Coagulants and anti coagulants

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Coagulants & anticoagulants:

Coagulants & anticoagulants Dr.Ramya.R Asst Prof of Pharmacology

Introduction :

Introduction What is Hemostasis? Stoppage of bleeding from vessels at the site of injury 3 steps 1.Initially vasospasm of small capillaries 2.Formation of platelet plug 3.Blood clot

Coagulation:

Coagulation Complex process of enzymatic reactions in which Clotting factors activates other clotting factors in a fixed sequence until a clot is formed Disorders of coagulation can lead to an increased risk of bleeding or clotting (thrombosis). 3 stages of coagulation: 1-Intrinsic/extrinsic 2.Thrombin formation 3.Fibrin formation

Coagulation cascade:

Coagulation cascade

coagulants:

coagulants substances which promote coagulation Indicated in Hemorrhagic states- Haemophilia,Von willibrands disease Fresh whole blood or plasma -best therapy for deficiency of any clotting factor but carries the risk of HIV, hepatitis transmission, They act immediately 1.Hemophilia- antihemophilic factor (8 th ,9 th factor) 2.Fibrinogen- heamophilia,acute afibrinogenemia -I.V. infusion 3.Desmopressin –Analogue of vasopressin used in von willibrand disease stimulate release of vwf from endothelial cells(3 to 5 fold increase) –I.V., S.C,Intra nasal No risk of HIV and hepatitis

4.Vitamin k :

4.Vitamin k It is a fat soluble vit required for the synthesis of clotting factors(2,7,9,10) Dietary sources - cabbage,spinach,liver , cheese etc. Forms: phytonadione k1 leafy veg natural, menaquinone –k2, menadione k3 water soluble synthetic

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Deficiency : 50-100mcg/day RDA Liver disease like Obstructive jaundice Malabsorption Long-term antimicrobial therapy Deficient diet Th uses : 5 -10 mg /day orally/parenterally Newborn vit k( phytona )I.M routine 1mg Def due to chronic use of antibiotics Antidote to oral anticoagulants Osteoporosis adjuvant

Other coagulants:

Other coagulants 5.Adrenochrome semicarbazone – decrease capillary fragility,control microvessel bleeding 6.Antifibrinolytics : Decrease fibrinolytic activity Fibrinolysis – dissolution of blood clot Eg of antifibrinolytics :Amino caproic acid(EACA) Tranexemic acid is better tolerated ,7-10 times more potent than EACA ,high dose – DVT Aprotinin Rutin -plant glycoside used along with vit c Ethamsylate - Anti hyaluronidase activity

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Th.uses : 1.Over dose of fibrinolytics 2.Traumatic and surgical bleeding -prostatectomy, tonsillectomy, tooth extraction 3.Abruptio placentae, PPH, menorrhagia( meftal spas+tranexamic acid combo),recurrent epistaxis. 4.Adjuvant therapy in haemophilia Adverse reactions: Vomiting, diarrhea, abdominal discomfort, dyspepsia,Hypotension , conjunctival erythema, Nasal stuffiness Rare but lethal DIC.

7.Local hemostatics -styptics:

7.Local hemostatics -styptics control bleeding from a local and approachable site Local application-Tooth extraction,abrasions,nasal bleeds Eg : Thrombin Fibrin sealant-fibrinogen and aprotinin –biodegradable-powder, patch Gelatin foam Oxidized cellulose strips 0.1% epinephrine soaked in sterile cotton gauze 1% tannic acid -astringent Ice(natural)

8.Sclerosing agents:

8.Sclerosing agents Irritants which cause inflammation,coagulation and fibrosis Used in varicose veins, heamorrhoids Local injection only Eg : phenol 5% Hypertonic saline Ethanolamine oleate Sodium tetradecyl sulphate

Anticoagulants:

Anticoagulants Drugs which helps prevent the clotting of blood. prevent formation of new clots or an existing clot from enlarging. They don't dissolve already formed blood clot. Natural : Prostacyclin PG I2 –platelet aggregation Antithrombin –Inactivates factor 2 Heparan sulfate(leech)-not heparin –increase activity of antithrombin Protein C- Inactivates 5,7

