blood drugs Adama science and technology University

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1. Drugs acting on the blood and blood forming organs

2. Introduction Hematopoiesis: is the process of production of RBCs, platelets, and WBCs from undifferentiated stem cells . over 200 billion new blood cells per day are produced in the normal person and even greater numbers of cells in people with conditions that cause loss or destruction of blood cells . main components of the haemopoietic system : blood , bone marrow, lymph nodes and thymus important accessory organs : spleen , liver and kidneys

3. Blood consists of formed elements ( RBC , WBC and platelets ) and plasma. The most imp’t site of formation of RBCs in adults is the bone marrow, whereas the spleen acts as their graveyard. The liver stores vitamin B 12 and is involved in the process of breakdown of the Hb liberated when RBC are destroyed.

4. Cotd … The kidney manufactures erythropoietin . The hematopoietic machinery resides primarily in the bone marrow in adults and requires a constant supply of three essential nutrients: iron, vitamin B 12 , and folic acid - as well as the presence of hematopoietic growth factors , proteins that regulate the proliferation and differentiation of hematopoietic cells. Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells.

5. Anemia a reduction in RBC count , hemoglobin content, both RBC count and Hb content or hematocrit ( % of whole blood that is comprised of red blood cells). During anemia oxygen (O 2 ) transport capacity is decreased. It may give rise to fatigue, pallor, tachycardia, dizziness, dyspnea etc . Types of anemia: 1 . Aplastic anemia Occurs as a result of decrease in pluripotent stem cells (bone marrow depression ) can be caused by cancer therapy, radiation therapy or bone marrow diseases .

6. 2 . Hemolytic anemia : hemolysis (break down) of RBCs due to antimalarial toxicities, infections etc 3. Nutritional anemia Microcytic hypochromic anaemia small RBC with insufficient Hb caused by iron deficiency

7. Cotd … Macrocytic hyperchromic anaemia or Megaloblastic anemia (large red cells, few in number) deficiencies of vitamin B12 or folic acid → insufficient DNA synthesis → inhibit cell multiplication Pernicious anemia : type of megaloblastic anemia caused by Vit B12 deficiency. Neurological abnormalities would occur b/c Vit B12 is vital for myelination of nerve fibers

8. AGENTS USED IN TREATMENT OF ANEMIAS dietary sources of iron : Liver, egg York and dry fruits. Route of use: orally(common); parenterally in special circumstances. are used to treat iron deficiency anaemia , which can be caused by: chronic blood loss (e.g. with menorrhagia , hook worm infestation, colon cancer) increased demand (e.g. in pregnancy and early infancy) inadequate dietary intake inadequate absorption (e.g. following gastrectomy ). Iron forms the nucleus of the iron- porphyrin heme ring, which together with globin chains forms hemoglobin . 1. Iron Preparations

9. Pharmacokinetics of Iron Absorption Iron is normally absorbed in the duodenum and proximal jejunum absorption increases in response to low iron stores or increased iron requirements. Iron in heme ( e.g. from meat) can be absorbed easily Non- heme iron ( inorganic iron) need reduction to Fe 2+ for absorption Divalent metal transporter, DMT1 , transports ferrous iron across the luminal membrane of the intestine Iron crosses the basolateral membrane by the transporter known as ferroportin1.

10. heme carrier protein 1 (HCP1). Apoferritin (AF), Transferrin ( Tf ), Transferrin receptors ( TfR ), & Ferritin (F) Fig Absorption, transport, and storage of iron.

11. Cotd … Transport bound to transferrin ( β-globulin that binds two molecules of ferrous iron ) Storage sites : intestinal mucosal cells, macrophages, liver, spleen, and bone, …as ferritin Apoferritin synthesis is regulated by the levels of free iron. Low Fe level: apoferritin synthesis is inhibited and the balance of iron binding shifts toward transferrin . High Fe levels: more apoferritin is produced to sequester more iron. Elimination no mechanism for excretion of iron Small amounts are lost in the feces trace amounts are excreted in bile, urine, and sweat Therefore, regulation of iron balance must be achieved by changing intestinal absorption & storage, in response to the body's needs.

