascorbic acid stimulates iron absorption partly by forming soluble iron-ascorbate chelates and partly by reducing ferric iron to the more soluble ferrous form. The site of iron absorption is the duodenum and upper jejunum, The stomach plays a role in iron absorption through dissolving iron by HCL and forming soluble complex together with Vitamin C(reducing agent) to aid its reduction into ferrous absorbable form.and absorption is a two-stage process involving first a rapid uptake across the brush border and then transfer into the plasma from the interior of the epithelial cells. The second stage, which is rate limiting, is energy dependent. Haem iron in the diet is absorbed as intact haem and the iron is released in the mucosal cell by the action of haem oxidase. Non-haem iron is absorbed in the ferrous state. Within the cell, ferrous iron is oxidised to ferric iron, which is bound to an intracellular carrier, a transferrin-like protein; the iron is then either held in storage in the mucosal cell as ferritin (if body stores of iron are high) or passed on to the plasma (if iron stores are low). Iron is carried in the plasma bound to transferrin, a -globulin with two binding sites for ferric iron, which is normally only 30% saturated. Plasma contains 4 mg iron at any one time, but the daily turnover is about 30 mg (Fig. 21.1). Most of the iron that enters the plasma is derived from mononuclear phagocytes, following the degradation of time-expired erythrocytes. Intestinal absorption and mobilisation of iron from storage depots contribute only small amounts. Most of the iron that leaves the plasma each day is used for haemoglobin synthesis by red cell precursors. These cells have receptors that bind transferrin molecules, releasing them after the iron has been taken up. Iron is stored in two forms-soluble ferritin and insoluble haemosiderin. Ferritin is found in all cells, the mononuclear phagocytes of liver, spleen and bone marrow containing especially high concentrations. It is also present in plasma. The precursor of ferritin, apoferritin, is a large protein of molecular weight 450000, composed of 24 identical polypeptide subunits that enclose a cavity in which up to 4500 iron molecules can be stored. Apoferritin takes up ferrous iron, oxidises it and deposits the ferric iron in its core. In this form, it constitutes ferritin, the primary storage form of iron, from which the iron is most readily available. The lifespan of this iron-laden protein is only a few days. Haemosiderin is a degraded form of ferritin in which the iron cores of several ferritin molecules have aggregated, following partial disintegration of the outer protein shells. The ferritin in plasma has virtually no iron associated with it. It is in equilibrium with the storage ferritin in cells and its concentration in plasma provides an estimate of total body iron stores. The body has no means of actively excreting iron. Small amounts leave the body through desquamation (peeling off) of mucosal cells containing ferritin, and even smaller amounts leave in the bile, sweat and urine. A total of about 1 mg is lost daily. Iron balance is, therefore, critically dependent on the active absorption mechanism in the intestinal mucosa. This absorption is influenced by the iron stores in the body, but the precise mechanism of this control is still a matter of debate: the amount of ferritin in the intestinal mucosa may be important, as may the balance between ferritin and the transferrin-like carrier molecule in these cells.

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Pharmacokinetics: AbsorptionDaily diet : 1015 mg absorbption 510%Location : duodenum and proximal jejunumHeme iron directly absorbed Nonheme iron reduced to ferrous (Fe2+) absorbedIron crosses the luminal membrane by active transport of ferrous iron and absorption of iron complexed with hemeDMT1 transporterabsorbed iron can be actively transported into the blood by ferroportin and oxidized to ferric iron (Fe3+)Excess iron can be stored in intestinal epithelial cells as ferritin

The average diet in the USA contains 1015 mg of elemental iron daily. A normal individual absorbs 510% of this iron, or about 0.51 mg daily. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 12 mg/d in menstruating women and may be as high as 34 mg/d in pregnant women.Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (Figure 331). Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferroreductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells.\ascorbic acid 50 mg increases iron absorption from a meal by 2-3 times. Food reduces iron absorption due to inhibition byphytates, tannates and phosphates.Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron and absorption of iron complexed with heme (Figure 331). The divalent metal transporter, DMT1, efficiently transports ferrous iron across the luminal membrane of the intestinal enterocyte. The rate of iron uptake is regulated by mucosal cell iron stores such that more iron is transported when stores are low. Together with iron split from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron (Fe3+) by a ferroxidase. Excess iron can be stored in intestinal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin. In general, when total body iron stores are high and iron requirements by the body are low, newly absorbed iron is diverted into ferritin in the intestinal mucosal cells. When iron stores are low or iron requirements are high, newly absorbed iron is immediately transported from the mucosal cells to the bone marrow to support hemoglobin production.

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Pharmacokinetics: TransportIron is transported in the plasma bound to transferrinTransferrin-iron complex receptor-mediated endocytosis enters maturing erythroid cells Endosomes: ferric ferrous transported by DMT1 hemoglobin synthesis or stored as ferritin. The transferrin-transferrin receptor complex is recycled to the plasma membrane, where the transferrin dissociates and returns to the plasma.

TRANSPORTIron is transported in the plasma bound to transferrin, a -globulin that specifically binds two molecules of ferric iron (Figure 331). The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptorsintegral membrane glycoproteins present in large numbers on proliferating erythroid cellsbind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis. In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cell, where it is funneled into hemoglobin synthesis or stored as ferritin. The transferrin-transferrin receptor complex is recycled to the plasma membrane, where the transferrin dissociates and returns to the plasma. This process provides an efficient mechanism for supplying the iron required by developing red blood cells.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.*

Pharmacokinetics: StorageStorage : in intestinal mucosal cells: 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 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.

STORAGEIn addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells (Figure 331). Apoferritin synthesis is regulated by the levels of free iron. When these levels are low, apoferritin synthesis is inhibited and the balance of iron binding shifts toward transferrin. When free iron levels are high, more apoferritin is produced to sequester more iron and protect organs from the toxic effects of excess 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.*

Pharmacokinetics: Eliminationno mechanism for excretion Small amounts are lost in the feces by :exfoliation of intestinal mucosal cellstrace amounts are excreted in bile, urine, and sweat no more than 1 mg of iron per day. regulation of iron balance : absorption and storage

ELIMINATIONThere is no mechanism for excretion of iron. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat. These losses account for no more than 1 mg of iron per day. Because the body's ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron, in response to the body's needs. As noted below, impaired regulation of iron absorption leads to serious pathology.*

http://izzrawda.wordpress.com/2009/03/16/do-you-have-anemia/

The normal daily requirement for iron is approximately 5 mg for men, and 15 mg for growing children and for menstruating women. A pregnant woman needs between two and ten times this amount because of the demands of the fetus and increased requirements of the mother.* The average diet in Western Europe provides 15-20 mg of iron daily, mostly in meat. Iron in meat is generally present as haem and about 20-40% of haem iron is available for absorptionHumans are adapted to absorb iron in the form of haem. It is thought that one reason why modern humans have problems in maintaining iron balance (there are an estimated 500 million people with iron deficiency in the world) is that the change from hunting to grain cultivation 10 000 years ago led to cereals, which have a relatively small amount of utilisable iron, constituting a significant proportion of the diet.The body of a 70 kg man contains about 4 g of iron, 65% of which circulates in the blood as haemoglobin. About one half of the remainder is stored in the liver, spleen and bone marrow, chiefly as ferritin and haemosiderin. The iron in these molecules is available for fresh haemoglobin synthesis. The rest, which is not available for haemoglobin synthesis, is present in myoglobin, cytochromes and various enzymes

Regulation of absorption may involve one or more of: control of mucosal uptake; retention of iron in storage form in the mucosal cell and transfer from the mucosal cell to the plasma.

