3rd unit coagulant and anticoagulant ppt

Introduction.
Classification .
Drugs used in Coagulant and Anticoagulant Agents
Mechanism of action .
Structure
Synthesis
Adverse Drug Reactions .
Uses.
Reference

1. 3 rd UNIT COAGULANT AND ANTICOAGULANT Prepared by G. Nikitha, M.Pharmacy Assistant Professor Department of Pharmaceutical Chemistry Sree Dattha Institute Of Pharmacy Hyderabad 1 Subject: Medicinal Chemistry-II Year: B.Pharmacy 3 rd Year Semister: 1 st Semister

2. Contents Introduction. Classification . Drugs used in Coagulant and Anticoagulant Agents Mechanism of action . Structure Synthesis Adverse Drug Reactions . Uses . Reference 2

3. COAGULANT AGENTS 3

4. Introduction COAGULANT: Coagulant drugs mean (the clotting of blood) the conversion of fluid blood to solid gel or clot. 4

5. COAGULANT FACTOR S Factor I - fibrinogen . Factor II -   prothrombin . Factor III  - tissue thromboplastin (tissue factor) Factor IV - ionized calcium ( Ca++ ) Factor V  - labile factor or proaccelerin . Factor VI  - unassigned. Factor VII  - stable factor or proconvertin . Factor VIII - antihemophilic factor-A Factor IX - plasma thromboplastin component, Christmas factor Factor X - Stuart- Prower factor or antihemophilic factor-C Factor XI - plasma thromboplastin antecedent Factor XII - Hageman factor Factor XIII - fibrin-stabilizing factor 5

6. MECHANISM OF B LOOD CLOTTING 6

7. Classification I. Vitamin k 1. From Plant source (Fat soluble): Phytonadione ( Phylloquinone ) 2. Synthetic: a. Fat soluble: Menadione , Acetomenapthone , Acetomenadione . b. Water soluble: Menadione sodium Bisulfide , Menadione sodium Diphosphate. 3. Miscellaneous: Fibrinogen (human), Antihaemophilic factor, Desmopressin , Adrenochrome , Monosemicarbazone , Rutin , Ethamsylate . 7

8. Menadione Structure: IUPAC: 2-methyl-naphthalene-1,4-dione Properties: Bright yellow crystals, Very faint acrid odor, slightly soluble in ethanol, acetic acid, and ligroin. Soluble in ethyl ether, benzene, chloroform, and sulfuric acid, Soluble in aromatic solvents. 8 Molecular Formula: C 11 H 8 O 2

9. Pharmacokinetics: After administration, Menadione is moderately absorbed in the GIT via the biliary route. Menadione accumulates in the liver. Menadione does not cross the placental barrier. Adverse Drug Reactions: Liver damage Brain damage Death occurs in rare cases This drug is banned by US FDA because of toxic effects Hemolytic anemia Therapeutic Uses: Used as nutritional supplements in animal feed. In research, it is used in combination with vitamin-C for the treatment of prostate cancer. 9

10. Dose: Intramuscular route: Severe hypoprothrombinaemia Adult:  2.5-10 mg daily. Intravenous route: Vitamin K deficiency Adult:  0.03 mcg/kg/day. Child:  Infants: 1-5 mcg/kg/day. Oral Severe hypoprothrombinaemia Adult:  10 mg 3-4 times daily. Oral Vitamin K deficiency Adult:  10 mg every 6 hr 10

11. Acetomenadione Structure: IUPAC: 2-Methyl-1,4-naphthalenediol Diacetate Properties: White to pale yellow solid, odorless or with a slight odor of acetic acid insoluble in water slightly soluble in cool alcohol 11 Molecular Formula: C 15 H 14 O 4

12. Pharmacokinetics: Oral, I.V route of administration, metabolized in liver, undergoes renal elimination. Adverse Drug Reactions: Dizziness, Flushing Irritation of skin, respiratory tract Hypersensitivity, Hyperbilirubinemia in premature infants Therapeutic Uses: It is used to prevent, control, treat, the coagulant disorder due to vitamin-K deficiency 12

13. Dose: Adults: By Mouth : For osteoarthritis: A combination product ( Wobenzym PS), providing 600 mg of rutin , 288 mg of trypsin , and 540 mg of bromelain in divided doses has been used. 13

14. ANTI- PLATELET AGENTS 14

15. Introduction Anti-platelets drugs are the agents that act against platelet function. Anti-platelets drugs prevent the formation of clot in case of vascular injuries. They inhibit platelet aggregation and thrombus formation . Antiplatelet are more effective in arterial circulation where as Anticoagulants are ineffective. 15

16. Classification 1. COX-1 inhibitor: Aspirin 2. Thienopyridine derivatives adenosine diphosphate: Clopidogrel , Ticlopidine 3. Adenosine deaminase and phospodiesterase inhibitor and adenosine reuptake inhibitors: Dipyridamole , Cilostazole 4. Glycoprotein GP IIb / IIIa inhibitor: Abciximab , Eptifibatide , Tirofiban 16

17. Clopidogrel Structure: IUPAC: methyl-2-(2-chlorophenyl)-2-{thieno-pyridine-5-yl}acetate Properties: White crystals, soluble in water, methanol, Clopidogrel hydrogen sulfate 17 Molecular Formula: C 16 H 16 ClNO 2 S

18. Pharmacokinetics: More than 50% 0f drug gets absorbed upon oral administration. It is a Prodrug which is metabolized by cytochrome enzyme P450 to give an active metabolite that is responsible for antiplatelet activity. Oral dose is excreted in urine, faeces . Adverse Drug Reactions: Headaches or dizziness. Nausea. Diarrhea or constipation. Indigestion (dyspepsia) Stomach ache or abdominal pain. Nosebleeds. Increased bleeding (your blood taking longer to clot – for example, when you cut yourself), or easy bruising. 18