12. iron therapy only ferrous salts should be used because ferrous iron is most efficiently absorbed, Ferrous sulfate, ferrous gluconate , and ferrous fumarate are all effective. ADR: GI disturbances: nausea, gastric discomfort, abdominal cramps, constipation, diarrhea, metallic taste and black stool. B. Parenteral iron therapy : should be reserved for patients who are unable to tolerate or absorb oral iron and for patients with extensive chronic blood loss who cannot be maintained with oral iron alone.

13. Cotd … This includes patients with various postgastrectomy conditions, malabsorption syndromes, and advanced chronic renal disease including hemodialysis and treatment with erythropoietin. Iron dextran (IM and IV), Iron sorbitol (IM), Iron sucrose (IV), and Iron sodium gluconate (IV) are parentral preparations. ADR of Parentral iron therapy local pain and tissue staining (brown discoloration) with IM route and hypersensitivity reactions (especially with Iron dextran ) manifested as flushing, bronchospasm , headache, nausea and vomitting . N.B. Iron preparations are contraindicated in case of hemolytic anemia, due to excessive accumulation of Fe.

14. Iron toxicity Acute iron toxicity , usually occurs after ingestion of large quantities of iron salts. severe GI irritation with vomiting, haemorrhage and diarrhea, followed by circulatory collapse. Chronic iron toxicity or iron overload by conditions other than ingestion of iron salts, for example chronic haemolytic anaemias or repeated blood transfusions. acute & chronic iron toxicity treated by use of iron chelators , such as desferrioxamine . Desferrioxamine is not absorbed from the gut but it is given po following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as IM and, if necessary, IV(slow infusion in severe poisoning). Desferrioxamine forms a complex with Fe 3+ , and, unlike unbound Fe, this is excreted in the urine.

15. 2. Vitamin B12 ( cyanocobalamine ) sources: Liver, meat, fish, and milk Enteral absorption requires the “intrinsic factor ”, which is synthesized in parietal cells of the stomach . b/se t he complex formed undergoes endocytosis in the ileum . A deficiency of either vitamin B12 or folic acid impairs DNA synthesis in any cell in w/c chromosomal replication and division are taking place. the hematopoietic system is especially sensitive to deficiencies of these vitamins b/c of the greatest rate of cell turnover

16. uses Vitamin B12 is clinically used during Megaloblastic or Pernicious anemia (due to lack of intrinsic factor or atrophic gastritis) increased demand (infants, pregnants etc) neuronal abnormalities . Preparations Parenterals: Hydroxycobalamine and Cyanocobalamine . Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation. Oral tablets: Methylcobalamine .

17. 3. Folic Acid Folic acid Dihydrofolate Tetrahydrofolate (THF) FR: Folate reductase DHFR: Dihydrofolate reductase THF is a co-enzyme involved in one carbon transfer during DNA synthesis. Deficiency of TH4, therefore causes default in DNA synthesis. Folic acid is clinically used during 1. Megaloblastic anemia 2. Infants and pregnants 3. Methotrexate toxicity Methtrexate is a drug used as an anticancer by inhibiting DHFR. Folic acid preparations include folic acid tablets, folic acid injection, and folinic acid injection (analogue of THF)

18. Stem cell 1 2 3 RBC WBC Platelets 1: Erythropoietin 2: Colony stimulating factor 3: Thrombopoietin HAEMOPOIETIC GROWTH FACTORS

19. 1. Erythropoietin Erythropoietin is produced in juxtatubular cells in the kidney in macrophages . Its action is to stimulate committed erythroid progenitor cells to proliferate and generate erythrocytes . With anemia, synthesis rapidly increases by 100 fold. This finely tuned feedback loop can be disrupted by kidney disease, marrow damage, or a deficiency in iron or an essential vitamin . Two forms of recombinant human erythropoietin, epoetin alfa and epoetin beta are available . Epoetin can be given IV, SC or IP. the response being greatest after SC and fastest after IV.