Increased erythropoietic activity also stimulates increased absorption.*

Iron Deficiency AnemiaThe daily requirement of ironMale : 1mg / dayFemale 2mg / day3mg / day (during pregnancy and lactation)Iron deficiency anaemia can occur under the following four conditions:Less Intake of Fe, Vitamins and ProteinDiminished AbsorptionIncreased LossExcessive Demand

Less Intake of Fe, Vitamins and ProteinIron rich foods areMutton especially liver Chicken, Fish (Tuna fish and sardine) Egg,Spinach, Plantain (unripe banana, Soya bean, Wheat Bran, Brown Bread, Green pea, Milk is a highly nutritious food containing protein, fat, carbohydrate, Vitamin A & D, Calcium, but it is poor in iron content.Diminished AbsorptionThe following factors favour absorbtion:Acidity of gastric juiceVit CHaem bound iron (animal protein)Alcohol consumptionLow serum iron levelFerrous iron better than Ferric formDiseases like Chron Disease &Malabsorbtion Syndrome hamper iron absorbtion.Increased LossThe commonest cause is chronic blood loss from any source:Monthly Menstrual Loss:It is one the commonest cause of anaemia in female of child bearing age.Hook Worm Infestation: Common among villagers who move about barefoot and defaecate in the openfield. The hook worm larva enters their body through their feetBleedingExcessive DemandPregnancy:The mother has to cater for her requirement as well as of the foetus. It is mandatory that all pregnant women must take iron and folic acid supplement during the 2ndand 3rdtrimester of pregnancy and continue during lactation. Growth during puberty

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Iron: IndicationBasically: Iron deficiencyApplication:Iron deficiency due to dietary lack or to chronic blood loss.Pregnancy: TM2GIT abnormality: malabsorptionPremature babyEarly treatment of pernicious anemia

Iron therapy is needed in:Iron deficiency due to dietary lack or to chronic blood loss.Pregnancy. The extra iron required by mother and fetus totals 1000 mg, chiefly in the latter half of pregnancy. The fetus takes iron from themother even if she is iron deficient. Dietary iron is seldom adequate and iron and folic acid (50-100 mg elemental iron plus folic acid 200-500 micrograms/day) should be given to pregnant women from the fourth month. Opinions differ on whether all women should receive prophylaxis or only those who can be identified as needing it. There are numerous formulations. Parents should be particularly warned not to let children get at the tablets.Abnormalities of the gastrointestinal tract in which the proportion of dietary iron absorbed may be reduced, i.e. in malabsorption syndromes such as coeliac disease.Premature babies, since they are born with low iron stores, and in babies weaned late. There is very little iron in human milk and even less in cow's milk.Early treatment of severe pernicious anaemia with hydroxocobalamin, as the iron stores occasionally become exhausted by the surge in red cell formation.

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Preparation Oral: ferrous sulfate, ferrous succinate, ferrous gluconate and ferrous fumarate. SE: GIT upset, blackened stool, teeth stainForm: tablet, liquid, sustained-release

Parenteral iron Indication: not able to absorb oral ironPrepDeep IM: iron-dextran (50 mg Fe/mL) or iron-sorbitol precaution: local reaction, anaphylaxisSlow IV: iron dextran, sodium ferric gluconate complex, iron sucrose Precaution: risk of anaphylacsis!!!Oral iron should not be given 24 h before i.m. begin and for 5 days after the last i.v. injection;

Oral:Several different preparations of ferrous iron salts are available for oral administration. The main one is ferrous sulfate, which has an elemental iron content of 200 g/mg. Others are ferrous succinate, ferrous gluconate and ferrous fumarate. These are all absorbed to a comparable extent. A small dose may be given at first and increased after a few days. The objective is to give 100-200 mg of elemental iron per day in an adult (3 mg/kg in a child). Iron given on a full stomach causes less gastrointestinal upset but less is absorbed than if given between meals; however, use with food is commonly preferred to improve compliance.A suggested course. Start a patient on ferrous sulphate taken on a full stomach once, then twice, then thrice a day. If gut intolerance occurs, stop the iron and reintroduce it with one week for each step. If this seems to cause gastrointestinal upset, try ferrous gluconate, succinate or fumarate. If simple preparations (above) are unsuccessful, and this is unlikely, then the pharmaceutically sophisticated and expensive sustained-release preparations may be tried. They release iron slowly and only after passing the pylorus, from resins, chelates (sodium iron edetate) or plastic matrices, e.g. Slow-Fe, Ferrograd, Feospan, so that iron is released in the lower rather than the upper small intestine. Patients who cannot tolerate standard forms even when taken with food may get as much iron with fewer unpleasant symptoms if they use a sustained-release formulation.Liquid formulations are available for adults who prefer them and for small children, e.g. Ferrous Sulphate Oral Solution, Paediatric: 5 ml contains 12 mg of elemental iron: but they stain the teeth. Polysaccharide-iron complex (Niferex): 5 ml contains 100 mg of elemental iron. There are numerous other iron preparations which can give satisfactory results.Sustained-release and chelated forms of iron (see above) have the advantage that poisoning is less serious if a mother's supply is consumed by young children, a real hazard.Iron therapy blackens the faeces but does not generally interfere with modern tests for occult blood (commonly needed in investigation of anaemia), though it may give a false positive with some older occult blood tests, e.g. guaiac test.

Parenteral:Parenteral iron is rarely given but may be necessary in individuals who are not able to absorb oral iron because of malabsorption syndromes or as a result of surgical procedures or inflammatory conditions involving the gastrointestinal tract. The preparations used are iron-dextran or iron-sorbitol, both given by deep intramuscular injection. Iron-dextran (but not iron-sorbitol) can be given by slow intravenous infusion, but this method of administration should only be used if absolutely necessary because of the risk of anaphylactoid reactions. oral therapy (at lower dose) should be continued for 3-6 months after the haemoglobin concentration has returned to normal or until the serum ferritin exceeds 50 microgram/1 (or as long as blood loss continues).*

Ferrous Sulphate Tabs, 200-600 mg/d (providing 67-195 mg/d of elemental iron): Iberet (sustained-release tab 105 mg)Ferrous Gluconate Tabs, 300-1200 mg daily (providing 35-140 mg/d of elemental iron), eg: Sangobion (syr, tab, drops 250 mg), Biosanbe (250 mg: cap), Inbion (250 mg: cap)Ferrous Furmarate Tabs, 200-600 mg daily (providing 130-195 mg/d of elemental iron), eg: Hemafort (cap 300 mg), Dasabion (cap 360 mg), Ferrofort (kapsul 250 mg), Hemobion (360 mg, kap), Prenamia (360 mg Kap)Ferrous sucdnate and ferrous glycine sulphate are alternatives.

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Therapeutic dose:3-6 mg/Kg/day of elemental ironInduces an Hb of 0.25-0.4 g/dl per day or 1%/day rise in hematocrit.Adequate response: Hb of 2 g/dl after 3 weeks of txFailure of response after 2 weeks of oral iron requires reevaluation for ongoing blood losses,infection,poor compliance or other causes of microcytic anaemia.Priority: oral preparation.

Making 25 mg of iron per day available to the bone marrow will allow an iron deficiency anaemia to respond with a rise of 1% of haemoglobin (0.15 g Hb/100 ml) per day; a reticulocyte response occurs between 4 and 12 days. An increase in the haemoglobin of at least 2 g/dl after 3 weeks of therapy is a reasonable criterion of an adequate response.Oral preparations are the treatment of choice for almost all patients due to their effectiveness, safety and low cost. Parenteral preparations should be restricted to the few patients unable to absorb or tolerate oral preparations. Red cell transfusion is necessary only in patients with severe symptomatic anaemia or where chronic blood loss exceeds the possible rate of oral or parenteral replacement.Iron stores are less easily replenished by oral therapy than by injection, and oral therapy (at lower dose) should be continued for 3-6 months after the haemoglobin concentration has returned to normal or until the serum ferritin exceeds 50 microgram/1 (or as long as blood loss continues).

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InteractionsIron chelates in the gut with tetracyclines, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, norfloxacin and ofloxacin;it also forms stable complexes with thyroxine, captopril and biphosphonates. Ingestion should be separated by 3 hours.absorption: vit C absorption: desferrioxamine, tea (tannins) , Ca, Zn, and bran

Contraindicationschronic infection in haemolytic anaemias unless there is also haemoglobinuriaincreased erythropoiesis associated with chronic haemolytic states stimulates increased iron absorption and adding to the iron load may cause haemosiderosis.

It is illogical to give iron in the anaemia of chronic infection where utilisation of iron stores is impaired; but such patients may also have true iron deficiency. This may be difficult to diagnose without direct visualisation of stores in a bone marrow aspirate. Iron should not be given in haemolytic anaemias unless there is also haemoglobinuria, for the iron from the lysed cells remains in the body. Moreover the increased erythropoiesis associated with chronic haemolytic states stimulates increased iron absorption and adding to the iron load may cause haemosiderosis.

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Unwanted effects of ironDose related, include nausea, abdominal cramps and diarrhoea.overcome : dose or by taking the tablets after or with meals Acute iron toxicityIngestion of large quantities of iron salts. Result: severe necrotising gastritis with vomiting, haemorrhage and diarrhoea collapseTreatment : gastric lavage with NaHCO3, iron chelating agent, and treatment of causes.Chronic iron toxicity Caused by conditions other than ingestion of iron salts, Cause pancreatic damage and leading to diabetes.

