coagulants

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COAGULANTS & ANTICOAGULANTS:

COAGULANTS & ANTICOAGULANTS DR.REENA VERMA

Objectives:

Objectives To learn how Blood Clots are formed? How the blood clots are broken down ? What drugs can be used to regulate clotting? How to rectify clotting deficiencies?

Classes of Drugs:

Classes of Drugs Prevent coagulation - anticoagulants Dissolve clots- thrombolytics Prevent bleeding and hemorrhage - Hemostatics Overcome clotting deficiencies (replacement therapies)

Blood Clotting:

Blood Clotting Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase

Vascular Phase:

Vascular Phase Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor

Platelet phase:

Platelet phase endothelial cells prevent platelet adhesion and aggregation platelets contain receptors for fibrinogen and von Willebrand factor after vessel injury Platelets adhere and aggregate. Release permeability increasing factors (e.g. vascular permeability factor, VPF) Loose their membrane and form a viscous plug

Slide 7:

Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fibrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit . K dependent Factors Affected by Oral Anticoagulants

Slide 8:

INTRINSIC PATHWAY All clotting factors are within the blood vessels Clotting slower Activated partial thromboplastin test ( aPTT ) EXTRINSIC PATHWAY Initiating factor is outside the blood vessels - tissue factor Clotting - faster - in Seconds Prothrombin test (PT)

COAGULATION:

COAGULATION Coagulation is a complex process by which blood forms clots. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage ) or clotting ( thrombosis). 9

THE COAGULATION CASCADE:

THE COAGULATION CASCADE 10

COAGULANTS:

COAGULANTS These are substances which promote coagulation, and are indicated in haemorrhagic states. Fresh whole blood or plasma provide all the factors needed for coagulation and are best therapy for deficiency of any clotting factor They also act immediately. 11

VITAMIN K:

VITAMIN K It is a fat soluble dietary principle required for the synthesis of clotting factors. Dietary sources - green leafy vegetables and liver, cheese, etc . acts as a cofactor in the synthesis of coagulation proteins- prothrombin , factors vii, ix and x . The vit K dependent change confers on them the capacity to bind Calcium and to get bound to phospholipid surfaces. 12

DEFICIENCY:

DEFICIENCY Deficiency of vit K :- Liver disease Obstructive jaundice Malabsorption Long-term antimicrobial therapy Deficient diet 13

USE:

USE Dietary deficiency Prolonged antimicrobial therapy Obstructive jaundice/ malabsorbtion syndromes Liver disease Newborns- use phytonadione Overdose of oral anticoagulants Prolonged high dose salicylate therapy 14

Other coagulants:

Other coagulants Fibrinogen Antihemophilic factor Desmopressin Adrenochrome monosemicarbazone Rutin ethamsylate 15

styptics:

styptics Fibrin Gelatin foam Oxidized cellulose Thrombin Vasoconstrictors astringents 16

ANTICOAGULANTS:

ANTICOAGULANTS An anticoagulant is a drug that helps prevent the clotting (coagulation) of blood. These drugs tend to prevent new clots from forming or an existing clot from enlarging. They don't dissolve a blood clot. Anticoagulants are also given to certain people at risk for forming blood clots, such as those with artificial heart valves or who have atrial fibrillation. 17

anticoagulants:

anticoagulants 18

CLASSIFICATION:

CLASSIFICATION Used in vivo:- Parenteral anticoagulants : Heparin, Heparinoids-Heparan sulfate, Danaparoid,Lepirudin,Ancrod . 19

Slide 20:

Oral anticoagulants : Coumarin derivatives:- Bishydroxycoumarin ( dicumarol ), Warfarin sodium Indandione derivative:- Phenindione 20

:

Used in vitro:- A. Heparin(150 U to prevent clotting of 100 ml blood.) B. Calcium complexing agents:- Sodium citrate(1.65 g for 350 ml of blood) Sodium oxalate(10 mg for 1 ml blood) 21

HEPARIN:

HEPARIN McLean - in 1916 that liver contains a powerful anticoagulant. Howell and Holt - in 1918 named it ‘ HEPARIN’ because it was obtained from liver. 22

CHEMISTRY OF HEPARIN:

CHEMISTRY OF HEPARIN Heparin - MW 10,000 to 20,000. It contains polymers of two sulfated disaccharide units: D-glucosamine-L- iduronic acid D-glucosamine-D- glucuronic acid It carries strong electronegative charges and is the strongest organic acid present in the body. 23

OCCURRENCE OF HEPARIN:

OCCURRENCE OF HEPARIN Heparin is found in the secretory granules of mast cells . Commercially it is produced from ox lung and pig intestinal mucosa. 24

PHARMACOLOGICAL ACTIONS:

PHARMACOLOGICAL ACTIONS ANTICOAGULANT:- Heparin - powerful , instantaneously acting -effective both in vivo and in vitro. MOA - by activating plasma antithrombin iii and may be other similar cofactors. 25

MECHANISM OF ACTION:

MECHANISM OF ACTION 15

Slide 27:

