Drugs used in haematological disorders
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This document summarizes drugs used to treat hematological disorders including anemias, thrombocytopenia, and disseminated intravascular coagulation (DIC). It discusses haematinics such as iron, vitamin B12, folic acid, and erythropoietin that are used to treat anemias. It also covers treatments for thrombocytopenia including steroids, immune globulins, and thrombopoietin receptor agonists. For DIC, the goal is to treat the underlying cause and provide supportive treatments like plasma or anticoagulants. Common anticoagulants discussed are heparin and warfarin.
![Drugs used in haematological disorders
(Aneamia, Thrombocytopenia, Disseminated
Intravascular Coagulation [DIVC])
S. Parasuraman, M.Pharm., Ph.D.,
Associate Professor,
Faculty of Pharmacy, AIMST University](https://image.slidesharecdn.com/l5drugsusedinhaematologicaldisorders-221219141426-5e796934/85/Drugs-used-in-haematological-disorders-1-320.jpg)
![Disseminated
Intravascular
Coagulation
[DIVC/ DIC]
Scanning electron micrograph of platelets](https://image.slidesharecdn.com/l5drugsusedinhaematologicaldisorders-221219141426-5e796934/85/Drugs-used-in-haematological-disorders-19-320.jpg)
Drugs used in haematological disorders
- 1. Drugs used in haematological disorders (Aneamia, Thrombocytopenia, Disseminated Intravascular Coagulation [DIVC]) S. Parasuraman, M.Pharm., Ph.D., Associate Professor, Faculty of Pharmacy, AIMST University
- 3. Haematinics • Haematinics are substances required in the formation of blood and are used for treatment of anaemias. • Anaemia occurs when the balance between production and destruction of RBCs is disturbed by: • Blood loss (acute or chronic) • Impaired red cell formation due to • deficiency of essential factors (iron, vitamin B12, folic acid) • bone marrow depression (hypoplastic anaemia) • erythropoietin deficiency. • Increased destruction of RBCs (haemolytic anaemia).
- 4. Haematinics
- 5. Haematinics • Iron • Iron is an essential body constituent Total body iron in an adult is 2.5–5 g (average 3.5 g). It is more in men (50 mg/kg) than in women (38 mg/kg). • It is distributed into: • Haemoglobin (Hb) : 62% • Iron stores as ferritin and : 25% • Haemosiderin Myoglobin (in muscles) : 7% • Parenchymal iron (in enzymes, etc.) : 6%
- 6. Haematinics • Iron - Daily requirement • Adult male : 0.5–1 mg (13 μg/kg) • Adult female : 1–2 mg (21 μg/kg) • Infants : 60 μg/kg • Children : 25 μg/kg • Pregnancy : 3–5 mg (80 μg/kg) (last 2 trimesters) • Dietary sources of iron • Rich : Liver, egg yolk, oyster, dry beans, dry fruits, wheat germ, yeast. • Medium : Meat, chicken, fish, spinach, banana, apple. • Poor : Milk and its products, root vegetables
- 7. Haematinics • Iron deficiency • Iron deficiency is the most common nutritional cause of anemia in humans. It can result from inadequate iron intake, malabsorption, blood loss, or an increased requirement, as with pregnancy. When severe, it results in a characteristic microcytic, hypochromic anemia. • Iron deficiency can affect metabolism in muscle independently of the effect of anemia on O2 delivery.
