During early 20th century, hemorrhagic diseases occurred in cattle that ate spoiled fodder (spoiled sweet clover silage). Chemists at Wisconsin Alumni Research Foundation extracted Bishydroxycoumarin responsible for this disease.
Afterwards warfarin was synthesized as coumarin derivative.
It was first used as Rodenticide
Afterwards during second half of 20th century, it was used as oral anticoagulant.
Mainly two chemical compounds are chosen for oral administration:
Coumarin –commonly used like Warfarin
Administered as racemic preparation, two enantiomers or isoforms exist:
1. S warfarin (levorotatory) 4 times more potent
2. R warfarin (dextrorotatory)
Mechanism of Action
Factor II, VII, IX, X are the glutamic acid residues and need to be carboxylated to alpha carboxy glutamic acid. This is required so that the Ca++ bridge with epithelium is formed.
During carboxylation, vitamin K is converted from reduced to oxidized form.
Oxidized form has to be converted back into reduced form, by vitamin K epoxide reductase for the reaction to continue.
Thus, reduced form is inhibited, and the process is suppressed.
The synthesis of factor II, VII, IX, X, protein C and S is suppressed, as no carboxylation occurs due to non-availability of reduced form of vitamin K.
The action of warfarin is delayed because of two reasons:
a. Delayed onset
Longer half life of about 40 hours, steady state is achieved after 2 days.
b. Anticoagulant effect
Already synthesized clotting factors are available in blood, warfarin effects can only be seen when new factors are synthesized.
As warfarin is given in racemic form, so S warfarin is 3-5 times potent than R warfarin.
Up till now no separate preparation has been prepared, and are given in combination.
Resistance to warfarin
Resistance to warfarin is genetic, due to mutation in epoxide reductase.
Administration & monitoring
Monitored by PTT and INR.
PT (Common and Extrinsic Pathway) – time taken for clotting of citrated plasma after addition of Ca+2 and standardized reference thromboplastin (12-14 s). Role of thromboplastin is not present in this clotting time as it is added from outside, so that only prothrombin is active.
Should be maintained at 2.5-3.5 times normal in warfarin therapy.
Different animal sources are used in different labs, due to differences in kits, various variations in prothrombin time are observed, and thus better method is introduced.
INR – International Normalized Ratio, which is the prothombin time ratio of a patient with reference value(2 – 3.5)
ISI is the international sensitivity index. Each thromboplastin is assigned a specific throboplastin number.
If INR is <1.5 there are more chances of thromboembolic phenomenon.
If INR is >4 there are more chances of bleeding.
Normal medicinal range is 2-3, while that for prosthetic heart valves is up to 3.5
Route of Administration
Most commonly orally, other routes include parenteral and rectal. After oral route, bioavailability is 100%.
Absorbed in GIT
Highly bound to plasma proteins (98-99%)
BBB & Placenta
Can cross BBB and placenta, thus not administered in pregnancy
Half life of S type is less than 25 hours.
Half life of R type is up to 50-60 hours.
On average, half life is 40 hours.
Metabolism is different for S and R types.
S type is metabolized by cytochrome P2C9
R type is metabolized by cytochrome P1A2, P3A4 and P2C19.
Excreted in urine.
1. Anticoagulant action –delayed onset (48hours) because clotting factors already present are not affected)
2. Also decreases synthesis of endogenous anticoagulants (protein C and S)
Prevention of thromboembolism
Not given in emergency, heparin is started, while warfarin is started as well. After 3-4 days, heparin is stopped, and then only warfarin is used.
Differences from heparin
Given in emergency
Not given in emergency
Can be given in surgery
Cannot be given in surgery
Can be given in pregnancy
Cannot be given in pregnancy
If minor and patient is stable, only drug is discontinued, patient is monitored.
a. .Phytonadione (K1)
If INR is greater than 5, vitamin K preparation is given orally or I/V according to the need of patient. Action of this is only after 12-24 hours.
If INR is much higher, fresh frozen plasma is administered.
c. Different preparations of clotting factors are administered.
As inhibits clotting factors and protein C (half life 8 hours) and S (natural anticoagulant).
First natural anticoagulant is affected, and are not formed, but small thrombi are formed, especially patients deficient in protein C and protein S. There are greater chances of skin and tissue necrosis (fatty tissue necrosis).
