Anticoagulants (VK)


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  • Deficienry of vitK occurs due to liver disease, obstructive jaundice, malabsorption,long-term antimicrobial therapy which alters intestinal flora. However, deficient diet is rarely responsible. The most important manifestation is bleeding tendency due to lowering of the levels of prothrombin and other clotting factors in blood.Haemafuria is usually first to occur; other conunon sites of bleeding are g.i.t., nose and under the skin-ecchymoses.
  • PPH:Post partum hemorrhage
  • 1. Indirect Thrombin Inhibitors: HMWH, LMWH
    2. Direct Thrombin Inhibitors: Hirudin, Lepirudin, Bivalirudin, Argatroban
  • A 2nd year medical student attempting to extract coagulant substances from various tissues during a vacation project. But found instead a powerful anticoagulant. He discovered in 1916 that liver contains a powerful anticoagulant. because it was obtained from liver
    bovine: cattle, buffalo
    porcine :pig
  • Aptt: activated partial thromboplastin time
  • CABG :coronary artery bypass graft
  • DIC: disseminated intravascular coagulation, Emboli: abstruction of affected part
  • The four Vitamin K dependent clotting factors are synthesized in the liver.
  • Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.
  • Anticoagulants (VK)

    2. 2. Thrombosis • Venous thrombosis is associated with stasis of blood Has small platelet component and large component of fibrin • Arterial thrombosis is associated with atherosclerosis -initiated due to endothelial injury leads to atheromatous plaque formation Plaque rupture, platelet adhesion, activation, aggregation initiates thrombus growth, it has large platelet component Arterial thrombus may break away, emboli form leads to ischemia and infarction
    3. 3. Hemostasis • Spontaneous Arrest of Bleeding from a Damaged Blood Vessel; This occurs by the following steps 1. Vasospasm 2. Platelet Adhesion 3. Platelet Aggregation 4. Platelet Plug 5. Fibrin Reinforcement of platelet plug
    4. 4. Coagulation This is the conversion of blood in the liquid form to a solid gel or clot. Normally there is a balance b/n Procoagulants (TXA2, thrombin, activated platelets etc.) and Anti-coagulants (heparan sulfate, Antithrombin III, Nitric oxide and Prostacyclin) • Imbalance occurs coagulation • Procoagulants > Anticoagulants • Injury to blood vessel • Blood stasis
    5. 5. Clotting Factors • • • • • • • • • • • • I - Fibrinogen II - Prothrombin III - Tissue Thromboplastin IV - Calcium V - Proaccelerin VII - Proconvertin VIII- Antihemophilic globulin IX - Christmas Factor X - Stuart Power Factor XI - Plasma Thromboplastin anticedent (PTA) XII - Hageman Factor XIII -Fibrin-stabilizing factor
    6. 6. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII HMW-Kininogen Thromboplastin XIa XI XIIa, Xia, Kallikrein ca+ IXa IX VIIa ca+ ca+ Xa X VII X XIII ca+ Factors affected Prothrombin By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants ca+ Thrombin XIIIa Fibrinogen Fribrin insoluble Stabilised Fibrin threads
    7. 7. COAGULANTS • These are substances which promote coagulation & are indicated in haemorrhagic states
    8. 8. Classification 1 .Vitamin K • K1(from plants, fat-soluable) – Phytonadione (phylloquinone) • K3(synthetic) – Fat-soluble :menadione,acetomenaphthone – Water soluble :menadione sod.bisulphate menadione sod.diphosphate 2 .Miscellaneous – Fibrinogen (human), Antihaemophilic factor, Desmopressin, Adrenochrome monosemicorbazone, Ruti, Ethamsylate
    9. 9. VITAMIN K • ACTION: - Acts as cofactor in the synthesis of coagulation factors II, VII, IX, X • DEFICIENCY: - Haematuria - GIT & Nose Bleeding - Ecchymoses
    10. 10. Use of Vitamin K: • • • • • • • Dietary deficiency Prolonged antimicrobial therapy Obstructive jaundice Malabsorption syndromes Liver disease Premature newborn To reverse effect of overdose of oral anticoagulants • Prolonged high dose salicylate therapy
    11. 11. MOA Decorboxy prothrombin (or VII, IX, X ) Prothrombin (or VII, IX, X ) Vit K hydroquinone Vit K epoxide NAD BLOCKED BY ORAL ANTICOAGULANTS NADH
    12. 12. MISCELLANEOUS Fibrinogen • The fibrinogen fraction of human plasma is employed to control bleeding in haemophilia, antihaemophilic globulin (AHG) deficiency and acute afibrinogenemic states; 0.5 gm i.v infusion
    13. 13. Antihaemophilic factor • It concentrated human AHG prepared from pooled human plasma. Indicated (along with human fibrinogen) in haemophilia and AHG deficiency • Highly effective in control bleeding episodes, but action is short-lasting (1-2 days) • Dose; 5-10 U /kg by i v infu, repeated 6-12 hrly
    14. 14. Desmopressin • It releases factor VIII and von Willebrand's factor from vascular endothelium and checks bleeding in haemophilia and von Willebrand's disease
    15. 15. Adrenochrome monosemicarbazone • It believed to reduce capillary fragility, control oozing from raw surfaces and prevent microvessel bleeding, ex:epistaxis, haematuria, retinal haemorrhage, secondary haemorrhage from wounds, etc Its efficacy is uncertain • Dose: 1-5 mg oral, i.m.