- 8. Haematinics • Treatment of Iron Deficiency: Orally administered ferrous sulfate is the treatment of choice for iron deficiency. • Side effects: Oral iron preparations include heartburn, nausea, upper gastric discomfort, and diarrhea or constipation. A good policy is to initiate therapy at a small dosage and then gradually to increase the dosage to that desired. • Parenteral Iron: When oral iron therapy fails, parenteral iron administration may be an effective alternative. • Iron Dextran – IV or IM - test dose of 0.5 mL (25 mg of iron); > 500 mg / iv • Sodium Ferric Gluconate – IV • Iron Sucrose – IV • Ferric Carboxymaltose – IV
- 9. Haematinics • Acute iron poisoning: • It occurs mostly in infants and children. • Manifestations are vomiting, abdominal pain, haematemesis, diarrhoea, lethargy, cyanosis, dehydration, acidosis, convulsions; finally shock, cardiovascular collapse and death. • In few cases death occurs early (within 6 hours), but is typically delayed to 12–36 hours, with apparent improvement in the intervening period. • Treatment: • To prevent further absorption of iron from gut. • Induce vomiting or perform gastric lavage with sodium bicarbonate solution—to render iron insoluble. • Give egg yolk and milk orally: to complex iron. Activated charcoal does not adsorb iron. • To bind and remove iron already absorbed: Desferrioxamine. Alternatively, diethylenetriaminepentaacetic acid (DTPA) or calcium edetate
- 10. Haematinics • Copper , Pyridoxine, and Riboflavin: • Copper has redox properties similar to those of iron, which simultaneously are essential and potentially toxic to the cell. • Pyridoxine responsive anaemia is a rare entity. It is due to inherent abnormality in haeme synthesis. Sideroblastic anaemia associated with isoniazid and pyrazinamide therapy needs to be treated with pyridoxine. • Riboflavin - red cell aplasia due to riboflavin deficiency
- 11. Haematinics • Vitamin B12: Cyanocobalamin and hydroxocobalamin are complex cobalt containing compounds present in the diet and referred to as vit B12. • Daily requirement: 1–3 μg, pregnancy and lactation 3–5 μg. • Vit B12 Therapy: • Oral liquids, multivitamin supplements • Vit B12 should be given prophylactically only when there is a reasonable probability that a deficiency exists or will exist. • Long-term therapy with vitamin B12 must be evaluated at intervals of 6–12 months in patients who are otherwise well.
- 12. Haematinics • Folic Acid: • Folic acid is used for preventing and treating low blood levels of folate (folate deficiency) and high blood levels of homocysteine (hyperhomocysteinemia). • Dietary sources Liver, green leafy vegetables (spinach), egg, meat, yeast. It is synthesized by gut flora, but this is largely unavailable for absorption. • Daily requirement: • Adult is < 0.1 mg (but dietary allowance of 0.2 mg/day is recommended). • During pregnancy, lactation: 0.8 mg/day
- 13. Haematinics • Folic Acid: • Folate deficiency occurs due to: • Inadequate dietary intake • Malabsorption • Biliary fistula • Chronic alcoholism • Increased demand • Drug induced: prolonged therapy with anticonvulsants and oral contraceptives. • Uses • Treatment of megaloblastic anaemias • Prophylaxis • Management of methotrexate toxicity • To enhance anticancer efficacy of • 5-fluorouracil • Adverse effects: Oral folic acid is entirely nontoxic. Injections rarely cause sensitivity reactions.
- 14. Erythropoietin • Erythropoietin (EPO) is a glycoprotein hormone, naturally produced by the peritubular cells of the kidney, that stimulates red blood cell production. • Epoetin α and β: It is recombinant human erythropoietin. It is administered by i.v. or s.c. injection and has a plasma t½ of 6–10 hr, but action lasts several days. • Use: • The primary indication for epoetin is anaemia of chronic renal failure which is due to low levels of EPO. • Other uses: • Anaemia in AIDS • Cancer chemotherapy induced anaemia • Preoperative increased blood production forautologous transfusion during surgery • Adverse effects: Epoetin is nonimmunogenic. sudden increase in haematocrit, blood viscosity and peripheral vascular resistance. • Darbepoetin α: This is a hyperglycosylated modified preparation of EPO that has a t½ of 24–36 hours. Indications, efficacy and adverse effects are similar to epoetin.