Acute:. Acute iron toxicity, usually seen in young children who have swallowed attractively coloured iron tablets in mistake for sweets, occurs after ingestion of large quantities of iron salts. This can result in severe necrotising gastritis with vomiting, haemorrhage and diarrhoea, followed by circulatory collapse. Typically acute oral iron poisoning has the following phases:0.5-1 h after ingestion there is abdominal pain, grey/black vomit, diarrhoea, leucocytosis and hyperglycaemia. Severe cases are indicated by acidosis and cardiovascular collapse which may proceed to coma and death.There follows a period of improvement lastin 6-12 h, which may be sustained or which ma deteriorate to the next stage.Jaundice, hypoglycaemia, bleeding, encephalopathy, metabolic acidosis and convulsions are followed by cardiovascular collapse, coma and sometimes death 48-60 h after ingestion.1-2 months later, upper gastrointestinal obstruction may result from scarring and stricture

ChronicChronic iron toxicity or iron overload is virtually always caused by conditions other than ingestion of iron salts, for example chronic haemolytic anaemias such as the thalassaemias (a large group of genetic disorders of globin chain synthesis) or repeated blood transfusions. Prolonged heavy excess of iron intake overwhelms the mechanism described and results in haemosiderosis, as there is no physiological mechanism to increase iron excretion in the face of increased absorption. Iron-deficient subjects absorb up to 20 times as much administered iron as those with normal stores. Abnormalities of the small intestine may interfere with either the absorption of iron, as in coeliac disease and other malabsorption syndromes, or possibly with the conversion of iron into a soluble and reduced form, e.g. following loss of acid secretion after a partial gastrectomy

Therapy:Raw egg and milk help to bind iron until a chelating agent is available.The first step should be to give desferrioxamine 1-2 g i.m.; the dose is the same in adults and children. Only after this should gastric aspiration or emesis be performed. If lavage is used, the water should contain desferrioxamine 2 g/1. After empty-ing the stomach, desferrioxamine 10 g in 50-100 ml water should be left in the stomach to chelate any remaining iron in the intestinal lumen; it is not absorbed.Subsequently, desferrioxamine should be administered by i.v. infusion not exceeding 15 mg/kg/h (maximum 80 mg/kg/24 h) or further i.m. Injections (2 g in sterile water 10 ml) should be given 12-hourly. Poisoning is severe if the plasma iron concentration exceeds the total iron binding capacity (upper limit 75 mmol/1) or the plasma becomes pink due to the large formation of ferrioxamine (see below). If severe poisoning is suspected i.v. Rather than i.m. administration of desferrioxamine is indicated without waiting for the result of the plasma concentration.

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Iron Overload

http://www.theironfiles.co.uk/MDS/General/Blood-Transfusions.html*

Iron chelators

http://www.theironfiles.co.uk/MDS/General/Blood-Transfusions.htmlWhen desferrioxamine comes into contact with ferric iron, its straight-chain molecule twines around it and forms a nontoxic complex of great stability (ferrioxamine), which is excreted in the urine giving it a red/orange colour, and in the bile. It is not absorbed from the gut and must be injected for systemic effect. In acute poisoning, as opposed to chronic overload, desferrioxamine 5 g chelates the iron contained in about 10 tablets of ferrous sulphate or gluconate. It has a negligible affinity for other metals in the presence of iron excess*

Iron chelatorsUsed for treatment of iron toxicity Desferrioxamine(Desferal) (t1/2 6 h). not absorbed from the gut but is nonetheless given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as IM and IVIn severe poisoning: slow IV too fast: hypotensionforms a complex with ferric iron, excreted in the urine. Deferiprone orally absorbed to treat iron overload in patients with thalassaemia majorcareful monitoring : Agranulocytosis and other blood dsyscrasias

The treatment of acute and chronic iron toxicity involves the use of iron chelators, such as desferrioxamine. This is not absorbed from the gut but is nonetheless given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as intramuscularly and, if necessary, intravenously. In severe poisoning, it is given by slow intravenous infusion. Desferrioxamine forms a complex with ferric iron, and, unlike unbound iron, this is excreted in the urine. A new, orally absorbed iron chelator, deferiprone (L1), was recently licensed in the UK to treat iron overload in patients with thalassaemia major, in whom desferrioxamine is contraindicated or not tolerated. Agranulocytosis and other blood dsyscrasias have been described, so its use requires careful monitoring. Serious adverse effects are uncommon but include rashes and anaphylactic reactions; with chronic use cataract, retinal damage and deafness can occur. Hypotension occurs if desferrioxamine is infused too rapidly and there is danger of (potentially fatal) adult respiratory distress syndrome if infusion proceeds beyond 24 h*

VITAMIN B12FarmakokinetikFarmakodinamikFarmakologi klinis

Vitamin B12: Structurea porphyrin-like ring with a central cobalt (Co) atom attached to a nucleotide

Vitamin B12 is a complex cobalamin compound consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide*

Structure of Vit B12(Therapeutic uses)CyanocobalaminHydroxocobalamin

Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins.Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans.Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the above active forms.Hydroxocobalamin is bound to plasma protein to a greater extent than is cyanocobalamin, with the result that there is less free to be excreted in the urine after an injection and rather lower doses at longer intervals are adequate. Thus hydroxocobalamin is preferred to cyanocobalamin, though the latter can give satisfactory results as the doses administered are much greater than are required physiologically. Cyanocobalamin remains available.

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Where You Can Get Some Vitamin B12!Mostly animal products:Meat FishEggsMilk and Milk products like yogurtfortified with Vitamin B12:Breakfast CerealsBread

Vitamin B12: IntroductionUltimate source: microbial synthesisnot synthesized by animals /plants.Must be converted to methyl-B12or ado-B12Daily diet = 5-25 g Daily requirement = 2-3 g.= extrinsic factorRole: DNA synthesis

All cobalamins, dietary and therapeutic, must be converted to methylcobalamin (methyl-B12) or 5'-deoxyadenosylcobalamin (ado-B12) for activity in the body. The average daily diet in Western Europe contains 5-25 g of vitamin B12 and the daily requirement is 2-3 g. The ultimate source of vitamin B12 is from microbial synthesis; the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12.Cobalamin is produced in nature only by cobalamin-producing microorganisms, and herbivores obtain their supply from plants contaminated with bacteria and faeces. Carnivores obtain their supply by ingesting the muscular and parenchymal tissues of these animals. Animal protein is the major dietary source of cobalamin in man. Although bacteria in the human colon synthesise cobalamin, it is formed too distally for absorption by the ileal transport system. Rabbits in the wild would suffer from B12 deficiency if they did not eat their own faeces.In the presence of intrinsic factor about 70% of ingested cobalamin is absorbed, in its absence < 2% is absorbed. Some cyanocobalamin may be absorbed by passive diffusion, i.e. independently of intrinsic factor, though less reliably and only with large doses.

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Vitamin B12: PharmacodynamicConversion of methyl-FH4 to FH4 synthesis DNAIsomerisation of methylmalonyl-CoA to succinyl-CoA.

