DRUGS

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

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
Antiplatelet
drugs
Aspirin Decrease platelet
aggregation
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase Fibinolysis Breakdown of
thrombi

11. Heparin
 Sulphated carbohydrate
 Different sizebovine lungs
 Administration - parenteral- Do not inject IM -
only IV or deep s.c.
 Half-life 1 - 5 hrs - monitor aPTT
 Adverse effect: hemorrhage
 Antidote : protamine sulphate

12. Heparin mechanism of
action
Heparin
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 8 - 12 hrs
 Overdose - reversed by vitamin K infusion
 Can cross placenta - do not use during late
pregnancies

14. Mechanism of action
Descarboxy Prothrombin Prothrombin
Reduced Vitamin K Oxidized Vitamin K
NADH
NAD
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. (
‫المطيري‬ ‫عبدهللا‬
)

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

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

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 - 1000 - 40,000 U/ml
 Warfarin (generic , Coumadin)
 Oral : 2 - 20 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 : 250000 - 1.5 million units per vial .
Lyophilized powder. Reconstitute for iv
 Urokinase ( Abbokinase)
 Parenteral : 250000 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