COAGULANTS AND ANTIOCOAGULANTS

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This is to brief about coagulants, anticoagulants as well as fibrinolytic agents.

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COAGULANTS AND ANTICOAGULANTS:

COAGULANTS AND ANTICOAGULANTS DR. SACHIN TUTU DEPTT. OF PHARAMCOLOGY& THERAPEUTICS K.G.M.U, Lucknow Email- tutusachin@gmail.com

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BLEEDING HAEMOSTASIS ( Arrest of blood loss)

INTRODUCTION:

INTRODUCTION Haemostasis - The process of arrest of blood loss and blood coagulation. There is a complex interaction between injured vessels, platelets and coagulation factors. There is a cascade of proteolytic reactions responsible for blood coagulation.

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Balance system operating to maintain blood in a fluid state PROCOAGULANTS ANTICOAGULANTS ( promote coagulation) ( inhibit coagulation) Whether blood will coagulate depends on the balance between these two groups of substances. In the blood stream, the anti- coagulants normally predominate, so that the blood does not coagulate.

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Haemostasis is maintained in the body through three mechanisms: Vascular spasm - The injured vessels constrict. Platelet plug formation- The platelets adhere to damaged endothelium to form platelets(primary haemostasis ) plug and then degranulate . Blood coagulation- Clots form due to conversion of fibrinogen to fibrin and its addition to the platelet plug (secondary haemostasis ).

CLOTTING FACTORS:

CLOTTING FACTORS These are proteins present in the plasma. On partial proteolysis they get activated and activates the next factor down in the cascade. There are 13 clotting factors. Deficiency of any one of them can lead to bleeding disorders.

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The clotting cascade can be triggered through two possible pathways. They are- Extrinsic pathway Intrinsic pathway. Both of them lead to the activation of final common pathway in which thrombin converts fibrinogen to fibrin.

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INTRINSIC SYSTEM EXTRINSIC SYSTEM XIIa Activated by contact XI XIa Ca 2+ IXa IX VIII a Pl.Ph . Ca 2+ Xa Pl.Ph . V Ca 2+ X PROTHROMBIN FIBRINOGEN (polymerization) THROMBIN FIBRIN (soluble) Thrombin XIIIa FIBRIN (insoluble) VIIa VII III Ca 2+ X XIIa XIa Kallikrein SLOW RAPID COAGULATION CASCADE Tissue damage

Diagnosis of Coagulation Defects:

Diagnosis of Coagulation Defects Prolonged aPTT No change in PT No change in aPTT Prolonged PT Prolonged APTT Prolonged PT Defect in Intrinsic pathway Defect in Extrinsic pathway Defect in Common pathway

Drugs for Bleeding Disorders:

Drugs for Bleeding Disorders A. Coagulants- 1. Vitamin K 2. Local and Systemic Haemostatic B. Anticoagulants 1. Heparin , Danaparoid , Lepirudin 2. Oral Anticoagulants- Warfarin , Dicumarol , Phenindione , Rivaroxaban , C. Thrombolytic Drugs 1. Streptokinase 2. Urokinase 3. Tissue Plasminogen Activator(t-PA)

COAGULANTS:

COAGULANTS These are substances which promote coagulation. They are indicated in hemorrhagic states. Fresh whole blood or plasma provide all the factors needed for coagulation and are the best therapy for deficiency of any clotting factor. They also act immediately.

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1. Vitamin K K1 (from plants, : Phytonadione fat-soluble) ( Phylloquinone ) K3 (synthetic) —Fat-soluble : Menadione , Acetomenaphthone —Water-soluble : Menadione sod. Bisulfite , Menadione sod. diphosphate .

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2. Miscellaneous Fibrinogen (human) Antihaemophilic factor Desmopressin Adrenochrome monosemicarbazone Rutin Ethamsylate

Vitamin K:

Vitamin K It is a fat-soluble vitamin required for the synthesis of clotting factors. Vit K has a basic naphthoquinone structure, with or without a side chain (R) at position 3. The side chain in K1 is phytyl , in K2 prenyl , while in K3 there is no side chain. Dietary sources are—green leafy vegetables, such as cabbage, spinach; and liver, cheese, etc. Daily requirement is uncertain, because a variable amount of menaquinone ( vit K2) is produced by colonic bacteria.However , the total requirement of an adult has been estimated to be 50–100 μg /day.

