Anticoagulants

Frederick Villamena, PhD

Associate Professor of Pharmacology

College of Medicine

The Ohio State University

Block Objective

Describe• the mechanisms of action• indications• and major side effects of drugs affecting blood coagulation.

Learning Objectives

Understand

• the mechanism of normal clotting.

Name

• the conditions for the use of anticoagulants and antithrombotics.

Classify and nam

e

• commonly used anticoagulants and antithrombotics.

Identify

• the properties, mechanisms of action, pharmacokinetics, side effects, and contraindications of various anticoagulants and antithrombotics.

References

Lilly, L. Pathophysiology of Heart Disease, 5th ed. 2010. Chapter 17, pp. 422-423, 427-431

Harvey, R.A. and Champe, P. C. Pharmacology, 2nd ed. Lippincott Illustrated Reviews.

Mechanism of Normal Clotting

endothelium

platelets (thrombocytes)

collagen fibers

ADP

Thromboxane A2

(TXA2)

GP IIb/IIIa receptors activation

fibrinogenCa2+

thrombin

ADP, thrombinTXA2 synthesis

XII XIIa

XI XIa

IX IXa

X Xa

Ca2+

Ca2+

Ca2+

VIIVIIa

XCa2+

fibrinogen fibrinCa2+

prothrombin (II) thrombin (IIa)Ca2+

fibrin

Intrinsic Pathway (platelets)

Extrinsic Pathway (tissue damage)

Thrombus

Clot adherent to vessel wall or heart chamber wall (as opposed to embolus which is a clot that floats in the blood). Therefore, thrombus may become an embolus.

Indications

A. Thromboembolic disease1. Deep vein thrombosis (DVT), thrombophlebitis

2. Pulmonary embolism

B. Prevention of thrombosis in high risk patients1. Post op

2. Bedridden patients

C. Heart disease1. Arrhythmias (atrial fibrillation and flutter)

2. Mechanical prosthetic heart valves

3. After myocardial infarction of anterior wall

Anticoagulants

Unfractionated Heparin (UFH)

Low molecular weight heparins (LMWH)

Parenteral direct thrombin inhibitors

Oral Anticoagulants (warfarin, Factor Xa and thrombin inhibitors)

Unfractionated Heparin: Properties

Mixture of high and low molecular weights glycosaminoglygans (3-40 kD; ave. m.w. = 15 kD)

Extracted from porcine intestinal mucosa. Highly negative-charged due to sulfate and carboxylate

groups Applied mostly as venous thrombosis prophylaxis in

hospitalized patients Also for prevention of pulmonary embolism, mural

thrombosis after myocardial infarction or atrial arrhythmias, and those with unstable angina and MI.

Heparin: Mechanism of Action

X XaCa2+

XCa2+

fibrinogen fibrinCa2+

prothrombin (II) thrombin (IIa)Ca2+

low heparin dose

high heparin dose

acceleratedbinding to coagulant factors inactivated Factor Xa

or Thrombin (IIa)(also inhibits other proteases)

heparin

antithrombin

Factor Xaor Thrombin (IIa)

heparin does not lyse clot

Heparin: Pharmacokinetics

Rapid-acting anticoagulant Parenterally (deep sub q or intravenously) as a bolus for

immediate anticoagulation followed by continuous infusion. Effect occurs 1-2 hours after sub q injection (or min after IV). Potential benefits may warrant use of the drug in pregnant

women despite potential risks (Cat. C) since it does not penetrate placental barrier.

Binds to plasma protein and taken up by phagocytes hence unpredictability of dose-response.

Excreted in the urine, therefore, dose is decreased for patients with renal impairment.

Heparin: Side Effects

Bleeding complications treated with protamine sulfate, a highly positively-charged peptide.

Antigenic (from porcine source) Thrombosis due to chronic or intermittent use can lead to

reduction of antithrombin III activity Heparin-induced thrombocytopenia (HIT) or immune

mediated heparin-induced thrombocytopenia syndrome (HITS)

HITS is dangerous and associated with bleeding and thrombosis at the same time

Osteoporosis and abnormal liver function from long term use.

Heparin: Contraindication

Bleeding disorder or active bleeding Immune mediated heparin induced thrombocytopenia

(HITS) Alcoholics Recent surgery of the brain, eye or spinal cord

Types of Low Molecular Weight Heparins (LMWH)

• Enoxaparin• Dalteparin• Tinzaparin

Heparin-derived

• FondaparinuxSynthetically derived

Heparin-Derived LMWH

Partially purified low average molecular weight of 5 kD. 1/3 the size of unfractionated heparin Mechanism of action: same as heparin but greater effect on Factor Xa Longer half-lives (3-7 hrs) than heparin (1.5 hrs) Given by injection to patients following surgery of the hip, knee or

abdominal surgery to prevent DVT. In treatment of DVT with or without pulmonary embolism and

management of acute coronary syndrome. Fewer side effects than that of heparin. Do not cross the placenta (Cat. B drug). Less monitoring than heparin therefore is cost effective and useful for

in- and outpatients.

