Acenocoumarol is an oral anticoagulant belonging to the vitamin K antagonist class, used widely for the prevention and treatment of thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, atrial fibrillation, and in patients with mechanical heart valves. It exerts its effect by inhibiting the synthesis of vitamin K–dependent clotting factors II, VII, IX, and X, thereby reducing blood coagulation. The development of acenocoumarol is rooted in the historical discovery of coumarin anticoagulants in the early 20th century, following observations of bleeding in cattle that consumed spoiled sweet clover, which led to the identification of dicoumarol. Building on this discovery, synthetic derivatives such as acenocoumarol were developed in the mid-20th century to provide more predictable anticoagulant effects and improved oral bioavailability. Introduced into clinical practice during the 1950s and 1960s, acenocoumarol gained acceptance due to its relatively shorter half-life compared to warfarin, allowing for easier dose adjustment and management through International Normalized Ratio (INR) monitoring. Despite the availability of newer direct oral anticoagulants, acenocoumarol continues to be used in many regions worldwide, supported by its long history, established efficacy, and well-understood pharmacological profile.
BRAND NAMES
Acitrom (marketed by Abbott, primarily in India)
Sintrom (marketed in various countries including in Europe, Canada, and parts of South America by companies like Merus Labs, Novartis, and SERB Laboratoires)
Acenomac (Macleods Pharmaceuticals)
Artiflo (Zuventus Healthcare)
Nimalin (Shinto Organics)
Nistrom (Neiss Labs)
Syncumar (Alkaloida)
Trombostop (Terapia)
MECHANISM OF ACTION
Acenocoumarol acts as an oral anticoagulant by inhibiting the vitamin K–dependent pathway of blood coagulation. It competitively inhibits the enzyme vitamin K epoxide reductase (VKOR), which is responsible for converting oxidized vitamin K back to its reduced, active form. Reduced vitamin K is essential for the γ-carboxylation of glutamic acid residues on clotting factors II (prothrombin), VII, IX, and X, as well as the natural anticoagulant proteins C and S. By blocking this regeneration of active vitamin K, acenocoumarol decreases the synthesis of functionally active clotting factors in the liver. As a result, the blood’s ability to form clots is reduced, leading to prolonged coagulation time. The anticoagulant effect is delayed until existing clotting factors are cleared from circulation, which is why regular monitoring using the International Normalized Ratio (INR) is required to ensure safe and effective therapy.
PHARMACOKINETICS
Absorption
Acenocoumarol is quickly and efficiently absorbed from the gastrointestinal tract following oral administration, exhibiting an average bioavailability of about 60%. Maximum plasma levels are generally attained within 1 to 3 hours after dosing.
Distribution
The volume of distribution of acenocoumarol typically falls within the range of 0.16 to 0.34 L/kg.
Metabolism
Acenocoumarol is mainly metabolized in the liver through the cytochrome P450 enzyme system, chiefly by CYP2C9, and its metabolites are subsequently eliminated via both urinary and fecal routes.
Excretion
Acenocoumarol is eliminated from the body primarily in the form of inactive metabolites. Following hepatic metabolism, these metabolites are excreted mainly through the urine, with a smaller proportion eliminated via the feces. Only minimal amounts of unchanged drug are excreted, reflecting its extensive metabolism in the liver.
PHARMACODYNAMICS
Acenocoumarol is a vitamin K antagonist that exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, leading to reduced synthesis of vitamin K–dependent clotting factors II, VII, IX, and X. This prolongs blood coagulation time, increases INR, and requires regular monitoring to ensure safe and effective therapy.
DOSAGE AND ADMINISTRATION
Route: Oral administration
Initial dose: Usually 2–4 mg once daily.
Maintenance dose: Typically 1–8 mg per day, individualized based on INR.
Monitoring: Regular INR checks are essential to maintain the therapeutic range.
Timing: It may be taken with or without food, but should preferably be taken at the same time every day.
Dose adjustment: Required for elderly patients, liver impairment, or drug interactions.
DRUG INTERACTIONS
Acenocoumarol has significant drug and food interactions. Its anticoagulant effect may be increased, raising the risk of bleeding, when used with antiplatelets (e.g., Clopidogrel), NSAIDs (e.g., Celecoxib), Heparin, Amiodarone, Cimetidine, Allopurinol, Linezolid, and certain antibiotics. Conversely, its effectiveness can be reduced by some antiretroviral agents (e.g., Efavirenz, Atazanavir/ritonavir, Raltegravir). Additionally, alcohol, cranberry or grapefruit juice, phenytoin, carbimazole, and bosentan can alter its activity. Careful INR monitoring is essential when these substances are co-administered.
FOOD INTERACTIONS
Acenocoumarol interacts notably with foods rich in vitamin K, such as spinach, kale, and broccoli. Rather than avoiding them completely, patients should maintain a consistent intake to prevent reduced drug effectiveness. It also interacts with alcohol, cranberry products, grapefruit, and various herbal supplements, which can increase the risk of bleeding. Therefore, a stable diet, avoiding sudden changes, and consulting a doctor before taking any supplements are essential.
CONTRAINDICATIONS
Acenocoumarol is contraindicated in patients with active bleeding or conditions that carry a high risk of hemorrhage, such as gastrointestinal or intracranial bleeding. It should not be used in individuals with severe liver disease or hepatic failure that affects coagulation, severe uncontrolled hypertension, or known hypersensitivity to acenocoumarol or other coumarin derivatives. The drug is also contraindicated during pregnancy, particularly in the first trimester, due to the risk of fetal malformations. Additionally, acenocoumarol should be avoided in patients with hemorrhagic tendencies, blood clotting disorders, or those undergoing major surgery with a high bleeding risk unless anticoagulation can be carefully managed under medical supervision.
SIDE EFFECTS
Bleeding gums.
Nosebleeds.
Easy bruising.
Blood in the urine (hematuria) or in the stool, such as melena or black/tarry stools.
Headache.
Dizziness.
Nausea and vomiting.
Diarrhea.
Loss of appetite.
Skin rash or allergic reactions.
OVERDOSE
Unusual bleeding from the gums or prolonged nosebleeds.
Easy or severe bruising (ecchymosis).
Blood in urine (hematuria).
Bloody or black, tarry stools (melena), or vomiting blood.
Heavy or increased menstrual bleeding.
Sudden, severe headache or back pain (which may indicate internal bleeding, such as a spinal or intracranial hematoma).
Other symptoms of internal bleeding, such as dizziness, weakness, or difficulty breathing.
TOXICITY
Acenocoumarol toxicity, typically caused by an overdose, mainly poses a risk of serious bleeding and hemorrhage due to its strong anticoagulant action. This happens because the drug inhibits the activation of blood clotting factors.