Action:

Action Vit K acts as a cofactor at a late stage in the synthesis of coagulation proteins by liver—II, VII, IX and X. The vit K is responsible for γ carboxylation of glutamate residues of these zymogen proteins. This confers on them the capacity to bind Ca 2+ and to get bound to phospholipid surfaces—properties essential for participation in the coagulation cascade.

Deficiency:

Deficiency Deficiency of vit K occurs due to liver disease, obstructive jaundice, malabsorption , long-term antimicrobial therapy which alters intestinal flora. 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. Haematuria is usually first to occur; other common sites of bleeding are g.i.t ., nose and under the skin— ecchymoses .

Use:

Use The only use of vit K is in prophylaxis and treatment of bleeding due to deficiency of clotting factors in the following situations: a) Dietary deficiency: It is very rare in adults. However, when it occurs 5–10 mg/day oral or parenteral vit K rapidly corrects the defects. b) Prolonged antimicrobial therapy: treat in the same way as dietary deficiency. c) Obstructive jaundice or malabsorption syndromes : vit K- 10 mg i.m ./day, or orally along with bile salts. d)Liver disease (cirrhosis, viral hepatitis): synthesis of clotting factors is inadequate despite the presence of vit K.

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e)Newborns: All newborns have low levels of prothrombin and other clotting factors. Vit K 1 mg i.m . soon after birth has been recommended routinely. Menadione (K3) should not be used for this purpose . f)Overdose of oral anticoagulants: This is the most important indication of vit K. Phytonadione (K1) is the drug of choice. Higher doses render the patient unresponsive to oral anticoagulants for several days

Adverse Effects:

Adverse Effects Rapid i.v . injection of emulsified Vit K produces flushing, breathlessness, chest infection, fall in BP. Death is very rare. Menadione and its water-soluble derivatives can cause haemolysis in a dose-dependent manner. Patients with G-6-PD deficiency and neonates are especially susceptible. In the newborn menadione or its salts can precipitate kernicterus :

Other Coagulants:

Other Coagulants Fibrinogen - employed to control bleeding in haemophilia , antihaemophilic globulin (AHG) deficiency and acute afibrinogenemic states. 0.5 g is infused i.v . Antihaemophilic factor - It is concentrated human AHG ( antihaemophilic globulin) It is indicated in haemophilia and AHG deficiency. It is highly effective in controlling bleeding episodes, but action is short-lasting

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Desmopressin It releases factor VIII and von Willebrand’s factor from vascular endothelium Checks bleeding in haemophilia and von Willebrand’s disease. Adrenochrome monosemicarbazone Reduces capillary fragility, control oozing from raw surfaces and prevent microvessel bleeding. Its efficacy is uncertain. Dose: 1–5 mg oral, i.m .

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Rutin – It is a plant glycoside claimed to reduce capillary bleeding. Used in a along with vit C which is believed to facilitate its action. Its efficacy is uncertain. dose of 60 mg oral BD– TDS Ethamsylate - It reduces capillary bleeding when platelets are adequate. Used in the prevention and treatment of capillary bleeding in menorrhagia , after abortion, PPH, epistaxis , malena etc. Dose: 250–500 mg TDS oral/ i.v .;

Styptics:

Styptics Substances used to control bleeding from a local and approachable site. They are particularly effective on oozing surfaces, e.g. tooth socket, abrasions, etc. Absorbable materials like fibrin (prepared from human plasma and dried as sheet or foam), Gelatin foam, Oxidized cellulose (as strips ) . Thrombin fro m bovine plasma may be applied as dry powder or fresh solution. Vasoconstrictors like 0.1% Adr solution may be soaked in sterile cotton gauze. Astringents such as tannic acid or metallic salts are occasionally applied for bleeding gums, bleeding piles,

Sclerosing agents:

Sclerosing agents These are irritants, cause inflammation, coagulation and ultimately fibrosis, Injected into haemorrhoids (piles) or varicose vein mass. They are used only for local injection. The substances include- 1. Sod. tetradecyl sulfate (3% with benzyl alcohol 2%):0.5–2 ml at each site. 2. Polidocanol (3% inj ): 2 ml 3. Ethanolamine oleate .

