Coagulant and anticoagulants

Coagulant and anticoagulants

1. Coagulants and anti-coagulants Dr. Rupendra K. Bharti MBBS MD

2. Coagulants Coagulation : The process of changing of blood from a fluid state to a solid state is known as coagulation. Normally, this is a natural process in the body to prevent blood loss by plugging the injured site. The vascular system must maintain an intricate balance between the tendency to clot or form a solid state, and the need to “ unclot ,” or reverse coagulation, to keep the vessels open and the blood flowing.

3. After an injury to the body tissues, there is a natural mechanism, which helps to stop the blood loss by involvement of a complex haemostatic mechanism. This mechanism is as follows:

4. BLOOD CLOTTING FACTORS Component or Factor Common Synonym I Fibrinogen II Prothrombin III Tissue thromboplastin IV Calcium V Proaccelerin VI Accerin, supposed to be active form of factor V VII Proconvertin VIII Antihemophilic factor (AHF) IX Christmas factor, plasma thromboplastin component (PTC) X Stuart-Prower factor XI Plasma thromboplastin antecedent (PTA) XII Hageman factor XIII Fibrin-stabilizing factor XIV Prekallekrein XV kallekrein XVI Platelet factor

5. COAGULANTS Coagulants are the drugs that promote coagulation and control bleeding. They are also called hemostatic agents. These drugs are of two types Systemic coagulants. Local coagulants (styptics).

6. COAGULANTS Systemic coagulants Local coagulants (styptics) Vitamin-K Ethamsylate Desmopressin Fibrinogen Anti- hemophillic factor Tranexamic acid Epsilon aminocaproic acid Adrenaline Fibrin glue Gelatin Thrombin Oxidizes cellulose Hemocoagulase Tranexamic acid

7. Systemic coagulants Vitamin-K Vitamin K (Coagulation vitamin) is essential for the coagulation process. It is not directly involved in the clotting process but required for the synthesis of four clotting factors in the liver: Factor II,VII,IX and X.

8. It occurs naturally in two forms: Phylloquinone (K 1 ) from plant source and Menaquinone (K 2 ) which is synthesized by colonic bacteria ( E.coli ) in the colon. K 3 is the synthetic form and is available as Fat-soluble forms ( Menadione , Acetomenaphthone ) and water-soluble forms ( Menadione sod. Bisulfate and Menadione sod. Diphosphate ).

9. Dietary sources: Green leafy vegetables such as cabbage, spinach and liver, cheese, cereals, nuts, and egg yolk etc. Wheat germ oil is the richest source. Physiological functions: Vit -K is essential for formation of clotting factor-II, VII, IX, X, protein-C & S.

10. Deficiency Symptoms Vit -K is only temporarily concentrated in liver and this store can be exhausted within one week. The deficiency of vit -K occurs due to liver disease, obstructive jaundice, malabsorption, long-term antimicrobial therapy, which alters intestinal flora. The most important manifestation is bleeding tendency due to lowering of the levels of prothrombin and other clotting factors in blood.

11. Haematuria is usually first to occur; other common sites of bleeding are gastrointestinal tract, nose and under the skin where it presents in the form of haemorrhagic spots. Recommended dietary allowance (RDA) Normal adult requirement is 50–100 μg/day. As it can be synthesized in the colon, even 3–10 μg/day may be sufficient.

12. Vit -K use: For prevention of haemorrhagic disease of the newborn : All newborns especially premature infants have low levels of prothrombin and other clotting factors. Vit - K: 1 mg IM soon after birth has been recommended routinely. Alternatively, 5–10 mg IM to the mother 4–12 hours before delivery can be given.

13. Patients on prolonged antimicrobial therapy. As an antidote in overdose of oral anticoagulants. In patients suffering from liver disease (cirrhosis, viral hepatitis).

14. Patients with obstructive jaundice or malabsorption syndromes (sprue, regional ileitis, steatorrhoea , etc ). The therapy given is Vit -K 10 mg IM/day, or orally along with bile salts for better absorption. Menadione (K3) should not be used in patients with G-6-PD deficiency. In the newborn menadione or its salts can precipitate kernicterus.

15. Ethamsylate It increases capillary wall stability by antihyaluronidase action. It decreases PGI 2 synthesis, and corrects abnormalities of platelet adhesion and promotes platelet aggregation. It is used in the prevention and treatment of capillary bleeding.

