1. Anticoagulants and Thrombolytic

2. 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

3. Classes of Drugs Prevent coagulation Dissolve clots
Prevent bleeding and hemorrhage - Hemostatic
Overcome clotting deficiencies (replacement therapies)

4. Blood Clotting Vascular Phase Platelet Phase Coagulation Phase
Fibrinolytic Phase

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

6. Platelet phase
blood vessel wall (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

7. Coagulation Phase Two major pathways Both converge at a common point
Intrinsic pathway
Extrinsic pathway
Both converge at a common point
13 soluble factors are involved in clotting
Biosynthesis of these factors are dependent on Vitamin K1 and K2
Normally inactive and sequentially activated
Hereditary lack of clotting factors lead to hemophilia -A

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)

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

10. Anticoagulant drugs to treat thromboembolism
Drug Class Prototype Action Effect
Anticoagulant
Parenteral
Heparin
Inactivation of clotting
Factors
Prevent venous
Thrombosis
Anticoagulant
Oral
Warfarin
Decrease synthesis of
Clotting factors
Prevent venous
Thrombosis
Prevent arterial
Thrombosis
Antiplatelet
drugs
Aspirin
Decrease platelet
aggregation
Breakdown of
thrombi
Thrombolytic
Drugs
Streptokinase
Fibinolysis

11. Heparin Sulphated carbohydrate Different sizebovine lungs
Administration - parenteral- Do not inject IM - only IV or deep s.c.
Half-life hrs - monitor aPTT
Adverse effect: hemorrhage
Antidote : protamine sulphate

12. Heparin mechanism of action
Antithrombin III
Thrombin

13. Oral anticoagulants Examples: Coumarins - warfarin, dicumarol
Structurally related to vitamin K
Inhibits production of active clotting factors
Clearance is slow - 36 hrs
Delayed onset hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - do not use during late pregnancies

14. Mechanism of action Reduced Vitamin K Oxidized Vitamin K Warfarin
Descarboxy Prothrombin
Prothrombin
Reduced Vitamin K
Oxidized Vitamin K
NAD
NADH
Warfarin
Normally, vitamin K is converted to vitamin K epoxide in the liver.
→This epoxide is then reduced by the enzyme epoxide reductase.
→The reduced form of vitamin K epoxide is necessary for the synthesis of many coagulation factors (II, VII, IX and X, as well as protein C and protein S).
→Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting coagulation. (عبدالله المطيري)

15. Warfarin Side Effect Severe Side effects: Severe bleeding
Bleeding from the rectum or black stool
Skin conditions such as hives, a rash or itching
Swelling of the face, throat, mouth, legs, feet or hands
Bruising that comes about without an injury you remember
Chest pain or pressure
Nausea or vomiting
Fever or flu-like symptoms
Joint or muscle aches
Diarrhea
Difficulty moving
Numbness of tingling in any part of your body
Painful erection lasting four hours or longer

16. Warfarin Side Effect Other less serious warfarin side effects: Gas
Feeling cold
Fatigue
Pale skin
Changes in the way foods taste
Hair loss

17. Drug interaction- with Warfarin
Category Mechanism Representative Drugs
Drugs that Increase
Warfarin Activity
Decrease binding to
Albumin
Inhibit Degradation
Decrease synthesis of
Clotting Factors
Aspirin, Sulfonamides
Cimetidine, Disulfiram
Antibiotics (oral)

18. Drug interaction with Warfarin
Drugs that promote
bleeding
Inhibition of platelets Aspirin
Inhibition of clotting heparin
Factors antimetabolites
Induction of metabolizing Barbiturates
Enzymes Phenytoin
Promote clotting factor Vitamin K
Synthesis
Reduced absorption cholestyramine
colestipol
Drugs that decrease
Warfarin activity

19. Antiplatelet drugs Example: Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus
Myocardial infarction (MI), stroke, heart valve replacement and shunts
Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine

20. Mechanism of action Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)
Inhibits platelet aggregation

21. Prophylactic use of Aspirin
Low dose daily.
Prevents ischemic attack (ministroke) and MI
335 mg/day reduced the risk of heart attack in patients over 50
More than 1000 mg/day NO EFFECT
Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency

22. Fibrinolysis Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is converted to Plasmin (active form)
Plasmin breaks down fibrin clots

23. Fibrinolysis Exogenously administered drugs
Streptokinase - bacterial product
- continuous use - immune reaction
Urokinase - human tissue derived –
no immune response
Tissue plasminogen activator (tPA) - genetically cloned
no immune reaction
EXPENSIVE

24. Drug preparations : To reduce clotting
Heparin (generic, Liquaemin sodium)
Parenteral ,000 U/ml
Warfarin (generic , Coumadin)
Oral : mg tablets
Dipyridamole (Persantine)
Oral : 25,50,75 mg tablets

25. Drug preparations : to lyse clots
Alteplase recombinant (tPA, Activase)
20, 50 mg Lyophilized powder - reconstitute for iv
streptokinase (Kabikinase, streptase)
Parenteral : million units per vial . Lyophilized powder. Reconstitute for iv
Urokinase ( Abbokinase)
Parenteral : units per vial. Powder to reconstitute to 5000 u/ml for injection

26. Drug preparations: clotting deficiencies
Vitamin K ( Phytonadione (K1), Mephyton
Oral : 5 mg tablets
Plasma fractions - for hemophilia
Antihemophilic factor ( VIII, AHF)
Parenteral
Factor IX complex (konyne HT, proplex T)
Parenteral : in vials

27. Drug preparations : to stop bleeding
Systemic use : aminocaproic acid (Amicar); Tranexamic acid (cyclokapron),Vitamin K
Local adsorbable drugs
Gelatin sponge (Gelfoam)
Gelatin film
Oxidized cellulose ( Oxycel)
Microfibrillar collagen (Avitene)
Thrombin