Usage
Acenocoumarol is prescribed to prevent and treat thromboembolic disorders, including:
- Deep vein thrombosis (DVT)
- Pulmonary embolism (PE)
- Atrial fibrillation (with associated risk of blood clots)
- Transient ischemic attacks (TIAs or mini-strokes), in combination with other medications
- Blood clots in the heart (in combination with other medications)
It’s classified as an anticoagulant (specifically, a coumarin derivative and vitamin K antagonist), sometimes referred to as a “blood thinner,” although it does not actually thin the blood. It works by inhibiting the synthesis of certain clotting factors in the liver, thereby reducing the blood’s ability to clot.
Alternate Names
- Nicoumalone
- Sintrom® (and variants like Mini-sintrom®, Neo-Sintrom®, Sintrom Mitis®)
- Sinthrome®
- Acebron™
- Acenox™
- Acitrom™
- Antitrom™
- Azecar™
- Coarol™
- Cumarol™
- Fortonol™
- Isquelium™
- Saxion™
- Syncumar™ (and Синкумар)
How It Works
Pharmacodynamics: Acenocoumarol inhibits the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as protein C and protein S. This leads to a decrease in the concentration of these factors in the blood, prolonging the time it takes for blood to clot.
Pharmacokinetics:
- Absorption: Well-absorbed orally.
- Metabolism: Primarily metabolized in the liver by CYP2C9, with some contribution from CYP1A2 and CYP3A4. S-acenocoumarol, the more potent enantiomer, is rapidly metabolized and excreted. Thus R-acenocoumarol is responsible for majority of pharmacological effect.
- Elimination: Excreted mainly in urine and feces, with a half-life of approximately 8-10 hours.
Mode of Action: Acenocoumarol acts as a vitamin K antagonist, inhibiting the enzyme vitamin K epoxide reductase. This enzyme is essential for the regeneration of the reduced form of vitamin K, which is a cofactor necessary for the gamma-carboxylation of glutamic acid residues in clotting factors II, VII, IX, and X. By blocking this regeneration, acenocoumarol renders these clotting factors inactive.
Receptor binding, enzyme inhibition, or neurotransmitter modulation: Vitamin K epoxide reductase enzyme inhibition.
Elimination pathways: Primarily hepatic metabolism (CYP2C9), followed by renal and fecal excretion.
Dosage
Standard Dosage
Adults:
- Initial: 2-4 mg daily for two days, or a loading dose of 6 mg on the first day followed by 4 mg on the second day.
- Maintenance: 1-8 mg daily, adjusted based on the patient’s International Normalized Ratio (INR) response. Individualized dosing is essential.
Children:
Limited data available. Loading doses based on age and weight have been suggested (e.g., <1 year: 0.20 mg/kg; >1-5 years: 0.09 mg/kg; 6-10 years: 0.07 mg/kg; 11-18 years: 0.06 mg/kg). Pediatric use requires careful monitoring and specialist guidance.
Special Cases:
- Elderly Patients: Start with lower doses (e.g., 1 mg initially) and titrate cautiously due to increased sensitivity and potential age-related decline in organ function.
- Patients with Renal Impairment: Severe renal impairment is a contraindication. Reduce the dose in patients with mild to moderate renal impairment.
- Patients with Hepatic Dysfunction: Severe hepatic impairment is a contraindication. Exercise caution and adjust the dose in mild to moderate hepatic impairment.
- Patients with Comorbid Conditions: Patients with heart failure, protein C or S deficiency, vitamin K deficiency, infections, or thyroid disease require careful monitoring and potential dose adjustments.
Clinical Use Cases
Dosage recommendations for specific clinical scenarios are similar to standard dosing, with adjustments based on patient-specific factors and INR monitoring. Consult hematology/cardiology specialists for optimal management. For emergency situations (e.g., life-threatening thromboembolism) heparin is the anticoagulant of choice.
Dosage Adjustments
Dose modifications are necessary based on INR values, renal/hepatic function, age, drug interactions, and genetic factors (CYP2C9 and VKORC1 variants). Regular INR monitoring is crucial. Algorithms incorporating these factors can aid in personalized dosing.
Side Effects
Common Side Effects
- Bleeding (e.g., nosebleeds, gum bleeding, easy bruising, heavy menstrual bleeding)
- Bruising
Rare but Serious Side Effects
- Major hemorrhage (internal bleeding, intracranial hemorrhage)
- Skin necrosis or gangrene (especially in patients with protein C or S deficiency)
- Purple toe syndrome (bluish discoloration of toes due to microemboli)
- Calciphylaxis (calcium deposits in blood vessels, causing skin lesions)
- Anaphylaxis (severe allergic reaction)
- Liver injury
Long-Term Effects
Chronic complications from long-term acenocoumarol use are primarily related to bleeding risks and potential drug interactions.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include major bleeding, skin necrosis, purple toe syndrome, calciphylaxis, anaphylaxis, and liver injury. Any of these require immediate medical attention.