16. Common indications menorrhagia, PPH, after abortion, epistaxis, after tooth extraction and hematuria. Side effects nausea, rash, headache, and acute hypotension if given by fast IV injection. It is given in a dose of 250–500 mg TDS orally or IV.

17. Desmopressin It is an analogue to vasopressin & increases the plasma concentration of factor-VIII, von Willebrand factor and directly activates platelets. It is a selective V 2 agonist, 12 times more potent than AVP. Desmopressin is useful for the treatment of hemophilia-A and von- willebrand disease.

18. Fibrinogen It is obtained from human plasma and is a promising haemostatic agent. It is used to control bleeding in Haemophilia Hypofibrinogenemia Antihaemophilic globulin deficiency. It is available as IV infusion 0.5 per bottle.

19. Anti- hemophillic factor It contains coagulation factor VIII and is concentrated human (Antihaemophilic globulin) AHG obtained from pooled human plasma. It is also synthesized by recombinant DNA technology. It is therapeutically used in haemophilia and AHG deficiency. It is given in a dose of 10–20 IU/kg by IV infusion, repeated 6–12 hourly.

20. Tranexamic acid & Epsilon aminocaproic acid They are antifibronolytic agent. They inhibit the activation of plasminogen and dissolution of clot. They are available as oral and IV form. Tranexamic acid is given in a dose of 500-1000mg TDS, orally & IV. Side effects nausea, vomiting, thromboembolic states, allergic reactions, disturbed colour vision, etc.

21. They are indicated in: To counteract the effect of fibrinolytic drugs. For controlling the bleeding in tonsillectomy, prostatic surgery, tooth extraction in haemophiliacs . Menorrhagia, menometrorrhagia & DUB. Recurrent epistaxis.

22. LOCAL COAGULANTS (STYPTICS) Local coagulants are also known as styptics or haemostatics ( haemo -blood and statics- to stop ). These substances are used locally to stop the bleeding from the oozing surfaces such as abrasions, bleeding tooth socket after tooth extraction etc.

23. Normal haemostasis involves three steps: Vasoconstriction or contraction of injured vessel wall for a few minutes. Adhesion and aggregation of platelets to form a plug. Formation of a blood clot.

24. This is followed by dissolution of the clot by the process of fibrinolysis and maintenance of normal circulation. The most preferred and effective method of stopping the external bleeding is manual pressure, cotton-gauze pressure pack or by suturing.

25. Role of adrenaline Control of bleeding may be aided by applying adrenaline locally as it causes local vasoconstriction. A cotton pad soaked with 0.1% adrenaline is used to control capillary bleeding such as epistaxis and after tooth extraction etc. Adrenaline is available in combination with lignocaine to provide better surgical field, but should be avoided in patients suffering from hypertension or cardiovascular disease.

26. Thrombin Obtained from bovine plasma is used topically to control capillary bleeding. It may cause hypersensitivity reactions also.

27. Gelatin foam, oxidized cellulose Theses are absorbable materials, available as film or sponge and are used in surgical procedures to control the bleeding of capillaries or arterioles. After applied dry, they swell up and form meshwork, which helps in the clotting mechanism and stops bleeding. These materials are absorbed within 4 weeks. The main adverse effects seen with these are tissue necrosis, vascular stenosis & nerve damage.

28. Astringents Such as tannic acid or metallic salts (alum) are occasionally applied for bleeding gums, cuts during shaving, bleeding piles, etc.

29. ANTI-COAGULANTS

30. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit . K dependent Factors Affected by Oral Anticoagulants Recall !

31. Why anticoagulants ? To reduce the coagulability of blood Blood clots – Thrombus Arterial Thrombosis : Adherence of platelets to arterial walls – “ White ” in color - Often associated with MI, stroke and ischemia Venous Thrombosis : Develops in areas of stagnated blood flow (deep vein thrombosis), “ Red ” in color- Associated with Congestive Heart Failure, Cancer, Surgery Thrombus dislodge from arteries and veins and become an embolus Venous emboli can block arterioles in the lung and pulmonary circulation Thromboembolism

32. Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fIXa indicates factor IXa . *Indirectly inhibit coagulation by interacting with antithrombin. †AVE5026 is an ultralow-molecular-weight heparin that primarily inhibits fXa and has minimal activity against thrombin.

