acenocoumarol

Actions and Spectrum: 

The mechanism of action of acenocoumarol involves interfering with the synthesis of certain clotting factors in the liver, specifically factors II, VII, IX, and X, which are vitamin K-dependent clotting factors. acenocoumarol inhibits the enzyme vitamin K epoxide reductase (VKORC1), which is responsible for the recycling of vitamin K.

This inhibition leads to a decrease in the available active form of vitamin K, thereby impairing the production of these clotting factors. By inhibiting the production of clotting factors II, VII, IX, and X, acenocoumarol reduces the ability of the blood to clot. This helps to prevent the formation of new blood clots and also prevents existing blood clots from growing larger.  

acenocoumarol has a broad spectrum of anticoagulant activity. It is effective in preventing clot formation in both arterial and venous circulation. It is commonly used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE). acenocoumarol is also used for preventing stroke and systemic embolism in patients with atrial fibrillation, a condition characterized by irregular heart rhythms. 

DRUG INTERACTION

Contraindicated  

Serious Use Alternative  

Monitor Closely  

Minor  

Frequency not defined 

Skin necrosis 

Hemorrhage 

Priapism 

Hepatotoxicity 

Black box warning: 

None 

Contraindications/caution: 

Contraindications: 

• Hypersensitivity or allergic reactions: Individuals with a known hypersensitivity or allergic reaction to acenocoumarol or its components should not use this medication.  
• Active bleeding: acenocoumarol is an anticoagulant that can increase bleeding risk. Therefore, its use is contraindicated in individuals with active bleeding, including gastrointestinal bleeding, intracranial bleeding, or significant hemorrhage in any other location. 
• Recent major bleeding: Individuals who have experienced recent major bleeding, such as a stroke or gastrointestinal bleeding, should not use acenocoumarol until the bleeding has resolved and the underlying cause has been addressed. 
• Severe liver disease: acenocoumarol is primarily metabolized in the liver, and severe liver disease can affect its metabolism and increase the risk of bleeding.  
• Severe kidney disease: Severe kidney disease can affect the elimination of acenocoumarol from the body, leading to an increased risk of bleeding. acenocoumarol should be used cautiously or avoided in individuals with severe kidney dysfunction. 

Caution: 

• Bleeding risk: acenocoumarol is an anticoagulant that increases the risk of bleeding. Caution should be exercised in individuals with a history of bleeding disorders, recent surgery or trauma, gastrointestinal ulcers, or other conditions that may increase the risk of bleeding.  
• Drug interactions: acenocoumarol interacts with numerous medications, including other anticoagulants, antiplatelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), certain antibiotics, etc. These interactions can potentiate or decrease the anticoagulant effects of acenocoumarol, leading to an increased risk of bleeding or reduced efficacy.  
• Genetic factors: Certain genetic factors can influence an individual’s response to acenocoumarol. Variations in genes encoding enzymes involved in drug metabolism (such as CYP2C9) or drug targets (such as VKORC1) can affect the dosage requirements and response to acenocoumarol. Genetic testing may optimize dosing and reduce the risk of adverse effects. 

Pregnancy consideration: It is contraindicated during pregnancy, particularly in the first trimester, due to the risk of foetal abnormalities. 

Lactation: Excretion of the drug in human breast milk is known and contraindicated during breastfeeding, as it can pass into breast milk and potentially cause bleeding in the infant. 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology: 

• The synthesis of coagulation factors IX, II, VII, and X, as well as proteins C and S, requires the presence of vitamin K. These clotting factors undergo a process called post-translational modification, where carboxyl groups are added to specific glutamic acid residues within their structure. This carboxylation reaction is essential for activating these clotting factors and is catalyzed by an enzyme called gamma-glutamyl carboxylase. 
• During carboxylation, vitamin K is oxidized and converted to its inactive form, known as vitamin K epoxide. Subsequently, the inactive vitamin K epoxide must be reduced to its active form by an enzyme called the vitamin K epoxide reductase complex 1 (VKORC1). This reduction step is crucial for the regeneration of active vitamin K, which is required for the carboxylation and activation of clotting factors. 
• Coumarin derivatives, such as acenocoumarol, exert their anticoagulant effects by inhibiting the action of VKORC1. By inhibiting VKORC1, these medications interfere with the regeneration of active vitamin K, leading to a depletion of functional vitamin K reserves within the liver. As a result, the synthesis of active clotting factors becomes impaired, ultimately reducing the ability of the blood to clot effectively. 
• The inhibition of VKORC1 by coumarin derivatives disrupts the balance between coagulation and anticoagulation, favoring an anticoagulant state. This anticoagulant effect is measured by monitoring the patient’s prothrombin time (PT) or international normalized ratio (INR), which reflects the time it takes for blood to clot compared to a standardized reference value. 

