Pharmacotherapy of anaemia dr jayesh vaghela
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This document discusses various oral and parenteral iron preparations used to treat iron-deficiency anemia. Oral iron preparations include ferrous sulfate, ferrous gluconate, and carbonyl iron. Parenteral options include iron dextran, ferrous sucrose, ferric carboxymaltose, and sodium ferric gluconate. The ideal daily elemental iron dose is 200 mg in divided doses. Therapy may need to continue for 2-4 months after hemoglobin levels normalize to replenish iron stores. Adverse effects and drug interactions are also reviewed.
Pharmacotherapy of anaemia dr jayesh vaghela
- 5. Oral Iron Preparations • Ferrous sulfate • Ferrous gluconate • Ferrous fumarate • Colloidal ferric hydroxide • Carbonyl iron
- 6. Ferrous sulfate ferrous sulfate (exsiccated) Ferrous gluconate Ferrous fumarate Polysaccharide iron complex Carbonyl iron Elemental iron (%) 20 30 12 33 100 100 Elemental iron provided • 60–65 mg/324– 325 mg tablet • 18 mg iron/5 mL syrup • 44 mg iron/5 mL elixir • 15 mg iron/0.6 mL drop • 65 mg/200 mg tablet • 60 mg/187 mg tablet • 50 mg/160 mg tablet • 36 mg/325 mg tablet • 27 mg/240 mg tablet • 33 mg/100 mg tablet • 63–66 mg/200 mg tablet • 106 mg/324– 325 mg tablet • 15 mg/0.6 mL drop • 33 mg/5 mL suspension • 150 mg capsule • 50 mg tablet • 100 mg/5 mL elixir • 50 mg caplet Ferrous salts available in the market
- 7. • Oral preparations – strong protein precipitating action – can not be injected • Variations in the ferrous salts have relatively little effect on the bioavailability. • Sulfate, fumarate, and gluconate salts are absorbed approximately same extent. • Addition of cobalt, copper, or other substances only adds in expense without significant benefit. • Iron is best absorbed in ferrous (Fe2+) reduced form • Maximum absorption in duodenum (∵ acidic nature of stomach) • Only 10 – 20 % of administered dose is absorbed from G.I.T.
- 8. • Slow-release or sustained release iron preparations do not undergo sufficient dissolution until they reach the small intestine ⇓ In the alkaline environment of the small intestine ⇓ iron tends to form insoluble complexes ⇓ significantly reduces absorption
- 9. • Many oral formulations available in India contain iron compounds along with many vitamins, yeast, amino acids and other minerals. • But they are considered irrational. • Technical advisory board (India) has recommended that even B complex vitamins and zinc should not be added to iron preparations. • Combination of iron with strychnine, arsenic and yohimbine and all fixed dose combination of haemoglobin in any form are banned in India.
- 10. Treatment strategy Elemental iron content is to be taken into account, not the total iron compound • Recommended – 200 mg elemental iron daily in 2 – 3 divided doses ⇛ Maximum haematopoietic effect • If not tolerated ⇛ - small amounts - e.g.Tab. Fe sulfate 325 mg ⇛ 65 mg (20%) • Generally, start with low dose ⇛ escalation gradually to full dose
- 11. Administration: • 1 hour before meal (food interferes with absorption), but side effects are more • some prefer giving larger amounts after meals, while others like to give smaller doses in between meals • Liquid preparations stain the teeth; should be put on back of tongue. • Less satisfactory in general.
- 12. Adverse Drug Reactions • Epigastric pain, • Heartburn, • Nausea, vomiting, • Bloating, • Staining of teeth, metallic taste, • Colic • Constipation (astringent action of iron) is more common than diarrhoea (irritant action)
- 13. Common Preparations of oral iron oFerrous sulfate: • The cheapest; preferred; Leaves metallic taste oFerrous fumarate: • Less water soluble than ferrous sulfate; tasteless oCarbonyl iron: • High purity metallic iron in very fine powder form (particle size < 5 μM) • Absorbed from intestines over a long time, better gastric tolerance • Bioavailability is about 3/4th that of ferrous sulfate
- 14. Ferric hydroxy polymaltose: • Vigorously promoted for its high iron content, no metallic taste, good g.i. tolerability and direct absorption from the intestines • Because the complex releases little free iron in the gut lumen — g.i. irritation is minimal • High bioavailability observed in rats has not been found in humans. • Reports of its poor efficacy in treating iron deficiency anaemia have appeared • Therapeutic efficacy is questionable.