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Methyl-FH4 donates the methyl group to B12, the cofactor. The methyl group is then transferred to homocysteine to form methionineDeficiency: methylfolate trap

Vitamin B12: PharmacodynamicSynthesis of DNA

The conversion of methyl-FH4 to FH4 The role of vitamin B12 in folate coenzyme synthesis is illustrated in Figure 21.4. It is through these mechanisms that the metabolic activities of vitamin B12 and folic acid are linked and implicated in the synthesis of DNA. It is also through this pathway that folate/vitamin B12 treatment can lower plasma homocysteine concentration. Since increased homocysteine concentrations may have undesirable vascular effects (Ch. 18), this has potential therapeutic implications. The reaction involves conversion of both methyl-FH4 to FH4 and homocysteine to methionine. The enzyme that accomplishes this is homocysteine-methionine methyltransferase; the reaction requires vitamin B12 as cofactor and methyl-FH4 as methyl donor. Methyl-FH4 donates the methyl group to B12, the cofactor. The methyl group is then transferred to homocysteine to form methionine (Fig. 21.4). This vitamin-B12-dependent reaction generates active FH4 from inactive methyl-FH4 and converts homocysteine to methionine. Vitamin B12 deficiency thus traps folate in the inactive methyl-FH4 form, thereby depleting the folate polyglutamate coenzymes needed for DNA synthesis (see above). Vitamin B12-dependent methionine synthesis also affects the synthesis of folate polyglutamate coenzymes by an additional mechanism. The preferred substrate for polyglutamate synthesis is formyl-FH4, and the conversion of FH4 to formyl-FH4 requires a formate donor such as methionine

In one,methylcobalamin serves as an intermediate in the transfer of a methyl group from N5-methyltetrahydrofolate to methionine (Figure 331 A; Figure 332, reaction 1). In the absence ofvitamin B12, conversion of the major dietary and storage folate, N5-methyltetrahydrofolate, totetrahydrofolate, the precursor of folate cofactors, cannot occur. As a result, a deficiency of folatecofactors necessary for several biochemical reactions involving the transfer of one-carbon groupsdevelops. In particular, the depletion of tetrahydrofolate prevents synthesis of adequate supplies ofthe deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells asshown in Figure 333, reaction 2. The accumulation of folate as N5-methyltetrahydrofolate and theassociated depletion of tetrahydrofolate cofactors in vitamin B12 deficiency have been referred to asthe "methylfolate trap." This is the biochemical step whereby vitamin B12 and folic acid metabolismare linked and explains why the megaloblastic anemia of vitamin B12 deficiency can be partiallycorrected by ingestion of relatively large amounts of folic acid. Folic acid can be reduced todihydrofolate by the enzyme dihydrofolate reductase (Figure 332, reaction 3) and thus serve as asource of the tetrahydrofolate required for synthesis of the purines and dTMP that are needed for DNA synthesis*

Vitamin B12: PharmacodynamicVit B12 deficiency : acummulation of methyl malonate-CoA basis of neuropathy in vit B12 deficiency

Isomerisation of methylmalonyl-CoA to succinyl-CoA This isomerisation reaction is part of a route by which propionate is converted to succinate. Through this pathway, cholesterol, odd-chain fatty acids, some amino acids and thymine can be used for gluconeogenesis or for energy production via the tricarboxylic acid cycle. Ado-B12 is an essential cofactor, so methylmalonyl-CoA accumulates in vitamin B12 deficiency. This distorts fatty acid synthesis in neural tissue and may be the basis of neuropathy in vitamin B12 deficiency.

The other enzymatic reaction that requires vitamin B12 is isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase (Figure 331 B). In vitamin B12 deficiency, this conversion cannot take place, and the substrate, methylmalonyl-CoA, accumulates.In the past, it was thought that abnormal accumulation of methylmalonyl-CoA causes the neurologic manifestations of vitamin B12 deficiency. However, newer evidence instead implicates the disruption of the methionine synthesis pathway as the cause of neurologic problems. Whateverthe biochemical explanation for neurologic damage, the important point is that administration of folic acid in the setting of vitamin B12 deficiency will not prevent neurologic manifestations even though it will largely correct the anemia caused by the vitamin B12 deficiency.*

Mechanism for Peripheral NeuropathyCobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoA.

Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin.

If no Vitamin B12, methylmalonyl-CoA goes on to form abnormal fatty acids and causes subacute degeneration of the nerves. Only B12 can correct this problem.

Vitamin B12: PharmacokineticNormal B-12 absorption:Dietary B-12 binds to R factor in saliva and gastric juices.In duodenum, pancreatic enzymes promote dissociation from R factor and binding to Intrinsic Factor (IF)IF-B12 complex taken up by ileal receptor cubilin.Released into plasma bound to transcobalamines TC I, II, or III.Enters cells through receptor mediated endocytosis and metabolized into two coenzymes: adenosyl-Cbl and methyl-Cbl.

Vitamin B12 in physiologic amounts is absorbed only after itcomplexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa.Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomachand duodenum, and the intrinsic factor-vitamin B12 complex is subsequently absorbed in the distalileum by a highly specific receptor-mediated transport system. Vitamin B12 deficiency in humansmost often results from malabsorption of vitamin B12, due either to lack of intrinsic factor or to lossor malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency israre but may be seen in strict vegetarians after many years without meat, eggs, or dairy products.Once absorbed, vitamin B12 is transported to the various cells of the body bound to a plasmaglycoprotein, transcobalamin II. Excess vitamin B12 is transported to the liver for storage.Significant amounts of vitamin B12 are excreted in the urine only when very large amounts aregiven parenterally, overcoming the binding capacities of the transcobalamins (50100 g).*

Vitamin B12: PharmacokineticAnother mechanism for B12 absorption involves diffusion and not IF : jejunumIn circulation, cobalamin binds to transcobalamin II; transporting the vitamin from the enterocyte to the liver and other organsBiliary excretion of B12 is much higher than excretion in urine or feces

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Vitamin B12: Absorption& Distribution

The daily requirement of cobalamin is about 3.0 micrograms. The average diet in the USA contains 530 mcg of vitamin B12 daily, 15 mcg of which is usually absorbed. Absorption takes place mainly in the terminal ileum, and it is carried in plasma bound to proteins called transcobalamins (TCs). .90% of recently absorbed or administered cobalamin is carried on transcobalamin II an important transport protein which is rapidly cleared from the circulation (t1/2 6-9 minutes). Hereditary deficiency of transcobalamin II causes severe cobalamin deficiency. 80% of all circulating cobalamin is bound to transcobalamin I (t1/2 9-12 days) which is possibly a plasma storage form (hereditary deficiency of which is of no consequence). Cobalamin in its reduced formcob(I)alamin functions as a coenzyme for methionine synthase in a reaction that generates tetrahydrofolate,and is critical for DNA and RNA synthessis.Cobalamin is not significantly metabolised and passes into the bile (there is enterohepatic circulation which can be interrupted by intestinal diseaseand hastens the onset of clinical deficiency), and is excreted via the kidney. Only trace amounts of vitamin B12 are normally lost in urine and stoolBody stores amount to about 3-5 mg (mainly in the liver) and are sufficient for 2-4 years if absorption ceases. This store is so large compared with the daily requirement that if vitamin B12 absorption is stopped suddenly-as after a total gastrectomy-it takes 2-4 years for evidence of deficiency to become manifest. it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption were stopped. Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin B12 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin B12 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products.

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Vitamin B12: Absorption& DistributionVegetarianPerniciousAnemiaIleal diseaseIiverdisease

Absorption and distribution of vitamin B12Def vit B12 can result from congenital or acquired defect in any of one of the following:Inadequate dietary supplyInadequate secretion of intrinsic factor (classic pernicious anemia)Illeal diseaseCongenital absence of transcobalamin II (TcII)Rapid depletion of hepatic stores by interference with reabsorption of vitamin B12 excreted in bile

The utility of measurement of the conc B12 in plasma to estimate supply available to tissue can be compromised by liver disease and (6) the appearance of abnormal amount of transcobalamin I and III (TcI and III) in plasma. Finally, the formation of methylcobalamin requires (7) normal transport into cells and adequate suply of folic acid as CH3H4PteGlu1

Inthe presence of gastric acid and pancreatic proteases, dietary vitamin B12 is released from food andbound to gastric intrinsic factor. When the vitamin B12intrinsic factor complex reaches the ileum,it interacts with a receptor on the mucosal cell surface and is actively transported into circulation.Adequate intrinsic factor, bile, and sodium bicarbonate (to provide a suitable pH) all are requiredfor ileal transport of vitamin B12. Vitamin B12 deficiency in adults rarely results from a deficientdiet per se; rather, it usually reflects a defect in one or another aspect of this sequence of absorption(Figure 538). Achlorhydria and decreased secretion of intrinsic factor by parietal cells secondaryto gastric atrophy or gastric surgery is a common cause of vitamin B12 deficiency in adults.Antibodies to parietal cells or intrinsic factor complex also can play a prominent role. A number ofintestinal diseases can interfere with absorption, including pancreatic disorders (loss of pancreaticprotease secretion), bacterial overgrowth, intestinal parasites, sprue, and localized damage to ilealmucosal cells by disease or as a result of surgery.Once absorbed, vitamin B12 binds to transcobalamin II, a plasma b-globulin, for transport totissues. Two other transcobalamins (I and III) also are present in plasma; their concentrations arerelated to the rate of turnover of granulocytes. They may represent intracellular storage proteins thatare released with cell death. Vitamin B12 bound to transcobalamin II is rapidly cleared from plasmaand preferentially distributed to hepatic parenchymal cells, which comprise a storage depot forother tissues. In normal adults, as much as 90% of the bodys stores of vitamin B12, from 1 to 10 mg,is in the liver. Vitamin B12 is stored as the active coenzyme with a turnover rate of 0.58 mg/day,depending on the size of the body stores. The recommended daily intake of the vitamin in adultsis 2.4 mg.Approximately 3 mg of cobalamins is secreted into bile each day, 5060% of which is not destinedfor reabsorption. This enterohepatic cycle is important because interference with reabsorptionby intestinal disease can progressively deplete hepatic stores of the vitamin. This process may helpexplain why patients can develop vitamin B12 deficiency within 34 years of major gastric surgery,even though a daily requirement of 12 mg would not be expected to deplete hepatic stores of morethan 23 mg during this time*