27

Heparin mechanism of action:

Heparin mechanism of action Heparin Antithrombin III Thrombin

Inactivation of clotting enzymes by heparin:

Inactivation of clotting enzymes by heparin 16

ROLE OF HEPARIN/ATIII COMPLEX:

ROLE OF HEPARIN/ATIII COMPLEX 30

ACTIONS:

ACTIONS 2. ANTIPLATELET:- in higher doses inhibits platelet aggregation and prolongs bleeding time. 3. LIPAEMIA CLEARING:- release a lipoprotein lipase which hydrolyses triglycerides of chylomicra and very low density lipoproteins to free fatty acids;these then pass into tissues and the plasma looks clear. 31

PHARMACOKINETICS:

PHARMACOKINETICS large, highly ionized molecule; therefore not absorbed orally. Injected i.v . it acts instantaneously,but after s.c . injection anticoagulant effect develops after 60 min. Heparin does not cross blood-brain barrier or placenta. It is metabolized in liver by heparinase and fragments are excreted in urine.Heparin released from mast cells is degraded by tissue macrophages. 32

ADVERSE EFFECTS:

ADVERSE EFFECTS Bleeding due to overdose.Haematuria is generally the first sign. Thrombocytopenia is another common problem. Alopecia -Transient and reversible. Osteoporosis may develop on long-term use of relatively high doses. Hypersensitivity reactions are rare. 33

CONTRAINDICATIONS:

CONTRAINDICATIONS Bleeding disorders, heparin induced thrombocytopenia. Severe hypertension, threatened abortion, piles, g.i.ulcers . Subacute bacterial endocarditis , large malignancies, tuberculosis. Chronic alcoholics, cirrhosis, renal failure. Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy. 34

Low molecular wt. heparin:

Low molecular wt. heparin 35

LMWH:

LMWH MOA-act by inducing conformational change in AtIII &not by bringing together ATIII &thrombin. PK ADVANTAGES- better s.c availaibility Longer &consistent half life- o.d dosage Since aPTT /clotting times not prolonged,lab monitoring not required 36

HEPARIN ANTAGONIST:

HEPARIN ANTAGONIST PROTAMINE SULFATE:- It is a strongly basic , low molecular weight protein obtained from the sperm of certain fish. Given i.v . it neutralises heparin weight for weight,i.e . 1 mg is needed for every 100 U of heparin. In the absence of heparin, protamine itself acts as a weak anticoagulant by interacting with platelets and fibrinogen. 37

ORAL ANTICOAGULANTS:

ORAL ANTICOAGULANTS Oral anticoagulants are medicines used for people who are at risk of developing abnormal blood clotting. The oral anticoagulants are a class of pharmaceuticals that act by antagonizing the effects of vitamin K. Abnormal blood clotting can occur in arteries, veins or heart. Clotting in the brain vessels leads to stroke while in the heart vessels causes heart attack. Clotting in the limb vessels can cause gangrene. Clots can dislodge and go to the lungs, known as pulmonary embolism. 38

EXAMPLES OF ORAL ANTICOAGULANTS:

EXAMPLES OF ORAL ANTICOAGULANTS Recemic Warfarin sodium Bishydroxycoumarin ( Dicumarol ) Acenocoumarol ( Nicomalone ) Ethylbiscoumacetate Phenindione 39

WARFARIN:

WARFARIN Warfarin is a synthetic derivative of coumarin , a chemical found naturally in many plants, like, woodruff ( Galium odoratum , Rubiaceae ), and at lower levels in licorice, lavender, species. Warfarin is prescribed to people with an increased tendency for thrombosis or in those individuals that have already formed a blood clot (thrombus). Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus. 40

MECHANISM OF ACTION:

MECHANISM OF ACTION Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C. 41 ADVERSE EFFECTS Hemorrhage Warfarin necrosis Osteoporosis Purple toe syndrome

MECHANISM OF ACTION:

MECHANISM OF ACTION 42

ADVERSE EFFECTS:

ADVERSE EFFECTS Bleeding Alopecia Dermatitis Urticaria Hematuria TREATMENT : give fresh blood transfusion, supplies clotting factors & replenishes lost blood. Give vit K-specific antidote but it takes 6-24 hours for clotting factors to be resynthesised & released in blood after vit K administration. 43

Fetal hydantoin syndrome:

Fetal hydantoin syndrome Hypoplasia of nose Eye socket hypoplasia Hand bones Growth retardation CNS defects Fetal haemorrhage Fetal death 44

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45

USES :

USES The aim of using anticoagulants is to prevent thrombus extension and embolic complications by reducing the rate of fibrin formation. USES :- 1.Deep vein thrombosis and pulmonary embolism. 2.Myocardial infarction 3.Unstable angina 4.Rheumatic heart disease;Atrial fibrillation 46

USES:

USES 5.Cerebrovascular disease 6.Vascular surgery, prostatic heart valves,retinal vessel thrombosis,extracorporeal circulation, haemodialysis . 7.Defibrination syndrome 47

thanks:

thanks 48

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