2. Skin / Tissue necrosis
Occurs early in adults.
As warfarin can cross placental barrier, it is teratogenic and inhibits gamma carboxylation of proteins. In fetus bone and soft tissues are not properly formed. Also hemorrhagic disorders occur in fetus.
4. As it decreases activity of protein C, it leads to cutaneous necrosis and infraction of breast fatty tissue, intestine and extremities (rare)
5. warfarin induced depression of protein C also leads to venous thrombosis
Warfarin Sensitivity – CYP2C9
Polymorphism occurs, less dose is required, as unable to metabolize at the natural rate (rate decreased)
Warfarin Resistance – VKORC1
Polymorphism occurs, leading to change in dose. In certain patients larger dose is required to produce therapeutic effects.
Dosing algorithms are prepared taking genotype, etc. in account, to calculate individualized dose.
Occur in two categories:
Mostly due to:
i. enzyme induction
ii. enzyme inhibition
iii. decreased PPB
1. Pyrazolone, Phenylbutazone and Sulfinpyrazone decrease metabolism of S-warfarin and displace albumin bound warfarin leading to increased warfarin and increased anticoagulant effects (increased risk of bleeding)
i. Augment hypoprothrombinemia
ii. Decrease platelet function
iii. May induce peptic ulcer disease
2. Barbiturates and Rifampicin (enzyme inducers) increase metabolism of warfarin, decreasing its effects.
3. Metronidazole, Trimethoprim-sulfamethoxazole (co-trimoxazole) and Fluconazole decrease metabolism of S-warfarin, increasing its effects.
4. Amiodarone, Disulfiram and Cimetidine decrease metabolism of both S and R warfarin, enhancing the effects.
5. Cholestyramine binds warfarin in intestine and decreases absorption and bioavailability.
Heparin is commonly administered anticoagulant in emergency. It was discovered in 1912 by a medical student at John Hopkins Institute, while experimenting on thromboplastic drug. It was extracted from the liver.
Heparin occurs naturally in human mast cells in lungs and liver. The concentration is low and physiological anticoagulant effects are not marked.
It is prepared conveniently from two sources (animal sources):
Porcine intestinal mucosa
Organic acid with electronegative charge. It is made of hydrated mixture of sulphated mucopolysaccharide.
Two disaccharide units form polymers and are:
They form chains of variable lengths; some small, some large, as number of saccharide units are variable.
If smaller in length called low molecular weight heparin (LMWH)
If long polymer of larger length called high molecular weight heparin (HMWH).
It is a heterogenous mixture containing both high molecular weight and low molecular weight heparin. Heparin is normally present in this form.
Normal unfractionated heparin is of 5000-30,000
Low molecular weight heparin is of 1000-10,000
They have differences in pharmacokinetics and mechanism of action.
Mechanism of Action
Normally existing antithrombin binds factors II, IX and X, acting as suicide substrate and inactivates them.
Once antithrombin binds, it is used up along with the factors. This process is slow and is accelerated by administration of heparin. Heparin acts as accelerating catalytic template. Its binding causes conformational change in antithrombin, exposing its active sites. Clotting factors attach. The reaction is accelerated 1000 times (no. of units accelerated/unit time).
For normal binding, only requires structure of pentasaccharide polymer on heparin. When present, then heparin binds.
30% of commercially prepared heparin has these units. Thus 1/3 is biologically active.
For binding thrombin, heparin requires more than 18 monosaccharide units, if length is more than this, only then the heparin binds. If less than this, thrombin cannot bind but factor X still binds, requiring only pentasaccharide units.
By unfractionated heparin, thrombin can be inactivated.
By low molecular weight heparin, thrombin cannot be inactivated. Heparin has action only by inhibiting factor X.
Administration and Monitoring
Heparin is available in different forms.
Sodium and Calcium salts for in vivo administration
Lithium salts for in vitro administration (not used in humans because of toxicity)
As heparin contains a heterogenous mixture of different length chains, there is poor relation between concentration and therapeutic effect. In such biological preparations, bioassays are used for standardization instead of molecular weight.
Unit of Heparin
Thus given in biological units
“1 unit of heparin is equal to the amount which prevents 1 ml of citrated sheep plasma from clotting, for 1 hour after additional of 0.2 ml of 1:100 CaCl2. This is called biological standardization.
