ANTI-COAGULANTS

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Hello friends....!!Myself Vishnu.R.Nair...a third year Pharm.D (Doctor od Pharmacy) student, from Calicut, Kerala state.... This is my first entrance into this site.....where i publish my first ppt on ANTICOAGULANTS........Hope the ppt helps and is worthwhile !! Thank you !! :)

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ANTI-COAGULANTS : A BRIEF OUTLOOK:

ANTI-COAGULANTS : A BRIEF OUTLOOK PRESENTED BY: VISHNU.R.NAIR PHARM-D THIRD YEAR NATIONAL COLLEGE OF PHARMACY (NCP), KERALA STATE SUBJECT : PHARMACOLOGY

INDEX::

INDEX: DEFINITION OF ANTICOAGULANTS CLASSIFICATION BLOOD CLOTTING FACTORS BRIEF OUTLOOK OF PARENTERAL ANTICOAGULANTS BRIEF OUTLOOK OF ORAL ANTICOAGULANTS BIBLIOGRAPHY

 DEFINITION OF ANTICOAGULANTS  ::

 DEFINITION OF ANTICOAGULANTS  : “ Drugs, that are used to reduce the COAGULABILITY (coagulating capacity) of blood “……………………………..

 Classification of anti-coagulants  ::

 Classification of anti-coagulants  : IN – VIVO DRUGS : PARENTERAL ANTICOAGULANTS: HEPARINS: High molecular weight Heparins : Unfractionated heparin (UFH) 2. Low molecular weight Heparins : Enoxaparin Dalteparin Tinzaparin

CONTINUED………………………….:

CONTINUED…………………………. Reviparin Danaparoid B. HEPARINOIDS: Heparan sulphate Hirudin Lepirudin Bivalirudin Argatroban

CONTINUED……………………………..:

CONTINUED…………………………….. ORAL ANTICOAGULANTS: COUMARIN DERIVATIVES: Bishydroxycoumarin (Dicumarol) Warfarin sodium Acenocoumarol (Nicoumalone) Ethyl biscoumacetate 2. INDANDIONE DERIVATIVES : * Phenindione

CONTINUED……………………………..:

CONTINUED…………………………….. IN – VITRO DRUGS: Heparin Sodium citrate (used in blood banks to store blood) Sodium oxalate (used as anticoagulant in laboratory) Sodium edetate (used as anticoagulant in laboratory)………………….

 Blood clotting factors  ::

 Blood clotting factors  : FACTOR I : FIBRINOGEN FACTOR II : PROTHROMBIN FACTOR III : TISSUE FACTOR / THROMBOPLASTIN FACTOR IV : CALCIUM FACTOR V : PROACCELERIN (LABILE FACTOR ) FACTOR VI : NOT AN INDEPENDENT FACTOR FACTOR VII : PROCONVERTIN (STABLE FACTOR) FACTOR VIII : ANTI-HEMOPHILIC FACTOR (GLOBULIN) ‘A’ FACTOR IX : ANTI-HEMOPHILIC FACTOR ‘B’ (CHRISTMAS FACTOR)

CONTINUED…………………………………:

CONTINUED………………………………… FACTOR X : STUART- PROWER FACTOR FACTOR XI : PLASMA PROTHROMBIN ANTECEDENT FACTOR FACTOR XII : HAGEMANN FACTOR FACTOR XIII : FIBRIN- STABILIZING FACTOR (LAKI-LORAND FACTOR)…………………………

 PARENTERAL ANTICOAGULANTS  ::

 PARENTERAL ANTICOAGULANTS  : Here , we will discuss on HEPARIN and associated HEPARINOIDS………………….

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 HEPARIN 

1. GENERAL PROPERTIES ::

1. GENERAL PROPERTIES : Discovered by McLean Howell and Holt named the word “HEPARIN” in 1918 Mainly occurs in MAST CELLS Richest source of MAST CELLS: Lungs Liver Intestinal mucosa Commercial heparin is synthesized from : Porcine intestinal mucosa Bovine lungs

CONTINUED……………………………….:

CONTINUED………………………………. HEPARIN : A mixture of STRAIGHT CHAIN (ANIONIC) GLYCOSAMINOGLYCANS, with a wide range of molecular weights Strongly acidic, due to the presence of sulphate and carboxylic acid groups………………………..