33. Anticoagulant drugs to treat thromboembolism Drug Class Prototype Action Effect Anticoagulant Parenteral Heparin Inactivation of clotting Factors Prevent venous Thrombosis Anticoagulant Oral Warfarin Decrease synthesis of Clotting factors Prevent venous Thrombosis Antiplatelet drugs Aspirin Decrease platelet aggregation Prevent arterial Thrombosis Thrombolytic Drugs Streptokinase Fibinolysis Breakdown of thrombi

34. Available Anticoagulants Parenteral anticoagulants: Indirect thrombin inhibitors : Heparin, Low molecular weight heparin, Fondaparinux, Danaparoid Direct thrombin inhibitors: Lepirudin , Bivalirudin

35. CLASSIFICATION OF ORAL ANTICOAGULANTS Coumarin Derivatives Warfarin, Acenocoumarol ( Acitrom ) Indandione Derivatives Phenindione, Anisindione Newer anticoagulants Direct thrombin inhibitor Dabigatran etexilate (Pradaxa) Direct factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban Edoxaban (DU-176b) Betrixaban

36. WARFARIN 1948: synthesis of warfarin by student Harold Campbell. Most widely used anticoagulant in the world Coumarin derivative, water soluble vit K antagonist. Low cost and highly effective, if given in right way . The name warfarin is derived from WARF ( Wisconsin Alumni Research Foundation ) and – arin from coumarin .

37. Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z) Epoxide Reductase  -Carboxylase ( GGCX ) MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle Warfarin Inactivation CYP2C9 Pharmacokinetic Post translational modification

38. PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Peak anticoagulant effect may be delayed by 72 to 96 hours COAGULATION FACTORS HALF-LIFE (h) II 60 VII 4-6 IX 24 X 48-72 Protein – C 8 Protein- S 30

39. VKORC1: New Target Protein for Warfarin Epoxide Reductase  -Carboxylase ( GGCX ) Clotting Factors (FII, FVII, FIX, FX, Protein C/S/Z) Rost et al. & Li, et al., Nature (2004) ( VKORC1 )

40. Effect of VKORC1 Genotype on Anticoagulation Three polymorphic variants of VKORC1 Non-A, Non-A : wild type – Requiring more warfarin dose Non-A/A : Heterozygous – Requiring 25% dose reduction A/A : Homozygous - Requiring 50% dose reduction Means wild type having more resistance to warfarin while homozygous is more sensitive. Asians have the highest prevalence of VKORC1 variants, followed by whites and blacks Polymorphisms in VKORC1 likely explain 30% of the variability in warfarin dose requirements. VKORC1 variants are more prevalent than variants of CYP2C9 Genotype Freq in Asians (%) Dose reduction Non-A,Non-A : wild type 7 -- Non-A/A : Heterozygous 30 26 A/A : Homozygous 63 50

41. DOSING Usual dose is 5 mg/day (1-20 mg) Lower doses require in Elderly Pt on increased risk of bleeding eg . Pt on aspirin Heart failure Liver disease Renal impairment Malnutrition Thyrotoxicosis Asian patients: Explained by genetic variation in hepatic enzymes ( CYP3C9 & VKORC1 Polymorphism) High intake dietary Vit -K (green vegetables e.g. broccoli) reduces the efficacy of Warfarin. Practically best time to give warfarin is ~ 6 PM.

42. Why to add concomitant parenteral anticoagulation ? Because of delayed onset of action , concomitant parenteral anticoagulant should be given in pts with established thrombosis or high risk for thrombosis until INR has been in therapeutic range for at least 2 days. Warfarin monotherapy decreases the levels of two endogenous anticoagulants, proteins C and S , thus increasing thrombogenic potential. Overlapping warfarin for at least 5 days with an immediately effective parenteral anticoagulant counteracts the procoagulant effect of unopposed warfarin. Usually a minimum 5 days of concomitant parenteral anticoagulation is recommended.

43. Commencement of oral anticoagulant therapy If the baseline INR≤1.3 the patient will receive 5mg of warfarin once daily on days 1 and 2. The INR is checked on day 3 and 4 and the warfarin dose is adjusted according to the schedule.

44. Monitoring B/z of narrow therapeutic window of warfarin Standard procedure is to check the PT-INR as follows: INR daily until it is in therapeutic range 3 times weekly for 2 weeks Once stable & warfarin dose is known INR every 3-4 weeks or more frequently if introduction of any new medications

45. What is PT-INR Warfarin therapy is most often monitored using the prothrombin time, a test sensitive to reductions in the levels of prothrombin, factor VII, and factor X. This test involved addition of thromboplastin (a reagent containing TF, phospholipid & Ca ++ ) to citrated plasma and determining the time to clot formation. Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors INR represent the PT according to international reference thromboplastin, as approved by WHO.