Contraindications
- Active bleeding or high risk of serious bleeding
- Severe hypertension
- Pregnancy (especially first trimester)
- Severe renal impairment
- Severe hepatic impairment
- Hypersensitivity to acenocoumarol
- Conditions associated with high bleeding risk (e.g., recent surgery, peptic ulcer, haemophilia)
Drug Interactions
Acenocoumarol interacts with many drugs, including:
- CYP2C9 inhibitors: Amiodarone, azole antifungals (fluconazole, ketoconazole, itraconazole), some antibiotics (co-trimoxazole, metronidazole), cimetidine. These can increase acenocoumarol levels and bleeding risk.
- CYP2C9 inducers: Barbiturates, carbamazepine, rifampicin. These can decrease acenocoumarol levels and reduce efficacy.
- Antiplatelet drugs: Aspirin, clopidogrel. These can increase bleeding risk.
- NSAIDs: Ibuprofen, naproxen. These can increase bleeding risk, especially gastrointestinal bleeding.
- Vitamin K-rich foods: Leafy green vegetables. These can reduce acenocoumarol’s efficacy.
- Alcohol: Can enhance anticoagulant effect and increase bleeding risk.
- Cranberry juice and other cranberry products: Can affect INR levels.
- Herbs and supplements: Garlic, ginger, bilberry, danshen, piracetam, ginkgo biloba, and St. John’s wort. These can increase bleeding risk.
Pregnancy and Breastfeeding
- Pregnancy: Contraindicated, especially in the first trimester, due to the risk of fetal warfarin syndrome (warfarin embryopathy) including skeletal and central nervous system abnormalities. Avoid during pregnancy unless benefits outweigh risks.
- Breastfeeding: Acenocoumarol is present in breast milk at low levels. Generally considered compatible with breastfeeding, as the risk to the infant is low, and no adverse effects have been consistently reported. Close monitoring of the infant is advisable.
Drug Profile Summary
- Mechanism of Action: Vitamin K antagonist, inhibits vitamin K epoxide reductase.
- Side Effects: Bleeding, bruising, rarely major hemorrhage, skin necrosis, purple toe syndrome.
- Contraindications: Active bleeding, severe hypertension, pregnancy, severe hepatic/renal impairment.
- Drug Interactions: Numerous, including CYP2C9 inhibitors/inducers, antiplatelet drugs, NSAIDs, vitamin K.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy, generally compatible with breastfeeding with careful monitoring.
- Dosage: Initial: 2-4 mg/day or 6 mg then 4 mg; Maintenance: 1-8 mg/day (INR-guided).
- Monitoring Parameters: INR (regularly), hepatic function, complete blood count (CBC), signs of bleeding.
Popular Combinations
Acenocoumarol is typically used as monotherapy. Combinations with other anticoagulants or antiplatelet drugs are generally avoided due to increased bleeding risk. Consult hematology specialists for any combined antithrombotic therapy.
Precautions
- General Precautions: Pre-screening for bleeding disorders, liver and kidney function tests, monitoring INR.
- Pregnant Women: Avoid use.
- Breastfeeding Mothers: Monitor infant.
- Children & Elderly: Start with lower doses, monitor closely.
- Lifestyle Considerations: Avoid excessive alcohol, consistent vitamin K intake, caution with activities that might cause injury, avoid cranberry products.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Acenocoumarol?
A: Initial: 2-4 mg/day for two days, or 6 mg on the first day followed by 4 mg on the second day. Maintenance: 1-8 mg/day adjusted based on INR. Individualized dosing is crucial, especially in elderly patients and those with renal or hepatic impairment.
Q2: What are the most common side effects?
A: Bleeding (nosebleeds, gum bleeding, easy bruising, heavy menses) and bruising.
Q3: What are the serious side effects I should watch out for?
A: Major hemorrhage, skin necrosis, purple toe syndrome, calciphylaxis, and anaphylaxis.
Q4: Can Acenocoumarol be used during pregnancy?
A: No, it’s contraindicated in pregnancy, particularly the first trimester, due to teratogenic risk.
Q5: Can it be used during breastfeeding?
A: Generally considered compatible with breastfeeding, but close monitoring of the infant is necessary.
Q6: How does diet affect Acenocoumarol therapy?
A: Consistent intake of vitamin K-rich foods (leafy green vegetables) is important. Avoid drastic dietary changes, as this can alter INR levels.
Q7: What are the key drug interactions I should be aware of?
A: Numerous drugs interact, notably amiodarone, azole antifungals, certain antibiotics, aspirin, clopidogrel, NSAIDs. Alcohol and cranberry products can also interact. Always review patient’s medication list carefully.
Q8: What genetic factors can influence Acenocoumarol dosing?
A: Variants in CYP2C9 and VKORC1 genes can affect acenocoumarol metabolism and dose requirements. Pharmacogenetic testing may be considered to optimize dosing.
Q9: What is the mechanism of action of Acenocoumarol?
A: It inhibits the enzyme vitamin K epoxide reductase, blocking the regeneration of reduced vitamin K, which is essential for the synthesis of active clotting factors II, VII, IX, and X.
Q10: How often should INR be monitored in patients taking Acenocoumarol?
A: Initially, INR should be monitored daily or every other day, then at longer intervals based on response and stability. Frequency is tailored to the individual patient’s needs and clinical situation.