- 16. Thrombocytopenia • Thrombocytopaenia (low platelet count) can be due to either a failure of platelet production or a shortened platelet lifespan. • Thrombopoietin (TPO), produced mainly in the liver but also in the kidneys, is a key regulator of platelet production. TPO is removed from the circulation by platelets via the c-MPL receptor. • A normal platelet count ranges between 150 and 400 x 109/litre. • Platelets Lifespan: 7 - 10 days. • Pathophysiology thrombocytopaenia: • Anti-platelet antibody production • Abnormalities of T-helper cells, regulatory T-cells and cytotoxic T-cells. Ref: Radia D. Thrombocytopenia. Medicine. 2013;41(4):225-7. doi: 10.1016/j.mpmed.2013.01.017
- 17. Causes of thrombocytopenia Ref: https://www.aafp.org/pubs/afp/issues/2022/0900/thrombocytopenia.html
- 18. Thrombocytopenia/ immune thrombocytopenia (ITP) – Management • Steroids: Dexamethasone, Methylprednisolone, Prednisolone • Immune globulin: Intravenous immune globulin (IVIG) • Drugs that boost platelet production: Avatrombopag, Eltrombopag, Romiplostim (stimulate the bone marrow to produce more platelets) • Other drugs: Rituximab helps to increase platelet count by reducing the immune system response that's damaging platelets. • Surgery: Splenectomy (only useful in cases of autoimmune thrombocytopenia) • Emergency treatment: Transfusions of platelet concentrates
- 19. Disseminated Intravascular Coagulation [DIVC/ DIC] Scanning electron micrograph of platelets
- 20. DIVC • Disseminated intravascular coagulation (DIC) is a serious disorder in which the proteins that control blood clotting become overactive. • Causes: Usually caused by inflammation from an infection, injury, or illness. • Risk factors • Blood transfusion reaction • Cancer, especially certain types of leukemia • Inflammation of the pancreas • Infection in the blood, especially by bacteria or fungus • Liver disease • Pregnancy complications Recent surgery or anesthesia • Severe tissue injury • Large hemangioma Ref: https://medlineplus.gov/ency/article/000573.htm
- 21. DIVC • Treatment: There is no specific treatment for DIC. The goal is to determine and treat the underlying cause of DIC. • Supportive treatments may include: • Plasma transfusions to replace blood clotting factors if a large amount of bleeding is occurring. • Blood thinner medicine/ anticoagulants (heparin) to prevent blood clotting if a large amount of clotting is occurring. Ref: https://medlineplus.gov/ency/article/000573.htm https://www.nhlbi.nih.gov/health/disseminated-intravascular-coagulation
- 22. Anticoagulants
- 23. Anticoagulant • The anticoagulant drugs inhibit either the action of the coagulation factors (heparin) or interfere with the synthesis of the coagulation factors (warfarin).
- 24. Anticoagulant - Heparin • Heparin or Unfractionated heparin (UFH) is a heterogeneous mixture of sulfated mucopolysaccharides with MW 10,000 to 20,000 g/mol. Its biologic activity is dependent upon the endogenous anticoagulant antithrombin.
- 25. Anticoagulant - Heparin • The shorter-chain, low-molecular-weight (LMW) fractions of heparin (enoxaparin, dalteparin, and tinzaparin) inhibit activated factor X but have less effect on thrombin than the high-molecular-weight (HMW) species. • Monitoring of Heparin Effect: Close monitoring of the activated partial thromboplastin time (aPTT or PTT) is necessary in patients receiving UFH. Levels of UFH may also be determined by protamine titration (therapeutic levels 0.2–0.4 unit/mL) or anti-Xa units (therapeutic levels 0.3–0.7 unit/mL).
- 26. Anticoagulant - Heparin • Toxicity: Bleeding, loss of hair and reversible alopecia, heparin-Induced thrombocytopenia. • Contraindications: Heparin should be avoided in patients who have recently had surgery of the brain, spinal cord, or eye; and in patients who are undergoing lumbar puncture or regional anesthetic block. • Reversal of Heparin Action: Protamine antagonize the heparin. Intravenous injection of protamine neutralises heparin weight for weight, i.e. 1 mg is needed for every 100 U of heparin.
