Nicoumalone

Usage

• Medical Conditions: Nicoumalone is prescribed for the prevention and treatment of thromboembolic disorders. These include deep vein thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation with embolization, and as an adjunct treatment in coronary occlusion. It helps prevent the formation of harmful blood clots in patients at risk, such as those with atrial fibrillation or who have undergone heart valve replacement. It is also used to prevent existing clots from enlarging.
• Pharmacological Classification: Anticoagulant (Vitamin K antagonist).
• Mechanism of Action: Nicoumalone inhibits the enzyme vitamin K epoxide reductase complex 1 (VKORC1). This enzyme is crucial for activating vitamin K, which is essential for the synthesis of clotting factors II (prothrombin), VII, IX, and X, as well as proteins C and S. By inhibiting VKORC1, Nicoumalone reduces the production of these clotting factors, thus prolonging the time it takes for blood to clot.

Alternate Names

• International/Regional Variations: Acenocoumarol
• Brand Names: Acitrom, Sintrom, Sinthrome

How It Works

• Pharmacodynamics: Nicoumalone decreases the synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X) and proteins C and S by inhibiting VKORC1. This leads to a reduced ability of the blood to clot.
• Pharmacokinetics:
  • Absorption: Rapidly absorbed from the gastrointestinal tract.
  • Bioavailability: Approximately 60%.
  • Time to Peak Plasma Concentration: 1-3 hours.
  • Distribution: Crosses the placenta and enters breast milk in small amounts.
  • Metabolism: Extensively metabolized in the liver.
  • Elimination: Primarily eliminated through renal excretion (about 60%), with the remainder eliminated through hepatic routes.
• Mode of Action: Nicoumalone acts as a competitive inhibitor of VKORC1, the enzyme responsible for reducing vitamin K epoxide back to its active form, vitamin K hydroquinone. This active vitamin K is needed as a cofactor in the post-translational modification (gamma-carboxylation) of glutamic acid residues on the clotting factors, making them functional. By inhibiting VKORC1, Nicoumalone disrupts this process.
• Elimination Pathways: Renal (approximately 60%) and hepatic.

Dosage

Standard Dosage

Adults:

• Initial: 2-4 mg daily for 2 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 according to the patient’s International Normalized Ratio (INR) response. Administer at the same time each day.

Children:

• Nicoumalone is generally not recommended for children. If used, very close monitoring and more frequent INR checks are necessary. Dosage should be individualized based on the child’s weight and INR response.

Special Cases:

• Elderly Patients: Start with a lower dose (e.g., 1 mg) and titrate cautiously based on INR. Close monitoring is recommended.
• Patients with Renal Impairment: Severe renal impairment is a contraindication. Dose reduction may be necessary in mild to moderate impairment. Close INR monitoring is crucial.
• Patients with Hepatic Dysfunction: Severe hepatic impairment is a contraindication. Dose reduction may be necessary in mild to moderate impairment, with careful INR monitoring.
• Patients with Comorbid Conditions: Dose adjustments might be needed for patients with conditions like heart failure, protein C or S deficiency, and vitamin K deficiency. Close monitoring is essential.

Clinical Use Cases

• Intubation: Dosage adjustments are not typically needed for intubation itself, but the underlying condition requiring intubation may influence Nicoumalone dosing.
• Surgical Procedures: Nicoumalone should generally be discontinued 5 days before elective surgery.
• Mechanical Ventilation: Similar to intubation, mechanical ventilation does not usually require dose changes, but underlying disease may necessitate adjustments.
• Intensive Care Unit (ICU) Use: Close monitoring of INR and dosage adjustments based on clinical status and other medications are vital.
• Emergency Situations: In emergency situations, the use of Nicoumalone might not be appropriate. Other anticoagulants like heparin might be preferred.

Dosage Adjustments

• Dose modifications should be based on patient factors such as age, renal and hepatic function, concurrent medications, and INR values.
• Consider pharmacogenetic factors like CYP2C9 polymorphisms, which can influence metabolism.