46. INTERNATIONAL NORMALISED RATIO (INR) INR = [ PT pt ] ISI [ PT Ref ] PT pt – prothrombin time of patient PT Ref – prothrombin time of normal pooled sample ISI – International Sensitivity Index Highly sensitive thromboplastins have an ISI of 1.0 Most current thromboplastins have ISI values that range from 1.0 to 1.4

47. Common drugs influencing INR values : INR  / PT decreases INR  /PT increases amoxicillin Quinolones cephalosporin's macrolid antibioti cs paracetamol salicylat e amiodaron allopurinol omeprazole heparin NSAID & COX2 inh . tricycli c antidepressan t s Rifampicin A ntihistamines barbiturates carbamazepine digoxin D iuretic s Caffeine's pentoxiphyllin Vitamin K

48. Indications Atrial fibrillation Prosthetic heart valve Venous thromboembolism Primary pulmonary hypertension Rarely after Acute MI (If associated with high risk of thromboembolism e.g. AF, mobile or pedunculated mural thrombus or prior venous thromboembolism)

49. Side effects of Warfarin Bleeding Skin necrosis Purple toe syndrome Teratogenicity Osteoporosis Others: Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.

50. Bleeding Most common complication In form of Mild: epistaxis , hematuria Severe: Retroperotoneal or gastrointestinal bleeding Life-threatening : Intracranial bleed Rate of major bleeding (defined as any visit to hospital for hemorrhage ) is 1- 3% per person-year Half of the complications occurs because INR exceeds therapeutic range Can be minimized by keeping INR in therapeutic range

51. Interventions according to INR/symptoms Asymptomatic pts with raised INR INR INTERVENTION 3.5 - 4.5 Withhold warfarin until in therapeutic range Decrease the dose of warfarin > 4.5 Low dose sublingual/oral Vit K (not routinely) 4.5 – 9.0 Vit k 1 mg > 9.0 Vit k 2-3 mg Higher doses of vitamin K (up to 10 mg) can be administered if more rapid reversal of the INR is required Although vitamin K administration results in a more rapid reduction in the INR, there is no evidence that it reduces the risk of hemorrhage

52. Symptomatic pts with raised INR SYMPTOMS INTERVENTION Mild bleeding Withhold warfarin Severe bleeding Vit K 10 mg slow i /v infusion ± FFP (15 ml/kg) Life threatening bleeding or pt can’t tolerate volume overload Prothrombin complex concentrate (II,IX & X) Prosthetic valves pts Vit K should be strictly avoided , unless there is life threatening intracranial bleed ( Valve thrombosis ) Subcutaneous Vit K gives variable results and should be avoided

53. SKIN NECROSIS Rare but very serious complication of warfarin (prevalence of 0.01-0.1 %) Occurs 2 to 5 days after initiation of warfarin Usually occurs after high dose of warfarin Typical presentation is : Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. Typically, the center of the lesion becomes progressively necrotic. Examination of skin biopsies taken from the borders of these lesions reveals thrombi in the microvasculature

54. Warfarin (Coumadin)–induced skin necrosis on the lower abdomen & breast

55. Mechanism : Not well understood but a precipitous fall in plasma protein C or S levels (natural anticoagulants) before warfarin exert anticoagulant effect, results in procoagulant state triggering thrombosis of adipose tissue microvasculatures . Treatment : Discontinuation of warfarin and reversal with vitamin K, if needed An alternative anticoagulant, such as heparin or LMWH, should be given to patients with thrombosis Protein C concentrates or recombinant activated protein C may accelerate healing of the skin lesions in protein C deficient patients Frozen plasma may be useful for those with protein S deficiency Occasionally, skin grafting is necessary when there is extensive skin loss. Prevention : Start with low dose warfarin in pts with known Protein C or S deficiency Overlapping with a parenteral anticoagulant when initiating warfarin therapy

56. Purple toes syndrome Extremely uncommon cutaneous complication Characterized by the sudden appearance of bilateral, painful, purple nonhemorrhagic lesions on the toes and sides of the feet that blanch with pressure Usually develops 3-8 weeks after the start of warfarin therapy Mechanism: release of atheromatous plaque emboli Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary. Pharmacotherapy. 2003 May;23(5):674-7

