Novel oral anticoagulants

Direct thrombin inhibitors: Dabigatran

The only representative of this group within the scope of this topic is dabigatran. By mechanism of action, it is a direct thrombin inhibitor. The drug binds directly to the catalytic active site of the enzyme. The type of inhibition is reversible and competitive (this distinguishes it from hirudin).

Dabigatran is unique in that it blocks thrombin in two states:

• Free thrombin in blood plasma.
• Fibrin-bound thrombin (this allows it to disrupt the growth of an already formed thrombus).

As a result, the drug prevents the conversion of fibrinogen to fibrin and inhibits thrombin-induced platelet aggregation.

Pharmacokinetics: The drug is administered per os as a prodrug — dabigatran etexilate. Upon entering the bloodstream, it is rapidly hydrolyzed by esterases and converted into the active compound. Normal absorption requires an acidic environment, so tartaric acid is added to the tablet. Bioavailability is extremely low, at about 6.5%. It is metabolized via conjugation to form active glucuronides and is excreted primarily by the kidneys unchanged. The half-life is 12–14 hours.

Direct factor Xa inhibitors: Rivaroxaban and Apixaban

These drugs act on a different stage of the coagulation cascade. Their target is the active site of coagulation factor Xa. Inhibition is reversible and selective.

The site of action of factor Xa inhibitors covers the enzyme in two states:

1. In free form.
2. As part of the prothrombinase complex (where factor Xa works in conjunction with factor Va and $Ca^{2+}$ ions).

The final effect is the interruption of thrombin generation.

Pharmacokinetics: Unlike dabigatran, these drugs are rapidly absorbed when taken orally and have high bioavailability: about 50% for apixaban and up to 80% for rivaroxaban.

Crucial clinical feature: they are substrates for the P-glycoprotein transporter protein and cytochrome P-450 isoenzymes. This creates a high risk of drug interactions. Any drugs that are inducers or inhibitors of these systems will alter the concentration of anticoagulants in the blood. The half-life depends on age: in young patients, it is 5–9 hours for rivaroxaban, while in elderly patients, it is prolonged to 12–13 hours.

Clinical use and side effects

Novel oral anticoagulants are actively used in two main areas:

• Traumatology and orthopedics: Prevention of venous thrombosis and pulmonary embolism (PE) during major joint replacement (knee, hip). Here they surpass low-molecular-weight heparins in ease of use, as they do not require injections.
• Cardiology: Prevention of ischemic stroke and systemic thromboembolism in atrial fibrillation. Pathogenesis: in this arrhythmia, thrombi form in the atrial appendages, from which they can migrate to cerebral vessels, causing ischemia.

Dosing regimen: Rivaroxaban is taken once daily, apixaban twice daily.

Side effects: The main risk for the entire group is hemorrhagic complications (bleeding). Gastrointestinal bleeding occurs less frequently with dabigatran than with warfarin. An important issue is the absence of a specific antidote. Specific side effects of dabigatran include hepatotoxicity (elevated liver transaminases) and dyspepsia, which is caused by the irritating effect of tartaric acid in the tablet.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The role of blood esterases in the activation of prodrugs using dabigatran etexilate as an example.
• Structure and functions of the prothrombinase complex (interaction of factors Xa, Va, and calcium ions).
• Pathogenesis of thrombus formation in the atrial appendages during atrial fibrillation.
• Comparative characteristics of novel oral anticoagulants and low-molecular-weight heparins.
• Mechanisms of hepatic metabolism: conjugation to form glucuronides.

Other topics in the section "Drugs affecting hemostasis and thrombosis"

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