ANTICOAGULATIONLEARNING OBJECTIVES

At the end of lecture students should be able to know,

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

Coagulation Factors Factor Name I Fibrinogen II Prothrombin III Tissue Factor or thromboplastin IV Ca++ V Proaccelerin VII Proconvertin VIII Antihemophilic A factor IX Antihemophilic B factor or Christmas

factorClasses 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

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) COAGULATION DISORDERS THROMBOSIS BLEEDING CLOTTING MECHANISM Physical trauma to vascular system causes: Vasoconstriction Platelet aggregation Formation of fibrin meshwork and clot Initially platelets adhere to the blood vessel at the site

of injury and adhered platelets release chemicals that cause aggregation of platelets thus a plug is formed.

Platelet activation and aggregation is promoted by exposure to collagen, thromboxane A2 (powerful stimulator), decreased prostacyclins and ADP.

Platelet aggregation is essential for the clot formation. Factors released by injured tissues and platelets

stimulate the intrinsic and extrinsic pathways of clotting cascade that lead to the formation of fibrin that forms meshwork with aggregated platelets and strengthen the plug.

Intrinsic system takes several minutes for formation of activated factor X, in extrinsic system activated factor X is produced very rapidly within seconds.

As wound heals fibrinolytic pathway is activated in that plasminogen is converted to plasmin (fibrinolysin) that interferes with clot propagation and dissolves fibrin network.

Clotting mechanism may be pathologically activated resulting in thrombosis and embolism that produce ischemia of various organs.

PLATELET AGGREGATION Platelet activation and aggregation is promoted by: Exposure to collagen Thromboxane A2 (powerful stimulator) Decreased prostacyclins ADP

ANTICOAGULANTS Parenteral:

o HEPARINo HIRUDIN

Oral: Coumarin Derivatives:

o WARFARINo DICOUMAROLo ACENOCOUMAROL

ANTICOAGULANTS Indanedione Derivatives: PHENINDIONE DIPHENADIONE BROMINDONE Out of all these orally effective drugs warfarin is the most important and most widely used.

o HEPARIN

WARFARIN DICOUMAROL PHENINDIONE

o SODIUM CITRATEo SODIUM OXALATEo EDTA

HEPARIN:

Heparin is highly acidic drug and is mixture of mucopolysaccharides.

It occurs in mast cells, richest source being lungs, liver and intestine.

It is obtained from bovine lung and porcine intestine for commercial use.

Commercial preparations of heparin available in un-fractionated form (UFH) are composed of high molecular weight heparin and low molecular weight heparin fractions.MECHANISM OF ACTION:

Antithrombin III a naturally occurring anticoagulant, normally prevents the coagulation by blocking the activated factors II, IX, & X.

Normally the activity of antithrombin III is very slow, heparin accelerates the activity of antithrombin III 1000 fold.

Antithrombin III acts as heparin cofactor and inhibits activated factors of clotting; factor IIa and factor Xa are most sensitive to inhibition. MECHANISM OF ACTION:o Heparin blocks antithrombin III without being

consumed itself. Once antithrombin binds with activated clotting factors, heparin detaches from antithrombin III intact and binds with other molecules of antithrombin III.

o HMW heparin has high affinity for antithrombin III and markedly blocks blood coagulation.

o LMW fraction inhibits activated factor X but has less effect on antithrombin III and on coagulation.

ACTIONS OF HEPARIN Heparin prevents blood coagulation within body and

outside the body, it decreases thrombus formation.

It does not act as thrombolytic agent i.e. it does not dissolve already formed thrombus.

Heparin also decreases the platelets by increasing the platelet aggregation that may lead to paradoxical thromboembolism and by the formation of antibodies against platelets.Unfractionated heparin (UFH)

Advantage: A short half-life(60 minutes) easily reversed (by protamine sulfate) Disadvantage: Intravenous administration necessitates

hospitalization before surgery, Inconvenient and expensive.

L ow-molecular-weight-heparin (LMWH) Allowed bridging therapy to be administered to

outpatients. Doses of LMWH that are recommended for treatment

of venous thromboembolism are administered once or twice daily, generally for 3 days before surgery.

Required to determine whether the benefit of bridging therapy outweighs the associated risks of bleeding.

Low-molecular weight heparin Low-molecular weight heparin is gradually replacing

heparin for treatment of most patients with venous

thromboembolism and acute coronary syndromes because it has more convenient and cost-effective

It has similar results to heparin Administered by subcutaneous injection LOVENOX® is an example PHARMACOKINETICS: Heparin does not cross cell membrane and is not

absorbed from gut. It is given subcutaneously or intravenously.

Heparin should not be given intramuscularly as it produces hematoma.

Heparinase present in liver degrades heparin. Some of the parent drug and inactive metabolites are

excreted in urine; half-life of heparin is 80 minutes. Heparin does not cross placenta but should be used

carefully during pregnancy as it can produce maternal bleeding.

SIDE EFFECTS: Main problem with heparin therapy is hemorrhage,

careful monitoring of APTT (Activated Partial

Thromboplastin Time) is essential to prevent bleeding.