20. Clinical uses of epoietin Anaemia of chronic renal failure (Patients with anemia secondary to chronic kidney disease) are ideal candidates for epoetin alfa therapy . Anaemia during chemotherapy for cancer Prevention of the anaemia that occurs in premature infants . Anaemia of AIDS (which is exacerbated by zidovudine treatment ) Highly competitive athletes have used epoetin alfa to increase their hemoglobin levels ("blood doping") and improve performance . Unfortunately, this misuse of the drug has been implicated in the deaths of several athletes and is strongly discouraged.

21. Unwanted effects: Hypertension is common and can cause headache, disorientation and sometimes convulsions. Iron deficiency can be induced because more iron is required for the enhanced erythropoiesis . Blood viscosity increases as the haematocrit (i.e. the fraction of the blood that is occupied by red blood cells) rises, increasing the risk of thrombosis, especially during dialysis.

22. 2. Colony-Stimulating Factors G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor), are the two growth factors currently available for clinical use . Both GM-CSF and G-CSF can be given either SC or IV infusion . They are used to stimulate synthesis of leukocytes . 3. Thrombopoietin stimulates proliferation of the progenitor cells of the platelet lineage and strikingly increases platelet production.

23. DRUGS AFFECTING BLOOD COAGULATION Haemostasis and thrombosis Haemostasis :is the arrest of blood loss from damaged vessels and is essential to life. The main phenomena are: platelet adhesion and activation blood coagulation (fibrin formation). Thrombosis : is a pathological condition resulting from inappropriate activation of haemostatic mechanisms (in the absence of bleeding)

24. Mechanisms of blood coagulation In the absence of bleeding, the endothelial cell layer lining blood vessels has an anticoagulant phenotype circulating blood platelets and clotting factors do not normally adhere to it to an appreciable extent due to : the release of plasminogen activators , which activate the fibrinolytic pathway. ( 2) the activation of protein C , which degrades coagulation factors The endogenous anticoagulants protein C attenuate the blood clotting cascade by proteolysis of the two cofactors Va and VIIIa . (3) the production of heparin-like proteoglycans , which inhibit coagulation. (4) the release of prostacyclin (PGI 2 ) , a potent inhibitor of platelet aggregation.

25. Cotd … In the setting of vascular injury, the endothelial cell layer rapidly undergoes a series of changes resulting in a more procoagulant phenotype. Injury exposes reactive subendothelial matrix proteins such as collagen and von Willebrand factor , which results in: Platelet adherence and activation. Secretion and synthesis of vasoconstrictors. Secretion and synthesis of platelet-recruiting and activating molecules.

26. Products secreted from platelet granules include: Thromboxane A 2 (TXA 2 ) :is synthesized from arachadonic acid and is a platelet activator and potent vasoconstrictor. Adenosine diphosphate (ADP) , a powerful inducer of platelet aggregation. Serotonin (5-HT ) , which stimulates aggregation and vasoconstriction.

27. Fig: Factors activating and inhibiting platelets and their aggregation. Antiplatelet prostacyclin (PGI 2 ) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A 2 (TXA 2 ), and serotonin (5-HT).

28. Fig: Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting factors. GPIa / IIa and GPIb are platelet membrane proteins that bind to collagen and von Willebrand factor ( vWF ), causing platelets to adhere to the subendothelium of a damaged blood vessel. GP IIb / IIIa , which binds fibrinogen and other macromolecules.

29. Cotd … Activation of platelets results in a conformational change in the ( IIb / IIIa ) receptor , enabling it to bind fibrinogen, which cross-links adjacent platelets, resulting in aggregation and formation of a platelet plug. Simultaneously , the coagulation system cascade is activated, resulting in thrombin generation and a fibrin clot, which stabilizes the platelet plug. Coagulation refers to the conversion of fluid blood to solid gel or clot (due to conversion of fibrinogen to fibrin by thrombin ) There are two pathways of blood coagulation:

30. T wo pathways of blood coagulation: Both pathways culminate in activation of thrombin which converts fibrinogen to fibrin. 1. Intrinsic pathway All the components of coagulation are present in the blood. The process is slower.

