Anticoagulant Therapy Quiz

Antiplatelets, Anticoagulants, and Anti-Hemorrhagic Drugs

• Antiplatelets (P2Y12 receptor antagonists): Ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor inhibit ADP binding to its receptors on platelets, preventing platelet activation and aggregation. Cangrelor is injectable, while the others are oral. Ticagrelor and cangrelor bind reversibly, while the other agents bind irreversibly.

• Mechanism of Action (Antiplatelets): P2Y12 receptor antagonists prevent the binding of ADP to its receptors on platelets, thus inhibiting platelet activation of GP IIb/IIIa receptors, and, consequently, platelet aggregation.

• Maximum Inhibition Time (Antiplatelets): Maximum platelet inhibition is achieved in 2 minutes with intravenous cangrelor, 1-3 hours with ticagrelor, 2-4 hours with prasugrel, 3-4 days with ticlopidine, and 3-5 days with clopidogrel.

• Therapeutic Use (Clopidogrel): Approved to prevent atherosclerotic events in patients with recent MI or stroke, and in those with established peripheral arterial disease.

• Therapeutic Use (Prasugrel and Ticagrelor): Approved to decrease thrombotic cardiovascular events in patients with acute coronary syndromes, such as unstable angina.

• Therapeutic Use (Cangrelor): Approved as an adjunct during percutaneous coronary intervention (PCI) to reduce thrombotic events.

• Pharmacokinetics (Antiplatelets): Oral loading doses are required for faster antiplatelet effects, except for cangrelor, which is administered intravenously. Food interferes with the absorption of ticlopidine. All agents are extensively bound to plasma proteins and undergo hepatic metabolism via the cytochrome P450 (CYP) system to active metabolites. Clopidogrel is a prodrug, and its efficacy depends on its active metabolite, which is produced via metabolism by CYP2C19. Genetic variation in CYP2C19 can lead to reduced clinical response in "poor metabolizers."

• Adverse Effects (Antiplatelets): These agents can cause prolonged bleeding, for which there is no antidote. All P2Y12 inhibitors have a risk of thrombotic thrombocytopenic purpura (TTP), but it is considered rare. Clopidogrel can cause neutropenia, but to a lesser extent than ticlopidine.

Glycoprotein IIb/IIIa Receptor Antagonists

• Mechanism of Action (Eptifibatide and Tirofiban): These agents block the GP IIb/IIIa receptors, which are crucial for platelet aggregation, thereby preventing platelet aggregation. Eptifibatide is a cyclic peptide, while tirofiban is not.

• Therapeutic Use (Eptifibatide and Tirofiban): Administered intravenously along with heparin and aspirin, as an adjunct to PCI for prevention of cardiac ischemic complications.

• Adverse Effects (Major): Bleeding.

Dipyridamole

• Action: A coronary vasodilator that increases intracellular cAMP levels by inhibiting phosphodiesterase, resulting in reduced thromboxane A2 synthesis.

• Additional Action: May potentiate prostacyclin effects, reducing platelet stickiness and decreasing platelet adhesion to thrombogenic surfaces.

• Therapeutic Use: Stroke prevention, usually given in combination with aspirin. Not for use in patients with unstable angina, due to its vasodilating properties and potential for worsening ischemia.

• Adverse Effect (Major): Orthostatic hypotension (especially with IV administration).

Cilostazol

• Action: Oral antiplatelet agent with vasodilating activity. Inhibits phosphodiesterase type III, increasing cAMP levels in platelets and blood vessels, preventing platelet aggregation, and promoting vasodilation.

• Therapeutic Use: Reducing symptoms of intermittent claudication and favorably altering lipid profiles by decreasing triglycerides and increasing high-density lipoprotein cholesterol.

Anticoagulants

• General Mechanism: Inhibit coagulation factors' action or interfere with their synthesis. Examples include vitamin K antagonists (e.g., warfarin) and factor Xa inhibitors (e.g., fondaparinux, rivaroxaban, apixaban).

Heparin and Low Molecular Weight Heparins (LMWHs)

• Action (Heparin): Injectable, rapidly acting anticoagulant that interferes with thrombin formation. Naturally occurring as a complex in mast cells.

• Action (LMWHs): Similar to heparin but smaller, with less chance of unwanted interactions. Produced by enzymatic depolymerization of unfractionated heparin.

• Mechanism of Action: Heparin binds to and activates antithrombin III, which inhibits thrombin (factor Ila) and factor Xa, thus leading to inactivation of the coagulation factors. LMWHs primarily inhibit Xa.

• Pharmacokinetics (Heparin): administered subcutaneously or intravenously, anticoagulant effect of heparin occurs within minutes of IV administration (or 1-2 hours after subcutaneous injection), maximal anti-factor Xa activity of the LMWHs occurs about 4 hours after subcutaneous injection

• Therapeutic Use: Treatment of acute venous thromboembolism, used for prophylaxis of postoperative venous thrombosis (e.g., hip replacement) and those with Acute MI. Used to treat pregnant women, as they do not pass through the placenta, do not require intensive monitoring, and save laboratory and nursing costs.

• Adverse Effects (Major): Bleeding is the chief complication.

• Treatment of Excessive Bleeding: Protamine sulfate. When slowly administered, it forms a stable 1:1 complex with heparin neutralising its anticoagulant effect.

• Other Adverse Effects: Heparin-induced thrombocytopenia (HIT), which is an immune-mediated adverse reaction, carrying a risk of venous and arterial embolism. Chills, fever, urticaria, and anaphylactic shock may also occur (antigenic properties of porcine-derived heparin). Heparin can be replaced by other anticoagulants like argatroban in cases of HIT.

