1. ANTICOAGULANT DRUGS
Dr.V.V.Gouripur

2. Clotting Process
Formation of a blood clot (thrombus) in blood vessels or the heart.
may be life saving (when it plugs a severed vessel) or life-threatening if it occludes a vessel supplying a vital structure.
may break loose to create an embolus that flows downstream to lodge at a distant site.
The potential consequence is ischemic necrosis of cells and tissues known as infarction.
Cerebral vascular accidents (stroke), myocardial infarction and pulmonary embolisms are examples of disorders resulting from thrombosis or embolism.

3. Thrombophlebitis is the term used for a venous thrombosis with associated inflammation.
1. Arterial thrombosis—Result is localized tissue injury owing to lack of perfusion
2. Venous thrombosis—Usually develops when blood flow is slow; this initiates coagulation cascade; part can become embolus

4. Hemostasis Physiologic process by which bleeding is stopped
Stage 1: formation of a platelet plug—Begins when platelets come in contact with collagen on exposed surface of damaged vessel, adhere to area, release adenosine diphosphate (ADP) and thromboxane A2 platelet plug and bleeding stopped. Platelet aggregation ends with fibrinogen bridges

5. Stage 2: coagulation (reinforcement of platelet plug with fibrin)—Occurs in series of cascading reactions from extrinsic and/or intrinsic systems. Four of the coagulation factors (VII, IX, X and prothrombin) require vitamin K for synthesis
Stage 3. Keeping hemostasis under control—Antithrombin III prevents widespread coagulation
Stage 4. Physiologic removal of clots—Essential in healing process using plasmin

6. Physical Process of Clotting

7. Chemical Process of Clotting

10. IXa and VIIIa work together to
convert X into Xa.
Xa and Va work together to convert II into IIa.
IIa works on a number of steps.
HMWK and TF are initiation points
CLOT is the end point

11. Anti-coagulants
Anti-coagulants are molecules that prevent blood from clotting.
They inhibit the chemical process of proteolytic formation of the three-dimensional fibrin polymer.
These include heparin, low molecular weight heparin, coumarins, and 1,3-indanediones.

12. anti-platelet agents.
Molecules that do not allow platelets to aggregrate and thus prevent clotting, especially in the arteries, are called anti-platelet agents
These include aspirin, sulfinpyrazone, dipyridamole, and ticlopidine.

13. Fibrinolytic agents.
Molecules that disintegrate a pre-formed clot are called fibrinolytic agents.
Some examples are
-streptokinase
-Altaplase
-Tenactaplase

14. Coagulation factors Factor Name I Fibrinogen II Prothrombin
III Tissue Factor or thromboplastin
IV Ca++
V Proaccelerin
VII Proconvertin
VIII Antihemophilic A factor
IX Christmas factor or Stuart-Prower factor
XI Plasma thomboplastin antecedent
XII Hageman factor
XIII Fibrin stabilizing factor
HMWK- High molecular weight kininogen

15. Endogenous Inhibitors of Clotting
 Thrombin plays a pivotal role in blood coagulation and
Nature has designed several serine protease inhibitors (SERPINS) to regulate the its activity.
These include
- antithrombin (major),
-Protein C
-Thrombomodulin
      

16. Antithrombin Antithrombin is present in the plasma ,primarily neutralizes factor Xa and thrombin, in addition to inhibiting most active serine proteases of the clotting system..)
 Protein C is another plasma protein that limits clotting by being activated by thrombin to proteolytically inactivate proaccelerin (V) and antihemophilic factor (VIII).
Thrombomodulin, a cell membrane bound glycoprotein lining the vascular endothelium, specifically binds thrombin so as to convert it to a form with decreased ability to catalyze clot formation but with a >1,000-fold increased capacity to activate protein C.       

17. Heparin
Heparin is a naturally occurring, strongly acidic mucopolysaccharide found in granules of mast cells and basophils.
These polysaccharides possess a wide range of molecular weights (3000 to 30,000) and are negatively charged making them highly polar and unable to readily cross membranes.
The dosage is measured in units of activity determined by its ability to prevent clotting of plasma standards.
In contrast to coumarin derivatives, it is only administered parenterally.

