Cardiovascular System - Drugs for Coagulation Disorders

What is the process of hemostasis?

Upon injury to small blood vessels

1. Initial vasospasms

Blood vessels constrict to limit blood flow to site of injury

2. Platelet activation

Platelets bind to damaged blood vessel due to collagen exposure

3. Platelet aggregation

Activated/Bound platelets release ADP and TA2, which stimulates activation of more platelets, platelet aggregation, and vasoconstriction

4. Fibrin formation

Thrombin converts fibrinogen to fibrin, which provides scaffolding necessary for a stable clot

What are the two pathways that activate fibrin formation?

Extrinsic pathway

Activated by thromboplastin released by damaged tissue

Intrinsic pathway

Activated by exposed collagen from vascular injury

Overall result is formation of factor Xa in the common pathway, which converts prothrombin to thrombin, which converts fibrinogen into fibrin

What is the process of fibrinolysis?

Breaking down of a formed clot

Tissue plasminogen activator is released by cells surrounding the tissue damage, which converts plasminogen into plasmin

Plasmin digests the fibrin and destroys the clot

What are anticoagulant drugs?

Used for prevention of clot formation for MI or CVA

Inhibits clotting factors and reduces clotting action of platelets, prevents clots from forming or growing larger and lengthens clotting times

Includes

-Heparin

-Low Molecular Weight Heparins

-Warfarin

-Direct Thrombin Inhibitors

-Direct Acting Factor Xa Inhibitors

What is heparin? (Use, Mechanism of Action, Route of Administration, Adverse Effects, Antidote)

Use

Type of anticoagulant used to inhibit clot formation

Mechanism of Action

Enhances activity of antithrombin III< results in inactivation of thrombin and clotting factor Xa. Due to its dual action, it has a very narrow TI and is a high alert drug, and as a result, cannot be prescribed within a community setting

Heavy binding to plasma proteins - ADME impact, drug interactions, and prolonged action

Route of Administration

IV and SC

Adverse Effects

Thrombocytopenia - Decline of platelets due to activation of antibodies from heparin therapy

Increased bleeding - clot inhibition

Antidote

Protamine sulphate

What is the use of heparin?

Type of anticoagulant used to inhibit clot formation

What is the mechanism of action of heparin?

Enhances activity of antithrombin III, results in inactivation of thrombin and clotting factor Xa. Due to its dual action, it has a very narrow TI and is a high alert drug, and as a result, cannot be prescribed within a community setting

Heavy binding to plasma proteins - ADME impact, drug interactions, and prolonged action

What are adverse effects of heparin?

Thrombocytopenia - Decline of platelets due to activation of antibodies from heparin therapy

Increased bleeding - clot inhibition

What is the antidote for heparin?

Protamine sulphate

Why is heparin not prescribed in a community setting?

Very narrow TI due to dual mechanism of action (inactivation of thrombin and factor Xa)

Also risk of thrombocytopenia requires frequent monitoring

What is low molecular weight heparin? (Use, Mechanism of Action, Route of Administration,. Adverse Effects, Antidote)

Use

Type of anticoagulant used to inhibit clot formation. Can be prescribed in community setting compared to heparin

Mechanism of Action

Enhances activity of antithrombin III, however, has more pronounced effects with inactivating factor Xa compared to thrombin, resulting in more stable and safer outcomes.

Can be used in community setting due to reduced risk of thrombocytopenia and decreased binding to plasma proteins, necessitating less monitoring

Route of Administration

SC

Adverse Effects

Increased bleeding - clot inhibition

Antidote

Protamine sulphate

What is the use of low molecular weight heparin?

Type of anticoagulant used to inhibit clot formation. Can be prescribed in community setting compared to heparin

What is the mechanism of action of low molecular weight heparin?

Enhances activity of antithrombin III, however, has more pronounced effects with inactivating factor Xa compared to thrombin, resulting in more stable and safer outcomes.

Can be used in community setting due to reduced risk of thrombocytopenia and decreased binding to plasma proteins, necessitating less monitoring

What is the antidote for low molecular weight heparin?

Protamine sulphate

What is warfarin? (Use, Mechanism of Action, Route of Administration, Adverse Effects, Drug-Drug interactions, Antidote)

Use

Type of anticoagulant used to inhibit clot formation

Mechanism of action

Inhibits epoxide reductase, an enzyme which recycles vitamin K - used in carboxylation to activate precursor clotting factors (specifically thrombin, factor VII, IX, and X). Overall result is reduced vitamin K and inhibition of producing active coagulation factors

Route of Administration

PO

If transitioning from heparin to warfarin therapy, both drugs must be co-administered for 3-5 days due to warfarin requiring time before exerting its therapeutic effects after administration. There is a heavy increased risk of bleeding during this time.