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1.Drugs used in vivo:- Parenteral anticoagulants : Heparin, Heparinoids-Heparan sulfate,Dermatan sulphate,hirudin,Lepirudin,Ancrod Oral anticoagulants : Coumarin derivatives: Bishydroxycoumarin ( dicumarol ), Warfarin sodium Indandione derivative:-Phenindione 2.Used in vitro : Heparin(150 U to prevent clotting of 100 ml blood.) Calcium complexing agents:- Sodium citrate & Sodium oxalate Heparin-both in vivo and In vitro

Heparin:

Heparin McLean, a medical student ,discovered that liver contains a powerful anticoagulant.Howell and Holt named it ‘HEPARIN’ -obtained from liver. Mixture of mucopolysaccharides with MW 10,000 to 20,000. It contains D-glucosamine-L-iduronic acid and D-glucosamine-D-glucuronic acid It carries strong electronegative charge and is the strongest organic acid present in the body. Found in the secretory granules of mast cells. Richest sources are lung,liver and intestinal mucosa. Commercially produced from ox lung and pig intestinal mucosa. Heparin produces its anticoagulant effect by activating plasma antithrombin iii and inhibiting factors 2A and XA

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2 . Other actions of heparin :ANTIPLATELET:- Higher doses inhibits platelet aggregation,prolongs bleeding time,Thrombocytopenia 3. LIPAEMIA CLEARING:-Injection of heparin clears turbid post-prandial lipaemia by releasing a lipoprotein lipase from the vessel wall ANAGONIST:Protamine sulfate:- It is a strongly basic, low molecular weight protein obtained from the sperm of certain fish. Weight basis:I.V . 1 mg is needed for every 100 U of heparin. In the absence of heparin, protamine itself acts as a weak anticoagulant

PHARMACOKINETICS:

PHARMACOKINETICS large, highly ionized molecule; therefore not absorbed orally. I.V. -instantaneously, s.c. injection -after 60 min. Does not cross blood-brain barrier or placenta. safe in pregnancy It is metabolized in liver by heparinase and fragments are excreted in urine.

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Low molecular weight heparins Commercially prepared by fractionation(molecular weight 4000 - 6500) Advantages over conventional heparin: Uniform absorption, Longer duration of action. Less antigenic, less interaction with platelets- Less risk of thrombocytopenia,allergies S.C.,No need of I.V infusion Aptt monitoring isn’t required Examples: ENOXAPARIN,DALTEPARIN,TINZAPARIN,PARNAPARIN,REVIPARIN Fondaparinux - only inactivation of Xa MOA : above picture Block Xa more than IIa

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DALTEPARIN P rophylaxis Therapeutic 2500 U SC 1hr before 100 U / kg BD for 5 surgery, then 2500 U every days. day for 5-7 days. Thrombin inhibitors : Inactivates free as well as fibrin – bound thrombin, does not require antithrombin III like heparin No antidote. Parenteral thrombin inhibitors : Hirudin (leech), lepirudin (Recombinant DNA) Orally used : dabigatran,epixaban,rivoroxiban

ORAL ANTICOAGULANTS:

ORAL ANTICOAGULANTS Given by oral route Teratogenic More drug interactions Eg : Warfarin sodium, Bishydroxycoumarin ( Dicumarol ), Acenocoumarol / Nicomalone , Phenindione

Warfarin:

Warfarin synthetic derivative of coumarin Mechanism of action: Inhibits vitamin K-dependent synthesis of active forms of the clotting factors II, VII, IX and X. Monitoring of PT (time to take the clot to form)is required, Highly protein bound DDI: Increased effect 1.Enzyme inhibitors – mtnz,disulfiram,allopurinol,cemitidine 2.Displace from protein binding sites – phenytoin,probenecid 3.liquid paraffin – increased excretion of vit K 4.long term antibiotics-decreased vit K synthesis and with Aspirin Decreased effect:Enzyme inducers,hereditary resistance,cholestyramine,sucralfate -decrease absorption

MECHANISM OF ACTION 2,7,9,10:

MECHANISM OF ACTION 2,7,9,10

ADVERSE EFFECTS of anticoagulants:

