anticoagulants 2[1]

8/3/2019 Anticoagulants 2[1]

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Anticoagulants andThrombolytics

Anil Sharma MCC



Objectives

To learn how Blood Clots are

formed.

How the blood clots are brokendown ?

What drugs can be used to regulate

clotting ? How to rectify clotting deficiencies



Blood clots - ThrombusThrombus dislodge from arteries and

veins and become an embolus.

Venous emboli can block arterioles inthe lung and pulmonary circulation

Thromboembolism



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

Non-nucleated - arise fr om magakaryocytes

blood vessel wall (endothelial cells) preventplatelet adhesion and aggregation

platelets contain receptors f or fibrinogen andvon Willebrand factor

after vessel injury Platelets adhere and

aggregate. Release permeability increasing factors (e.g.

vascular permeability factor, VPF)

Loose their membrane and f orm a viscous

plug



Platelets and

Thromboemolism Arteries : White

Thr ombus

Platelets adhere

Release ADP

More adhesion/aggregation

Reduced blood flow(stasis)

Fibrin clot

Veins low pressure :Red thr ombus isf ormed

Especially in valvepockets

Contains a long tail of fibrin

Can detach and f ormemboli



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 dependenton Vitamin K1 and K2

Most of these factors are pr oteases

Normally inactive and sequentially activated

Hereditary lack of clotting factors lead to

hemophilia -A



Intrinsic Pathway

All clotting factorsare within theblood vessels

Clotting slower

Activated partialthromboplastintest (aPTT)

Extrinsic Pathway

Initiating factor isoutside the bloodvessels - tissuefactor

Clotting - faster - inSeconds

Prothrombin test(PT)



Prothrombin time (PT)

Tissue Thromboplastin factor III

Mix with phospholipid extract

Add calcium and blood sample

Determine clotting time

Generally 12 - 14 seconds

Used to detect defects in extrinsic pathway



Activated partialthromboplastin time (APTT)

Blood sample + EDTA or Citrate

No clot ( recalcification will result in clot in about 2 - 4 min)

Add calcium

Mix with negatively charged phospholipid

Kaoline (aluminum silicate)

Determine clotting time

Generally clotting occurs in 26 to 33 seconds

Used to detect defects in the intrinsic pathway



Diagnosis of

coagulation defectsProlonged APTT Defective Intrinsic Pathway

No change in PT

No change in APTT Defective Extrinsic Pathway

Prolonged PT

Prolonged APTT Defective in Common pathway

Prolonged 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 affected

By Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants



Activation

Inactive XI Active XIa

XIIa

+



Thrombosis

Arterial Thr ombosis :

Adherence of platelets to arterial walls - White in

color - Often associated with MI, stroke andischemia

Venous Thr ombosis :

Develops in areas of stagnated blood flow (deep

vein thr ombosis), Red in color- Associated withCongestive Heart Failure, Cancer , Surgery.



Anticoagulant drugs to

treat thromboembolismDrug Class Prototype Action Effect

Anticoagulant

Parenteral

Heparin Inactivation of clotting

FactorsPrevent 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



Heparin

Sulphated carbohydrate

Purified fr om bovine lungs

Different size Active in vitr o and in vivo

Administration - parenteral- Do not inject IM -only IV or deep s.c.

Half-life 1 - 5 hrs - monitor aPTT Adverse effect - hemorrhage - antidote -

pr otamine sulphate



Heparin mechanism of action

Heparin

Antithrombin IIIThrombin



Oral anticoagulants :

warfarin, dicumarol Coumarins - warfarin, dicumar ol

Isolated fr om clover leaves

Structurally related to

vitamin K Inhibits pr oduction of active clotting factors

Absorption rapid - binds to albumin

Clearance is slow - 36 hrs

Delayed onset 8 - 12 hrs Overdose - reversed by vitamin K infusion

Can cr oss placenta - do not use during latepregnancies



Mechanism of

actionDescarboxy Prothrombin Prothrombin

Reduced Vitamin K Oxidized Vitamin K

NADH NAD

Warfarin



Antiplatelet drugs

Aspirin

Prevents platelet aggregation /adhesion

Clinical use - prevents arterial thr ombus Myocardial infarction (MI), str oke, 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 thr omboxane 2(pr ostaglandins)

Inhibits platelet aggregation



Prophylactic use of Aspirin

Low dose daily ( 180 mg/day)

Prevents ischemic attack (ministr oke) and MI

335 mg/day reduced the risk of heart attack

in patientsover 50

More than 1000 mg/day NO EFFECT High dose inhibits pr ostacyclin synthesis in cells

surr ounding vessels. PS normally prevents plateletaggregation. Theref ore, inhibition of PS leads to

abr ogation of the pr ophylactic benefit of Aspirin

Contraindication - DO NOT give to patientswith glucose 6-PO4 dehydr ogenasedeficiency



Drug interaction-

prototype Warfarin

Drugs that IncreaseWarfarin Activity

Decrease binding toAlbumin

Inhibit Degradation

Decrease synthesis of

Clotting Factors

Aspirin, Sulfonamides

Cimetidine, Disulfiram

Antibiotics (oral)

Category Mechanism RepresentativeDrugs



Drug interaction-

prototype WarfarinDrugs that promote

bleeding

Inhibition of platelets Aspirin

Inhibition of clotting heparin

Factors antimetabolites

Drugs that decreaseWarfarin activity

Induction of metabolizing Barbiturates

Enzymes Phenytoin

Promote clotting factor Vitamin K

Synthesis OC

Reduced absorption cholestyramine

colestipol



Fibrinolysis

Enhance degradation of clots

Activation of endogenous pr otease

Plasminogen (inactive f orm) isconverted to Plasmin (active f orm)

Plasmin breaks down fibrin clots



Fibrinolysis

Exogenously administered drugs Streptokinase - bacterial pr oduct - continuous use

- immune reaction

Ur okinase - human tissue derived - no immuneresponse

Tissue plasminogen activator (tPA) - geneticallycloned - no immune reaction - EXPENSIVE

Inhibitorsof fibrin

olysis - amin

ocapr

oic acid

Lysine analog- inhibits pr oteases



Drug preparations : To

reduce clottingHeparin (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 f or iv

streptokinase (Kabikinase, streptase) Parenteral : 250000 - 1.5 million units per vial .

Lyophilized powder. Reconstitute f or iv

Ur okinase ( Abbokinase)

Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml f or injection



Drug preparations

: clotting deficiencies Vitamin K ( Phytonadione (K1), Mephyton

Oral : 5 mg tablets

Plasma fractions - f or hemophilia Antihemophilic factor ( VIII, AHF)

Parenteral

Factor IX complex (konyne HT, pr oplex T) Parenteral : in vials

Due to HIV risks in blood pr oductsrecombinant pr oteins of the factors are made. E.g. transgenic goats secreting factors into milk



Drug preparations

: to stop bleeding Systemic use : aminocapr oic acid (Amicar);

Tranexamic acid (cyclokapr on),Vitamin K

Local adsorbable drugs

Gelatin sponge (Gelf oam)

Gelatin film

Oxidized cellulose ( Oxycel)

Micr ofibrillar collagen (Avitene)

Thr ombin

anticoagulants 2[1]

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