31. Cotd … 2. Extrinsic pathway Some components which are essential for coagulation come from outside the blood. It is activated upon tissue injury and the process is rapid compared with intrinsic pathway. The components of blood coagulation called factors are present in blood as inactive precursors (zymogens) of proteolytic enzymes and cofactors. They are activated by proteolysis, the active forms being designated by the suffix 'a'.   Each protease factor then activates the next clotting factor, culminating in the formation of thrombin.

32. Fibrinolysis refers to the process of fibrin digestion by the fibrin-specific protease, plasmin . The precursor form of plasmin circulates in an inactive form as plasminogen . In response to injury, endothelial cells synthesize and release tissue plasminogen activator (t-PA) , which converts plasminogen to plasmin Plasmin remodels the thrombus and limits its extension by proteolytic digestion of fibrin . Urokinase and streptokinase activate the fibrinolytic system and conversely Aminocaproic acid is a clinically useful inhibitor of fibrinolysis .

33. Drugs Anticoagulants Parentral eg.heparin Oral eg.warfarin Antiplatelates Fibrynolytics ( thrombolytics )

34. ANTICOAGULANTS A . Parentral Anticagulants i . Indirect Thrombin Inhibitors are so-named because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin . Heparin Heparin is a glycosaminoglycan found in the secretory granules of mast cells . Its biologic activity is dependent upon the endogenous anticoagulant antithrombin . Antithrombin inhibits clotting factor proteases, especially thrombin, IXa , and Xa , by forming stable complexes with them.

35. Cotd … In the absence of heparin, these reactions are slow; in the presence of heparin, they are accelerated 1000-fold. The active heparin molecules bind tightly to antithrombin and cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its reactive site for more rapid interaction with the proteases (the activated clotting factors). Heparin functions as a cofactor for the antithrombin -protease reaction without being consumed. Once the antithrombin -protease complex is formed, heparin is released intact for renewed binding to more antithrombin .

36. Cotd … Two types of heparin are used clinically. The first & older ( unfractionated ) heparin, is an animal extract. The second and newer type, called low-molecular-weight heparin (LMWH), is derived from unfractionated heparin. Heparin is not absorbed after oral administration and therefore must be given parenterally (IV& SC ). LMWH is available for subcutaneous administration as enoxaparin , dalteparin , ardeparin , and tinzaparin . I.M adminstration must be avoided b/c of potential hematoma formation.

37. uses b/se of its rapid onset of action it is used whenever immediate initiation of anticoagulant is needed: Pulmonary embolism and deep vein thrombosis Prophylactically to prevent post operative embolism . Limitations: Heparin stops expansion of thrombi and prevents formation of new thrombi . it does not dissolve existing thrombi .

38. Toxicity Bleeding ( Haemorrhage ) Heparin-Induced Thrombocytopenia (The incidence of thrombocytopenia is lower with LMWH ). Patients may develop heparin induced antiplatelet antibodies Allopecia &osteoporosis :after prolonged use. Hypersensitivity rxns ( chills , fever or urticaria ) Heparin does not cross the placenta probably it is the preferred anticoagulant drug for pregnant women but it is not risk free. so use cautiously during pregnancy especially during the last trimester. C.I. SURGERY of brain, eye, hypersensitivity, bleeding disorder, infective endocarditis.

39. Cotd … Reversal of Heparin Action Excessive anticoagulant action of heparin is treated by discontinuance of the drug. If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity. Excess protamine must be avoided; it also has an anticoagulant effect.

40. Cotd … ii. Direct Thrombin Inhibitors (DTI) The DTIs exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin's downstream effects. Hirudin and bivalirudin are bivalent DTIs in that they bind at both the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site. Ximelagatran is an oral prodrug that is metabolized to the DTI melagatran

41. B. Oral Anticoagulants Warfarin & the coumarin anticoagulants The oral anticoagulants are antagonists of vitamin K . Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are synthesized mainly in the liver. are biologically inactive unless 9 to 13 of the amino-terminal glutamate residues are carboxylated to form the Ca 2+ -binding g- carboxyglutamate ( Gla ) residues. This rxn of the descarboxy precursor protein requires CO 2 , O 2 , and reduced vit K , and is catalyzed by g- glutamyl carboxylase in the rough endoplasmic reticulum.