2. MECHANISM OF ACTION (M.O.A) OF HEPARINS ::

2. MECHANISM OF ACTION (M.O.A) OF HEPARINS : At low doses, heparin shows 2 actions: Inactivates FACTOR Xa Inhibits conversion of PROTHROMBIN to THROMBIN At high doses, heparin shows 2 actions: Inactivates factors IX, X, XI, XII, and thrombin Inhibits conversion of FIBRINOGEN to FIBRIN Drug  inhibits activation of FACTOR VIII Overall precisely: Drug  binds to Antithrombin-III  forms ‘Heparin- AT-III complex’  inactivates clotting factors Xa, IIa, IXa, XIIa, and XIIIa…….

PICTORICAL REPRESENTATION OF HEPARIN MOA::

PICTORICAL REPRESENTATION OF HEPARIN MOA:

3. COMPARISON BETWEEN LOW AND HIGH MOL. WT. HEPARINS::

3. COMPARISON BETWEEN LOW AND HIGH MOL. WT. HEPARINS: CRITERIA HMW HEPARINS LMW HEPARINS Molecular weight High (30,000 Daltons) Low (5,000 Daltons) Biotransformation Low High (90%) Half-life Shorter (dose- dependent) Longer (dose- independent) M.O.A Inactivates both factor IIa, and Xa Inactivates Xa Anti-coagulant effect More effective Less effective Monitoring By a PTT ( Activated prothrombin time ) Can be given once or twice daily without monitoring ADRs High risk of thrombocytopenia, long term osteoporosis Less chance of thrombocytopenia and long term osteoporosis Excretion Cleared by reticuloendothelial system Cleared unchanged by kidneys Reversal By protamine Not fully reversed by protamine Expense Not expensive Expensive

4. ADVANTAGES OF LMWH OVER HMWH ::

4. ADVANTAGES OF LMWH OVER HMWH : Better s.c availability: LMWH : 70-90% HMWH : 20-30 % Better and consistent half life Since a PTT/ clotting times are not prolonged  LMWH requires fewer lab monitorings Lower incidence of hemorrhagic complications LMWH  Decreased antiplatelet action  decreased interference with thrombosis…………………………….

5. PHARMACOKINETICS OF HEPARIN::

5. PHARMACOKINETICS OF HEPARIN: HEPARIN  Highly charged  poorly crosses cell membranes  thus given parenterally For low dose : give s.c For high dose : give s.c and i.v Metabolism : by liver Half-life depends on dose given………………………….

6. PHARMACOLOGICAL ACTIONS OF HEPARIN ::

6. PHARMACOLOGICAL ACTIONS OF HEPARIN : ANTICOAGULANT ACTIVITY: Powerful and instantaneous acting anti-coagulant Effective both in-vivo and in-vitro Sudden stoppage of conventional- dose therapy  causes rebound increase in coagulability for few days B. ANTI-PLATELET EFFECT: In high doses, heparin has 2 effects : Inhibits platelet aggregation Prolongs bleeding time

CONTINUED……………………………….:

CONTINUED………………………………. 3. IN LIPAEMIA CLEARING: - HEPARIN (low dose), when injected  causes release of LIPOPROTEIN LIPASE from vessel wall and tissues  Hydrolyzes triglycerides of chylomicra and VLDLs to Free Fatty Acids  causes clearing of post-prandial lipaemic plasma (plasma looks clear)……………………………….

7. ADRs OF HEPARIN::

7. ADRs OF HEPARIN: Bleeding (most common) Allergy Anaphylaxis Alopecia Long term osteoporosis  spontaneous susceptibility to fractures Thrombocytopenia: Once thrombocytopenia is determined  stop heparin  give DIRECT THROMBIN INHIBITOR - Do not give platelets  platelets react with antibody already being produced by human  increased chance of thrombosis………………

8. DRUG INTERACTIONS OF HEPARIN ::

8. DRUG INTERACTIONS OF HEPARIN : HEPARIN + CORTICORELIN  Increased toxicity of CORTICORELIN  increased risk of SEVERE HYPOTENSION HEPARIN + MIFEPRISTONE  Excessive post abortion bleeding HEPARIN + ASPIRIN  Both increase anticoagulation  dangerous interaction HEPARIN + FLUOROURACIL  Both increase bleeding effects HEPARIN + MIPOMERSEN  Increased hepatic enzymes level…………………..