Argatroban - Direct Thrombin Inhibitor

• Action: Synthetic parenteral anticoagulant, derived from l-arginine, is a direct thrombin inhibitor.

• Therapeutic Use: Prophylaxis or treatment of venous thromboembolism in patients with HIT, and is used during PCI in patients with or at risk for HIT.

• Pharmacokinetics: Anticoagulant effects are immediate. Metabolized in the liver; half-life is about 39-51 minutes. Dose reduction is recommended for patients with hepatic impairment.

• Adverse Effects: Bleeding, which is the major side effect.

Fondaparinux

• Action: Synthetic pentasaccharide anticoagulant that selectively inhibits factor Xa, potentiating its innate neutralization of factor Xa by antithrombin III.

• Therapeutic Use: Treatment of DVT and PE, and for prophylaxis of venous thromboembolism. Drug is well-absorbed from subcutaneous administration, with less monitoring required compared to heparin.

• Adverse Effects: Bleeding is the major side effect.

Warfarin

• Action: Vitamin K antagonist that inhibits the synthesis of clotting factors II, VII, IX, and X.

• Mechanism of Action: Antagonizes vitamin K, preventing the formation of active clotting factors.

• Monitoring: International Normalized Ratio (INR) is used to monitor anticoagulation activity. Target INR is 2-3 for most indications.

• Pharmacokinetics: Rapid absorption after oral administration. Warfarin is highly protein bound. Drugs that affect albumin binding can displace warfarin and alter anticoagulation activity. Typically a half-life of approximately 40 hours. Metabilised through the CYP450 system into inactive components.

• Therapeutic Use: Prevention and treatment of DVT and PE, stroke prevention, stroke prevention in case of atrial fibrillation or prosthetic heart valves.

• Adverse Effects: Hemorrhage is the most important adverse effect. Dose must be carefully monitored. Minor bleeding may be treated by stopping warfarin or administering vitamin K1, but severe bleeding requires larger doses of vitamin K given intravenously. Whole blood, frozen plasma, and plasma concentrates are also options, to reverse the effect of warfarin. Warfarin is teratogenic.

Direct Oral Anticoagulants (DOACs)

• Dabigatran: Dabigatran etexilate is an oral direct thrombin inhibitor.

• Therapeutic Use: Prevention of stroke and systemic embolism in patients with atrial fibrillation. Used in treatment of DVT and PE, and as prophylaxis to prevent or reduce recurrence of DVT and PE.

• Apixaban and Rivaroxaban: Inhibitors of factor Xa

• Therapeutic Use: Prevention of stroke in atrial fibrillation, treatment of DVT , PE or as prophylaxis to prevent or reduce risk of recurrence of DVT and PE. Prevention of major cardiovascular events in patients with coronary artery disease or peripheral artery disease.

• Pharmacokinetics: Well-absorbed after oral administration and have a half-life of 10 to 20 Hours. Both drugs are metabolized by CYP3A4,

  • Apixaban is primarily metabolized by CYP3A4 and 27% is renally excreted.
  • Rivaroxaban is metabolized by CYP3A4/5. One third is excreted into urine and the inactive metabolites in urine and faeces.

• Drug Interactions: They are substrates of P-glycoprotein (P-gp) and dosages should be reduced (in some cases, concomitant use should be avoided) with P-gp inhibitors (clarithromycin, verapamil, amiodarone). Should not be used with P-gp or CYP3A4 inducers(e.g., phenytoin, carbamazepine, rifampin), as this can cause potential reduction in efficacy of factor Xa inhibitors.

Thrombolytic Agents

• Mechanism of Action (Alteplase, Tenecteplase): Directly or indirectly convert plasminogen to plasmin, which then breaks down fibrin in thrombi, causing clot lysis. The conversion of plasminogen to plasmin is more efficient early after clot formation.

• Therapeutic Use: Treatment of myocardial infarction (MI), massive pulmonary embolism (PE), and acute ischemic stroke.

• Adverse Effects (Major): Hemorrhage (bleeding) is a significant risk. The thrombolytic agents do not differentiate between the fibrin of a clot and that of beneficial hemostatic plugs. Therefore, they should be used with caution.

• Contraindications: Pregnancy, healing wounds, history of cerebrovascular accident, intracranial bleeding.

• Alteplase: Said to be "fibrin-selective", at low doses, and is appropriate for treatment of MI and massive PE. Has a very short half-life (5-30 minutes) and requires different administration methods compared to Tenecteplase.

• Tenecteplase: Has a longer half-life and can be administered as an intravenous bolus.

Drugs Used to Treat Bleeding

• General: Concentrated preparations of coagulation factors from human donors are available. Blood transfusion is also an option for severe hemorrhage cases.

• Tranexamic Acid: Synthetic, orally active, urine excreting drug that inhibits plasminogen activation, helpful in cases with fibrinolytic states. A potential side effect of intravascular thrombosis needs careful consideration.

• Protamine Sulfate: Neutralises the anticoagulant action of heparin by forming a stable 1:1 complex with the drug.

• Vitamin K: Phytonadione (Vitamin K1) administration can stop bleeding problems due to warfarin. It may be administered orally, subcutaneously, or intravenously. Response is gradual (~24 hours).

• Factor Xa (Pro-drug): Recombinant modified human protein administered parenterally can reverse the effect of apixaban and rivaroxaban, if life-threatening or uncontrolled bleeding occurs.