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

Prevent coagulation Dissolve clots Prevent bleeding and hemorrhage Hemostatic

Overcome clotting deficiencies (replacement therapies)

Blood Clotting

Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase

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

Tissue Factor

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

Coagulation Phase

Two major pathways

y Intrinsic pathway y 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

Intrinsic Pathway

Extrinsic Pathway

All clotting factors are within the blood vessels

Initiating factor is outside the blood vessels - tissue factor

Clotting slower Activated partial thromboplastin test (aPTT)

Clotting - faster - in Seconds

Prothrombin test (PT)

Intrinsic Pathway
Blood Vessel Injury XII XI IX X Factors affected By Heparin Prothrombin Fibrinogen XIII XIIa XIa IXa Xa

Extrinsic Pathway
Tissue Injury Tissue Factor Thromboplastin

VIIa X Thrombin

VII

Fribrin monomer Fibrin polymer

Vit. K dependent Factors Affected by Oral Anticoagulants

Anticoagulant drugs to treat thromboembolism

Drug Class Anticoagulant Parenteral Prototype Heparin Action Inactivation of clotting Factors Effect Prevent venous Thrombosis Prevent venous Thrombosis Prevent arterial Thrombosis Breakdown of thrombi

Anticoagulant Warfarin Decrease synthesis of Clotting factors Oral Antiplatelet drugs Thrombolytic Drugs Aspirin Decrease platelet aggregation

Streptokinase Fibinolysis

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

Heparin mechanism of action

Heparin Antithrombin III

Thrombin

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

Mechanism of action
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. ( )

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

Warfarin Side Effect

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

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)

Drug interaction with Warfarin

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

Antiplatelet drugs

Example: Aspirin Prevents platelet aggregation /adhesion Clinical use - prevents arterial thrombus
y Myocardial infarction (MI), stroke, heart valve

replacement and shunts

Other antiplatelet drugs are Dipyridamole, sulfinpyrazone and Ticlopidine

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

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

y Contraindication - DO NOT give to patients with

glucose 6-PO4 dehydrogenase deficiency

Fibrinolysis

Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form)

Plasmin breaks down fibrin clots

Fibrinolysis

Exogenously administered drugs

y Streptokinase - bacterial product - continuous use - immune reaction y Urokinase - human tissue derived no immune response y Tissue plasminogen activator (tPA) - genetically

cloned

no immune reaction EXPENSIVE

Drug preparations : To reduce clotting

Heparin (generic, Liquaemin sodium)

y Parenteral - 1000 - 40,000 U/ml

Warfarin (generic , Coumadin)

y Oral : 2 - 20 mg tablets

Dipyridamole (Persantine)
y Oral : 25,50,75 mg tablets

Drug preparations : to lyse clots

Alteplase recombinant (tPA, Activase)

y 20, 50 mg Lyophilized powder - reconstitute for iv

streptokinase (Kabikinase, streptase)

y Parenteral : 250000 - 1.5 million units per vial .

Lyophilized powder. Reconstitute for iv

Urokinase ( Abbokinase)
y Parenteral : 250000 units per vial. Powder to

reconstitute to 5000 u/ml for injection

Drug preparations: clotting deficiencies

Vitamin K ( Phytonadione (K1), Mephyton

y Oral : 5 mg tablets

Plasma fractions - for hemophilia

y Antihemophilic factor ( VIII, AHF) y Parenteral

Factor IX complex (konyne HT, proplex T)

y Parenteral : in vials

Drug preparations : to stop bleeding

Systemic use : aminocaproic acid (Amicar); Tranexamic acid (cyclokapron),Vitamin K Local adsorbable drugs
y Gelatin sponge (Gelfoam) y Gelatin film y Oxidized cellulose ( Oxycel) y Microfibrillar collagen (Avitene) y Thrombin