anticoagulants, direct and indirect thrombin inhibitors

8/13/2019 Anticoagulants, Direct and Indirect Thrombin Inhibitors

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ANTICOAGULANTAn anticoagulantis a substance that prevents or

reduces coagulation (clotting) of blood. This group ofpharmaceuticals can be used in vivo as a medication for

thrombotic disorders.

Thrombosisis the

formation of a blood clot(thrombus) inside a blood

vessel, obstructing the flow

of blood through the

circulatory system.

If the clot becomes mobile and is carried away by the

blood circulation, it is called an embolus.


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Anticoagulants is required if one has been diagnosed with

or treated for one or more of the following:

Atrial fibrillation (AF)-

lack of an organized atrial contraction can result in some

stagnant blood in the left atrium (LA)

thrombus formation

heparin, warfarin, dabigatran, rivaroxabanArterial embolism-

sudden interruption of blood flow to an organ or body

part due to an embolus adhering to the wall of an artery

blocking the flow of bloodwarfarin, heparin


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Deep vein thrombosis (DVT)-

formation of a blood clot (thrombus) in a deep vein,

predominantly in the legs

venous stasis, hypercoagulability, and changes in endothelialblood vessel lining (such as physical damage)

LMWH, fondaparinux, unfractionated heparin, warfarin

Pulmonary embolism (PE)-

blockage of the main artery of the lung or one of its branchesdue to an embolus

most commonly results from deep vein thrombosis

LMWH, fondaparinux, unfractionated heparin, warfarin

Stroke-rapid loss of brain function due to disturbance in the blood

supply to the brain

thrombosis, arterial embolism

Warfarin


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Genetic clotting disorders like prothrombin

thrombophilia, Factor V Leiden thrombophilia

congenital thrombophilia -an inborn abnormality of

blood coagulation that increases risk of thrombosis as a

result of overactivity of coagulation factors

prothrombin thrombophilia- a mutation in prothrombin

factor V Leiden thrombophilia- a mutation in the F5 genewarfarin and during pregnancy LMWH


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ANTICOAGULANT DRUGS


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DIRECT THROMBIN INHIBITORS

Drug name Bivalent/

Univalent

Route of

administration

Binding to

active siteand/or

exosite

Indications

Argatroban Univalent Parenteral (iv) Reversible Prevention and

treatment of

thrombosis

Dabigatran

etexilate

Univalent Oral Reversible Prevention of

stroke and

embolism in

patients with AF

Lepirudin Bivalent Parenteral (iv/sc) Irreversible Prevention of

further

thrombosis


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Mechanism:Thrombin has three domains: one active site and two

exosites. Exosite 1 acts as a dock for substrates such as fibrin in order

to promote orientation for active site binding. Exosite 2 is the

heparin-binding domain. Thus, DTIs are able to inactivate both fibrin-

bound and unbound thrombin, unlike UFH and LMWH.

Side-effects:Heart failure; bleeding in injection site, wounds and

allergic skin reactions; nosebleed; gastrointestinal and rectal bleeding;abnormal kidney function, blood in urine


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INDIRECT THROMBIN INHIBITORS

A, To inactivate thrombin,

unfractionated heparin

forms a ternary complex

with antithrombin and

thrombin.

B, Because of their lower

molecular weight, LMWH

species are unable to form

the ternary complexes

with antithrombin and

thrombin. Thus, LMWHs

produce their

anticoagulant effect

mainly by inhibiting factor

Xa.

Mechanism of action of UFH and LMWH


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Fondaparinux: Mechanism of action

Drug name Route of

administration

Excretion Indications

Fondaparinux SC Renal (Eliminated

unchanged in urine)

Prophylaxis & treatment of

acute deep vein thrombosis

Overview:


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Side-effects of fondaparinux:Anemia; Hematoma; Hypokalemia;

Hypotension; Thrombocytopenia; Urinary tract infection; edema; fever;;local irritation (injection site bleeding; rash); nausea

Side effects of heparin:1.Haemorrhagethe risk is greatest in the elderly, and may be

exacerbated by alcohol intake. This is by far the most common side

effect.2.Osteoporosiscan occur if the drug is used for more than a few

weeks. This does not occur with LMWHs.

3.Thrombocytopaeniacan occur after 7-10 days of therapy. It is a

result of heparin induced antiplatelet antibodies.

4.Hyperkalaemiadue to inhibition of aldosterone secretion

5.Hypersensitivity


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VITAMIN K ANTAGONISTS

Side-effects:Haemorrhagethis is especially common to the bowel

and brain; hematuria; epistaxis; teratogenicity; necrosis of soft tissues;

leukopenia, agranulocytosis


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DIRECT Xa INHIBITORSRivaroxaban and Apixaban

oral, reversible, specific inhibitors

of both free and fibrin-boundfactor Xa

do not involve antithrombin III

(ATIII) to exert their

anticoagulant effects

decrease thrombin generationand thrombus development

side-effects: upper GI, lower GI,

and rectal bleeding (0.1% to 1%);

skin rash (less than 1%);

anaphylactic reactions (such asallergic edema) (less than 1%);

intracranial bleeding (0.33%);

syncope (less than 1%);

intraocular bleed (0.21%)

anticoagulants, direct and indirect thrombin inhibitors

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