- 27. Use of anticoagulant • The aim of using anticoagulants is to prevent thrombus extension and embolic complications by reducing the rate of fibrin formation. • Deep vein thrombosis and pulmonary embolism • Myocardial infarction • Unstable angina • Rheumatic heart disease; Atrial fibrillation • Cerebrovascular disease • Vascular surgery, prosthetic heart valves, retinal vessel thrombosis, extracorporeal circulation, haemodialysis • Defibrination syndrome
- 28. Direct factor Xa inhibitors • Rivaroxaban: It is an orally active direct inhibitor of activated factor Xa which has become available for prophylaxis and treatment of Deep Vein Thrombosis (DVT). • Apixaban: Indications similar to rivaroxaban. Oral direct thrombin inhibitor • Dabigatran etexilate: It is a prodrug which after oral administration is rapidly hydrolysed to dabigatran, a direct thrombin inhibitor. Dabigatran reversibly blocks the catalytic site of thrombin and produces a rapid anticoagulant action.
- 29. Choice of anticoagulants for various clinical indications Ref: K.D. Tripathi. Essentials of medical pharmacology. 8th ed.
- 32. Thrombolytics • These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery). They are therapeutic rather than prophylactic and work by activating the natural fibrinolytic system. Drugs: Streptokinase, Urokinase, Alteplase (rt-PA), Reteplase, Tenecteplase.
- 33. Thrombolytics • Streptokinase is a protein synthesized by Streptococci that combines with the proactivator plasminogen. • Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. • Alteplase is recombinant tissue plasminogen activator (rt-PA) • Reteplase • Tenecteplase
- 34. Thrombolytics • Uses of fibrinolytics: • Administration of fibrinolytic drugs by the i.v. route is indicated in cases of pulmonary embolism with hemodynamic instability, severe deep venous thrombosis such as the superior vena caval syndrome, and ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema. • These drugs are also given intra-arterially, especially for peripheral vascular disease.
- 35. Platelet aggregation inhibitors Image source: Jackson SP. The growing complexity of platelet aggregation. Blood. 2007;109(12):5087-95.
- 36. Platelet aggregation inhibitors Aspirin: • Platelet aggregation inhibitors decrease the formation of a platelet-rich clot or decrease the action of chemical signals that promote platelet aggregation. • The platelet aggregation inhibitors described below inhibit cyclooxygenase-1 (COX-1) or block GP IIb/IIIa or ADP receptors, thereby interfering with the signals that promote platelet aggregation. • Use: Aspirin is used in the prophylactic treatment of transient cerebral ischemia.
- 37. Platelet aggregation inhibitors Ticlopidine, clopidogrel, prasugrel, and ticagrelor: • These drugs inhibit the binding of ADP to its receptors on platelets and, thereby, inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other. Ticagrelor binds to the P2Y12 ADP receptor in a reversible manner. • Use: Clopidogrel is approved for prevention of atherosclerotic events in patients with a recent MI or stroke and for prophylaxis of thrombotic events in acute coronary syndromes.
- 38. Platelet aggregation inhibitors Ticlopidine, clopidogrel, prasugrel, and ticagrelor: • Use: Ticlopidine is indicated for the prevention of transient ischemic attacks and strokes in patients with a prior cerebral thrombotic event. It is generally reserved for patients who are intolerant to other therapies. • Prasugrel is approved to decrease thrombotic cardiovascular events in patients with acute coronary syndromes. • Ticagrelor is approved for the prevention of arterial thromboembolism in patients with unstable angina and acute MI.
- 39. Platelet aggregation inhibitors Abciximab, eptifibatide, and tirofiban: • A chimeric monoclonal antibody, abciximab, eptifibatide inhibits the glycoprotein IIb/IIIa receptor complex. • Use: These agents are given intravenously, along with heparin and aspirin, as an adjunct to percutaneous coronary intervention (PCI) for the prevention of cardiac ischemic complications.
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