Synthetic LMWH

Example is Fondaparinux. Selectively inhibits Xa Do not bind to protamine FDA approved for deep vein thrombosis leading to pulmonary

embolism. Subq administration to patients with hip fracture/replacement/

surgery. No adverse effects in pregnant women. Lower risk of HIT than with LMWH and heparin. Contraindicated in patients with renal impairement

Direct Thrombin Inhibitors (DTIS)

Bivalirudin Desirudin Lepirudin Argatroban

Dabigatran

(will be discussed under oral

anticoagulants)

BIVALIRUDIN is the most commonly used especially for patients with heparin-induced thrombocytopenia syndrome (HITS)

Major side effect is bleeding.

All are parenterally administered except for Dabigatran which is orally administered.

Oral Anticoagulants

• Warfarin• Dicumarol (rarely used)

Vitamin K antagonist

• DabigatranThrombin inhibitor

• Rivaroxaban• ApixabanXa inhibitors

Warfarin: Mechanism of ActionXII XIIa

XI XIa

IX IXa

X Xa

Ca2+

Ca2+

Ca2+

VIIVIIa

XCa2+

fibrinogen fibrinCa2+

prothrombin (II) thrombin (IIa)Ca2+

Polypeptide precursors to Factors II, VII, IX and X

Active Factors II, VII, IX and X

Vit K (red)O2, CO2

Vit K (ox)

NADP+

NADPH

Warfarin

Warfarin: Indication and Pharmacokinetics

Prevention of thrombosis and thromboembolism. Rapidly absorbed after oral administration. Mostly binds to plasma albumin preventing diffusion into

cerebrospinal fluid, urine, and breast milk. Half-life is ~ 40 hrs. Metabolized by CYP450.

Warfarin: Side Effects

Hemorrhage (principal risk) IV injection of Vit K or whole blood, frozen

plasma/concentrates are used as antidotes for warfarin Purple toe syndrome due to cholesterol emboli Alcohol, aspirin and antiarrhythmic agents can potentiate

anticoagulant effect of warfarin. Antibiotics can reduce the amount of gut flora, therefore, also

potentiating the effect of warfarin. Frequent monitoring of the prothrombin time (INR) needed Phenobarbital and ibuprofen attenuate the effect of warfarin. Teratogenic (FDA pregnancy category X) can cause abortion

or fetal defects (instead heparin or LMWH are used).

Dabigatran

Oral direct thrombin inhibitor Dabigatran etexilate is a prodrug of the active moiety

dabigatran FDA approved for prevention of stroke and systemic

embolism in patients with atrial fibrillation NOT associated with heart valve disease and for treatment of DVT and pulmonary emboli

Prevention of DVT. Pregnancy category C. Only recommended if there is no

alternative. No antidote.

Dabigatran: Mechanism of ActionXII XIIa

XI XIa

IX IXa

X Xa

Ca2+

Ca2+

Ca2+

VIIVIIa

XCa2+

fibrinogen fibrinCa2+

prothrombin (II) thrombin (IIa)Ca2+

Rivaroxaban and Apixaban

Oral Factor Xa inhibitor with rapid onset of action. Prevention of deep vein thrombosis (DVT) in patients

with hip fracture or hip/knee replacement surgery. Used following an acute DVT and pulmonary embolism. As stroke prophylaxis for patients with non-valvular atrial

fibrillation. Both are not indicated for prosthetic heart valves, or for

mitral stenosis, or as an add-on to dual antiplatelet therapy.

No antidote

Rivaroxaban and Apixaban: Mechanism of Action

XII XIIa

XI XIa

IX IXa

X Xa

Ca2+

Ca2+

Ca2+

VIIVIIa

XCa2+

fibrinogen fibrinCa2+

prothrombin (II) thrombin (IIa)Ca2+

Thrombolytics (Fibrinolytics)

Dissolve blood clots Hemorrhage is a major side effect since it cannot distinguish

between fibrin from unwanted thrombus and fibrin from beneficial hemostatic plug.

Tissue plasminogen activator (tPA) is most commonly employed. Used in myocardial infarction with ST segment elevation on ECG. Unstable patients with pulmonary emboli Clotted mechanical prosthetic heart valves. Acute ischemic stroke

Contraindicated in patients with healing wounds or recent major surgery, pregnancy, brain tumor and head trauma/intracranial bleeding.

Antidote is aminocaproic acid.

Thrombolytics: Mechanism of action

plasminogen

plasmin

Tissue plasminogen activator (t-PA)Streptokinase Urokinase

Comparison of Major Anticoagulant Drugs

Drugs

Mechanism of action

Indications

(all used to prevent thrombosis as well)

Route of administration

Adverse effect

Unfractionated Heparin

Thrombin, Xa

Thrombosis (hospitalized

patients)

IV

Subcutaneous

Thrombocytopenia,

bleeding

LMWH

Xa

After orthopedic surgery, DVT and

PE

Subcutaneous

Bleeding, thrombocytopenia, osteoporosis (from

long term use)

Direct Thrombin Inhibitors

Thrombin

Heprain-Induced Thrombocytopenia

(HITS)

IV

Bleeding (contraindicated in renal and hepatic

diseases)

Warfarin

Vitamin K antagonist (II, VII,

IX, X)

Thrombosis (outpatients)

Oral

Bleeding with overdose

Drug interactions

Anticoagulant Drugs Quiz

Thank you for completing this module

• I hope that I was able to teach the subject clearly.• If you have any questions, write to me. [villamena.1@osu.edu]

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