- 15. Daily Dose of Iron and Improvement in Hb level • Suppose Ferrous sulphate (hydrated - 7H2O) is administered 300 mg tid total daily FeSO4 = 900 mg • 20 % of elemental iron = per day 180 mg (20 % of 900 mg) elemental iron is given • Presuming that 10 % of this gets absorbed 18 mg available for Hb synthesis • This increases Hb by about 0.16 g/dl, means correction of Hb deficit is by 1 % per day • If Hb is deficient by more than 3 g/dl, an average increment of 0.1 - 0.2 g/dl/day is observed with usual therapeutic doses
- 16. How long the therapy will be needed? • Considering daily rate of about 0.2 g/dl rise in Hb and normal level of 14.8 g/dl, • if Hb level in an anaemic patient is 5 g/dl it may take about 50 days (approx. 2 months) to reach normal level • As the anaemic status improves, rate of absorption decreases • Iron stores (total 40-50 mg/kg) may increase at a rate not more than 100 mg per month • Hence, therapy should be continued for a 2-4 months after Hb level becomes normal.
- 17. DrugsThat Decrease Iron Absorption Object Drugs Affected by Iron Al-, Mg-, and Ca +2 -containing antacids Levodopa ↓ (chelates with iron) Tetracycline and doxycycline Methyldopa ↓ (decreases efficacy of methyldopa) Histamine2 antagonists Levothyroxine ↓ (decreased efficacy of levothyroxine) Proton pump inhibitors Penicillamine ↓ (chelates with iron) Cholestyramine Fluoroquinolones ↓ (forms ferric ionquinolone complex) Tetracycline and doxycycline ↓ (when administered within 2 hours of iron salt) Mycophenolate ↓ (decreases absorption) Drug interactions of iron
- 18. Failure to respond to therapy • Poor patient adherence, inability to absorb iron, incorrect diagnosis, continued bleeding o Iron test: (To rule out malabsorption) Administration of 50 mg of elemental iron as liquid Fe2+ sulfate ⇓ Plasma iron levels are determined at half-hour intervals for 2 hours ⇓ If plasma iron levels increase by >50 mcg/dL during this time ⇓ Absorption is satisfactory
- 19. Parenteral Iron Preparations • Iron-dextran • Iron-sorbitol-citric acid • Ferrous-sucrose • Ferric carboxymaltose • Sodium ferric gluconate • Ferumoxytol
- 20. Indications of Parenteral Therapy • Oral iron not tolerated • Oral iron not absorbed • Non-compliance to oral iron • Severe deficiency with chronic bleeding • Along with erythropoietin Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit (g/dl)
- 21. • High molecular weight colloidal solution The only preparation which can be used i.m. & i.v. • i.m. injection ⇓ Absorbed through lymphatics ⇓ Circulates without binding to transferrin ⇓ Engulfed by RE cells ⇓ Iron dissociates & available for haeme synthesis • Low MW complex • Binds with transferrin ⇓ Saturates it if in large quantity ⇓ Remaining free iron is highly toxic ⇓ Not suitable for i.v. Only i.m. is safe • Direct absorption into circulation, not lymphatics Iron dextran Iron-Sorbitol-Citrate
- 22. • No local binding in muscles • But, 30% dose excreted in urine ⇓ Dose needs to be increased accordingly ADRs: • V-Tach, hypotension, A-V block, flushing • C/I in Kidney disease Iron dextran Iron-Sorbitol-Citrate • 10–30% of the dose remains locally bound in muscles ⇓ • Unavailable for utilization for several weeks ⇓ • 25% extra needs to be added to the calculated dose ADRs: • Anaphylactic reaction (dextran)
- 23. Therapeutic concerns about iron dextran Intramuscular injection Intravenous injection • Deeply in the gluteal region using Z – track technique Preparation: • iron dextran 100 mg in 2 ml Administration: • 2 ml daily, or on alternate days, Or • 5 ml each side on the same day Problems: • Discomfort, tissue necrosis, atrophy Test dose: (Black box warning) • 0.5 ml iron dextran injected i.v. over 5–10 min • Observe for 1 hour • If untoward reaction ⇛ Give epinephrine, diphenhydramine or corticoids • Administration: • Method 1: • 2 ml (100 mg) can be injected per day taking 10 min for the injection.