1 gram standardly contains 120-150 units, which is diluted on administration.
a. Can be I/V infused
b. as bolus form in emergency
c. long term intermittent subcutaneous administration
APTT Activated Partial Thromboplastin Time (Intrinsic and Common)
Therapeutic effects are monitored through APTT, time taken by plasma to clot from which Ca+2 is removed by EDTA then recalcified and added with negatively charged phospholipids and kaolin. Normal APTT time is 26-33 seconds. In patients should be 1.5-2.5 times normal. If more than 3 times, there are large chances of bleeding.
Other tests used include:
Protamine titration (0.2-0.4 units/ml)
Antifactor Xa (0.3-0.7 units/ml)
Pharmacologically stable, with weight adjusted dosage. Levels are monitored in certain patients with:
Only antifactor Xa monitoring test is performed. (0.5-1 unit/ml for BD use, 1.5 unit/ml for OD use)
Same for all factors (little higher for AT)
High for Xa
Determined by protamine titrationAlso anti-Xa units
Derived from UFH
I/V or I/M
Heparin is a large molecular weight, polar compound which is not absorbed by oral route of administration.
Unfractionated (units) is given I/V, subcutaneously or in bolus form. In people who cannot tolerate warfarin, intermittent subcutaneously given.
LMWH has low molecular weight, subcutaneously administered once or twice daily.
Why heparin cannot be given orally?
i. it is a big molecule
ii. it is mucopolysaccharide
iii. it is negatively charged
b. Half Life
Dose determines the half life.
100 units/kg Half life 1 hour
More than 800 units/kg Half life 5 hours
Thus there is direct relation between dose and half life.
LMWH has longer half life.
c. Heparin does not cross BBB or placenta. It is safe in pregnancy. Unfractionated heparin is well established for pregnancy. LMWH is less established.
Reticuloendothelial system degrades heparin. Heparinase is present in liver which converts polymers into small chains, which are excreted in urine.
Unfractionated heparin has low bioavailability 20-30%, subcutaneously
Low molecular weight heparin has 70-90% bioavailability, given once or twice daily.
On repeated administration
Anti-platelet –in very high doses inhibits platelet aggregation so affects bleeding time
Lipemia clearing –in large doses release of lipoprotein lipase occurs from endothelial lining and tissues, which acts on lipids (TGs), converting them into free fatty acid and glycerol. Heparin has more effects on post prandial lipemia.
1. Treatment & prevention of thromboembolism
Thrombolytic in cases of thrombus, but once formed, extension also occurs. To prevent this extension, anticoagulants are given.
I/V bolus, 5000 units of which are given I/V.
2. Concurrent oral t/m
Along with heparin, orally acting warfarin is started straight away, which requires 4-5 days to act, till the time warfarin takes up whole function.
3. Short / long-term t/m
Heparin is also given in short term treatment but if others cannot be given, it is used subcutaneously for long term.
– Unstable angina / acute MI
– Pulmonary embolism
– Coronary angioplasty / stent
– Vascular surgery
– Selected DIC cases
– Rheumatic valvular disease / Prosthetic valves
– Atrial fibrillation
– Peripheral arterial occlusion
– Extracorporeal circulation
– PICC line (peripherally induced cerebral cancer)
– Hip replacement surgery -prophylactically
1. Bleeding (most common hemeaturia)
Bleeding occurs in 1-5% of the patients on administration of heparin
It can be avoided by proper patient selection. In high risk individuals it is contraindicated.
Even if administered, careful monitoring with repeated APTT and other assays should be done.
In cases of mild bleeding, only discontinuation of heparin is required, the effects subside immediately.
In cases of intense bleeding, protamine sulphate is used, which is antagonist.
a. Chemistry – basic polypeptide, having positive charge.
b. Mechanism of Action
It complexes with the negatively charged heparin, and thus neutralizes it.
c. Administration – 1mg – 100 U of heparin
d. Neutralization of LMWH is incomplete, and does not have effect on the synthetic derivative of protamine sulphate, Fondaparinux.
i. Overdosage of heparin
ii. When heparin is used in surgical operations, after operation to reverse the effects.
2. Heparin induced thrombocytopenia (HIT)
a. Incidence – 1-4% of people.