57. Teratogenicity Occurs in 3.5 – 6 % Depends on time of gestation and dose of warfarin given Usually in first trimester of pregnancy It causes characteristic embryopathy consist of : Nasal hypoplasia and Chondrodysplasia punctata (epiphyseal and vertebral bone stippling) Cleft lip and (or) palate Choanal stenosis / atresia Central nervous system abnormalities Coarctation of aorta (Rare malformations described following first trimester exposure to warfarin ) Occurs especially if warfarin dose is > 5 mg/day

58. Lateral view X-ray showing calcifications and irregular ossification of lumbar and sacral vertebrae, consistent with warfarin embryopathy

59. OSTEOPOROSIS Long- term use of warfarin (> 1 yr) More common in males 60% increased risk of osteoporosis-related fracture in men Mechanism: combination of reduced intake of vitamin K, which is necessary for bone health, and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional   Beta-adrenergic antagonists may protect against osteoporotic fractures

60. Warfarin in special conditions…

61. Pregnancy It causes… Fetal abnormalities ( Teratogenic )- in first trimister Chances of intracranial bleeding in baby while passage through birth canal – in third trimister Because of this, warfarin is contraindicated in 1 st (first 12 weeks) & 3 rd trimsters (last 2 weeks) Warfarin does not passes in breast milk & is safe for nursing mothers.

62. ACENOCOUMAROL (acitrom) Same as warfarin with following differences: Shorter half life 10-16 hrs More rapid onset of action Shorter duration of action (2 days) Causes GI disturbances, oral ulcerations and dermatitis 4 mg on day one, 4-8 mg on the day 2 nd then maintenance dose 1-8 mg according to response by PT test

63. THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROL 72% 67% 64% 66% 68% 70% 72% % Responders Warfarin Acenocoumarol Thrombosis And Haemostasis 1994; 71(2): 188-191

64. Newer Oral Anticoagulants

65. What’s wrong with warfarin? Narrow therapeutic range Slow onset of action Slow offset of action (long duration of action, long elimination half life) Multiple drug and dietary interactions Monitoring required to maintain in therapeutic range Difficult to manage for invasive procedures Under-use of therapy due to fear of adverse events and complexity of management

66. Newer oral anticoagulants

67. Classification Direct thrombin ( IIa ) inhibitor Dabigatran (Pradaxa) Factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban Edoxaban

68. Dabigatran etexilate (Pradaxa) Oral Direct thrombin (factor IIa) inhibitor It is a prodrug & does not exhibit any pharmacological activity Initially recommended by FDA on October 19, 2010 for Non-valvular AF

69. Mechanism of Action Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

70. Pharmacokinetics Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran , the active moiety. The t1/2 is 15 to 17 hrs. 90% is excreted unchanged in urine. The absolute bioavailability of dabigatran following oral administration is approximately 3 to 7% .

71. Dabigatran is also a substrate for P- glycoprotein ( a trans-membrane pump expelling drugs out of cell). So P- glycoprotein inhibitors (e.g. amiodarone , verapamil & clarithromycin) can increase whereas inducers (e.g. rifampicin, st. john’s wart) may reduce dabigatran level in plasma.

72. INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Non- valvular Atrial Fibrillation Treatment of Deep Venous Thrombosis and Pulmonary Embolism Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

73. Recommended dose

74. SOME SPECIAL POINTS TO MENTION….

75. If a dose of dabigatran is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of dabigatran should not be doubled to make up for a missed dose .

76. Converting pts from or to Warfarin From warfarin to dabigatran Stop warfarin & start dabigatran once INR fall below 2 From dabigatran to warfarin Adjust the starting time of warfarin based on creatinine clearance CrCL (ml/min) Days before stopping dabigatran > 50 3 days 50 - 30 2 days 30 - 15 1 day < 15 or dialysis not recommended

77. Converting pts from or to parenteral anticoagulants From parenteral anticoagulants to dabigatran Intermittent parenteral anticoagulant Start dabigatran 0-2 hrs before next dose Continuous parenteral anticoagulant (e.g. UFH) Start dabigatran at the time of stopping parenteral anticoagulant From dabigatran to parenteral anticoagulants Wait for 12 hrs ( CrCl > 30 ml/min) or 24 hrs ( CrCl < 30 ml/min) after last dose of dabigatran before starting parenteral anticoagulant