Vitamin B12: IndicationPernicious anaemia :deficiency IFDietary deficiency: vegetarian Malabsorption syndromes (>>>) : stagnant loop syndrome ,Crohns disease, Fish tape worm infestation, gastrectomyrequirements: pregnancy, hemolytic anemia, hepatic diseaseVit b12 absorption testNeurologic syndrome: Vit B12 deficiency

Pernicious (Addisonian) anaemia. The atrophic gastric mucosa is unable to produce intrinsic factor (and acid) due to an autoimmune reaction to gastric parietal cells and intrinsic factor itself, there is failure to absorb vitamin B12 in the terminal ileum so that deficiency results. Despite its name (given when no treatment was known and it was believed to be a neoplastic disorder due to the appearance of the megaloblastic bone marrow), the prognosis of a patient with uncomplicated pernicious anaemia, properly treated with hydroxocobalamin, is little different from that of the rest of the population. The neurological complications, particuarly spasticity, develop only after prolonged severe deficiency but may be permanent; they are rarely seen today. Total removal of the stomach or atrophy of the mucous membrane in a postgastrectomy remnant may, after several years, lead to a similar anaemiaMalabsorption syndromes. In stagnant loop syndrome (bacterial overgrowth which competes for the available cobalamin and can be remedied by a broad-spectrum antimicrobial), ileal resection, Crohn's disease and chronic tropical sprue affecting the terminal ileum, vitamin B12 deficiency is commonalthough megaloblastic anaemia occurs only relatively late. The fish tape worm Diphyllobothrum latum which can infest humans who eat raw orpartially cooked freshwater fish roe can grow up to 10 meters in the gut and competes for ingested cobalaminTobacco amblyopia has been attributed to cyanide intoxication from strong tobacco which interferes with the coenzyme function of vitamin B12; hydroxocobalamin (not cyanocobalamin) may be given.

Cyanocobalamin is indicated in the treatment of vitamin B12 deficiency caused by Inadequate utilization of vitamin B12; dietary deficiency of vitamin B12 occurring in strict vegetarians, malabsorption syndrome of various causes (e.g., pernicious anemia, GI pathology, fish tapeworm infestation, malignancy of pancreas or bowel, gluten enteropathy, small bowel bacterial overgrowth, gastrectomy, accompanying folic acid deficiency); Supplementation because of increased requirements (e.g., associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage,malignancy, hepatic and renal disease); vitamin B12 absorption test (e.g., Schilling test

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Vitamin B12 : DeficiencyCaused by absorption intrinsic factor Interference of absorption in the terminal ileume.g. Colon resection in Crohn's disease Clinical form:Pernicious anemiaNeurological diseaseperipheral neuropathy, Dementia, subacute combined degeneration of the spinal cordAbnormalities of epithelial tissue, e.g. sore tongue andmalabsorption

vitamin B12 deficiency also causes important disorders of nerves, which are not corrected (or may even be made worse) by treatment with folic acid. Deficiency of either vitamin causes megaloblastic haemopoiesis in which there is disordered erythroblast differentiation and defective erythropoiesis in the bone marrow. Large abnormal erythrocyte precursors appear in the marrow, each with a high RNA:DNA ratio as a result of decreased DNA synthesis. The circulating erythrocytes ('macrocytes') are large fragile cells, often distorted in shape. Mild leucopenia and thrombocytopenia usually accompany the anaemia, and the nuclei of polymorphonuclear leucocytes are abnormal (hypersegmented). Neurological disorders caused by deficiency of B12 include peripheral neuropathy and dementia, as well as subacute combined* degeneration of the spinal cord. Vitamin B12 deficiency, however, is usually caused by decreased absorption, caused either by a lack of intrinsic factor (see below) or conditions that interfere with its absorption in the terminal ileum, for example resection of diseased ileum in patients with Crohn's disease (a chronic inflammatory bowel disease that can affect this part of the gut). Intrinsic factor is a glycoprotein secreted by the stomach and is essential for vitamin B12 absorption. It is lacking in patients with pernicious anaemia and in individuals who have had total gastrectomies. In pernicious anaemia there is atrophic gastritis caused by autoimmune injury of the stomach, and antibodies to gastric parietal cells are often present in the plasma of such patients.

megaloblastic anemia. The typical clinical findings inmegaloblastic anemia are macrocytic anemia (MCV usually > 120 fL), often with associated mildor moderate leukopenia or thrombocytopenia (or both), and a characteristic hypercellular bonemarrow with megaloblastic maturation of erythroid and other precursor cells. Vitamin B12deficiency also causes a neurologic syndrome that usually begins with paresthesias and weakness inperipheral nerves and progresses to spasticity, ataxia, and other central nervous systemdysfunctions. A characteristic pathologic feature of the neurologic syndrome is degeneration ofmyelin sheaths followed by disruption of axons in the dorsal and lateral horns of the spinal cord andin peripheral nerves. Correction of vitamin B12 deficiency arrests the progression of neurologicdisease, but it may not fully reverse neurologic symptoms that have been present for severalmonths. Although most patients with neurologic abnormalities caused by vitamin B12 deficiencyhave full-blown megaloblastic anemias when first seen, occasional patients have few if anyhematologic abnormalitiesThe most common causes of vitamin B12 deficiency are pernicious anemia, partial or totalgastrectomy, and diseases that affect the distal ileum, such as malabsorption syndromes,inflammatory bowel disease, or small bowel resection.*

Vitamin B12 : Diagnosis of DeficiencyLab:serum vit B12 (N: 170-925 nanogram/1)Blood film: pancytopenia, anisopoikilocytosis with oval macrocytes and hypersegmented neutrophils; the marrow is megaloblasticSchilling test : distinguish between gastric and intestinal causes

The serum concentration of vitamin B12 is low (normal 170-925 nanogram/1). In severe deficiency there is pancytopenia, the blood film shows anisopoikilocytosis with oval macrocytes and hypersegmented neutrophils; the marrow is megaloblastic. In many patients with pernicious anaemia antibodies to intrinsic factor can be identified in the serum.Absorption of radioactive vitamin B12 (Schilling test) helps to distinguish between gastric and intestinal causes.First: the patient is given a small dose of radioactive vitamin B12 orally, with a simultaneous large dose of nonradioactive vitamin B12 intramuscularly. The large injected dose saturates binding sites so that any of the oral radioactive dose that is absorbed cannot bind and will be eliminated in the urine where it can easily be measured (normally > 10% of the administered dose appears in urine collected for 24 h, if renal function is normal). In pernicious anaemia and in malabsorption, gut absorption and therefore subsequent appearance of radioactivity in the plasma (measured 8-12 h later) and urine are negligible.Second: the test is repeated with intrinsic factor added to the oral dose. The radioactive vitamin B12 is now absorbed in pernicious anaemia (but not in intestinal malabsorption) and is detected in plasma and urine. Both stages of the test are needed to maximise reliability of diagnosis of pernicious anaemia.

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Megaloblastic Anemia

Megaloblastic Anemia

Vitamin B12 : Contraindication & InteractionContraindicationInconclusively diagnosed anaemiaAllergic to cobaltInteractionAlcohol, aminosalicylic acid, neomicine and colchicine may decrease the absorption of oral vit B12

Inconclusively diagnosed anaemia is an important contraindication. Therapy of pernicious anaemia must be both adequate and lifelong, so that accuratediagnosis is essential. Even a single dose of vitamin B12 interferes with the haematological picture for weeks (megaloblastic haematopoiesis reverts to normal within 12 hours), although the Schilling test remains diagnostic.*

Vitamin B12: PreparationHydroxocobalamin is preferred to cyanocobalamin:First choice : injectionInitial dose:hydroxocobalamin 1 mg i.m. every 2-3 days for 5 doses to induce remission and to replenish storesMaintanance dose: 1 mg/3 monthsResponse:Feel better : 2 daysReticulocyte peak : 5-7 daysHb, RBC, Ht : first week normalize: 2 monthsWatch: hypokalemia!!