Incidence is less with low molecular weight heparin.
iii. Pediatric / pregnant
In certain patients, immune response occurs and heparin binds platelet factor IV, a complex is formed. Antibodies are formed against this complex; platelet aggregation takes place, leading to formation of thrombi and decrease in platelet count (thrombocytopenia).
d. Monitoring & diagnosis
– Platelet count after 5-7 days of administration, if new thrombus forms, thrombocytopenia occurs
– Heparin-dependent platelet activation assay
– Antibody assay
Incidence is low with LMWH, we go for this if patient is a known case of HIT or if cross-immunity occurs, direct thrombin inhibitors are used or Fondaparinux
–leading to fever, rashes, urticaria, anaphylaxis
4. Transient elevation of LFTs
On prolonged usage, leads to:
6. Osteoporosis –due to demineralization
7. Aldosterone synthesis inhibition – leading to hyperkalemia
8. Mineralocorticoid deficiency
9. Lipid clearance –releases LPL increasing clearance of post prandial lipidemia
Some patients develop heparin resistance, 3 phenomena are involved:
Deficiency of antithrombin or change in antithrombin
Elevated levels of plasma proteins, other than antithrombin, to which heparin binds
Erythropoietin is a glycosylated protein produced by peritubular cells of kidney. It is essential for normal reticulocyte production.
Stimulus for release is hypoxia.
Recombinant form is available as apoprotein, which is commonly used. Glycosylated form is Darbipoietin Alpha. It has additional 2 carbohydrate chains, which improve biological activity. Its half life is 3 times more and has delayed onset. It is of no value in acute treatment of anemia. Used in supplementation with iron.
Erythropoietin binds to cytokine receptors (belong to JAK-STAT super-family). When bind these receptors, activation of JANUS kinases take place, which in turn lead to activation and phosphorylation of STAT. STAT travels to nucleus and brings about transcription responsible for biological response.
Proliferation & differentiation of erythroid
Erythropoietin binding causes proliferation and differentiation of erythroid cells.
Since erythropoietin increases hemoglobin, hematocrit and reticulocyte count, it can aggravate hypertension and thrombotic events, as well as can cause allergies.
1. Chronic Renal Failure
Normally inverse relation is seen between hemoglobin and erythropoietin. When hemoglobin decreases, erythropoietin increases exponentially. In chronic renal failure, this inverse relation is lost. Kidneys are not able to produce erythropoietin normally, thus patients have to be given exogenous erythropoietin.
2. Primary bone marrow disorders
Selected patients of anemia due to primary disorders of bone marrow
3. Secondary anemias
Secondary anemias, including myeloproliferative myelodisplastic conditions, aplastic anemia, multiple myeloma and different cancers. So given to treat these anemias.
In patients of AIDS, Zidovudine causes anemia.
Patients of phlebotomy are given to accelerate erythropoiesis.
6. Anemia of prematurity
In sports, banned by international Olympic committee due to the fact that it increases RBCs, oxygen delivery and performance.
50-200 micrograms are absorbed from dietary folic acid (i.e. 500-700 micrograms/day)
5-20 mg folates are stored in liver and other tissues.
In diet it occurs in polyglutamate form, and has to be converted to monoglutamate form for absorption (hydrolyzed by a-L-glutamyl transferrase).
In our diet, it is obtained from meat, eggs, liver and green leafy vegetables like spinach.
This is why overcooking of food usually destroys folic acid. It is also synthesized by our gut flora, but that is largely unavailable for absorption.
Folic acid is absorbed in proximal portion of small intestine and transported in plasma as methyl tetrahydrofolate form both by active and passive transport. It is widely distributed. Once it enters the cells, it is converted to tetrahydrofolic acid by demethylation that requires vit B12.
Bound to plasma proteins.
Catabolism & Excretion
The catabolism and elimination of vitamin B9 is more than vitamin B12, and hepatic stores are sufficient for 1-3 months. (B12 up to 5 years)
In cells it is stored in polyglutamate form and total body folate stores are about 5-10 mg. this folic acid is essential for synthesis of amino acids, purines and DNA.
Reduced forms are required for the synthesis of:
In presence of folate reductase, methyl cobalamine is converted into tetrahydrofolate, otherwise it is known as methylcolbalamine trap.
Methyl tetrahydrofolate is required for synthesis of purines. Serine is converted to glycine by conversion of tetrahydrofolate to methylenetetrahydrofolate.