ADVERSE EFFECTS of anticoagulants Bleeding Alopecia Hypersenstivity - Dermatitis,Urticaria Thrombocytopenia Teratogenecity (warfarin)-Fetal warfarin syndrome-hypoplasia of nasal bridge,c.heart defects,Growth retardation,laryngomalacia Warfarin poisoning : increased bleeding,no 2,7,9,10 synthesis TREATMENT : Give fresh blood transfusion(acts immediately)- clotting factors & lost blood. Give vit K-specific antidote-But it doesn’t act immediately It takes 6-24 hours for clotting factors to be re- synthesised & released in blood

TH.USES OF ANTICOAGULANTS:

TH.USES OF ANTICOAGULANTS Heparin and warfarin both are started initially later heparin is discontinued after 5 days and warfarin continued .warfarin action starts only after 3-4 days USES :- 1.Prophylaxis of Deep vein thrombosis and pulmonary embolism. In bed ridden patients and those undergoing knee, hip replacement surgeries 2.Myocardial infarction 3.Unstable angina 4.Rheumatic heart disease; Atrial fibrillation 5.During bypass surgery ,Vascular surgery 6.prostatic heart valves, retinal vessel thrombosis, hemodialysis. 7.D.I.C

Fibrinolytic system & drugs:

Fibrinolytic system & drugs FIBRINOLYSIS: Process of dissolution of clot Once damage is repaired ,clot is dissolved Drugs – plasminogen activators / fibrinolytics 6 are available Streptokinase- natural,urokinase , alteplase (recombinant) tenecteplase,reteplase,antistreplase MOA: Plasminogen incorporates into clot and release TPA from endothelial cells and activates plasmin –enzyme which digests fibrin

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Th uses: Acute M.I in 12 hrs –AS SOON AS POSSIBLE DVT , pul embolism ADRs: Heamorrhage Hypersensitivity- streptokinase Don’t repeat within 1yr

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ANTI PLATELET DRUGS I. Prostacyclin (PGI 2 ) II. Inhibitors of TXA 2 formation eg : Aspirin III. ADP receptor antagonists eg : Ticlopidine, Clopidogrel IV.PDE inhibitors eg : Dipyridamole V.Glycoprotein IIb/ IIIa antagonists eg : Abciximab VI. TP receptor antagonist:Tirotroban Prostacyclin Inhibits platelet aggregation by stimulating adenylate cyclase leading to increased cAMP Vasodilatation,Hypotension , headache and intense facial flushing. t ½ 3 mts.

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INHIBIT PLATELET AGGREGATION

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2.ASPIRIN Prevents synthesis of TXA2 by inhibiting COX and TX synthetase Dose related Th uses : 1.75-100mg for unstable angina, M.I. prophylaxis ( platelet aggregation inhibition ) 2.300-600 mg -Analgesic 3.3-6 gm/day – O.A,R.A(anti-inflammatory) 4. 50mg/kg body Wt -Cataract progression prevention(Recent )

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3.CLOPIDOGREL & TICLOPIDINE Reduce platelet aggregation by inhibiting the ADP pathway of platelets Adverse effects: Nausea,Dyspepsia,Diarrhoea,Haemorrhage Dosage: Clopidogrel 75mg orally 4.DIPYRIDAMOLE,Cilostazole Acts by inhibiting PDE leading to cAMP resulting in potentiation of PGI 2 induced Platelet inhibition.

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5.GLYCOPRTEIN IIb / IIIa RECEPTOR ANTAGONISTS Normally Gp is in inactive state which wont support binding of fibrinogen On activation of platelets, receptors-become active-binding of fibrinogen-platelet aggregation Eg : Abxicimab (Human monoclonal antibody), eptifibatide,tirofiban TP receptor antagonist: Txa2 receptors on platelets (TP ) receptors inhibited by terutroban-3 actions-anti platelet,V.D,Anti atherosclerotic

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Th.Uses : 1.Prevention of M.I reinfarction –low dose 75mg aspirin/75mg aspirin +75mg clopidogrel 2.Preventing occurrence of M.I in patients with unstable angina 3.Coronary bypass implants – patency maintenance 4.Preventing C.V.A, T.I.A 5.Patients undergoing coronary bypass surgery & angioplasty. 6.Prosthetic heart valves 7.DVT prophylaxis before surgeries

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