ANTICOAGULANTS:

ANTICOAGULANTS (Drug used to reduce coagulability of blood.)

CLASSIFICATION:

CLASSIFICATION I. Used in vivo A. Parenteral anticoagulants ( i ) Indirect thrombin inhibitors : Heparin, Low molecular weight heparins, Fondaparinux , Danaparoid (ii) Direct thrombin inhibitors : Lepirudin , Bivalirudin, Argatroban B. Oral anticoagulants ( i ) Coumarin derivatives : Bishydroxycoumarin ( dicumarol ), Warfarin sod, Acenocoumarol ( Nicoumalone ), Ethylbiscoumacetate (ii) Indandione derivative: Phenindione . (iii) Direct factor Xa inhibitors : Rivaroxaban (iv) Oral direct thrombin inhibitor : Dabigatran etexilate

CLASSIFICATION:

CLASSIFICATION II. Used in vitro A. Heparin B. Calcium complexing agents: Sodium citrate Sodium oxalate Sodium edetate

HEPARIN:

HEPARIN Howell and Holt (1918) named an anticoagulant ‘heparin’ as it was obtained from liver. Straight chain mucopolysaccharides MW- 10,000 to 20,000 Present in all tissues containing mast cells Richest sources- Lung, Liver and Intestinal mucosa

ACTIONS:

ACTIONS As an anticoagulant- Powerful and instantaneously acting Effective both in vivo and in vitro Mode of action: by inhibition of factor Xa and Thrombin ( IIa ) mediated conversion of fibrinogen to fibrin. Low conc.- prolong aPTT (Intrinsic pathway) High conc.- prolong aPTT and PT(Common pathway)

ACTIONS:

ACTIONS As Antiplatelet: High doses- inhibit platelet aggregation; prolongs bleeding time (BT) As Lipaemia clearing Agent: Injection of low conc. Heparin- clears post- prandial lipaemia by releasing lipoprotein lipase from vessel wall and tissues.

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PHARMACOKINETICS: Not absorbed orally. Does NOT cross B.B.B. or Placenta. Metabolized by liver by heparinase - fragments excreted in urine. Released from mast cells- degraded by tissue macrophages.

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DOSAGE: i.v . bolus- 5,000 to 10,000 U (children 50 to 100 U/kg) every 4- 6 hrs. Initial bolus followed by continuous infusion of 750-1000 U/hr. Deep s.c . injection- 10,000 to 20,000 U every 8- 12 hrs. Low dose s.c . regimen- 5000 U every 8- 12 hrs. (started before surgery and continued for 7- 10 days).

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ADVERSE EFFECTS: Bleeding Thrombocytopenia Alopecia (transient and reversible) Osteoporosis Hypersensitivity reactions- eg . Urticaria , rigor, fever, anaphylaxis

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CONTRAINDICATIONS: Bleeding disorders, Heparin induced thrombocytopenia Severe hypertension, Threatened abortion, Piles, g.i . ulcers Subacute bacterial endocarditis , Large malignancies, Tuberculosis Ocular and neurosurgery, Lumbar puncture Chronic alcoholic cirrhosis, Renal failure Aspirin and other antiplatelet drug therapy- used cautiously

LOW MOLECULAR WEIGHT HEPARINS (LMWH) :

LOW MOLECULAR WEIGHT HEPARINS (LMWH) Heparin- fractioned into LMW forms (MW 3000- 7000). Selectively inhibit factor Xa (little effect on IIa ). Act by inducing conformational change in AT III.

Advantages of LMWH Over UFH:

Advantages of LMWH Over UFH Throbmbocytopenia - less frequent. Lower incidence of hemorrhagic complications. Better subcutaneous bioavailability (70-90%). Longer t ½ (4-6 hrs) Smaller effect on aPTT and clotting time (not prolonged) Risk of osteoporosis is less.