9. HEPARIN IN PREGNANCY ::

9. HEPARIN IN PREGNANCY : Drug  does not cross placenta  should be used instead of warfarin in pregnancy Warfarin  crosses placenta  causes changes in fetus to cause fetal warfarin syndrome  not good…………………..

10. CONTRAINDICATIONS OF HEPARIN ::

10. CONTRAINDICATIONS OF HEPARIN : Documented hypersensitivity Bleeding disorders (hemophilia) Thrombocytopenia Intracranial hemorrhage GI ulcerations Threatened abortion Advanced renal/ hepatic disease……………………..

11. FOR HEPARIN TOXICITY ::

11. FOR HEPARIN TOXICITY : Give antidote as PROTAMINE SULPHATE Protamine  combines with heparin  forms stable complex  devoid of anticoagulant activity Also used to reverse hemorrhage if 1 mg of protamine is given / 100 U of heparin……………………

12. USES OF HEPARIN ::

12. USES OF HEPARIN : Treatment and prevention of DEEP VEIN THROMBOSIS (DVT) in: Immobilized patients (bedridden) Old people Post-operative Post-stroke patients Leg fractures Elective surgery In IHD: For unstable angina, Post MI After angioplasty, CABG, Stent replacement  For prophylaxis

CONTINUED…………………………………….:

CONTINUED……………………………………. c. In Rheumatic Heart Disease/ Atrial Fibrillation: Decreases stroke due to emboli d. In cerebrovascular diseases: In cerebral emboli (to prevent recurrence) e. In vascular surgery, prosthetic heart valves, hemodialysis : To prevent thromboembolism f. In Defibrination syndrome/ DIC: - To prevent malignancies / infections…………………

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 ASSOCIATED HEPARINOIDS 

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They are drugs, that bind to thrombin without additional binding proteins such as anti-thrombin HIRUDIN and BIVALIRUDIN : Bind at both catalytic and / active site of thrombin Also bind at substrate recognition site 3. ARGATROBAN : Binds only at thrombin active site 4. LEPIRUDIN : Monitored by a PTT Action independent of anti-thrombin

CONTINUED……………………………………..:

CONTINUED…………………………………….. Used in thrombosis related to heparin induced thrombocytopenia No antidote available ADR: Antibody formation against thrombin-Lepirudin complex 5. BIVALIRUDIN : Inhibits platelet activation Used in percutaneous coronary angiography 6. ARGATROBAN : Used in heparin induced thrombocytopenia , with/ without thrombosis Monitored by a PTT Dose is reduced in liver disease………………………

 Oral anticoagulants :

 Oral anticoagulants  Here, we are focusing mainly on WARFARIN……………………….

1. M.O.A OF WARFARIN ::

1. M.O.A OF WARFARIN : WARFARIN  Interferes with hepatic synthesis of Vitamin K dependent clotting factors ( II, VII, IX, and X) , as well as anticoagulant proteins ‘C’ and ‘S’ Drug  depletes functional Vit. K reserves  Competitively inhibits subunit 1 of multi unit Vitamin K epoxide reductase complex 1 (VKOR 1 )  Reduces synthesis of active clotting factors ……………..

2. PHARMACOKINETICS OF WARFARIN ::

2. PHARMACOKINETICS OF WARFARIN : Rapidly and completely absorbed after oral administration 100% bioavailability High plasma protein binding capacity : 99% Crosses placenta  TERATOGENIC Drug  appears in milk  thus, infants are given Vitamin K Shows hepatic clearance Metabolism: By liver , via oxidation, glucuronidation Take 12-16 hours before effect is observed………………..

3. ADRs OF WARFARIN ::

3. ADRs OF WARFARIN : BLEEDING: Common ADR Hematuria GI bleeding Internal hemorrhages CUTANEOUS NECROSIS : Due to decreased activity of Protein ‘C’ INFARCTION OF BREAST, FATTY TISSUES,INTESTINE and EXTREMITIES: Decreased activity of Protein ‘C’  venous thrombosis occurs  causes above symptoms……………………………..