78. Dabigatran in pts planned for elective surgery If possible, stop dabigatran 1-2 days before (CrCl> 50 ml/min) or 3-5 days before (CrCl< 50 ml/min) invasive or surgical procedures. Longer periods may be considered if pt undergoing Major surgery Spinal puncture Placement of spinal or epidural catheter or port

79. BLEEDING ON DABIGATRAN TREATMENT Pcc : prothrombin complex concn .

80. Monitoring anticoagulant effect of dabigatran Need not to assess regularly (ex. In the setting of emergency surgery ) In emergency most accessible tests are TCT aPTT If the TCT is normal, it is safe to assume that the level of dabigatran is very low and that the patient’s risk of bleeding development is similar to that of other patients undergoing the procedure

81. Antidote Specific agent not available Though limited data, following agents may be used Activated prothrombin complex concentrate Recombinant factor VIIa Concentrate of coagulant factors II, IX and X Hemodialysis ( because only 35% of dabigatran is bound to plasma proteins ) Protamine sulfate and Vit -K are not helpful

82. Adverse effects Bleeding – increases with age GI events Dyspepsia (12%) Abdominal pain Gastritis including GERD, esophagitis, erosive gastritis, gastric hemorrhage and GI ulcers Hypersensitivity reaction (<0.1%) An unexplained increase in acute myocardial infarction in the dabigatran group versus warfarin (~0.2% increased risk for a AMI re-ly trial)

83. Factor Xa inhibitors Rivaroxaban Apixaban

84. Rivaroxaban (Xarelto)

85. Rivaroxaban (Xarelto) Direct factor Xa inhibitor Half life: 7 - 9 hours Peak plasma concentration 0.5 – 3 hours after administration Have excellent bio-availability of 80-100% 2/3 rd of rivaroxaban is metabolized by CYP3A4 system in liver 1/3 rd of rivaroxaban excreted unchanged in urine while ½ of the metabolized excreted renally while other half via fecal route.

86. To reduce the risk of DVTs and PEs in patients undergoing knee or hip replacement surgery (Jul  1, 2011) For prevention of thromboembolism and stroke in patients with nonvalvular atrial fibrillation (Nov  4, 2011 ) Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as to reduce the risk of recurrent DVT and PE (Nov  2, 2012) Rivaroxaban : FDA Approval (First approved in July 1st, 2011)

87. Doses of rivaroxaban Therapeutic dose : 20 mg once daily Prophylactic dose : 10 mg once daily No specific dose adjustment advised in moderate renal function impairment but it should be used with caution Contraindicated in severe renal impairment No dose adjustment required for body weight

88. Apixaban (Eliquis)

89. Apixaban (Eliquis) Direct factor Xa inhibitor Half life – 8 to 11 hours Peak plasma concentration 1 – 3 hours after administration Have excellent bio-availability of 66% Metabolized in liver 25 % of apixaban is renally excreted, so no dose adjustment are required in renal failure pts 75% excreted by fecal route

90. Apixaban only partially metabolized by CYP3A4 system, so strong CYP3A4 inhibitor/ inducer may affect its plasma level but this appears to be minimal as per its anticoagulants effect are concerned Apixaban is minimally interact with P glycoprotein hence its effects are not affected significantly. Hence no clinically significant drug interactions

91. To reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem (Dec 28, 2012 ) FDA recommendation (FDA first approved on Dec. 28, 2012)

92. Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose of apixaban for most patients is 5 mg taken orally twice daily. The recommended dose is 2.5 mg twice daily in patients with any 2 of the following characteristics: • age ≥80 years • body weight ≤60 kg • serum creatinine ≥1.5 mg/ dL

93. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. • In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days. • In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.

94. Treatment of DVT and PE The recommended dose of apixaban is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. Reduction in the Risk of Recurrence of DVT and PE The recommended dose of apixaban is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.

95. Parenteral anticoagulants A. Parenteral anticoagulants ( i ) Indirect thrombin inhibitors : Heparin, Low molecular weight heparins, Fondaparinux, Danaparoid (ii) Direct thrombin inhibitors : Lepirudin , Bivalirudin, Argatroban

96. Low-Molecular-Weight Heparin and Unfractionated Heparin

97. Heparin In 1916, McLean discovered an anticoagulant substance in liver. In 1918, Howell and Holt named it heparin (due to its extraction from liver). In 1937, heparin was used in clinical practice after extracting the purified form. It is a strong organic acid having molecular weight of 10,000-30,000 Da .