Hydroxocobalamin is bound to plasma protein to a greater extent than is cyanocobalamin, with the result that there is less free to be excreted in the urine after an injection and rather lower doses at longer intervals are adequate. Thus hydroxocobalamin is preferred to cyanocobalamin, though the latter can give satisfactory results as the doses administered are much greater than are required physiologically. Cyanocobalamin remains available.The initial dose in cobalamin deficiency anaemias, including uncomplicated pernicious anaemia, is hydroxocobalamin 1 mg i.m. every 2-3 days for5 doses to induce remission and to replenish stores. Maintenance may be 1 mg every 3 months; higher doses will not find binding sites and will be eliminated in the urine. Higher doses are justified during renal or peritoneal dialysis where hydroxycobalamin clearance is increased, and resultan raised plasma methylmalonic acid and homocysteine represent an independent risk factor for vascular events in these patients (see later).Routine low dose supplements of hydroxycobalamin, folate and pyridoxine fail to control hyperhomocysteinaemia in 75% of dialysis patientsbut supraphysiological doses are effective: hydroxycobalamin 1 mg/d, folic acid 15 mg/d and pyridoxine 100 mg/d.After initiation of therapy, patients feel better in 2 days, reticulocytes peak at 5-7 days and the haemoglobin, red cell count and haematocrit rise by the end of the first week. These indices normalise within 2 months irrespective of the starting level.

Failure to respond implies a wrong or incomplete diagnosis (coexistent deficiency of another haematinic).The initial stimulation of haemoglobin synthesis often depletes the iron and folate stores and supplements of these may be needed.Hypokalaemia may occur at the height of the erythrocyte response in severe cases. It is attributed to uptake of potassium by the rapidly increasing erythron (erythrocyte mass). Oral potassium should be given prior to initiating therapy in a patient with low or borderline potassiuim levels.Once alternative or additional causes of the anaemia have been excluded, inadequate response should be treated by increased frequency of injections as well as increased amount (because of urinary loss with high plasma concentrations). The reversal of neurological damage is slow (and rarely marked) and the degree of functional recovery is inversely related to the extent and duration of symptoms. Haemoglobin estimations are necessary at least every 6 months to check adequacy of therapy and for early detection of iron deficiency anaemiadue to achlorhydria (common in patients with pernicious anaemia > 60 years) or carcinoma of the stomach, which occurs in about 5% of patients with pernicious anaemia.The parenteral route is used becausethe vitamin is ineffective orally due to the absence of theintrinsic factor in the stomach, which is necessary forutilization of vitamin B12. After*

Vitamin B12: PreparationIf injections are refused rare allergy, bleeding disorderAlternative: snuff , aerosol , oralLarge daily oral doses (1000 micrograms) depleted stores must be replaced by parenteral cobalamin before switching to the oral preparation; the patient must be compliant; monitoring of the blood must be more frequent adequate serum vitamin B12 levels must be demonstrated.

When injections are refused or are impracticable (rare allergy, bleeding disorder), administration as snuff or aerosol has been effective, but these routes are less reliable. Large daily oral doses (1000 micrograms) are probably preferable; depleted stores must be replaced by parenteral cobalamin before switching to the oral preparation; the patient must be compliant; monitoring of the blood must be more frequent and adequate serum vitamin B12 levels must be demonstrated.

The choice ofa preparation always depends on the cause of the deficiency. Although oral preparations may beused to supplement deficient diets, they are of limited value in the treatment of patients with deficiencyof intrinsic factor or ileal disease. Even though small amounts of vitamin B12 may beabsorbed by simple diffusion, the oral route of administration cannot be relied upon for effectivetherapy in the patient with a marked deficiency of vitamin B12 and abnormal hematopoiesis or neurologicaldeficits. Therefore, the treatment of choice for vitamin B12deficiency is cyanocobalaminadministered by intramuscular or subcutaneous injection.

followingprinciples:1. Vitamin B12 should be given prophylactically only when there is a reasonable probability thata deficiency exists or will exist. Dietary deficiency in the strict vegetarian, the predictable malabsorptionof vitamin B12 in patients who have had a gastrectomy, and certain diseases of thesmall intestine constitute such indications. When GI function is normal, an oral prophylacticsupplement of vitamins and minerals, including vitamin B12, may be indicated. Otherwise, thepatient should receive monthly injections of cyanocobalamin.2. The relative ease of treatment with vitamin B12 should not prevent a full investigation of theetiology of the deficiency. The initial diagnosis usually is suggested by a macrocytic anemia oran unexplained neuropsychiatric disorder. Full understanding of the etiology of vitamin B12deficiency involves studies of dietary supply, GI absorption, and transport.3. Therapy always should be as specific as possible. While a large number of multivitamin preparationsare available, the use of shotgun vitamin therapy in the treatment of vitamin B12 deficiencycan be dangerous. With such therapy, there is the danger that sufficient folic acid willbe given to result in a hematological recovery, which can mask continued vitamin B12 deficiencyand permit neurological damage to develop or progress.4. Although a therapeutic trial with small amounts of vitamin B12 can help confirm the diagnosis,acutely ill, elderly patients may not be able to tolerate the delay in the correction of a severeanemia. Such patients require supplemental blood transfusions and immediate therapy withfolic acid and vitamin B12 to guarantee rapid recovery.5. Long-term therapy with vitamin B12 must be evaluated at intervals of 612 months in patientswho are otherwise well. If there is an additional illness or a condition that may increase therequirement for the vitamin (e.g., pregnancy), reassessment should be performed morefrequently.*

Vitamin B12: PreparationSynthetic vitamin B12Cyanocobalamin, hydroxocobalaminOral cyanocobalamin : well absorbed, highly protein bound to the transcobalaminsMetabolize in the liver, followed by biliary and urinary excretionT1/2 is about 6 daysCyanocobalamin injection containing benzyl alcohol : should not be used for neonates or immature infants

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Vitamin B12: interactionReduction of absorption of B12 from GI tractexcessive consumption of ethanol for longer than 2 weeksprolonged use of cholestyramine, colchicinelarge doses of ascorbic acid may destroy B12

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Vitamin B12: Adverse EffectUsually do not occurwhen a megaloblastic anaemia due to pernicious anaemia is incorrectly diagnosed as due to folate deficiency; here folic acid, if used alone (see below) may accelerate progressionof subacute combined degeneration of the nervous system.

Adverse effects virtually do not occur, but use of vitamin B12 as a 'tonic' is an abuse of a powerful remedy for it may obscure the diagnosis of pernicious anaemia, which is a matter of great importance in a disease requiring lifelong therapy and prone to serious neurological complications. The latter danger is of particular significance when a megaloblastic anaemia due to pernicious anaemia is incorrectly diagnosed as due to folate deficiency; here folic acid, if used alone (see below) may accelerate progressionof subacute combined degeneration of the nervous system.*

ASAM FOLATFarmakokinetikFarmakodinamikFarmakologi Klinis

Folic Acidcomposed of a heterocycle, p-aminobenzoic acid, and glutamic acid

Folate: Pharmacodynamics

Dihydrofolate (FH2) and tetrahydrofolate (FH4) act as carriers and donors of methyl groups (1-carbon transfers) in a number of important metabolic pathways. The latter is essential for DNA synthesis as cofactor in the synthesis of purines and pyrimidines. It is also necessary for reactions involved in amino acid metabolism. For activity, folate must be in the FH4 form, in which it is maintained by dihydrofolate reductase. This enzyme reduces dietary folic acid to FH4 and also regenerates FH4 from FH2 produced from FH4 during thymidylate synthesis (see Figs 21.2 and 21.3). Folate antagonists act by inhibiting dihydrofolate reductase (see also Chs 45 and 50). Folates are especially important for the conversion of deoxyuridylate monophosphate to deoxythymidylate mono-phosphate. This is rate limiting in mammalian DNA synthesis and is catalysed by thymidylate synthetase, with folate acting as methyl donor (Fig. 21.3). The clinical use of folic acid is given in the box.