4. HYPO-ACTIVITY OF WARFARIN CAUSES…………..:

4. HYPO-ACTIVITY OF WARFARIN CAUSES………….. Affected pregnancy (due to increase in clotting factors) Nephrotic syndrome Warfarin resistance (Genetic)…………………

5. HYPER-ACTIVITY OF WARFARIN CAUSES……………:

5. HYPER-ACTIVITY OF WARFARIN CAUSES…………… Malnutrition Debility Affects newborns (due to Vitamin K deficiency) Liver disease Chronic alcoholism (due to decrease in clotting factors) Hyperthyroidism (due to increased degradation of clotting factors)………………………………

6. FOR WARFARIN TOXICITY…………………:

6. FOR WARFARIN TOXICITY………………… Stop warfarin Administer Vitamin K (Antidote) The following can also be given : Fresh frozen plasma Prothrombin complex concentrates Recombinant factor VIIa……………………..

7. CONTRAINDICATIONS OF WARFARIN::

7. CONTRAINDICATIONS OF WARFARIN: In pregnancy: Fetal protein in bone and blood affected Birth defects Abnormal bone formation Bone hyperplasia CNS defects Fetal hemorrhage Fetal hypoprothrombinemia Fetal death - Other contraindications same as that of heparin………………

8. DRUG INTERACTIONS OF WARFARIN::

8. DRUG INTERACTIONS OF WARFARIN: PHARMACOKINETIC INTERACTIONS: Drugs, that inhibit warfarin metabolism: Cimetidine Imipramine Co-trimoxazole Chloramphenicol Ciprofloxacin Amiodarone Metronidazole

CONTINUED………………………………..:

CONTINUED……………………………….. ii. Drugs, that increase warfarin metabolism: Barbiturates Rifampin iii. Drugs, that displace warfarin from binding sites on plasma albumin : Chloral hydrate NSAIDs iv. Drugs, that decrease GI absorption of warfarin: - Cholestyramine

CONTINUED………………………………….:

CONTINUED…………………………………. B. PHARMACODYNAMIC INTERACTIONS: Shows synergistic effects with heparin and aspirin Antibiotics +warfarin  decreased bacterial flora  decreased Vitamin K synthesis  increased warfarin effects……………….

9. USES OF WARFARIN ::

9. USES OF WARFARIN : Same as that of heparin and other anticoagulants Monitoring is necessary, due to low therapeutic index Prothrombin Time (PT) should be noted (Time taken for blood to clot) Usually, patients on heparin are shifted to oral warfarin only after 3-5 days…………………………………..

10. GENERAL COMPARISON BETWEEN WARFARIN AND HEPARIN ::

10. GENERAL COMPARISON BETWEEN WARFARIN AND HEPARIN : CRITERIA HEPARIN WARFARIN ROUTE OF ADMINISTRATION Parenteral Oral POLARITY Polar charged molecule Uncharged ONSET OF ACTION Rapid 12-16 hours M.O.A Inactivates clotting factors by AT- III Inhibits gamma-carboxylation of glutamic acid residues of clotting factors THERAPEUTIC INDEX Not low  safe Low  not safe MONITORING Via a PTT Via PT ADRs Alopecia, osteoporosis, thrombocytopenia… Cutaneous necrosis, breast and other fatty tissue infarction…. MANAGEMENT OF PATIENT Start with heparin Switch over to warfarin in 3-5 days ANTIDOTE Protamine sulphate Vitamin K CONTRAINDICATION IN PREGNANCY No Yes INTERACTIONS Not much significant Significant

 BIBLIOGRAPHY  ::

 BIBLIOGRAPHY  : Nichols.W.L ; Bowie E.J.W ; Standardization of Prothrombin Time ; Mayo Clinical Procedure 1993 ; 68 : 897-98 Lippincott’s Pharmacology Reviews Essentials of Medical Pharmacology by Dr. Tripathi. K. D The Pharmacological basis of Therapeutics by GOODMAN and GILMANN www.emedicine.net www.healthline.com

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