Dose of heparin is so adjusted that APTT is raised to 2–2½ times to that of control value. (Normal 30 seconds).

Patients with hepatic and renal impairment are more prone to develop hemorrhage.

Risk of hemorrhage is less with LMW heparin than with HMW heparin.

SIDE EFFECTS: As heparin for commercial use is of animal origin it

may produce hypersensitivity reactions. Chills fever, urticaria, itching and anaphylactic shock may occur.

On prolonged use heparin may produce osteoporosis, spontaneous fractures of bones and alopecia.

Heparin also produces thrombocytopenia that is either mild or transient due to platelet aggregation or severe due to platelet antibodies.SIDE EFFECTS

Bleeding Hypersensitivity reactions Osteoporosis Spontaneous fractures of bones Alopecia Thrombocytopenia

TREATMENT OF HEPARIN OVERDOSE Protamine sulfate is antidote of heparin It binds with heparin

1 mg of protamine sulfate neutralizes 100 units of heparinCONTRA-INDICATIONS

HypersensitivityINDICATIONS

Prevention of thromboembolism in: Deep vein thrombosis Prolonged immobilization Myocardial infarction In vitro: To prevent blood coagulation during blood sampling Hemodialysis

DEEP VEIN THROMBOSIS

BOLUS 5000–10000 IU I/V

M.DOSE 5000 IU 2–3 TIMES DAILY S/C

HIRUDIN: Hirudin is powerful and specific thrombin inhibitor Its action is independent of antithrombin III. It can inactivate the fibrin bound thrombin in thrombi. ORAL ANTICOGULATS Oral anticoagulants are chemically related to

vitamin K; They prevent coagulation within body and are not

effective outside the body (In vitro) Warfarin Warfarin is an oral medication It is a synthetic derivative of coumarin, a chemical

found naturally in many plants -- it decreases blood coagulation by interfering with vitamin K metabolism

It stops the blood from clotting within the blood vessels and is used to stop existing clots from getting bigger (as in DVT) and to stop parts of clots breaking off and forming emboli (as in PE)

Dicumarol

It is a potent oral anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent clotting factors (prothrombin and factors VII, IX and X) in the liver; it is starting to largely replace warfarin

Dicumarol is produced naturally by conversion of nontoxic coumarin in moldy sweet clover hay, lespepeza hay or sweet vernal hay

It is used especially in preventing and treating thromboembolic disease

Formerly called bishydroxycoumarinMECHANISM OF ACTION:

Warfarin and other anticoagulants resemble vitamin K and vitamin K is essential for the formation of activated clotting factors II, VII, IX and X by the liver. Only reduced form of vitamin K is effective for this purpose.

Reduced form of vitamin K is oxidized to vitamin K epoxide during the activation of clotting factors. MECHANISM OF ACTION:

Vitamin K epoxide is reduced back by vitamin K epoxide reductase and is used for the formation of clotting factors.

Oral anticoagulants inhibit the enzyme vitamin K epoxide reductase competitively thus they prevent the formation of active form of vitamin K and its action.

Unlike the heparin, their peak effect appears after 36–48 hours, and they have long duration of action (4–7 days).

PHARMACOKINETICS They are well absorbed from gut; food delays their

absorption, are highly bound to plasma proteins

(99%) and are mainly concentrated in liver, which is the main site of their action.

They do not cross blood brain barrier but cross placenta and predispose fetal and neonatal bleeding.

Drugs have high affinity for protein binding like sulfonamides can displace oral anticoagulants and increase their effects.

Oral anticoagulants are metabolized in liver and their metabolites are excreted in urine. DRUGS INCREASING WARFARIN ACTION

DRUGS DECREASING WARFARIN ACTION

SIDE EFFECTS OF ORAL ANTICOAGULANTS Bleeding Phenindione can produce skin rashes, blood

dyscrasias, jaundice, fever, nausea, vomiting and red discoloration of urine.Warfarin-induced Skin Necrosis

CONTRAINDICATIONS

Pregnancy & lactation Bleeding disorders Thrombocytopenia Uncontrolled hypertension Gastrointestinal ulcers CONTRAINDICATIONS Tuberculosis With aspirin With tetracyclines and other broad spectrum

antibiotics Vitamin K deficiency INDICATIONS To prevent thrombus formation in: Acute myocardial infarction Deep vein thrombosis Pulmonary embolism Cerebrovascular accident (Stroke) Atrial fibrillation Prosthetic heart valves Thromboembolic Risk When Discontinuing

Warfarin Venous thromboembolism (VTE): The absence of OAC during the first month of an

acute VTE event－Recurrence 40%/month

During the second and third month－ Recurrence 10%/2month

After the 3 month treatment－15%/year Surgery should be deferred following an acute

episode of venous thromboembolism until patients

have received at least 1 month, and preferably 3 months, of anticoagulation.

REFERENCES BASIC AND CLINICAL

PHARMACOLOGY,KATZUNG,11th EDITION.

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