During conversion of methylenetetrahydrofolate to dihydrofolate, deoxy uridine monophosphate (dUMP) is converted into deoxy thymidine monophosphate (dTMP), leading to DNA synthesis.
The combined catalytic activity of the above mentioned three enzymes is known as dTMP synthesis cycle.
2 important anti-cancer drugs act at this cycle:
Methotrexate inhibits folate reductase
5-fluorouracil inhibits thymidylate synthase
As cancer cells are rapidly dividing, DNA synthesis is impaired.
When DNA synthesis is impaired, in blood RBC synthesis is impaired, giving megaloblastic picture (megakaryocytes).
Deficiency of Folic Acid
Deficiency causes megaloblastic anemia that is indistinguishable from that caused by vitamin B12 deficiency (not associated neurological disorders)
Diagnosed by measuring:
Serum folic acid levels –do not reflect tissue levels
RBCs folic acid levels (greater diagnostic value)
Folic acid deficiency is seen in:
Inadequate dietary intake of folates
Occasionally associated with cancers, Leukemias
Drugs interfering with folate absorption or metabolism e.g. Phenytion, carbamazapines, Trimethoprim, Methotrexate, pyrimethamine.
Manifestations of deficiency
Signs and symptoms of epithelial damage
Neural Tube defect
If deficiency occurs during pregnancy –spina bifida
General manifestations of weight loss and weakness.
Treatment of Folic Acid Deficiency
Parenteral administration is rarely needed.
Oral therapy Dose
1mg/day – continued until underlying cause is corrected or removed.
Very rare. Only a few allergic manifestations have been reported.
Treatment of megaloblastic anemia
Prophylaxis of megaloblastic anemia
Also given in methotrexate toxicity. Toxicity is in form of encephalopathy. Folic acid is not given, rather reduced form of folic acid 5-formyl tetrahydrofolate, also known as Leucovorin/citrovorum, but has to be given within an hour of toxicity. This should not be delayed.
Essential for DNA synthesis, fatty acid metabolism
Vit B12, Vit B6 & folic acid participate in metabolism of homocysteine. If accumulation of homocysteine occurs due to deficiency of these vitamins, atherosclerosis is accelerated.
Deficiency leads to:
Deficiency may occur due to:
Porphyrin like ring with central cobalt atom attached to a nucleotide
Various organic groups may be covalently bound to cobalt atom forming cobalamines.
Accumulation of methyltetrahydrofolate and deficiency of tetrahydrofolate leads to methylfolate trap, due to deficiency of vitamin B12.
This is an important biochemical step, where metabolism of vitamin B12 and folic acid are linked; this is why megaloblastic anemia due to vitamin B12 deficiency can be partially corrected by folic acid.
Deoxyadenosyl cobalamine converts methylmalonyl-CoA to succinyl-CoA, which is an important step in propanoic acid metabolism, linking carbohydrate and lipid metabolism.
Cyanocobalamine and hydroxycobalamine are exogenous cobalamines, available as pharmacological preparations used for correction of megaloblastic anemias.
In the body they are converted to deoxy adenosylcobalamine and methyl cobalamine respectively.
Dietary requirement is 2 micrograms
Stored in liver
Storage pool is 3000-5000 micrograms
Transport & Absorption
Complexes with intrinsic factor(glycoprotein) in stomach
Absorbed in distal ileum by highly selective receptor mediated transport system
In plasma bound to transcobalamin II
Stored in hepatocytes in liver
Loss is very slow
Hepatic stores are sufficient for 5 years.
Animal source –meat, eggs, dairy products, liver
Deficiency of Vitamin B12
Vitamin B12 deficiency causes:
Blood related problems
Blood related problems
Megaloblastic macrocytic anemia, associated with:
Mild to moderate leukopenia
Hypercellular bone marrow with accumulation of erythroid and other precursor cells
Paresthesias (in peripheral nerves)
And progresses to
Other CNS dysfunctions
In the past, it was supposed to be caused by accumulation of L-methylmalonyl CoA
Now believed to be due to disruption in methionine synthesis.
Main uses include pernicious anemia and anemia caused by gastric resection.
Once diagnosis of megaloblastic anemia is made, first it is determined whether the cause is vitamin B12 deficiency or folic acid deficiency.
This is done by measuring the vitamin levels.
