Anticoagulants 22

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

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

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)

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 polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affectedBy Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

Drug Class Prototype Action Effect

AnticoagulantParenteral

Heparin Inactivation of clottingFactors

Prevent venousThrombosis

AnticoagulantOral

Warfarin Decrease synthesis ofClotting factors

Prevent venousThrombosis

Antiplateletdrugs

Aspirin Decrease plateletaggregation

Prevent arterialThrombosis

Thrombolytic Drugs

Streptokinase Fibinolysis Breakdown ofthrombi

HeparinSulphated carbohydrateDifferent sizebovine lungsAdministration - parenteral- Do not inject IM -

only IV or deep s.c. Half-life 1 - 5 hrs - monitor aPTTAdverse effect: hemorrhage Antidote : protamine sulphate

Heparin

Antithrombin III Thrombin

Oral anticoagulants

Examples: Coumarins - warfarin, dicumarolStructurally related to vitamin KInhibits production of active clotting factorsClearance is slow - 36 hrs Delayed onset 8 - 12 hrsOverdose - reversed by vitamin K infusionCan cross placenta - do not use during late

pregnancies

Descarboxy Prothrombin Prothrombin

Reduced Vitamin K Oxidized Vitamin K

NADHNAD

WarfarinNormally, 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. (عبداللا المطيري)

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

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

Drugs that Increase Warfarin Activity

Decrease binding toAlbumin

Inhibit Degradation

Decrease synthesis ofClotting Factors

Aspirin, Sulfonamides

Cimetidine, Disulfiram

Antibiotics (oral)

Category Mechanism Representative Drugs

Drugs that promotebleeding

Inhibition of platelets Aspirin

Inhibition of clotting heparinFactors antimetabolites

Drugs that decreaseWarfarin activity

Induction of metabolizing BarbituratesEnzymes Phenytoin

Promote clotting factor Vitamin KSynthesisReduced absorption cholestyramine

colestipol

Antiplatelet drugsExample: AspirinPrevents platelet aggregation /adhesionClinical use - prevents arterial thrombus

Myocardial infarction (MI), stroke, heart valve replacement and shunts

Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine

Mechanism of actionAspirin 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

FibrinolysisExogenously 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), MephytonOral : 5 mg tablets

Plasma fractions - for hemophiliaAntihemophilic 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 drugsGelatin sponge (Gelfoam)Gelatin filmOxidized cellulose ( Oxycel)Microfibrillar collagen (Avitene)Thrombin