Adverse Effects

Increased bleeding - clot inhibition

Drug-Drug Interactions

Increased effect - acetaminophen , heparin, NSAIDS, thyroid hormone

Decreased effect - Barbiturates, bile-acid sequestrants, oral contraceptives

Mixed effect - corticosteriods

Antidote

Vitamin K supplementation- drug depletes vitamin K stores, so to reverse effect, increase vitamin K levels

What is the use of warfarin?

Type of anticoagulant used to inhibit clot formation

What is the mechanism of action of warfarin?

Inhibits epoxide reductase, an enzyme which recycles vitamin K - used in carboxylation to activate precursor clotting factors (specifically thrombin, factor VII, IX, and X). Overall result is reduced vitamin K and inhibition of producing active coagulation factors.

How do clotting factor precursors become activated?

Clotting factors are activated via carboxylation.

Carboxylation is a reaction linked to oxidation of vitamin K to Vitamin K epoxide -> in other words, carboxylation requires vitamin K

Vitamin K stores are replenished by the liver via the action of epoxide reductase, which converts Vitamin K epoxide into vitamin K

Epoxide reductase is the pharmacological target of warfarin

What is the antidote for warfarin?

Vitamin K supplementation- drug depletes vitamin K stores, so to reverse effect, increase vitamin K levels

What must be done if a patient is transferred from warfarin to heparin therapy?

If transitioning from heparin to warfarin therapy, both drugs must be co-administered for 3-5 days due to warfarin requiring time before exerting its therapeutic effects after administration. There is a heavy increased risk of bleeding during this time.

What are direct acting thrombin inhibitors? (Use, Mechanism of Action, Route of Administration, Adverse Effects, Antidote)

Use

Type of anticoagulant used to inhibit clot formation.

Beginning to replace px of warfarin and low molecular weight heparins in clinical practice due to PO route of administration, predictable effects, less required monitoring, and few drug interactions.

Mechanism of Action

Binds to and inhibits thrombin, which prevents conversion of fibrinogen to fibrin, inhibiting clot formation

Route of Administration

PO

Adverse Effects

Increased bleeding - clot inhibition

Antidote

Praxbind

Direct acting thrombin inhibitors display higher affinity for praxbind compared to thrombin, resulting in the drug being deactivated

What is the use of direct acting thrombin inhibitors?

Type of anticoagulant used to inhibit clot formation

Beginning to replace px of warfarin and low molecular weight heparins in clinical practice due to PO route of administration, predictable effects, less required monitoring, and few drug interactions.

What is the mechanism of action of direct acting thrombin inhibitors?

Binds to and inhibits thrombin, which prevents conversion of fibrinogen to fibrin, inhibiting clot formation

What is the antidote for direct acting thrombin inhibitors?

Praxbind

Direct acting thrombin inhibitors display higher affinity for praxbind compared to thrombin, resulting in the drug being deactivated

What are direct acting factor Xa inhibitors? (Use, Mechanism of Action, Route of Administration, Adverse Effects, Antidote)

Use

Type of anticoagulant used to inhibit clot formation.

Beginning to replace px of warfarin and low molecular weight heparins in clinical practice due to PO route of administration, predictable effects, less required monitoring, and few drug interactions.

Mechanism of Action

Selective inhibition of factor Xa, resulting in inhibition of formation of thrombin and development of clot

Route of Administration

PO

Adverse Effects

Increased bleeding - Clot inhibition

Antidote

Andenexanet

Direct acting factor Xa inhibitors display higher affinity for andenexanet compared to factor Xa, resulting in the drug being deactivated

What is the use of direct acting factor Xa inhibitors?

Type of anticoagulant used to inhibit clot formation.

Beginning to replace px of warfarin and low molecular weight heparins in clinical practice due to PO route of administration, predictable effects, less required monitoring, and few drug interactions.

What is the mechanism of action of direct acting factor Xa inhibitors?

Selective inhibition of factor Xa, resulting in inhibition of formation of thrombin and development of clot

What is the antidote for direct acting factor Xa inhibitors?

Andenexanet

Direct acting factor Xa inhibitors display higher affinity for andenexanet compared to factor Xa, resulting in the drug being deactivated

What are antiplatelet drugs?

Drugs that inhibit platelet aggregation, preventing clot formation in the arteries - especially for post MI patients - to prevent formation of new or bigger clots

Includes

-Irreversible cyclooxygenase inhibitors (NSAIDS) -> aspirin

-Adenosine diphosphate receptor antagonists

-Glycoprotein IIb/IIIa receptor antagonists

What is aspirin as an antiplatelet drug? (Use, Mechanism of Action, Dosing)

Use

A type of antiplatelet drug used to inhibit platelet aggregation and clot formation

Beneficial for secondary prevention of cardiovascular events (if you already had a cardiovascular event)

No effect on primary prevention of cardiovascular events (if you havent had a cardiovascular event yet)

Mechanism of Action

Blocks the activity of COX1 and *COX2* enzymes, resulting in inhibition of synthesis of prostaglandins, especially TA2, which is responsible for platelet aggregation

Dosing

Low dosing (~81 mg) is sufficient to achieve antiplatelet effects

What is the use of aspirin as an antiplatelet drug?