98. As it is present in the mast cells, it is normally present in all body tissues, which contain mast cells. Commercially, it is obtained from pig intestinal mucosa & ox lung. It acts as anticoagulant both in vivo & vitro. It is also known as unfractionated heparin (UFH).

99. Mechanism of action Heparin binds to antithrombin III (natural endogenous anticoagulant) and heparin-antithrombin-III complex is formed. This heparin-antithrombin-III complex inactivates the clotting factors of both intrinsic & common pathway ( XIIa , XIa , IX, Xa , XIIIa , II) by binding to them. Thus, the anticoagulant effect is exerted mainly by inhibition of factor Xa & thrombin mediated conversion of fibrinogen to fibrin (refer coagulation cascade).

100. Coagulation Cascade XIIa XIa IXa Intrinsic Pathway (surface contact) Xa Extrinsic Pathway (tissue factor) VIIa Thrombin ( IIa ) Thrombin-Fibrin Clot aPTT PT Heparin / LMWH (AT-III dependent) Hirudin/Hirulog (direct antithrombin) Courtesy of VTI

101. Only approximately one third of an administered dose of heparin   binds to AT, and this fraction is responsible for most of its anticoagulant effect. The remaining two thirds has minimal anticoagulant activity   at therapeutic concentrations, but at concentrations greater   than those usually obtained clinically, both high- and low affinity   heparin catalyze the AT effect of a second plasma protein, heparin   cofactor II

102. The heparin-AT complex inactivates a number of coagulation enzymes,   including thrombin factor ( IIa ) and factors Xa , IXa , XIa , and   XIIa . Thrombin and factor Xa are the most responsive   to inhibition, and human thrombin is 10-fold more sensitive   to inhibition by the heparin-AT complex than factor Xa . For inhibition of thrombin, heparin must bind to both the   coagulation enzyme and AT, but binding to the enzyme is less important   for inhibition of activated factor X (factor Xa ).

103. Molecules of heparin with fewer than 18 saccharides do not   bind simultaneously to thrombin and AT and therefore are unable to   catalyze thrombin inhibition. In contrast, very small heparin fragments   containing the high-affinity pentasaccharide sequence catalyze   inhibition of factor Xa by AT. By inactivating thrombin,   heparin not only prevents fibrin formation but also inhibits   thrombin-induced activation of factor V and factor VIII

104. Pharmacological effects of heparin As anticoagulant As antiplatelet agent: by inhibiting the platelet aggregation. By activating lipoprotein lipase from the vessels wall & tissues, it acts as lipaemia clearing agent.

105. Pharmacokinetics It is not absorbed by oral route due to its large size & highly ionized nature. Therefore, it is given by IV route (acts immediately) and subcutaneous route (acts within an hour). It does not cross BBB & placenta. Hence, can be given safely in pregnancy. It is metabolized in liver by heparinase enzyme and excreted through kidneys. The plasma t ½ is 1-2 hours and is dose dependent. It is prolonged in kidney & liver diseases and shortened in pulmonary embolism.

106. Dose Adult: 5000–10,000 IU, IV bolus dose followed by 750–1000 IU/ hr IV infusion. Children: 50–100 IU/kg.

107. Indications Prophylaxis of postoperative venous thrombosis. Post MI. Pulmonary embolism. Deep venous thrombosis. Heparinization of center line & chemo-pods.

108. Adverse effects First clinical sign of adverse effect of heparin is: hematuria. The other side effects are bleeding, thrombocytopenia, reversible alopecia, osteoporosis, hepatotoxicity, and rarely hypersensitivity reaction.

109. Heparin induced thrombocytopenia is a common entity and was generally manifested as decreased platelet count. In this condition, withdrawal of drug is helpful. On intramuscular injection, it may cause hematomas. The monitoring of activated partial thromboplastin time ( aPTT ) ratio is mandatory, if the ratio of aPTT is greater than three, there is increase risk of bleeding.

110. Protamine sulfate (heparin antagonist) It is a strong base and obtained from fish sperm. Protamine sulfate acts as an antidote for heparin overdose and is given in a dose of 1 mg IV for every 100 IU of heparin. It is used after cardiovascular surgeries when it has been administered in higher doses and the action needs to be terminated rapidly.

