Anticoagulants

Haemostasis

• Vascular spasm• Platelet plug formation• Blood coagulation

Clotting factors 1 Fibrinogen

2 Prothrombin

3 Tissue thromboplastin or tissue factor (TF)

4 Ca2+

5 Proaccelerin

6

7 Proconvertin

8 Antihaemophilic factor-A

9 Christmas factor or plasma thromboplastin component(PTC)

10 Stuart factor

11 Plasma thromboplastin antecedent (PTA)

12 Hageman factor

13 Fibrin stabilising factor

• Factor 6 is not yet known• Factor 2, 7, 9, 10 are dependent on vitamin K

for their synthesis in liver.

• Extrinsic pathway: • Stimulus for activation: Tissue trauma• Tissue factor (TF)(Factor 3) leaks into the

blood from cells outside to blood vessels.

• Intrinsic pathway: • Stimulus for activation: Damaged endothelium

Natural anticoagulant mechanismsAntithrombin 3 Blocks action of factor

12,11,9,10 and 2Protein C Blocks factor 5 and 8.

Classification of Anticoagulants

Parenteral Anticoagulants

Heparin

• Strong electronegatively charged acidic polymer.

• Not absorbed from GIT (being large and highly ionised molecule).

• Does not cross BBB or placental barrier.• Not administered I.M., to avoid hematoma

formation at injection site.

Heparin

Adverse effects of Heparin

• Bleeding• Heparin induced thrombocytopenia.• Transient and reversible alopecia• Osteoporosis• Hypersensitivity reactions.

Contraindications of Heparin

• Bleeding disorder• Heparin induced thrombocytopenia.• Severe hypertension(risk of cerebral

haemorrhage)• GI ulcers• Aspirin and other antiplatelet drugs should be

used very cautiously during heparin therapy.

Heparin antagonist

• Protamine sulfate

LMW Heparin(Advantages)• The more important advantages of LMW heparins are

pharmacokinetic:• Better subcutaneous bioavailability (70–90%) compared to

UFH (20–30%): Variability in response is minimized.• Longer and more consistent monoexponential t½: (4–6

hours); making possible once daily s.c. administration.• Since aPTT/clotting times are not prolonged, laboratory

monitoring is not needed; dose is calculated on body weight basis.

• Risk of osteoporosis after long term use is much less with LMW heparin compared with UFH.

Low Molecular Weight Heparin

Examples of LMW Heparins

• Enoxaparin• Dalteparin

Direct Thrombin Inhibitors

• Parenteral• Hirudin• Lepirudin• Bivalirudin• Argatroban

Lepirudin

• Recombinant form of Hirudin.• Used I.V. as anticoagulant in thrombotic events

associated with heparin induced thrombocytopenia.• Monitored by APTT• Patient may develop antibodies against thrombin-

lepirudin complex. These antigen- antibody complexes are not cleared by kidneys and may result in enhanced anticoagulant effect.

Argatroban

• Used in patients with heparin induced thrombocytopenia.

• Clearance not affected by renal disease.

Oral Anticoagulants

Oral anticoagulants (Warfarin)

Warfarin

• Mechanism of action: interfering with synthesis of vitamin K dependant clotting factors in liver.

• Factors 2, 7, 9 and 10 are inhibited.

Warfarin

• Adverse effect• Bleeding • Antidote of warfarin- vit K1

• Monitering of warfarin therapy- prothrombin time.

• Contraindicated in pregnancy.

Factors enhancing effects of oral anticoagulants

• Liver disease, chronic alcoholism: synthesis of clotting factors may be deficient.

• Newborns: have low level of vit K and clotting factors.

Drug interactions of warfarin

• Enhanced anticoagulant action• Broad spectrum antibiotics inhibit gut flora

and reduce vit K production.

Oral Thrombin Inhibitors

• Dabigatran : Direct thrombin inhibitor.• Rivaroxiban: factor Xa inhibitor.

Uses of Anticoagulants

• Deep vein thrombosis and pulmonary embolism

• Myocardial infarction• Unstable angina• Rheumatic heart disease; Atrial fibrillation• Cerebrovascular disease• Vascular surgery, prosthetic heart valves,

haemodialysis.