A type of antiplatelet drug used to inhibit platelet aggregation and clot formation

Beneficial for secondary prevention of cardiovascular events (if you already had a cardiovascular event)

No effect on primary prevention of cardiovascular events (if you havent had a cardiovascular event yet)

What is the mechanism of action of aspirin as an antiplatelet drug?

Blocks the activity of COX1 and *COX2* enzymes, resulting in inhibition of synthesis of prostaglandins, especially TA2, which is responsible for platelet aggregation

What are adp receptor antagonists? (Use, Mechanism of Action, Route of Administration)

Use

A type of antiplatelet drug used to inhibit platelet aggregation and clot formation.

Used as an alternative to aspirin and may be more beneficial in preventing cardiovascular events compared to aspirin.

Mechanism of Action

Irreversibly change molecular conformation of ADP receptors on platelets, preventing platelet aggregation and inhibiting clot formation

Route of Administration

PO

What is the use of adp receptor antagonists?

A type of antiplatelet drug used to inhibit platelet aggregation and clot formation.

Used as an alternative to aspirin and may be more beneficial in preventing cardiovascular events compared to aspirin.

What is the mechanism of action of adp receptor antagonists?

Irreversibly change molecular conformation of ADP receptors on platelets, preventing platelet aggregation and inhibiting clot formation

What is an adverse effect shared by all anticoagulant drugs?

Increased bleeding due to inhibition of clot formation

What are glycoprotein IIb/IIIa inhibitors? (Use, Mechanism of Action, Route of Administration)

Use

A type of antiplatelet drug used to inhibit platelet aggregation and clot formation.

Due to its high cost and relative safe efficacy as aspirin, it is reserved for prevention of clots during a percutaneous coronary intervention

Mechanism of Action

Antagonizes glycoprotein IIb/IIIa receptors, which are responsible for facilitating binding of platelets to fibrinogen and becoming sticky, thus preventing platelet aggregation and clot formation

Route of Administration

IV

What is the use of glycoprotein IIb/IIIa inhibitors?

A type of antiplatelet drug used to inhibit platelet aggregation and clot formation.

Due to its high cost and relative safe efficacy as aspirin, it is reserved for prevention of clots during a percutaneous coronary intervention

What is the mechanism of action of glycoprotein IIb/IIIa inhibitors?

Antagonizes glycoprotein IIb/IIIa receptors, which are responsible for facilitating binding of platelets to fibrinogen and becoming sticky, thus preventing platelet aggregation and clot formation

What are thrombolytic drugs?

Drugs that promote fibrinolysis (clot breakdown) by promoting conversion of plasminogen to plasmin, resulting in fibrin being dissolved.

It is used for acute management of clots and not used as a preventative measure

Thrombolytic therapy should be followed up with anticoagulant therapy to prevent formation of future clots

Includes

-Tissue plasminogen activators

What are tissue plasminogen activators - drug class? (Use, Mechanism of Action, Route of Administration, Contraindications, Monitoring, Antidote)

Use

Type of thrombolytic drug used to dissolve fibrin and breakdown clots

Mechanism of Action

Identical to human TPA, results in conversion of plasminogen to plasmin, which dissolves clots -> specific to fibrin bound plasminogen, resulting in less systemic effects

Route of Administration

IV, should be administered ASAP for MI and CVA

Contraindications

Recent trauma or bleeding disorders

(surgery, active internal bleeding, obstetrical delivery)

Monitoring

Monitor for cerebral hemorrhage

Antidote

Aminocaproic acid

Enzyme inhibitor which inactivates plasmin, reversing the effects of TPA. The patient should be assessed for excessive clotting when px with aminocaproic acid

What is the use of tissue plasminogen activators - drug class?

Type of thrombolytic drug used to dissolve fibrin and breakdown clots

What is the mechanism of action of tissue plasminogen activators - drug class?

Identical to human TPA, results in conversion of plasminogen to plasmin, which dissolves clots -> specific to fibrin bound plasminogen, resulting in less systemic effects

What are contraindications of tissue plasminogen activators - drug class?

Recent trauma or bleeding disorders

(surgery, active internal bleeding, obstetrical delivery)

What is the antidote for tissue plasminogen activators - drug class?

Aminocaproic acid

Enzyme inhibitor which inactivates plasmin, reversing the effects of TPA. The patient should be assessed for excessive clotting when px with aminocaproic acid