18. Mechanism of action Acts by combining with an antithrombin III.
Heparin-antithrombin complex combines with, and neutralizes, thrombin within seconds.
This complex also inhibits the action of activated factors XIIA, IXa, VIIA, and Xa.
Action - prolongs clotting time in vivo and in vitro.
Monitoring is via the activated partial thromboplastin time (APTT)
Duration of action <4hrs

19. Low-Molecular-Weight (LMW) Heparins
Enoxaparin (Lovenox
Lepirudin (Refludan)
These are heparins with shorter molecules than those found in standard (unfractionated) heparin.
They are as effective as standard heparin and do not require APTT monitoring
Only for prophylaxis of DVT after hip or abdominal surgery

20. Adverse Reactions Hemorrhage Thrombocytopenia
Chemical antagonism occurs with protamine sulfate, a strongly basic protein that neutralizes heparin.

21. Coumarin Derivatives
   Warfarin
   Dicoumarol
Coumarin
   4-Hydroxycoumarin

22. Coumarin Derivatives (Warfarin [Coumadin®])
Mechanism
Vitamin K antagonist
Inhibit formation of prothrombin (factor II) and factors VII, IX and X, which are synthesized in the liver, and the synthesis, is dependent upon vitamin K.
Action
Absorbed rapidly from GI tract
Lowering of prothrombin occurs slowly. Monitoring is via the prothrombin time (PT) or the international normalized ratio (INR)
Duration of action – 2-3 days
Other Agents-Anisindione—Like warfarin but greater side effects

23. Biochemical Mechanism of Action
Coumarins are competitive inhibitors of vitamin K in the biosynthesis of prothrombin.
        The coagulation cascade relies on the conversion of prothrombin to thrombin in a very important step. However, this conversion depends on the presence of 10 g-carboxyglutamic acid (GLA) residues in the N-terminus of prothrombin.
The multiple Gla residues form a binding site for Ca+2. Under normal circumstances 10 glutamic acid (Glu) residues of prothrombin are converted to Gla residues in a  post-translational modification.
       

24. Biochemical Mechanism of Action
This post-translation modification is catalyzed by an enzymes vitamin K reductase and vitamin K epoxide reductase.
Vitamin K is a co-factor in this conversion reaction.
Thus it cycles between a reduced form and an epoxide form. Because of their structural similarity with vitamin K coumarins are thought to bind the enzymes, vitamin K reductase and vitamin K epoxide reductase, without facilitating the conversion of Glu residues of prothrombin to Gla.
Thus prothrombin cannot be acted upon by factor Xa.

25. Adverse Reactions mild diarrhea, soft stools Hemorrhage
Treatment of overdose
Vitamin K1 is the antagonist to the coumarins, and administration of phytonadione (emulsion of vitamin K1) will restore prothrombin level after period of hours
When an immediate effect is desired, prothrombin is given (fresh blood, freeze dried plasma).
Possible risk of "rebound" with abrupt cessation of therapy,

26. Bleeding or hematological diseases Drug Interactions
Contraindications
Bleeding or hematological diseases
Drug Interactions
Stimulation of coumarin metabolism by administration of drugs
that induce microsomnzymes (barbiturates, meprobamate and
other sedative-hypnotic drugs; griseofulvin).
Inhibition of metabolism (e.g., allopurinol [Zyloprim®]); disulfiram (Antabuse®).
Displaced from binding sites by phenylbutazone, phenytoin, sulfinpyrazone, clofibrate and other drugs.
Others
Salicylates, indomethacin
Oral Contraceptives
Acetaminophen (Tylenol)inhibits warfarin degradation
Effect of anticoagulants on other drugs Coumarin agents prolong and intensify action of chlorpropamide, tolbutamide, phenytoin
and phenobarbital.

27. Comparison of Heparin and warfarin
Heparin warfarin
Onset of action Immediate Gradual to peak at 48hrs
Duration < 4 hours – 5 days
Route of adm Parenteral Oral
Lab.control of dose- [APTT] Prothrombintime[PT]/INR
Antidote Protamine/Fresh blood Vitamin K1
Cost Expensive Inexpensive
Active in vitro Yes No

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