    16. 16. Rutin • A plant glycoside claimed to reduce capillary bleeding • Dose 60 mg oral BD-TDS along with vit C which is believed to facilitate its action • Its efficacy is uncertain.
    17. 17. Ethamsylate • It reduces capillary bleeding when platelets are adequate; probably exerts antihyaluronidase action improves capillary wall stability, but does not stabilize fibrin (not an antifibrinolytic) • in the prevention and treatment of capillary bleeding in menorrhagia, after abortion, PPH, epistaxis, malena, hematuria and after tooth extraction, but efficacy is unsubstantiated • S/E:N,H, rash & ↓ BP (only after i.v inj) • Dose: 250-500 mg TDS oral/i.v
    18. 18. LOCAL HAEMOSTATICS(STYPTICS) • • • • • • • • Astringents Vasoconstrictors (Adrenaline) Thrombin Fibrin Gelatin Foam Calcium alginate Oxidized cellulose Russell's viper venom
    20. 20. CLASSIFICATION These are drugs used to reduce the coagulability of blood classified into: USED IN VIVO Parenteral anticoagulants a) Heparins (ITI) • High Molecular Weight Heparin Unfractionated Heparin (UFH) • Low molecular weight heparin (Enoxaparin, Dalteparin, Tinzaparin, Reviparin, Danaparoid) b) Heparinoids (DTI)-Heparan sulfate, Hirudin, Lepirudin, Bivalirudin, Argatroban
    21. 21. Oral anticoagulants (1)Coumarin derivatives :Bishydroxycoumarin (dicumarol), Warfarin sod, Acenocoumarol (Nicoumalone), Ethylbiscoumacetate (2)Indandione derivative: Phenindione. USED IN VITRO (a)Heparin (b)Sod. citrate :used in blood banks to store the blood (c)Sod. oxalate : used as an anticoagulant in laboratory (d)Sod. editate :
    22. 22. Parenteral anticoagulants History of Heparin • • • • • • McLean Howell and Holt in 1918 named it heparin Occurs in mast cells (richest source of mast cells are lungs, liver and intestinal mucosa) Commercial heparin , porcine intestinal mucosa and bovine lungs A mixture of straight chain anionic (negative charge) glycosaminoglycan with a wide range of mol wt It is strongly acidic because of presence of sulfate and carboxylic acid groups
    23. 23. PK of Heparin • Heparin is highly charged, thus crosses cell membranes very poorly, hence given Parenterally • Low dose: S.c • High Dose: S.c /IV Inj • Metabolized by liver, half life depends on dose
    24. 24. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII HMW-Kininogen Thromboplastin XIa XI XIIa, Xia, Kallikrein ca+ IXa IX VIIa ca+ ca+ Xa X VII X XIII ca+ Factors affected Prothrombin By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants ca+ Thrombin XIIIa Fibrinogen Fribrin insoluble Stabilised Fibrin threads
    25. 25. Mechanism Heparin No heparin Active clotting factors Active clotting factors Slow AT III Fast AT III + Heparin Inactive clotting factors Inactive clotting factors
    26. 26. Character HMW Heparins LMW Heparins Molecular Weight High Low (30000 Daltons) (5000 Daltons) Biotransformation Low High (90%) Half Life Shorter-depends on dose Longer-independent of dose Mechanism of Action Inactivate both factor IIa Inactivate Xa & Xa Anti-coagulant effect More effective less effective