- 24. Therapeutic concerns about iron dextran Intravenous injection • Method 2: (Total Dose Infusion) • Total calculated dose is diluted in 500 ml of glucose/saline solution ⇓ infused i.v. over 6–8 hours under constant observation. • Higher risk of ADRs • More risk in pre-existing immune- mediated disease Stop infusion if giddiness, paraesthesia, tightness in chest
- 25. Adverse Drug Reactions of iron dextran Local : • Pain at site of i.m. injection, pigmentation of skin. • Sterile abscess — especially in old and debilitated patient. Systemic: • Fever, headache, joint pains, flushing, palpitation, chest pain, dyspnoea, lymph node enlargement. • Rarely, An anaphylactoid reaction resulting in vascular collapse, death Precaution: • i.m. dose should not be >25 mg in 5 kg patient, >50 mg in 10 kg, and >100 mg for all other patients
- 26. Ferrous sucrose • Newer high MW compound complex of iron hydroxide with sucrose • i.v. injection ⇛ taken up by RE cells ⇛ iron dissociates ⇛ Utilized Administration: • 100 mg / 5 ml single-dose vials • 100 mg (max 200 mg/day) once a day to once a week can be given over 5 min • Only i.v. • Not to be given i.m. / s.c. (∵ solution is highly alkaline)
- 27. Indication: • Anaemia in chronic kidney diseases Precaution: • Total dose infusion is not possible • Oral iron therapy should not be given concurrently and till 5 days after the last injection (∵ it decrease absorption of oral iron)
- 28. Ferric carboxymaltose • Ferric hydroxide core is stabilized by CH shell • i.v. injection ⇛ macromolecule is taken up by RE cells (mainly by bone marrow, 80 % and also liver, spleen) Preparation: • 50 mg / ml, such 2 ml & 10 ml vials Administration: • Method – 1: - Daily 100 mg i.v. injection, • Method – 2: - Up to 1000 mg diluted in 100 ml saline & infused over 15 min or more
- 29. Advantage: • In clinical trials, it has caused rapid increase in haemoglobin level and replenished stores • very low incidence of acute reaction, rare anaphylaxis ADRs: • Mild Headache, nausea, abdominal pain Caution: • Due to lack of safety data, it is not recommended for children < 14 years.
- 30. Sodium Ferric Gluconate • High MW Iron complex bound to 1 gluconate & 4 sucrose molecules • i.v. injection of aqueous solution ⇛ complex taken up by phagocytes ⇛ iron is released ⇛ utilized. Preparation: • 62.5 mg in 5 ml vials Administration: (Only i.v.) • Method – 2: - 125 mg diluted in 100 ml NS ⇛ infused over 60 min • Method – 2: - slow i.v. injection @ 12.5 mg / min
- 31. Ferumoxytol • Approved by USFDA in June – 2009 • i.v. injection ⇛ complex taken up by macrophages in liver, spleen, bone marrow ⇛ iron is released ⇛ - Enters storage pool as ferritin, or -Transported by Tf to haeme synthesis Preparation: • 30 mg / ml elemental iron Administration: • Initial 510 mg dose i.v. ⇛ second dose of 510 mg after 3 – 8 days
- 32. • Advantage: • Can be administered at a higher rate than any other iron preparations • i.e. @ 30 mg / sec • No anaphylaxis, but should be observed for at least 30 min • Less g.i. upset, & peripheral oedema • Caution: • Higher incidence of hypotension, dizziness
- 33. Ferumoxytol Sodium Ferric Gluconate Iron Dextran Iron Sucrose Amount of elemental iron 30 mg/mL 62.5 mg iron/5 mL 50 mg iron/mL 20 mg iron/mL Composition Superparamagnetic iron oxide that is coated with a carbohydrate shell Ferric oxide hydrate bonded to sucrose chelates with gluconate in a molar rate of 2 iron molecules to 1 gluconate molecule Complex of ferric hydroxide and dextran Complex of polynuclear iron hydroxide in sucrose Indication Treatment of iron deficiency anemia for adult patients with chronic kidney disease (CKD) Treatment of iron- deficiency anemia for patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy Treatment of patients with documented iron deficiency in whom oral therapy is unsatisfactory or impossible Treatment of iron- deficiency anemia for patients undergoing chronic hemodialysis who are receiving supplemental epoetin alfa therapy
- 34. Ferumoxytol Sodium Ferric Gluconate Iron Dextran Iron Sucrose Usual dose • Initial 510 mg intravenous Injection ⇓ • second 510 mg intravenous injection 3 to 8 days later (rate 30 mg/s) • 125 mg (10 mL) diluted in 100 mL normal saline, infused over 60 minutes; • Also slow IV injection (rate of 12.5 mg/min). • 100 mg undiluted at a rate not to exceed 50 mg (1 mL) per Minute • 100 mg into the dialysis line at a rate of 1 mL (20 mg of iron) undiluted solution per Minute Treatment 2 doses × 510 mg = 1,020 mg 8 doses × 125 mg = 1,000 mg 10 doses × 100 mg = 1,000 mg Up to 10 doses × 100 mg = 1,000 mg Common adverse effects Diarrhea, constipation, nausea, dizziness, hypotension, peripheral edema Cramps, nausea and vomiting, flushing, hypotension, rash, pruritus Pain and brown staining at injection site, flushing, hypotension, fever, chills, Leg cramps, hypotension
- 35. Erythropoietin (EPO) • Sialoglycoprotein hormone (MW 34000) produced by peritubular cells of the kidney • Essential for normal erythropoiesis M/A: • EPO binds to specific receptors on the surface of its target cells • Alters phosphorylation of intracellular proteins and activates transcription factors to regulate gene expression • induces erythropoiesis in a dose dependent manner, but has no effect on RBC lifespan.