42. Cotd … Carboxylation is directly coupled to the oxidation of vitamin K to its corresponding epoxide . Reduced vitamin K must be regenerated from the epoxide for sustained carboxylation and synthesis of biologically competent proteins. The enzyme that catalyzes this, vitamin K epoxide reductase , is inhibited by therapeutic doses of warfarin.

43. . Vitamin K cycle ¾ metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K is activated by reduction to the hydroquinone form ( KH 2 )Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase . The reactivation of vitamin K epoxide is the warfarin -sensitive step

44. Cotd … Compared with heparin warfarin has delayed onset of action (8-12 hours )that relates to preformed vitamin k dependent clotting factors. It is used when long term anticoagulation is needed such as prevention of stroke. Drugs potentiate the action of warfarin alcohol , cimetidine , dislfirum , phenylbutzone

45. Drug interaction Acidic molecule : oral absorption decrease by drugs including bile acid sequestrants . Extensive (but weak) plasma protein binding: - displacement by other drugs may increase free fraction anticoagulant effects. Slow hepatic metabolism via cyp 450 . inducers or inhibitors of liver enzymes can modify anticoagulant effects. Actions increased by ASA, cimetidine , metronidazole , sulfonamides Actions decreased by barbiturates, carbamazepine , cholestyramine , rifampin, thiazides , vitamin K.

46. Toxicities: Bleeding Birth Defects: administration of warfarin during pregnancy causes birth defects and abortion Skin necrosis : warfarin-induced skin necrosis is a rare complication characterized by the appearance of skin lesions 3-10 days after treatment is initiated . Reversal of Warfarin Action Excessive anticoagulant effect and bleeding from warfarin can be reversed by stopping the drug and administering oral or parenteral vitamin K 1 ( phytonadione ).

47. CLINICAL INDICATIONS FOR ANTICOAGULANT THERAPY prophylactic tt of venous and arterial thromboembolic disorders . Anticoagulant drugs are ineffective against already formed thrombi, although they may prevent their further propagation. major with heparin and warfarin. A. Deep Vein Thrombosis Venous stasis resulting from prolonged bed rest, cardiac failure, or pelvic, abdominal, or hip surgery may precipitate thrombus formation in the deep veins of the leg or calf and may lead to fatal pulmonary embolism . Heparin may also be used prophylactically following surgery.

48. Cotd … B. Arterial Embolism Arterial embolism is treated more successfully with heparin than with the oral anticoagulants. C. Unstable Angina and Myocardial Infarction heparin along with antiplatelet therapy are thought to provide additive protection of the patient against myocardial infarction. Thrombolytic drugs are more effective than anticoagulants in treating coronary thromboembolism and in establishing reperfusion of occluded arteries after an infarction .

49. Cotd … D. Disseminated Intravascular Coagulation/ DIC is characterized by: : widespread systemic activation of the coagulation system consumption of coagulation factors occlusion of small vessels by a coat of fibrin, and a hypocoagulation state with bleeding. In conjunction with management of the underlying factor or factors leading to the disorder and coagulation factor and platelet replacement, bleeding may be managed with IV heparin and antithrombin III.

50. Basic Pharmacology of the Fibrinolytic Drugs Drugs: Streptokinase, urokinase , tissue plasminogen activator . Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin from plasminogen . Streptokinase : is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen . This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin . Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin . Plasmin itself cannot be used because naturally occurring inhibitors in plasma prevent its effects .

51. Cotd … However, the absence of inhibitors for urokinase and the streptokinase- proactivator complex permit their use clinically. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins , which allows it to lyse the thrombus from within. Anistreplase : consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme's active site. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptokinase- proactivator complex.

52. Cotd … Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs) . These activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Alteplase : Human t-PA is manufactured by means of recombinant DNA technology. Reteplase is another recombinant human t-PA from which several amino acid sequences have been deleted. Tenecteplase is a mutant form of t-PA that has a longer half-life, and it can be given as an IV bolus.