INDICATIONS:

INDICATIONS Prophylaxis: Deep vein thrombosis Primary embolism Stoke Immobilized patients Treatment: Deep vein thrombosis Unstable angina To maintain patency of cannulae and stents in dialysis patients

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Other parenteral anticoagulants Fondaparinux : The pentasaccharide with specific sequence that binds to AT III with high affinity to selectively inactivate factor Xa without binding thrombin (factor IIa ). Danaparoid is a preparation containing mainly heparan sulfate which is a heparin-like substance. DIRECT THROMBIN INHIBITORS- Unlike heparin, these anticoagulants bind directly to thrombin and inactivate it without the need to combine with and activate AT III. Lepirudin –A recombinant preparation of hirudin (from salivary glands of leech). Bivalirudin Argatroban HEPARIN ANTAGONIST: Protamine sulfate- 1 mg i.v . for every 100 U of heparin.

ORAL ANTICOAGULANTS:

ORAL ANTICOAGULANTS Warfarin sod. Bishydroxycoumarin ( Dicumarol ) Acenocoumarol Ethylbiscoumacetate Phenindione

WARFARIN:

WARFARIN Mode of action: Acts only in vivo ( NOT in vitro ) Interfere with the synthesis of vit K dependent clotting factors (II, VII, IX and X) in liver. Behaves as competitive antagonist of vit K

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Adverse effects: Bleeding- ecchymosis , epistaxis , hematuria , bleeding in the g.i.t . Intracranial or other internal hemorrhage Alopecia, dermatitis, diarrhoea Orange urine, rashes, fever, leukopenia , hepatitis, nephropathy, agranulocytosis (by Phenyndione ) Warfarin and acenocoumarol are considered to be better tolerated drugs

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The dose of oral anticoagulant must be individualized by repeated measurement of prothrombin time. Factors enhancing effect of oral anticoagulants are: Malnutrition, malabsorption and prolonged antibiotic therapy Liver disease, chronic alcoholism Hyperthyroidism:- the clotting factors are degraded faster. Newborns Factors decreasing effect of oral anticoagulants are: Pregnancy: plasma level of clotting factors is higher. Nephrotic syndrome. Genetic warfarin resistance.

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Drug interactions: I. Enhanced anticoagulant action: Broad spectrum antibiotics ( inhibit gut flora - reduce vit K production ) . Newer cephalosporins - eg.cefamandole , cefoperazone ( hypothrombinemia ) . Aspirin ( inhibits platelet aggregatio n - g.i . bleed) Long acting sulfonamides, indomethacin , phenytoin and probenecid ( displace warfarin from protein binding site ) . Chloramphenicol , erythromycin, celecoxib , cimetidine , allopurinol , amiodarone and metronidazole ( inhibit warfarin metabolism ). Tolbutamide and phenytoin ( inhibit warfarin metabolism and vice versa) Liquid paraffin ( reduce s vit K absorption ) .

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II. Reduced anticoagulant action: Barbiturates, rifampin and griseofulvin ( induce metabolism ). Oral contraceptives ( increase blood levels of clotting factors ).

USES OF ANTICOAGULANTS:

USES OF ANTICOAGULANTS Deep vein thrombosis Pulmonary embolism Myocardial infarction (MI) Unstable angina Rheumatic heart disease Atrial fibrillation Cerebrovascular disease (stroke, TIA) Vascular surgery Defibrination syndrome (DIC)

FIBRINOLYTICS (Thrombolytics):

FIBRINOLYTICS ( Thrombolytics )

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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. Venous thrombi are lysed more easily by fibrinolytics than arterial Recent thrombi respond better. They have little effect on thrombi > 3 days old The clinically important fibrinolytics are: Streptokinase Urokinase Alteplase ( rt -PA) Reteplase Tenecteplase

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Uses Acute myocardial infarction Deep vein thrombosis Pulmonary embolism Peripheral arterial occlusion Stroke ANTIFIBRINOLYTIC DRUGS- inhibit plasminogen activation and dissolution of clot, and are used to check fibrinolysis associated bleeding. Epsilon amino- caproic acid (EACA) Tranexamic acid

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