111. Low-molecular-weight heparin UH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans) LMWH (mw 5k) is obtained by alkaline degradation of heparin benzyl ester LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio

112. Low-Molecular-Weight Heparins Anti-Factor Xa : Anti - Factor IIa Ratios Agent Xa:IIa Mol Wt (d) Enosaparin 3.8 : 1 4,200 Dalteparin 2.7 : 1 6,000 Ardeparin 1.9 : 1 6,000 Nadroparin 3.6 : 1 4,500 Reviparin 3.5 : 1 4,000 Tinzaparin 1.9 : 1 4,500

113. Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows: Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for Injection q.s . Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5).

114. Advantages of LMWH over UH Decreased “ heparin resistance ” pharmacokinetics of UH are influenced by its bindings to plasma protein, endothelial cell surfaces, macrophages, and other acute phase reactants LMWH has decreased binding to nonanticoagulant-related plasma proteins

115. Advantages of LMWH over UH No need for laboratory monitoring when given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible Higher bioavailability - 90% vs 30% Longer plasma half-life 4 to 6 hours vs 0.5 to 1 hour renal (slower) vs hepatic clearance

116. Advantages of LMWH over UH Less inhibition of platelet function potentially less bleeding risk, but not shown in clinical use Lower incidence of thrombocytopenia and thrombosis (HIT syndrome) less interaction with platelet factor 4 fewer heparin-dependent IgG antibodies

117. Monitoring of LMWH Unnecessary in majority of patients May be useful in specific instances renal insufficiency (creatinine >2.0 mg/dl) obese patients with altered drug pK major bleeding risk factors aPTT not useful - low anti-IIa activity anti-factor Xa assay is more appropriate, but not widely available

118. Various LMWHs with dose Drug Therapeutic Dose Prophylactic Dose Enoxaparin 1mg/kg, subcutaneously, twice daily . 20-40 mg, subcutaneously, once daily. Deltaparin 200 IU/kg subcutaneously, once daily. 2500 IU subcutaneously, once daily. Parnaparin 6400 IU subcutaneously, once daily. 3200 IU subcutaneously, once daily. Reviparin 3436 IU subcutaneously, once daily. 0.25 mL (1432 IU) subcutaneously, once daily. Ardeparin 2500-5000 IU subcutaneously, once daily. 2500 IU subcutaneously, once daily. Nadroparin 4000-6000 IU subcutaneously, once daily/ twice daily. 3000 IU subcutaneously, once daily/ twice daily. Tinzaparin 3500 IU subcutaneously, once daily. 1700 IU subcutaneously, once daily. *All are available in prefilled syringes forms.

119. Indications of LMWHs Prophylaxis of deep venous thrombosis (DVT) in immobilized patients such as post-surgical or coma patients. Post MI . Prophylaxis of pulmonary embolism. Treatment of deep venous thrombosis. For the maintenance of patency of cannula in dialysis patient, centre line & chemo-pods.

120. Fondaparinux It is a synthetic derivative of heparin. It has pharmacological similarity to LMWHs with longer plasma half-life (17-21 hours). It has 100% bioavailability. It is given in a dose of 5-10mg SC, OD. The adverse effects like thrombocytopenia & osteoporosis are even lesser than LMWHs. Idraparinux is an ultra long acting derivative of fondaparinux with t ½ of 5-6 days.

121. Danaparoid It is a mixture of heparin like natural substances (84% heparin sulfate +12% dermatan salfate + 4% chondroitin sulfate). It is obtained from pig intestinal mucosa. It has longer plasma t ½ of 24 hours. It is used in patient with heparin induced thrombocytopenia as an alternative therapy.

122. DIRECT THROMBIN INHIBITORS ( Lepirudin , Bivalirudin, Argatroban )

123. Lepirudin It is a recombinant preparation of hirudin . It inhibits thrombin directly. Indicated in heparin induced thrombocytopenia. It cannot be given repeatedly due to formation of anti- hirudin antibodies and higher risk of anaphylaxis. There is no antidote available against lepirudin .

124. Bivalirudin Synthetic analogue of hirudin with pharmacological actions similar to lepirudin . It has fast onset & offset of action due to its reversible binding nature. It does not form anti- hirudin antibodies.

125. Argatroban It is a reversible direct thrombin inhibitor and given by IV infusion. It is used in-patients with heparin-induced thrombocytopenia as an alternative therapy.

126. COLOUR CODING OF VIALS