Anticoagulants, Antiplatelets, Antithrombotics

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Heparin (general characteristics)

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Mechanism of action: Unfractionated heparin binds to endogenous antithrombin III and irreversibly inactivates thrombin.

Antithrombin III proteolyzes thrombin and factor Xa 1000 fold faster in the presence of heparin.

Highly acidic and can be neutralized by basic molecules (protamine)

Front 2

Unfractionated Heparin

Back 2

Works on preformed blood components so begins working immediately.

Is used in combination with thrombolytics for revascularization.

Common uses include treatment/prophylaxis of deep vein thrombosis (DVT), pulmonary embolism, and acute mycardial infarction.

Is given IV or subcutaneously to avoid hematoma associated with intramuscular injection.

Does not cross Placenta

Front 3

LMW Heparin and Foundparinux

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Bind antithrombin (ATIII) and have the same inhibitory effect on Xa as unfractionated heparin.

More selective action (no effect on thrombin.

Same indications as unfractionated heparin.

Given IV or subcutaneously.

Advantages over unfractionated heparin:
Less bleeding
Longer T1/2 after SQ
No lab monitoring
Less likely to cause immune mediated thrombocytopenia

Disadantages:
Activated partial thromboplastin time (aPPT) does not reliably measure anticoagulation effects, potential problem in renal failure.

Hint 3

Enoxaprin, Dalteparin

Front 4

Protamine

Back 4

can lessen the risk of serious bleeding.
Only partially reverses the effects of LMW heparin and does not bind fondaparinux.

Front 5

Rivaroxaban

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Mechanism of action: direct inhibitor of factor Xa that inhibits both free and clot bound factor Xa.

Uses:
Prevention of deep vein thrombosis in patients undergoing knee and hip replacement surgery.
Reducing stroke risk in Nonvalvular Artial Fibrillation.

Risk of thrombotic events upon with premature discontinuation

Front 6

Direct Thrombin Inhibitors

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directly binds to thrombin to prevent thrombin-mediated activation of fibrinogen and factor XIII.

Used as an alternative to heparin

Binding to thrombin is irreversible

monitored by (aPPT)

Hint 6

Desirudin-modified forms of hirudin.

Bivalirudin– modified forms of hirudin. also inhibits platelet activation

Front 7

Lepirudin– recombinant form of hirudin.

Back 7

directly binds to thrombin to prevent thrombin-mediated activation of fibrinogen and factor XIII.

Used as an alternative to heparin

Binding to thrombin is irreversible

monitor via aPPT

Hint 7

disadvantage:

Prolonged t1/2 in renally compromised patients. – dose adjustments.

Can cause bleeding and no reversal agents exist.

Antibodies can form and induce anaphylactic reactions.

Front 8

Argatroban

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small molecule inhibitors
-mechanism of action: binds only to the active site of thrombin

Hint 8

Used for treatment of patients with heparin-Induced thrombocytopenia (HIT).

Safe to be given in renal insufficiency (excreted via biliary route; CYP3A4 dependent metabolism).

Front 9

Dabigatran (prodrug)

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small molecule inhibitors
-mechanism of action: binds only to the active site of thrombin

Hint 9

No need to monitor blood levels

Greater predictive PK and PD

No dose adjustments

No significant drug-interactions

Front 10

Warfarin

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Mechanism of action: inhibit vitamin K epoxide reductase needed for coagulation cascade

has a delayed onset that parallels the half-life of the coagulation factors. (18-24 hours)

Affected factors are II, VII, IX, and X but factor VII has the shortest half-life (6 hrs)

Hint 10

Bleeding is the most common.

Small lipid soluble and highly protein bound (>99%)

Drug interactions with sulfonamides and aspirins

CYP2C9 metabolism

Narrow therapeutic range – dose needs to be individualized.

Goal of the therapy is to ↑ PT

A period of hypercoagulability with dermal vascular necrosis can occur early in therapy
– inhibition of protein C

VKORC1 gene resistance

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Tissue plasminogen activator

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tPA is an enzyme that binds to fibrin in a newly formed clot and directly converts plasminogen to plasmin.

Clinical uses: prompt recanalization of occluded vessels.

Toxicity:
Bleeding with Cerebral Hemorrhage being the most serious.

Drug Interactions: Increases risk of bleeding with dicumarol, warfarn, heparin, aspirin, ticlopidine, abciximab.