Performed by administering radioactive B12. If B12 is eliminated, problem is in its absorption.
Treated by giving intrinsic factor.
Standard treatment is:
Parenteral Vit B12 is given (cyanocobalamin, hydroxycobalamin) but if patient cannot tolerate go for oral or intranasal route. Hydroxy cobalamin is preferred as has high PPB and remains for a longer duration
Malabsorptive disorder- life long treatment is required
With parenteral vitamin B12, improvement comes in about 7 days. The deficiency normalizes in 1-2 months.
Initial therapy -100-1000 micrograms/day, I/M for 1-2 weeks
Maintenance therapy -100-1000 micrograms/month, I/M for the rest of life
If neurological abnormalities are present, for maintenance therapy injections should be given 1-2 weeks, for 6 months, after which given on monthly basis.
Vit B12 deficiency seen in;
Pernicious anemia (as vit B12 complexes with intrinsic factor)
Small bowel resection
Inflammatory bowel disease
In strict vegetarians
Increased homocysteine levels can be used to diagnose vitamin B12 deficiency
Very few and very uncommon, even at high doses. Sometimes allergic manifestations are observed.
Free inorganic iron is very toxic, thus there are regulatory mechanisms for:
c. Storage of iron
Normal individual absorbs 0.5-1 mg/day iron.
Iron in meat
Easily absorbed as does not require conversion
Iron in vegetables and grains
Less absorbed as bound to organic compounds
Iron in heme form is readily absorbed across intestinal cells than inorganic iron.
In inorganic form, iron is readily absorbed in ferrous than ferric form.
i. Duodenum ii. Proximal jejunum iii. Distal intestine (in small amounts, if necessary)
For absorption, iron is converted into ferrous form in presence of ferroreductase
Mechanism of Absorption:
Absorbed by two mechanisms:
On luminal surface of intestinal epithelial cells, divalent metal transporter 1 (DMT-1) is present, through which ferrous form of iron is actively transported. This new iron along with that splits from heme, are transported to blood across basolateral membrane by ferroprotein (ferriportin 1). It is then oxidized to ferric form by ferro-oxidase.
Heme iron (present in meat) is absorbed without conversion to elemental form
Regulation of storage
If body requirements are low, iron is stored inside intestinal mucosal cells in form of ferritin.
Ferritin is water soluble complex consisting of a core of ferric hydroxide covered with a shell of specialized storage protein, apoferritin.
If body requirements are high, more iron is transported across basolateral membrane to blood.
In plasma, it binds transferrin, a globulin which binds to ferric iron. Transferrin-iron complex is carried to different organs including spleen, liver, and bone marrow. Transferrin acceptors are present in these organs (TFA) and as a result iron is internalized by these organs, and transferrin and transferrin receptor complex are recycled to plasma.
Storage of Iron:
Intestinal mucosal cells
Reticuloendothelial system (in macrophages, spleen, bone marrow, liver)
Liver parenchymal cells
Factors affecting Iron Absorption:
Factors facilitating Iron Absorption
Acid enhances dissolution and reduction of ferric iron.
Ascorbic acid reduces ferric iron and forms absorbable complexes
Meat also facilitates iron absorption by increasing HCl secretion
Due to increased iron requirement
Factors Impeding Iron Absorption:
Phosphates are present in egg yolk.
Phytates occur in wheat and maize
Alkalies form non-absorbable complexes as well and oppose the reduction
Tetracyclines impede absorption.
Presence of other foods in stomach
b. Transport of Iron
Transport occurs by transferrin, a beta globulin that binds two molecules of ferric iron, forming transferrin-iron complex. This complex binds transferrin receptors present in large number of erythroid cells. They bind and internalize the complex by receptor mediated endocytosis. In endosomes, ferric iron is released, and is reduced to ferrous form. It is then transported by DMT1 into cells, used:
For Hb synthesis
Stored as ferritin
Recycling of transferrin
Transferrin-transferrin receptor complex is recycled to cell membrane. Transferrin dissociates and returns to plasma.
Increased erythropoiesis leads to increased number of trasferrin receptors on cells
Iron deficiency leads to increased concentration of serum transferrin
No mechanism is present for elimination of iron from body except exfoliation of intestinal cells. Trace amounts of iron are lost in faeces, urine, bile and sweat.