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described earlier in the discussion of vitamin B12 , one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N5,N10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 333, section 2). Unlike all the other enzymatic reactions that use folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, 1 mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate are consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N5,N10-methylenetetrahydrofolate by the action of serine transhydroxymethylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs; methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 54).Cofactors of tetrahydrofolate participate in several other essential reactions. N5-Methylenetetrahydrofolate is required for the vitamin B12 -dependent reaction that generates methionine from homocysteine (Figure 332A; Figure 333, section 1). In addition, tetrahydrofolate cofactors donate one-carbon units during the de novo synthesis of essential purines. In these reactions, tetrahydrofolate is regenerated and can reenter the tetrahydrofolate cofactor pool.*

Folate:PharmacokineticsHuman requirement : varies from 25-35 mcg/d in infancy to up to 100 mcg/d in adultsTotal body folic acid stores : 5-10 mg, half of which is stored in the liver as N-5-methyltetrahydrofolate> 2% is degraded dailyso a continuous dietary is essential

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Folate:PharmacokineticsActive absorption : mainly in the proximal part of the small intestineConjugate in the epithelial cells converts the polyglutamates into absorbable monoglutamatesPharmaceutical product : completely absorbed in the upper duodenum, even in the presence of malabsorptionExcretion: entirely as metabolites by the kidney

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Folate:Pharmacokinetics

The average diet in the USA contains 500700 g of folates daily, 50200 g of which is usually absorbed, depending on metabolic requirements (pregnant women may absorb as much as 300400 g of folic acid daily). Normally, 520 mg of folates are stored in the liver and other tissues. Folates are excreted in the urine and stool and are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished.Since body stores of folates are relatively low and daily requirements high, folic acid deficiency and megaloblastic anemia can develop within 16 months after the intake of folic acid stops, depending on the patient's nutritional status and the rate of folate utilization.

Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, 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") within the brush border of the intestinal mucosa. The monoglutamate N5-methyltetrahydrofolate is subsequently transported into the bloodstream by both active and passive transport and is then widely distributed throughout the body. Inside cells, N5-methyltetrahydrofolate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12 (Figure 332, reaction 1).

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Folate: PharmacokineticsInadequate dietary supplySmall intestinal diseaseUremiaalcoholism,hepatic disease Vitamin B12 deficiency

Folate deficiency commonly result from:Inadequate dietary supplySmall intestinal diseaseIn patient with uremia, alcoholism, or hepatic disease there may be defects in the concentration of folate binding proteins in plasma and the flow of Ch3.Hpteglu into bile for reabsorption and transport to tissue (folate enterohepatic cycle)Vitamin B12 deficiency will trap folate as CH3H4PteGlu, reducing availability of tetrahydrofolates

Folates in food are in the form of polyglutamates. These are converted to monoglutamates before absorption and are transported in blood as such. They are converted back into polyglutamates, which are considerably more active than monoglutamates, in the tissues. Therapeutically, folic acid is given orally (or, in exceptional circumstances, parenterally) and is absorbed in the ileum. Methyl-FH4 is the form in which folate is usually carried in blood and which enters cells. It is functionally inactive until it is demethylated in a vitamin B12-dependent reaction (see below). This is because unlike FH2, FH4 and formyl-FH4, methyl-FH4 is a poor substrate for polyglutamate formation. This has relevance for the effect of vitamin B12 deficiency on folate metabolism, as is explained below. Folate is taken up into hepatocytes and bone marrow cells by active transport. Within the cells, folic acid is reduced and formylated before being converted to the active polyglutamate form. Folinic acid, a synthetic FH4, is converted much more rapidly to the polyglutamate form. The clinical use of folic acid is given in the box on p. 335.

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Folic acid deficiency anemiaEtiology :Most causes : inadequate diet, alcoholism, pregnancy, malabsorption syndromeOther causes : increased requirement, enhanced metabolism, interference in the metabolism

Several reasons for folate def. in alcoholics reduced dietary intakes, inactivation of folate conjugate, impaired enterohepatic cycling, depletion of liver folate stores

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Folate DeficiencyMore often malnourished than those with cobalamin deficiencyGastrointestinal manifestations More widespread and more severe than those of pernicious anemiaDiarrhea is often presentCheilosis Glossitis Neurologic abnormalities do not occur

Stages of folate deficiencyNegative folate balance (decreased serum folate)Decreased RBC folate levels and hypersegmented neutrophilsMacroovalocytes, increased MCV, and decreased hemoglobin

Diagnosis of folate deficiencyDiagnosis :Megaloblastosis possibly due to folic acid deficiency must be interpreted in the light of B12 statusPeripheral blood and bone marrow biopsy look exactly like B12 deficiencyReduced folate tissue levels : erythrocyte folate concentration

Folic acid deficiency anemiaManagement :Folic acid should not be given until B12 def. and pernicious anemia have been excludedOral dose: 1 mg/dayAbsorption is normal : 50-100 mcg/dMalabsorption : 250-500 mcg/dTo replenish depleted folate stores, a daily dose of 1-2 mg/d for 2-3 weeksDuration of therapy depend on underlying causes : 3-4 months to clear folate-deficient erythrocytes from the blood

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Folic acid deficiency anemiaProphylactic folate therapy : pregnancy, particularly in women with poor diets, multiple pregnancies, or thalassemia minor : 300 mcg/d in the last trimesterMonitoring :Reticulocyte count : peaks 5-8 days after treatmentIncrease HctDecrease to normal MCV

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Inappropriate Treatment of Pernicious Anemia With FolateVitamin B12 deficiency anemia can be temporarily corrected by folate supplementationHowever, this does not correct the neurologic deficitsFolate draws vitamin B12 away from neurologic system for RBC production and can exacerbate combined systems degeneration

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Therapeutic Uses of Folic Acid Megaloblastic Anemia due to inadequate dietary intake of folic acid due to chronic alcoholism, pregnancy, infancy, impaired utilization: uremia, cancer or hepatic disease.

Anemia associated with dihydrofolate reductase inhibitors. i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine (Antimalarial)Administration of citrovorum factor (methylated folic acid) alleviates the anemia.

Therapeutic Uses of Folic Acid (cont)Ingestion of drugs that interfere with intestinal absorption and storage of folic acid.Mechanism- inhibition of the conjugases that break off folic acid from its food chelators. Ex. phenytoin, progestin/estrogens (oral contraceptives)

Malabsorption Sprue, Celiac disease, partial gastrectomy.

Rheumatoid arthritis increased folic acid demand or utilization.

Treatment of folate deficiencyOral replacement therapyFolate prophylaxisWomen planning pregnancy are advised to take 400 g folic acid daily before conception and until 12 weeks of pregnancy to prevent neural-tube defects (5 mg/day for women with a previous affected pregnancy)Folate fortification of cereal grains at 14 mg/kg has been made mandatory in the USA as an additional method of improving the folate status of the population. Prophylactic folate is also recommended in other states of increased demand such as long-term hemodialysis and chronic haemolytic disorders

Foods With Folic AcidDark green leafy vegetables, like spinachBroccoli, asparagus, green peas and okraOrange juicePapaya

Beans, lentils and black-eyed peasSoybeans and tofuPeanut butterFortified foods: Cereal, rice, pasta, tortillas, grits

Be sure to eat 5 servings of fruits & vegetables such as these every day!

*Folic acid is present in a variety of foods.

Drugs implicated in causing :

* malabsorption ? * impaired metabolism- phenytoin - methotrexate- barbiturates- pyrimethamine- sulfasalazine- trimethoprim- cholestyramine - pentamidine- oral contraceptives

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Barriers to Folic Acid Absorption or UseAlcohol TobaccoAspirin, ibuprofen, naprosyn and acetaminophen Antacids & anti-ulcer medications

Some antiseizure medicationsSome anticancer drugs Some antibiotics/ antibacterials Oral hypoglycemic agents

Source: Folicacid.net.

*Ibuprofen like MotrinNaprosyn like AleveAcetaminophen like Tylenol

TUGAS BACA !!!FAKTOR PERTUMBUHAN HEMATOPOIETIKEritropoietinFaktor pertumbuhan mieloidFaktor pertumbuhan megakariosit

REFERENCESBasic and Clinical Pharmacology 11th Ed, KatzungPharmacology Rang et al 5th EditionGoodman & Gilmans The Pharmacological Basis of Therapeutics, 11th ed.Color atlas of pharmacologyClinical Pharmacology, 9th EdUSMLE Pharmacology RecallPharmacology for the health care profession

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umped by the heart, blood reaches every part of our bodies and 'feeds' each cell with everything it needs; from oxygen and sugar for energy, to the building blocks for new cells to be built.