    27. 27. Monitoring By aPTT Adverse Can be given once or twice daily without monitoring, but requires special assay if necessary Less chance of thrombocytopenia and long term osteoporosis Effects Excretion Cleared by the Cleared unchanged by kidneys Reticuloendothelial system Reversal By protamine Not fully reversed by protamine Expense Not expensive Expensive
    28. 28. Dose Response Use Less predictable dose response because of binding to plasma proteins, macrophages and endothelial cells Has a more predictable dose-response because it does not bind to plasma proteins, macrophages, or endothelial cells. More effective for a) Orthopedic procedures on lower limb b) Pulmonary Embolism c) Unstable Angina
    29. 29. Advantages of LMWH over UFH • Better S.c, BA (70-90%) compared to UFH(20-30%) • Longer and more consistent half life: once daily S.c administration • Since aPTT/clotting times are not prolonged, lab. monitoring is not needed • Lower incidence of haemorrhagic complications • Appear to have lesser antiplatelet action so less interference with haemostasis
    30. 30. Uses of Heparin (Anti-coagulants in General) 1.Treatment & Prevention of Deep Venous Thrombosis in • Bedridden (Immobilized patients) • Old people • Post-operative • Post-stroke patients • Leg fractures • Elective Surgery
    31. 31. 2. Ischemic Heart Disease Unstable angina After MI After angioplasty CABG, stent replacement; Prevent recurrence 3. Rheumatic Heart Disease/ Atrial Fibrillation Warfarin, heparin, low dose aspirin, Decrease stroke due to emboli
    32. 32. 4. Cerebrovascular Diseases Cerebral Emboli (Prevention of recurrence) 5. Vascular Surgery, Prosthetic heart valves, Retinal vessel thrombosis, Extracorporeal circulation, Hemodialysis To prevent Thromboembolism 6. Defibrination syndrome or DIC Abruptio placenta, malignancies, infections; increased consumption of clotting factors
    33. 33. Adverse Effects 1. Bleeding(most common) 2. Allergy and Anaphylaxis 3. Increased hair loss 4. Long term-Osteoporosis, spontaneous fractures 5. Thrombocytopenia
    34. 34. Heparin-induced Thrombocytopenia • Once thrombocytopenia is determined, heparin must be stopped. Direct thrombin inhibitor should be given • Platelets must NOT be given because they will react with antibody already being produced against them, causing greater chance of thrombosis.
    35. 35. Heparin in Pregnancy • It not cross placenta, it must be used instead of warfarin in cases of requiring anticoagulant therapy in pregnancy. • Warfarin cross placenta and induces changed in the fetus to produce the fetal warfarin syndrome – not good.
    36. 36. Contraindications 1. Hypersensitivity 2. Bleeding Disorders like Hemophilia 3. Thrombocytopenia 4. Intracranial Hemorrhage 5. GIT Ulcerations 6. Threatened abortion 7. Advanced renal or hepatic disease
    37. 37. Antidote –Protamine Sulfate • Is highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity • Hemorrhage – can be reversed by protamine sulfate titrated so that 1 mg of Protamine sulfate is administered for every 100 U of heparin remaining in the pt. • Is also an anticoagulant because it interacts with platelets, fibrinogen, and other clotting factors – so it can make hemorrhage worse if more is given than necessary.