Hint 11

Alteplase -is normal human tPA (so not antigenic)

Reteplase -is a mutated form with similar effects but faster onset of action and longer duration of action.

Tenecteplase -is a mutated form with longer half-life.

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anistreplase

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MOA: Combines with plasminogen to form an active complex that converts plasminogen to plasmin to dissolve the fibrin.

a preformed complex of streptokinase and plasminogen

Clinical uses: prompt recanalization of occluded vessels.

Toxicity:
Bleeding with Cerebral Hemorrhage being the most serious.

Drug Interactions: Increases risk of bleeding with dicumarol, warfarn, heparin, aspirin, ticlopidine, abciximab.

Hint 12

Streptokinase
Protein + bacterial = risk of production of antibodies

Loss of efficacy

Severe allergic reaction

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ASA

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Mechanism of action: irreversible inhibitor of cyclooxygenase in platelets, an enzyme that synthesizes TXA2.

Efficacy is not dose related.

Toxicity: High doses of aspirin inhibits COX1 in the GI and leads to bleeding, GI intolerance and ulceration. Adverse effect are mediated through inhibition of PGE2.

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Ticlopidine

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Mechanism of action:
irreversible inhibitors of platelet ADP receptors:

Converts to thiol metabolites that accumulate -->delay in action (8-11 days)

Prescribe w/ aspirin or give ticlopidine loading dose to shorten delay

prodrugs metabolized in the liver

Hint 14

BBW: life threatening hematological adverse reactions including neutropenia thrombotic thrombocytopenic purpura and aplastic anemia

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Clopidogrel

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Mechanism of action:
irreversible inhibitors of platelet ADP receptors:

Poor metabolizers may show higher rates of CV side effects. Metabolized via CYP2C19 (screen patients)

Prodrug

Hint 15

BBW: diminished effectiveness in poor metabolizers

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Prasugrel

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Mechanism of action:
irreversible inhibitors of platelet ADP receptors:

More effectively metabolized than clopidogrel -->higher levels of active metabolite--->greater P2Y ADP antagonism.

Metabolized via CYP3A4

Prodrug

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Ticagelor

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Mechanism of action:
irreversible inhibitors of platelet ADP receptors:

Parent drug and major metabolite reversibly interact with the P2Y12 ADP receptor.

Both parent and metabolite -equipotent

Metabolized via CYP3A4

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Platelet Glycoprotein IIb/IIIa Receptor Blockers

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Mechanism of Action:
bind to GP IIb/IIIa and prevent interaction with fibrinogen.

Cause Bleeding

Hint 18

Abciximab is a chimeric mouse-human monoclonal antibody

Eptifibatide and Tirofiban are small molecule inhibitors.

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Cilostazol

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↑ in concentration of intracellular cAMP leads to a ↓ in platelet aggregation.

2 mechanisms of action:

adenosine, which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase -->cellular cyclic AMP.

inhibitor of platelet phosphodiesterase --> ↑ intracellular cAMP -->↓ in platelet aggregation

Hint 19

Use: treats intermittant claudication, a manifestation of periferal arterial disease

contraindicated in patients with congestive heart failure

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Dipyridamole

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↑ in concentration of intracellular cAMP leads to a ↓ in platelet aggregation.

2 mechanisms of action:

adenosine, which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase -->cellular cyclic AMP.

inhibitor of platelet phosphodiesterase --> ↑ intracellular cAMP -->↓ in platelet aggregation

Hint 20

Dipyridamole + warfarin may be used to prevent thrombus on prosthetic heart valves

Dipyridamole + aspirin : ↓ incidence of thrombotic diathesis in pts.

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Fibrinolytic Inhibitors

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Mechanism of action: Lysine analog that competes for lysine binding sites on fibrinogen and plasmin >>>blocking plasmin fibrin interaction.

Hint 21

Aminocaproic acid: Reduce bleeding in hemophiliacs after prostatic surgery or tooth extractions.

Thrombi that form during drug treatment do not get lysed.

Tranexamic acid: to control heavy menstrual bleeding.

Front 22

Vitamin K

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Hemostatic Agents

MECHANISM: Essential cofactor required in γ-carboxylation of multiple glutamate residues of several clotting factors (II, VII, IX and X).

INDICATION: IV vitamin K1 in reversing bleeding episodes induced by oral anticoagulants like warfarin.

Hint 22

Caution: fast IV infusion can lead to dyspnea, chest pain and even death.