Less than 1 mg/day of iron is lost.
Serum iron is detectable, so can be used to estimate the total iron stores.
Increased iron levels lead to increased synthesis of apoferritin and vice versa.
Iron deficiency anemias
Iron deficiency anemia manifests as hypochromic, microcytic anemia, in which:
Erythrocyte mean cells volume is low (MCV <80fl)
Mean cell Hb concentration is low (MCHC <30%)
People with increased iron requirements:
Children during rapid growth
Pregnant and lactating women
Patients of chronic kidney disease (due to increased loss during hemodialysis)
Inadequate iron absorption, seen in
Females, menstrual bleeding
Males and postmenopausal most common site is GIT.
Adults, due to blood loss
Treatment of Iron Deficiency
Oral and parental preparations can be used. Oral preparation is present in the form of salts like:
Both are equally effective but oral therapy is preferred. Parenteral preparations are given only in:
Impaired GI absorption
Patients of chronic kidney disease undergoing dialysis
Patients who cannot tolerate oral iron
Oral Iron therapy
Only ferrous salts are used because iron is absorbed only in ferrous form.
Iron in tablet
Adult dose (/day)
Ferrous sulphate (hydrated-chocolate coloured)
Ferrous Sulfate (desiccated)
50-100 mg iron can be incorporated into Hb daily.
25% of oral iron as ferrous salt can be absorbed. So 200-400 mg/day elemental iron should be given. If patient cannot tolerate, less amount is given, which makes result slower but still complete relief.
Should be continued for 3-6 months after correction of cause of iron loss. This:
Replenishes iron stores
Adverse effects of Oral Administration
Mainly GIT –nausea, gastric irritation, abdominal discomfort, altered bowel habits, black staining of stools (can mask GIT bleeding).
Prevention includes decreasing the dose and taking tablets immediately after meal.
Parenteral Iron Therapy
Parenteral administration of free inorganic ferric iron produces serious dose dependent toxicity which limits the dose of iron.
A colloid containing particles is made with a core of iron oxydydroxide surrounded by a shell of carbohydrate (e.g. dextran polymers). In this way, bioactive iron is released slowly from stable colloid particles.
Forms of Parenteral Therapy
Iron dextran (Imferon)
Sodium ferric gluconate complex
Iron sucrose (Venofer)
Indications for Parenteral Administration
Conditions where patient cannot tolerate oral therapy
Absorption defects like hereditary absorption disorders, inflammatory bowel diseases, small bowel resections, trauma to small intestine, patients of gastrectomy, infants, children, pregnancy and in lactating women
Iron dextran can be given I/M or I/V. It is a stable combination of ferric hydroxide with low molecular weight dextran containing 50 mg elemental iron/ml of solution.
Iron Sucrose and Sodium Ferric Gluconate Complex
Iron sucrose and iron sodium gluconate complex are two compounds given I/V, however they are less antigenic and allergic manifestations are less commonly encountered.
Formula for Calculating total Dose of Iron in grams
0.25 x (normal Hb – Patients Hg)
Iron levels should be monitored in parenteral therapy as it is not subjected to normal regulatory mechanism (as in oral therapy)
Adverse Effects of parenteral route
Painful (esp. I/M inj of dextran)
Local tissue staining
GIT –nausea, vomiting, allergic manifestations
Dizziness, headache, light headedness
In very severe cases, anaphylaxis, which may lead to death
There are increased chances of hypersensitivity on patients who have already received parenteral iron dextran.
Test dose of 0.25-5 mg, I/V administered
Two different formulations are used
High molecular weight form (e.g. DexFerum)
Low molecular weight forms (e.g. InFeD)
There is increased risk of anaphylaxis with high molecular weight forms.
Estimation of Iron Stores
Can be estimated on the basis of:
Concentration of serum ferritin
Transferrin saturation = Total serum iron conc. /Total iron binding capacity
Toxicity occurs due to overdosage.
Acute Iron Toxicity
Seen after ingestion of tablets of iron. Common in children.
Lethal dose 10 or more tablets are lethal due to accidental ingestion. Adults can tolerate larger doses than children
Gastric lavage/aspiration of what is ingested, usually with sodium bicarbonate
Home made remedy of egg yolk and milk, which complexes iron and renders it non-absorbable.
Chelating agents –Deferroximine given I/V, binds iron and prevents its absorption and eliminates it from body.