- 36. Use: • Anaemia due to chronic renal failure • Only symptomatic patients with Hb ≤ 8 g/dl should be considered for EPO therapy • Epoetin 25–100 U/kg s.c. or i.v. 3 times a week (max. 600 U/kg/week) raises haematocrit and haemoglobin • Start with a low dose and titrate upwards to keep – - Haematocrit between 30–36%, and - Hb 10–11 g (max 12 g) per dl
- 37. ADRs: • Related to sudden increase in haematocrit, blood viscosity and peripheral vascular resistance (due to correction of anaemia) • Increased clot formation in the A-V shunts (most patients are on dialysis), • Hypertensive episodes, serious thromboembolic events, • Seizures • Flu like symptoms lasting 2–4 hr occur in some patients
- 38. Darbepoetin • Recently introduced • Hyperglycosylated modified EPO Advantages: • t½ >24 hours, • Longer acting • Can be administered once every 2–4 weeks
- 40. • General • Gastrointestinal symptoms shortly after ingestion with possible rapid progression to shock and coma • Symptoms • Vomiting, abdominal pain, and diarrhea within 1 to 6 hours • Lethargy, coma, seizures, bloody vomiting, bloody diarrhea, and shock within 6 to 24 hours • Signs • Hypotension and tachycardia within 6 to 24 hours • Liver dysfunction and failure possible in 2 to 5 days
- 41. Management oTo prevent further absorption of iron from gut: • (a) Induce vomiting or perform gastric lavage with sodium bicarbonate solution— to render iron insoluble. • (b) Give egg yolk and milk orally: to complex iron. Activated charcoal does not adsorb iron. oTo bind and remove iron already absorbed: • Desferrioxamine (an iron chelating agent) — is the drug of choice. • i.m. (preferably) 0.5–1 g (50 mg/kg) repeated 4–12 hourly as required, or • i.v. (if shock is present) 10–15 mg/kg/hour; max 75 mg/kg in a day till serum iron falls below 300 μg/dl.
- 42. Desferrioxamine • Ferrioxamine is a long chain iron containing complex obtained from an actinomycete • Chemical removal of iron from it yields desferrioxamine which has very high affinity for iron • 1 g is capable of chelating 85 mg of elemental iron. • Straight chain desferrioxamine molecule winds round ferric iron and forms a stable nontoxic complex ⇛ excreted in urine oAdvantage: • It removes loosely bound iron as well as that from haemosiderin and ferritin, but • Not from haemoglobin or cytochrome
- 43. oUses: Acute iron poisoning: Transfusion siderosis: • occurs in thalassemia patients who receive repeated blood transfusion oADRs: • Histamine release → fall in BP, flushing, itching, urticaria, rashes oPreparation: • 0.5 gm / vial
- 44. Deferiprone • Orally active iron chelator • Specially indicated for the treatment of transfusion siderosis in thalassemia patients • Less effective alternative to injected desferrioxamine • Other uses: • Acute iron poisoning • Iron load in Liver cirrhosis • Dose: 50–100 mg/kg daily in 2–4 divided doses.
- 46. Role of iron for therapeutic or prophylactic is considered only when – - Iron deficiency has already been established, or -To prevent further depletion of stores. Initial approach to treatment depends upon the severity and cause of IDA. However, the response of iron deficiency anemia to iron is influenced by several factors like – - Ability of patient to tolerate and absorb medicinal iron, - Presence of other complicating illness, - Severity of the anemia.
- 47. Take – Home Message The advantages and disadvantages of the various preparations and routes of administration should be fully weighed before selecting the form of therapy. In the first instance, Under normal circumstances, oral iron is the treatment of choice since it is simple, effective, safe and cheap. However, the ultimate decision depends on patient’s condition & compliance.
- 48. Thank You . . .