Pharmacodynamics: 

The anticoagulant effects of acenocoumarol develop gradually over several days, depleting the existing vitamin K-dependent clotting factors and inhibiting their synthesis. The therapeutic effect is measured and monitored using the international normalized ratio (INR), which represents the patient’s clotting time compared to a standardized reference value. 

The duration of action of acenocoumarol is prolonged, and its effects persist even after discontinuation due to the depletion of vitamin K-dependent clotting factors. Therefore, careful monitoring of INR is necessary to adjust the dosage and maintain therapeutic anticoagulation while minimizing the risk of bleeding complications. 

Pharmacokinetics: 

Absorption 

acenocoumarol is rapidly absorbed from the gastrointestinal tract. The peak anticoagulant effect of acenocoumarol is typically reached within 36 to 48 hours after oral administration. The bioavailability of acenocoumarol is approximately 60%, indicating the fraction of the administered dose that reaches systemic circulation. 

Distribution 

acenocoumarol has a relatively small volume of distribution (Vd) ranging from 0.16 to 0.34 L/kg.Approximately 99% of acenocoumarol is bound to plasma proteins, predominantly albumin. 

Metabolism 

acenocoumarol undergoes hepatic metabolism primarily through oxidation. The R-enantiomer is metabolized by CYP2C9 (primary enzyme), 1A2, and 2C19, while CYP2C9 primarily metabolizes the S-enantiomer. It can also undergo keto-reduction to inactive metabolites and nitro-reduction via gut flora. 

Elimination and Excretion 

The elimination half-life of acenocoumarol is approximately 11 hours for the R-enantiomer and less than 2 hours for the S-enantiomer. It reaches peak plasma concentrations within 1 to 3 hours after administration. acenocoumarol and its metabolites are primarily excreted in the urine, with approximately 60% excreted as metabolites and a minimal amount excreted as an unchanged drug. A portion of metabolites is also eliminated through feces. 

Administration: 

• acenocoumarol, an oral anticoagulant medication, is typically administered orally.  
• acenocoumarol is available in tablet form for oral administration. The tablets come in different strengths, and the prescribed dose will depend on the individual’s specific condition and the target level of anticoagulation. 

Patient information leaflet 

Generic Name: acenocoumarol 

Why do we use acenocoumarol? 

acenocoumarol is an oral anticoagulant medication commonly used for various medical conditions to prevent blood clot formation. Some of the primary uses of acenocoumarol include: 

• Thromboembolic Disorders: acenocoumarol is prescribed to prevent and treat thromboembolic disorders, which involve the formation of blood clots that can block blood vessels. It is commonly used to prevent venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients at risk. 
• Atrial fibrillation: acenocoumarol is often prescribed for patients with atrial fibrillation, a heart rhythm disorder characterized by irregular and rapid heartbeat. Atrial fibrillation increases the risk of blood clot formation in the heart, which can lead to stroke. acenocoumarol is used to reduce the risk of stroke in these patients. 
• Mechanical Heart Valves: acenocoumarol is used in individuals who have undergone heart valve replacement surgery with mechanical heart valves. Mechanical heart valves have a higher risk of blood clot formation, and anticoagulant therapy, such as acenocoumarol, is essential to prevent valve-related thrombosis. 
• Recurrent Deep Vein Thrombosis or Pulmonary Embolism: acenocoumarol may be prescribed for individuals with a history of recurrent DVT or PE to prevent further clotting episodes.