Supportive therapy required for correction of metabolic acidosis, treatment of shock and usually Diazepam for convulsions.
Activated charcoal does not bind iron so is not effective.
Chronic Iron Toxicity:
Slow and gradual accumulation of iron in body. Different organs are involved like heart, liver, and pancreas. Iron gets accumulated in these organs producing end organ failure and hemochromatosis. In thalassemia, when repeated blood transfusions are given, aplastic anemia might occur.
Intermittent Phlebotomy -1 unit blood is removed each week or till iron overload is corrected.
Iron Chelation therapy – Deferasirox, given orally. There is no role of deferoximine and is actually hazardous.
Enalapril is a prodrug, which is converted into enalaprilat in liver (active metabolite). Its duration of action is prolonged because of the active metabolite (24 hours). It is given in a dose of 5 mg which can be increased up to 40 mg.
Lisinopril is a lysine derivative of enalaprilat, but does not contain the sulphydral group. It has longer half life of about 12 hours. It is given in a dose of 5 mg, which can be increased up to 10 mg.
Mechanism of Action of ACE Inhibitors
Renin is released from juxtaglomerular apparatus.
Renin acts upon Angiotensinogen, to split off the inactive decapeptide Angiotensin I.
Angiotensin I is then converted primarily by endothelial angiotensin converting enzyme (ACE) to Octapeptide, angiotensin II.
Angiotensin II is the most powerful vasoconstrictor.
It also stimulates the synthesis and secretion of aldosterone which retains sodium & water.
ACE inhibitors inhibit the converting enzyme peptidyl dipeptidase & prevents formation of Angiotensin II. The same enzyme (under the name of plasma kinase) inactivates bradykinin, so it accumulates.
Hypotensive activity results from:
inhibitory action on Renin angiotensin system
stimulatory action on Kallikrein kinin system
Reverse ventricular hypertrophy
Decrease preload, afterload and sympathetic activity
Affect remodelling of heart
Congestive cardiac failure, improve survival of patient, providing symptomatic relief and having cardio protective effect
Myocardial infarction, increase survival rate
Diabetic neuropathy, decrease micro and macro vascular complications, decrease chances of end stage renal diseases and do not allow retinopathies to progress, increase creatinine clearance and decrease the requirement of dialysis, improving the life expectancy of patients
Combination of ACE inhibitors & Angiotensin receptor blockers offer a better control of renin angiotensin aldosterone system, thus cardio protective and renoprotective effects of both these classes of drugs are combined.
Adverse Effects of ACE inhibitors (Captopril)
GIT –abdominal discomfort, alteration of taste, apthous ulcers of mouth, angular stomatitis on prolonged use.
Renal –on prolonged use, patients of renal insufficiency have increased serum urea, creatinine levels and produce proteinurea. In patients with renal artery stenosis, can aggravate acute renal failure.
CVS –in sodium depleted patients cause excessive hypotension
CNS –headache, dizziness
Cough –in 30% of patients due to increase in bradykinin
Teratogenic Effects –in 1st trimester damage to kidneys of fetus, can produce anuria and renal failure
Liver –liver injury
Angiotensin Receptor Blockers
Losartan is converted into active metabolite, which is 10-40 times more potent than losartan. It has a half life of about 2 hours, while active metabolite has a half life of 9 hours. 4% is excreted as such in urine, while the rest is metabolized in liver. It does not cross blood brain barrier, thus devoid of effects on CNS.
Mechanism of Action
Angiotensin II is formed under the effect of two enzymes:
a. Angiotensin converting enzyme b. Kinase
When ACE inhibitors are given, angiotensin II is still formed under the effects of kinase. It acts on two types of receptors:
Angiotensin I receptor (AT-1)
Angiotensin II receptor ( AT-2)
When angiotensin I receptors are stimulated, they produce effects similar to angiotensin II.
When angiotensin II receptors are stimulated, they produce effects that of opposite to angiotensin II (hypotensive activity, beneficial in treatment of hypertension).
Basically they competitive block AT-1 receptors, thus have effects of angiotensin II through angiotensin II receptors.
Uses are same as ACE inhibitors except that efficiency and safety of angiotensin receptor blockers has not been established in so many chemical studies.
Like ACE inhibitors except dry cough, angioedema and rash are much less.