19. Therapeutic Uses: It is prescribed for the prevention of  heart attack, stroke or transient ischaemic attack (TIA) Clopidogrel when combined with aspirin is beneficial for acute coronary syndrome (minor heart attack or unstable angina), a coronary stent (a device to open up a blocked artery to the heart) It is used in an open heart operation It is used in the treatment of peripheral arterial disease It is used in a vascular operation. Dose: 75mg/day without taking food. 19

20. ANTI-COAGULANT AGENTS 20

21. ANTI-COAGULANT: Anti- Coagulants are the drugs which extend or prolong the coagulation time of blood. Anticoagulants are indicated for the patients which acute myocardial infarction in the long term therapy and in treatment of pulmonary and venous thrombosis. When prevention or extension of thrombus formation is desired anticoagulant therapy serves as the best option. 21 ANTI-COAGULANT

22. Ideal characteristics for anti-coagulants agents: It should have rapid Onset of action. Wide therapeutic index and long duration of action. Minimal adverse drug effects. Minimal interaction with drugs and food and should not result into any life threatening complications. Pharmacokinetics, pharmacodynamics aspects of drug should be reproducible such that monitoring blood coagulation is not essential. 22

23. Classification A. Based on action: 1. Directly Acting Anticoagulants: High Molecular Weight Heparin (HMWH) Low Molecular Weight Heparin (LMWH): Dalteparins , Enoxaparin New Heparin Derivatives: Fondaparinux , Idraparinux 2. In Directly Acting Anticoagulants: Coumarin Derivative: Dicumarol , Warfarin Indanedione Derivative: Phenindione , Anisindione 23

24. B. Based on route of administration: 1. Injectable Anticoagulants: Heparin Low Molecular Weight Heparin Heparinoids : Heparin sulphate, Danaparoid , Ancrod , Lepirudin Miscellaneous Drugs: Bivalirudin , Hirudin 2. Oral Anticoagulants: Coumarin Derivative: Dicumarol , Warfarin sodium, Acenocumarol Indanedione Derivative: Phenindione , Anisindione 24

25. Warfarin Structure: IUPAC: 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one It is an anti-coagulant is considered to be the drug of choice for maintaining an extended anticoagulant effect, initially it was considered to be unsafe in human. Properties: White crystalline powder, slightly bitter in taste, very slightly soluble in water, soluble in alcohol. 25 Molecular Formula:C 19 H 16 O 4

26. Synthesis: Step-I: Synthesis of 4-hydroxy Coumarin from Methyl Salicylate 26

27. Step-II: Michael Addition of 4-hydroxy Coumarin with Benzolactone 27

28. Mechanism of Action: The activation of factors II, VII, IX, and X depends upon reduced form of vitamin K and enzyme carboxylase . Due to structural similarity of warfarin with vitamin K, competes with the latter for reductase an enzyme which activates vitamin K is inhibited and therefore post translational ϒ-carboxylation of glutamic acid residues of factors II, VII, IX, and X I also inhibited. 28

29. Pharmacokinetics: Upon oral administration the drug gets completely absorbed from GIT. Pharmacological effects reach maximum level after 2 days of ingestion of the drug. It is metabolized in the liver mixed function oxidase P450 system. Adverse Drug Reactions: unusual bruising, such as: unexplainable bruises, bruises that grow in size Nosebleeds, bleeding gums, coughing up blood bleeding from cuts that takes a long time to stop heavier than normal menstrual or vaginal bleeding pink or brown urine, red or black stools Purple toes syndrome. Symptoms may include: pain and purple or dark color in your toe Death of skin tissue. This may happen when blood clots form and block blood flow to an area of your body. Symptoms may include: pain, color or temperature change to any area of your body, 29

30. Therapeutic Uses: Warfarin is used to treat blood clots and to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions if they form in your legs or lungs. reduce the risk of risk of heart attack, stroke, or death prevent and treat blood clots with  atrial fibrillation or heart valve replacement prevent and treat blood clots in parts of the body such as the legs (deep vein thrombosis) and in the lungs (pulmonary embolism) Dose: Warfarin is given in a dose of 10-15mg/day from the 3 rd or 4 th day of heparin therapy 30

31. Anisindione Structure: IUPAC: 2-(4-methoxyphenyl)-2,3-dihydro-1H-indene-1,3-dione Properties: Fine white to cream white crystalline powder, odorless or has slightly sweet odor, slightly soluble in ether, methanol, hydrochloric acid, insoluble in water, soluble in methylene chloride. 31 Molecular Formula: C 16 H 12 O 3

32. Pharmacokinetics: Oral route of administration, metabolized in liver excreted through urine Adverse Drug Reactions: Pyrexia Nausea, vomiting, diarrhea.   Hemorrhage.  Dermatitis, urticaria , alopecia. Sore mouth, mouth ulcers Abnormal bleeding Blurred vision Hemorrhage Thrombocytopenia 32

33. Therapeutic Uses: It prevents the formation of active procoagulation factors II, VII, IX, X. Dose: Anticoagulation: Adult: PO 300mg day1, 200mg day2, and then 100mg q.d . adjust dose to maintain desired PT level (dose range 25-250 mg) 33

34. Reference books Text book of Medicinal chemistry volume-1-3 rd edition by V.Alagarasamy. Text book of Medicinal chemistry volume-2-3 rd edition by V.Alagarasamy. Medicinal chemistry by Rama Rao Nadendla. Faye’s Principles of Medicinal Chemistry- 7 th edition by Thoms L.Lemke , Victoria F.Roche , S. Willam Zito . Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K Kapoor . 34

35. THANK YOU 35