Objectives

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To learn how Blood Clots are formed.

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What drugs can be used to regulate clotting ?

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How the blood clots are broken down ?

How to rectify clotting deficiencies

Classes of Drugs

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Prevent coagulation

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Dissolve clots

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Prevent bleeding and hemorrhage Hemostatic

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Overcome clotting deficiencies (replacement therapies)

Blood Clotting

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Vascular Phase

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Platelet Phase

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Coagulation Phase

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Fibrinolytic Phase

Vascular Phase

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Vasoconstriction

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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  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

Intrinsic Pathway

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All clotting factors are within the blood vessels

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Clotting slower

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Activated partial thromboplastin test (aPTT) Extrinsic Pathway

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Initiating factor is outside the blood vessels - tissue factor

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Clotting - faster - in Seconds

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Prothrombin test (PT)

Intrinsic Pathway Blood Vessel Injury XII XIIa XI XIa Extrinsic Pathway Tissue Injury Tissue Factor

Thromboplastin

IX IXa VIIa VII X Xa X Prothrombin Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants

Fibrinogen XIII

Thrombin

Fribrin monomer

Fibrin polymer

Anticoagulant drugs to treat thromboembolism

Drug Class

Anticoagulant Parenteral

Prototype Heparin Action

Inactivation of clotting Factors Anticoagulant Oral

Warfarin

Decrease synthesis of Clotting factors

Effect

Prevent venous Thrombosis Prevent venous Thrombosis Antiplatelet drugs

Aspirin

Decrease platelet aggregation Thrombolytic Drugs

Streptokinase

Fibinolysis Prevent arterial Thrombosis Breakdown of thrombi

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. ) يريطملا اللهدبع (

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 Aspirin, Sulfonamides Inhibit Degradation Cimetidine, Disulfiram Decrease synthesis of Clotting Factors Antibiotics (oral)

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 Enzymes Promote clotting factor Synthesis Reduced absorption Barbiturates Phenytoin Vitamin K cholestyramine colestipol

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

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  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  Streptokinase - bacterial product ○ - continuous use - immune reaction  Urokinase - human tissue derived – ○ no immune response  Tissue plasminogen activator (tPA) - genetically cloned ○ no immune reaction ○ EXPENSIVE

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

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

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

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