COAGULANTS,ANTICOAGULANTS

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COAGULANTS,ANTICOAGULANTS:

COAGULANTS,ANTICOAGULANTS Dr.Ramya.R M.D.PHARMACOLOGY

coagulation:

coagulation

COAGULANTS:

COAGULANTS Agents which promote coagulation used in heamorrhagic states like heamophilia Do not dissolve already formed clot They prevent clot/thrombus extension Eg : Fresh whole blood,plasma Drugs: 1.vitamin K –K1- from plants- phytonadione K2-Menaquinone K3-Fat soluble- menadione Water soluble- menadoine sod bisulfate m.sod.diphosphate Others: fibrinogen,antiheamophilic factor,ethamsylate,rutin,adrenochrome

Vitamin K:

Vitamin K Fat soluble vitamin used for synthesis of clotting factors 2,7,9,10 by gamma carboxylation of glutamate residues of zymogen proteins( C.factors 2,7,9,10) Structure : Naphthoquinone ring with aliphatic side chain

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RDA: 50-100mcg /day for adults Utilization: Absorbed from intestine Needed bile salts Synthesized from intestinal flora Stored in liver Metabolized in liver by side chain cleavage and glucoronide conjugation Excreted in bile and urine Toxicity of vit k : Rapid IV injection- flushing,breathlessness,BP fall Heamolysis in G6PD def Newborns – kernicterus

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Def: Due to liver disease,malabsorbtion,long term antimicrobial therapy, obstructive jaundice –all these alter microbes in intestine Symptoms: bleeding tendencies,heamaturia,epistaxis,ecchymoses Th.uses : prophylaxis and treatment of bleeding due to def of clotting factors 1.Dietary def : 5-10mg oral/IM 2.prolonged antimicrobial therapy,Ob ja,malab – sprue,iletis,steatorrhea – vit 10mg IM along with bile salts

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Newborns: low levels of clotting factors ,more in premature babies. Vitamin K 1mg IM K3 should not be used Over dose of anticoagulants overdose K1 is the choice Based on Hypoprothrombinemia Severe: 10mg IM-5mg every 4 th hrly Moderate : 10mg IM -5mg once Mild –omit few doses of anticoagulants High dose salicylate therapy - hypopro

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Other coagulants : Fibrinogen: Heamophilia , AHG def Antiheamophilic factor : conc form of AHG obtained from pooled human plasma Same uses Ethamsylate : Reduce capillary bleeding – antihyaluronidase activity ,inhibit PGI2 –no VD Uses : Menorrhagia,PPH,epistaxis ADRs:Nausea,headache,rash 250mg,500mg

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Local haemostatics -styptics : Stop bleeding from local approachable site Eg : 1.Thrombin - haeamophilia 2.Fibrin-haeamophilia 3.Gelatin foam-spongy gelatin in various shapes for packing wounds 4.Russels viper venom 5.Vasoconstrictors 6.Astringent-tannic acid for bleeding gums ,piles Sclerosing agents: Irritants cause inflammation,firbosis –piles ,varicose veins Phenol,ethanolamine oleate,sod tetradecyl sulphate

Anticoagulants:

Anticoagulants Drugs used to reduce coagulability of blood 2 types : 1. In vitro: Heparin,ca complexing agents-sod citrate,sod oxalate,sod edetate 2.In vivo: A.parenteral : Heparin,LMW heparins,heparinoids-heparan sulphate,danaparoid,hirudin,lepirudin,desirudin,agratrobanancrod B.Oral – coumarin : warfarin,acumarol Indandione-phenindione

Heparin:

Heparin Mc lean medical student discovered Obtained from liver M.P. with M.W 10K-15K D glucosamine L iduronic acid with D glucosamine D glucaronic acid E.N charge,strongest acid in body Present in mast cells Lung,liver,intestine

Actions and MOA:

Actions and MOA 1.Anticoagulant: Inhibits coagulation indirectly

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XA: II A – 1:1 Acts only on intrinsic and common pathway Not related to extrinsic pathway Prolongs aptt not pt 2.Antiplatelet: inhibits platelet aggregation at high conc and prolong B.T 3.Lipemia clearing: post prandial lipemic clearance due to release of lipoprotein lipase Dose less than needed for anticoagulation

P.K :

P.K ROA : Not absorbed orally S.C.60min I.V. Pregnancy : Doesn’t cross placenta/BBB so choice in pregnancy T1/2 long in cirrhosis, kidney failure Dose 5000-10000 I.U. Low dose S.C. 5000I.U. every 8 hrs started before surgery and continued till 10 days to prevent DVT