Side Effects

Common Side Effects:

• Bleeding (e.g., nosebleeds, easy bruising, increased menstrual bleeding)
• Gastrointestinal upset (e.g., nausea, vomiting, diarrhea)
• Skin rash

Rare but Serious Side Effects:

• Severe bleeding (e.g., intracranial hemorrhage, gastrointestinal bleeding)
• Allergic reactions (e.g., skin necrosis, urticaria)
• Purple toe syndrome

Long-Term Effects:

• Osteoporosis (with long-term use)

Adverse Drug Reactions (ADR):

• Hepatic dysfunction
• Jaundice
• Pancreatitis

Contraindications

• Hypersensitivity to acenocoumarol or coumarin derivatives
• Active bleeding or high risk of bleeding (e.g., recent surgery, peptic ulcer disease)
• Severe hypertension
• Severe renal or hepatic impairment
• Pregnancy
• Uncooperative patients

Drug Interactions

• Drugs that Increase Nicoumalone’s Effect: Amiodarone, quinidine, broad-spectrum antibiotics, tetracyclines, chloramphenicol, metronidazole, SSRIs (e.g., citalopram, fluoxetine), allopurinol, statins, CYP2C9 inhibitors.
• Drugs that Decrease Nicoumalone’s Effect: Azathioprine, 6-mercaptopurine, ritonavir, nelfinavir, thiazide diuretics, oral contraceptives, CYP2C9, CYP2C19, and CYP3A4 inducers (e.g., rifampicin, carbamazepine).
• Other Interactions: Foods high in vitamin K (e.g., green leafy vegetables) can decrease the effect. Alcohol can potentiate bleeding risk.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated in pregnancy.
• Fetal Risks: Teratogenic effects, including fetal malformations and embryopathy.
• Breastfeeding: Nicoumalone enters breast milk in small quantities. Monitor the infant for signs of bleeding. As a precaution, vitamin K may be administered to the infant.

Drug Profile Summary

• Mechanism of Action: Inhibits VKORC1, reducing the synthesis of clotting factors.
• Side Effects: Bleeding, bruising, gastrointestinal upset, rash, (rarely) severe bleeding, skin necrosis, purple toe syndrome.
• Contraindications: Active bleeding, severe hypertension, severe renal/hepatic impairment, pregnancy.
• Drug Interactions: Many; see Drug Interactions section above.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy; use with caution during breastfeeding.
• Dosage: Individualized based on INR. Initial: 2-4 mg/day for 2 days or 6 mg on day 1, 4 mg on day 2. Maintenance: 1-8 mg/day.
• Monitoring Parameters: INR (International Normalized Ratio), CBC, hepatic and renal function.

Popular Combinations

• Combination with heparin in the initial treatment phase of certain thromboembolic conditions, while the effect of Nicoumalone reaches therapeutic levels.

Precautions

• General Precautions: Monitor INR closely, especially at the start of therapy and after any dosage changes. Screen for allergies, bleeding disorders, liver and kidney function.
• Specific Populations: See “Special Cases” in the Dosage section.
• Lifestyle Considerations: Avoid alcohol, contact sports, and activities that increase bleeding risk. Use caution with sharp objects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Nicoumalone?

A: The dosage is individualized based on the INR. Initial doses range from 2-4 mg daily for two days, or 6 mg on the first day followed by 4 mg on the second day. Maintenance doses range from 1-8 mg daily.

Q2: How does Nicoumalone differ from warfarin?

A: Both are vitamin K antagonists, but Nicoumalone is more potent and has a longer half-life. This means dose adjustments may be less frequent than with warfarin.

Q3: What are the signs of Nicoumalone overdose?

A: Signs of overdose include hemorrhage (e.g., haematemesis, haematuria), hematoma formation, unusual bleeding, tachycardia, hypotension, and elevated INR.

Q4: How is Nicoumalone overdose treated?

A: Administer vitamin K1 (phytomenadione) for moderate to severe bleeding. For life-threatening bleeding, consider fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa, along with vitamin K1.

Q5: Can Nicoumalone be used during pregnancy?

A: Nicoumalone is contraindicated during pregnancy due to its teratogenic effects.

Q6: What are the key patient counseling points for Nicoumalone?

A: Educate patients about the importance of regular INR monitoring, potential side effects (especially bleeding), dietary restrictions (vitamin K intake), drug interactions, and the need to report any signs of unusual bleeding. Advise against sudden discontinuation of the drug.

Q7: How often should INR be monitored for a patient on Nicoumalone?

A: INR monitoring frequency varies depending on the patient’s clinical situation and the stability of their INR. Initially, it might be checked daily or on alternate days. Once stable, the frequency can be reduced, but regular checks are essential.

Q8: What is the role of CYP2C9 polymorphisms in Nicoumalone therapy?

A: CYP2C9 polymorphisms can affect the metabolism of Nicoumalone. Patients with certain variants may require lower doses to achieve therapeutic INR and are at higher risk of bleeding.

Q9: Does Nicoumalone dissolve existing blood clots?

A: No, Nicoumalone does not dissolve existing clots. It prevents new clots from forming and existing clots from getting larger.

Q10: Can a patient on Nicoumalone drink alcohol?

A: Alcohol consumption is generally discouraged while on Nicoumalone, as it can potentiate bleeding risk and interfere with the drug’s metabolism.