It also carries the waste products to be cleared away and transports the cells which patrol our bodies and make sure we do not get sick.

It is made up of several important parts: a fluid called 'plasma', white blood cells, red blood cells, and platelets.

The plasma contains all the nutrients from the things we eat.

The platelets make the blood clot if you cut yourself.

The white blood cells stop bugs getting into the body and fight infections, such as a cold or sore throat.

The red blood cells are what give your blood its colour. They pick up oxygen from your lungs and carry it around your body. These are the cells that are important in your sickle cell anaemia. Red blood cells are able to do this because they carry lots of copies of a special protein called 'haemoglobin'.Blood :Formed elements (red and white blood cells and platelets) plasma. Components of the haemopoietic systemMain: blood, bone marrow, lymph nodes and thymusAccessory : spleen, liver and kidneys*

*A schematic visual model of oxygen binding process, showing all four monomers and hemes, and protein chains only as diagramatic coils, to facilitate visualization into the molecule. Oxygen is not shown in this model, but for each of the iron atoms it binds to the iron (red sphere) in the flat heme. For example, in the upper left of the four hemes shown, oxygen binds at the left of the iron atom shown in the upper left of diagram. This causes the iron atom to move backward into the heme, which holds it, tugging the histidine residue (modeled as a red pentagon on the right of the iron) closer, as it does. This, in turn, pulls on the protein chain holding the histidine.*Classification: hypochromic, microcytic anaemia (small red cells with low haemoglobin; caused by iron deficiency) macrocytic anaemia (large red cells, few in number) normochromic normocytic anaemia (fewer normal-sized red cells, each with a normal haemoglobin content) mixed pictures.

Morphological (according to the size and Hb content of the RBCs)Basically, all anaemias can be classified into three groups as per morphology of the RBCs.1.Microcytic Hypochromic (RBCs are small in size andless haemoglobinised)(a)Iron Deficiency Anaemia(b)Thalassaemia2.Macrocytic normochromic (RBCs are large in size and normally haemoglobinised)(a) Megaloblastic Anaemia due to Folate/B12deficiency3.Normocytic Normochromic (RBCs are normal in size and normally haemoglobinised)(a)Haemolytic Anaemia(b)Post Haemorrhagic AnaemiaInternal BleedingMalaena (black tarry stool)HaemoptysisStreet AccidentBleeding during OperationPost Partum Bleeding (c)Aplastic Anaemia (d)Leukaemia (e)Anaemia due to Renal Failure

*CAUSES OF ANAEMIA (ETIOLOGY):It is not difficult to understand that anaemiacan occur either by diminished formation or excessive destruction of RBCS.A.Diminished Formation (Dyshaemopoietic) 1.Nutritional(a)Iron Deficiency (b)Folic Acid/ Vit B12Deficiency(c)Protein Deficiency 2.Decreased Synthesis(a)Aplastic Anaemia(b)Replacement of BM (e.g. Leukaemia)(c)Thalassaemia 3.Chronic Disorder(a)Kidney Disease(b)Advanced Malignancy(c)Chronic Liver DiseaseB.Excessive Destruction1.Post Haemorrhage(a)Acute Blood Loss(b)Ghronic Blood Loss2.Excessive Haemolysis(a)Intracellular Defect (Defective RBC)ThalassaemiaHaemoglobinopathies (Hb C/ E)Sickle Cell AnaemiaHereditary Spherocytosis (b)Extracellular Defect Rh Incompatibility Incompatible Blood Transfusion Auto Immune Haemolytic Anaemia Certain Snake Venom*The body of a 70 kg man contains about 4 g of iron, 65% of which circulates in the blood as haemoglobin. About one half of the remainder is stored in the liver, spleen and bone marrow, chiefly as ferritin and haemosiderin. The iron in these molecules is available for fresh haemoglobin synthesis. The rest, which is not available for haemoglobin synthesis, is present in myoglobin, cytochromes and various enzymes*Humans are adapted to absorb iron in the form of haem. Non-haem iron in food is mainly in the ferric state and this needs to be converted to ferrous iron for absorption. Ferric iron, and to a lesser extent ferrous iron, has low solubility at the neutral pH of the intestine; however, in the stomach, iron dissolves and binds to mucoprotein. In the presence of ascorbic acid, fructose and various amino acids, iron is detached from the carrier, forming soluble low-molecular-weight complexes that enable it to remain in soluble form in the intestine. Ascorbic acid stimulates iron absorption partly by forming soluble iron-ascorbate chelates and partly by reducing ferric iron to the more soluble ferrous form. The site of iron absorption is the duodenum and upper jejunum, The stomach plays a role in iron absorption through dissolving iron by HCL and forming soluble complex together with Vitamin C(reducing agent) to aid its reduction into ferrous absorbable form.and absorption is a two-stage process involving first a rapid uptake across the brush border and then transfer into the plasma from the interior of the epithelial cells. The second stage, which is rate limiting, is energy dependent. Haem iron in the diet is absorbed as intact haem and the iron is released in the mucosal cell by the action of haem oxidase. Non-haem iron is absorbed in the ferrous state. Within the cell, ferrous iron is oxidised to ferric iron, which is bound to an intracellular carrier, a transferrin-like protein; the iron is then either held in storage in the mucosal cell as ferritin (if body stores of iron are high) or passed on to the plasma (if iron stores are low). Iron is carried in the plasma bound to transferrin, a -globulin with two binding sites for ferric iron, which is normally only 30% saturated. Plasma contains 4 mg iron at any one time, but the daily turnover is about 30 mg (Fig. 21.1). Most of the iron that enters the plasma is derived from mononuclear phagocytes, following the degradation of time-expired erythrocytes. Intestinal absorption and mobilisation of iron from storage depots contribute only small amounts. Most of the iron that leaves the plasma each day is used for haemoglobin synthesis by red cell precursors. These cells have receptors that bind transferrin molecules, releasing them after the iron has been taken up. Iron is stored in two forms-soluble ferritin and insoluble haemosiderin. Ferritin is found in all cells, the mononuclear phagocytes of liver, spleen and bone marrow containing especially high concentrations. It is also present in plasma. The precursor of ferritin, apoferritin, is a large protein of molecular weight 450000, composed of 24 identical polypeptide subunits that enclose a cavity in which up to 4500 iron molecules can be stored. Apoferritin takes up ferrous iron, oxidises it and deposits the ferric iron in its core. In this form, it constitutes ferritin, the primary storage form of iron, from which the iron is most readily available. The lifespan of this iron-laden protein is only a few days. Haemosiderin is a degraded form of ferritin in which the iron cores of several ferritin molecules have aggregated, following partial disintegration of the outer protein shells. The ferritin in plasma has virtually no iron associated with it. It is in equilibrium with the storage ferritin in cells and its concentration in plasma provides an estimate of total body iron stores. The body has no means of actively excreting iron. Small amounts leave the body through desquamation (peeling off) of mucosal cells containing ferritin, and even smaller amounts leave in the bile, sweat and urine. A total of about 1 mg is lost daily. Iron balance is, therefore, critically dependent on the active absorption mechanism in the intestinal mucosa. This absorption is influenced by the iron stores in the body, but the precise mechanism of this control is still a matter of debate: the amount of ferritin in the intestinal mucosa may be important, as may the balance between ferritin and the transferrin-like carrier molecule in these cells.

*The average diet in the USA contains 1015 mg of elemental iron daily. A normal individual absorbs 510% of this iron, or about 0.51 mg daily. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 12 mg/d in menstruating women and may be as high as 34 mg/d in pregnant women.Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (Figure 331). Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferroreductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells.\ascorbic acid 50 mg increases iron absorption from a meal by 2-3 times. Food reduces iron absorption due to inhibition byphytates, tannates and phosphates.Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron and absorption of iron complexed with heme (Figure 331). The divalent metal transporter, DMT1, efficiently transports ferrous iron across the luminal membrane of the intestinal enterocyte. The rate of iron uptake is regulated by mucosal cell iron stores such that more iron is transported when stores are low. Together with iron split from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron (Fe3+) by a ferroxidase. Excess iron can be stored in intestinal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin. In general, when total body iron stores are high and iron requirements by the body are low, newly absorbed iron is diverted into ferritin in the intestinal mucosal cells. When iro