53. Inhibition of Fibrinolysis Aminocaproic Acid a lysine analog that competes for lysine binding sites on plasminogen and plasmin , thus blocking the interaction of plasmin with fibrin. a potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis . uses : to reduce bleeding after prostatic surgery or after tooth extractions in hemophiliacs. The main problem with its use is that thrombi that form during treatment with the drug are not lysed . in patients with hematuria , ureteral obstruction by clots may lead to renal failure after treatment with aminocaproic acid.

54. ANTIPLATELET DRUGS Platelet function is regulated by 3 categories of substances. 1. agents generated outside the platelet that interact with platelet membrane receptors, eg, catecholamines , collagen, thrombin, & prostacyclin . 2. agents generated within the platelet that interact with membrane receptors, eg, ADP, prostaglandin D 2 , prostaglandin E 2 , & serotonin. 3. agents generated within the platelet that act within the platelet, eg, prostaglandin, endoperoxides and thromboxane A 2 , the cyclic nucleotides cAMP and cGMP , and calcium ion.

55. several targets for platelet inhibitory drugs have been identified : inhibition of prostaglandin synthesis ( aspirin ), inhibition of ADP-induced platelet aggregation ( clopidogrel , ticlopidine ), and blockade of glycoprotein IIb / IIIa receptors on platelets ( abciximab , tirofiban , and eptifibatide ). Dipyridamole and cilostazol are additional antiplatelet drugs

56. Aspirin The prostaglandin thromboxane A 2 is an arachidonate product that causes platelets to change shape, release their granules, and aggregate. Drugs that antagonize this pathway prolong the bleeding time. Aspirin is the prototype of this class of drugs . Aspirin inhibits the synthesis of thromboxane A 2 by irreversible acetylation of the enzyme cyclooxygenase . Other salicylates and NSAIDS drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase ; that is, their action is reversible .

57. Clopidogrel and Ticlopidine reduce platelet aggregation by irreversibly blocking the ADP receptor on platelets. Unlike aspirin, these drugs have no effect on prostaglandin metabolism. Dipyridamole Dipyridamole interferes with platelet function by increasing the cellular concentration of adenosine cAMP . This effect is mediated by inhibition of cyclic nucleotide phosphodiesterase and/or by blockade of uptake of adenosine , which acts at adenosine A 2 receptors to stimulate platelet adenylyl cyclase .

58. Cotd … Glycoprotein IIb / IIIa Inhibitors This dimeric glycoprotein is a receptor for fibrinogen and von Willebrand factor, which anchor platelets to foreign surfaces and to each other, thereby mediating aggregation. The integrin heterodimer /receptor is activated by platelet agonists such as thrombin, collagen, or thromboxane A 2 to develop binding sites for its ligands , which do not bind to resting platelets. Inhibition of binding to this receptor blocks platelet aggregation induced by any agonist.

59. Cotd … Three agents are approved for use at present. Abciximab is the fragment of a humanized monoclonal antibody directed against the IIb / IIIa receptor. Eptifibatide is an analog of the sequence at the extreme carboxyl terminal of the delta chain of fibrinogen, which mediates the binding of fibrinogen to the receptor. Tirofiban is a smaller molecule with similar properties. Eptifibatide and tirofiban inhibit ligand binding to the IIb / IIIa receptor by their occupancy of the receptor.

60. DRUGS USED IN BLEEDING DISORDERS Vitamin K confers biologic activity upon prothrombin and factors VII, IX, and X by participating in their postribosomal modification. Two natural forms exist: vitamins K 1 and K 2 . Vitamin K 1 ( phytonadione ) is found in food. Vitamin K 2 ( menaquinone ) is found in human tissues and is synthesized by intestinal bacteria . Vitamins K 1 and K 2 require bile salts for absorption from the intestinal tract. Vitamin K 1 is available clinically in oral and parenteral forms.

61. Cotd … used treating depression of prothrombin activity by excess warfarin or vitamin K deficiency Onset of effect is delayed for 6 hrs but the effect is complete by 24 hrs . Iv administration of vitamin K 1 should be slow rapid infusion can produce dyspnea, chest and back pain, and even death. Vitamin K repletion is best achieved with iv or oral administration, because its bioavailability after SC administration is erratic. Vitamin K 1 is currently administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency, which is especially common in premature infants.