    38. 38. Direct Thrombin Inhibitors (DTIs) or Heparinoids • The DTIs bind thrombin without additional binding proteins, such as anti-thrombin, and they do not bind to other plasma proteins such as platelet factor 4. • Hirudin and Bivalirudin bind at both the catalytic or active site of thrombin as well as at a substrate recognition site • Argatroban bind only at the thrombin active site
    39. 39. Lepirudin • Monitored by aPTT • Action independent of antithrombin • Use in thrombosis related to heparin induced thrombocytopenia • No antidote • Adverse effect: Antibody formation against thrombin-lepirudin complex
    40. 40. Bivalirudin: Inhibits platelet activation also Use in percutaneous coronary angiography Argatroban: Used in heparin induced thrombocytopenia with or without thrombosis Monitored by aPTT Dose reduction in liver disease
    42. 42. Wisconsin Alumni Research Foundation Coumarin=Warfarin Warfarin-Pk 1. Rapidly and completely absorbed after oral administration 2. 100% Bioavailability 3. Highly PPB (99%) 4. Crosses the placenta (teratogenic) 5. Appears in milk; infants given Vit K 6. Variable but slow clearance;depends on hepatic P450s 7. Biotransformation by the liver: Oxidation, Glucuronidation 8. Takes 12-16 hrs before effect is observed
    43. 43. Vitamin K-Dependent Clotting Factors Vitamin K VII IX X II Synthesis of Functional Coagulation Factors
    44. 44. Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII IX X II Warfarin No Synthesis of Functional Coagulation Factors
    45. 45. Mechanism of Action • Coumarins block the Gamma Carboxylation of glutamic acid residues of Clotting factors II,VII, IX, X , endogenous anti-coagulants C & S. • This is coupled with oxidative deactivation of Vit K • Coumarins and Indanediones (-) enzyme Vit K epoxide reductase that converts Vit K epoxide to its active hydroquinone (reduced form) • Thus they prevent the activation of Vit K and hence along with it carboxylations of clotting factor residues
    46. 46. Why Carboxylation is necessary? • Necessary for ability of clotting factors to bind Ca+ and to get bound to phospholipid surfaces which is necessary for coagulation • Factor VII affected first, then IX, X, and finally Factor II (depends upon half lives of circulating factors)
    47. 47. H N Glu residues in prothrombin O H N O H COOH COOH COOH O OH CH3 CH3 vitamin K hydroquinone Gla residues in prothrombin O R R vitamin K 2,3-epoxide O OH vitamin K reductase vitamin K epoxide reductase O CH3 R O vitamin K Anticoagulant coumarins and 1,3-indandiones
    48. 48. Uses • Same as Heparin and other Anticoagulants • Monitoring necessary because of its low therapeutic index • PT noted; time taken for blood to clot • Pts on Heparin are shifted to oral warfarin after 3-5 days
    49. 49. Adverse Effects 1. Bleeding Common ,serious adverse effect; Epistaxis, hematuria, GIT Bleeding, internal hemorrhages 2. Cutaneous Necrosis This is due to decreased activity of Protein C Protein C and Protein S found in bone & other tissues also require Gamma carboxylations 3. Infarction of breast, fatty tissues, intestine and extremities due to venous thrombosis caused by again decreased activity of Protein C
    50. 50. Antidote of Warfarin • Stop Warfarin • Give Vit K (Antidote) • Also Fresh frozen plasma, Prothrombin complex concentrates and Recombinant factor VIIa can be administered
    51. 51. Contraindications 1. Pregnancy Fetal protein in bone and blood affected -Causes birth defects including abnormal bone formation, bone hyperplasia -CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetal death may occur 2. Other contraindications same as heparin
    52. 52. Drug Interactions of Warfarin A.Pharmacokinetic Interactions 1. Agents that inhibit metabolism of warfarin • Cimetidine • Imipramine • Cotrimoxazole • Chloramphenicol • Ciprofloxacin • Metronidazole • Amiodarone
    53. 53. 2. Drugs that increase metabolism of Warfarin • Barbiturates • Rifampin 3. Drugs that displace warfarin from binding sites on plasma albumin • Chloral hydrate • NSAIDs 4. Drugs that decrease GIT absorption of warfarin • Cholestyramine
    54. 54. B. Pharmacodynamic Interactions 1. Synergistic effect • Heparin • Aspirin • Antibiotics: Decrease bacterial flora—decrease Vit K synthesis—increased warfarin effect
    55. 55. Physiological/Pathological Factors affecting Warfarin Action 1. Increased warfarin action • Malnutrition, debility (Decreased Vit. K) • Liver disease, chronic alcoholism (Decreased clotting factors) • Hyperthyroidism (Increased degradation of Clotting factors) • Newborns (Decreased Vit K)
    56. 56. 2. Decreased Warfarin Action • Pregnancy (Increased clotting factors) • Nephrotic syndrome • Warfarin resistance (Genetic)
    57. 57. Character HEPARIN WARFARIN Route of Administration Parenteral Oral Polarity Polar charged molecule Uncharged Onset of Action Rapid Mechanism of Action Accelerates inactivation Inhibits gamma of clotting factors by Carboxylation of glutamic Antithrombin III acid residues of clotting factors 12-16 Hours
    58. 58. Therapeutic Index Not low; safe Low; not safe Monitoring aPTT PT Adverse Effect Differences Thrombocytopenia,,Oste Cutaneous Necrosis, oporosis, alopecia, Infarction of breast, fatty anaphylaxis and other tissues Management of Patient Start with Heparin Switch over to warfarin in 3-5 days Antidote Protamine Sulfate Vitamin K Contraindication Not Pregnancy Interactions Not significant Significant