ADRs, CI:

ADRs, CI Bleeding – M.C Heamaturia 1 st sign Thrombocytopenia due to aggregation of platelets Heparin –platelet complexes- Abs developed –depletion - discontinue Alopecia Osteoporosis Hypersensitive reactions

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C.I – Bleeding disorders,thrombocytopenia,severe HTN –cerebral heamorrhage,threatened abortion,piles Ocular ,neuro surgery Lumbar puncture T.B with hempotysis Cirrhosis Renal failure Chronic alcoholics SABE – Embolism Malignancy- central nectrotic bleeding

LMW Heparins:

LMW Heparins Fractioned to M.W 3000-7000 Inhibit XA mainly ,v. little effect on IIA because more than 18 polysacchride units are required,XA:IIA - 2/3:1 Do not bring together ATIII and Thrombin Advantages over heparin : No much effect on aptt than heparin Less antiplatelet action-less thrombocytopenia Less hemorrhages Better SC bioavailability – 70% Long t1/2- once daily No need of lab monitoring of aptt like heparin Dose no confusion- in mg unlike units for heparin

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Th.uses : Equally efficacious in prevention of DVT and embolism in P.O. patients Treatment of DVT Unstable angina To maintain patency of shunts and cannulae in dialysis patients Ex: Enoxaprin - 20mg and 40mg Reviparin,Nadroparin , Dalteparin,Ardeparin,pamparin

Heparinoids:

Heparinoids Heparan sulphate Danaparoid Lepirudin Ancrod Heparins Antagonist: protamine sulphate -basic compound obtained from sperm of fish 1mg neutralize 100IU heparin Needed when action needs to be terminated immediately like after cardiac or vascular surgery Basic - Histamine release-HSTV reactions

Oral anticoagulants:

Oral anticoagulants They act indirectly by interfering with synthesis of vit k dependent clotting factors so acts only invivo They prevent activation of vit k and final step that is gamma carboxylation of glutamate residues of 2,7,9,10 factors

Slide 22:

Factor 7 levels fall first .2 last basing on their half life PT is elevated .involves only with extrinsic pathway Anticoagulant effect develops slowly 10-15mg loading dose Effect lasts for 6days Warfarin exhibits chimerism S – levo form is more potent 99% PPB More DDI with drugs with high PPB Crosses placenta and secreted in B.milk so, CI

Slide 23:

ADRs: Bleeding tendencies Ecchymosis,epistaxis,heamaturia.GI bleeding ,intra cranial heamorrhages So proper monitoring of PT is needed Others: alopecia,dermatitis,diarrhea Treatment : with hold anticoagulant Fresh blood/plasma Vit K1 specific antidote

DOSE REGULATION :

DOSE REGULATION Individualised based on PT/INR Factors enhancing effect: malnutrition,mal absorption,prolonged antibiotic therapy Liver disorders Hyperthyroidism Newborns Decreasing effect : Pregnancy Nephrotic syndrome Genetic resistance

Slide 25:

CI : SAME LIKE HEPARIN Pregnancy: foetal warfarin syndrome – hypoplasia of nose ,eye sockets ,hand bones growth retardation CNS defects ,death later DDI : Enhanced action: broad spectrum antibiotics Cephalosporins 3 rd gen Aspirin- bleeding Phenylbutazone,probenicid,phenytoin Liquid paraffin – vit k absorption Enzyme inhibitors

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Reduced anticoagulant effect: enzyme enhancers Ocpills –enhance clotting factors Th.uses of A.c . Heparin-rapid action ,short term , P.O.discontinued after 4-7 days started with warfarin Warfarin – maintanence 1.DVT , P.embolism : venous thrombi Prophylaxis in p.o,p.p,p.s patients Prolonged immobilization patients prophylactic Low dose LWM heparin for those who are undergoing elective surgery

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2.MI: arterial thrmobi -platelets A.c prevent mural thrombus at infarction site nd prevent leg vein thrombus Heparin 2-8 days plus warfarin till 3months Heparin given during coronary angioplasty and stent placement 3.Unstable angina: MI prevent.aspirin + heparin+warfarin 4.RHD,AF: embolus prevention 5.CVD: cerebral thombus prevention TIA – antiplatelets preferable

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6.Other s: Vascular surgery Retinal vessel thrombus Prosthetic heart valves Extracorporeal circulation Heamodialysis Defibrination syndrome/DIC-clotting factors are used for intravascular thrombus formation Blood is incoagulable Heparin helps paradoxically by preserving clotting factors

Heparin s warfarin:

Heparin s warfarin

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