Acenocoumarol

Acenocoumarol is an anticoagulant agent belonging to Vitamin K Antagonist.

Acenocoumarol is an anticoagulant drug used in the prevention of thromboembolic diseases in infarction and transient ischemic attacks, as well as the management of deep vein thrombosis and myocardial infarction.

Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. Approximately 98.7% is bound to protein, mainly to albumin. The volume of distribution at steady state appeared to be significantly dose-dependent: 78 ml/kg for doses < or = 20 mg/kg and 88 ml/kg for doses > 20 mg/kg respectively. Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed into an acetamido metabolite. Metabolites do not appear to be pharmacologically active.

Acenocoumarol shows common side effects like Bleeding, Dizziness, Headache, Blood in urine, Blurred vision, etc.

Acenocoumarol is available in the form of an Oral tablet.

Acenocoumarol is available in India, Canada, Italy, Switzerland, Germany, Spain, France, and Russia.

Acenocoumarol belonging to the Vitamin K Antagonist acts as an anticoagulant agent.

Acenocoumarol inhibits vitamin K reductase, resulting in the depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent clotting factors, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S is inhibited resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

The Data on the onset of action of Acenocoumarol is not available.

The Duration of Action for Acenocoumarol in the body is approximately 2 days.

The Tmax was found within 1-3 hours following the administration of Acenocoumarol.

Acenocoumarol is available in the form of an Oral tablet.

Acenocoumarol Oral tablet is taken by mouth usually once a day.

Acenocoumarol is an anticoagulant or blood thinner which is used in the treatment and prevention of abnormal blood clots. Acenocoumarol does not dissolve the blood clot that has already formed but may prevent it from becoming larger and leading to more serious problems.

Acenocoumarol is an anticoagulant agent belonging to Vitamin K Antagonist.

Acenocoumarol, a coumarin derivative, is a vitamin K-epoxide-reductase complex 1 (VKORC1) antagonist, depleting functional vitamin K reserves, thus, reducing the synthesis of coagulation factors II (prothrombin), VII, IX, and X, as well as proteins C and S. It also reduces γ-carboxylation of certain glutamic acid molecules, important for blood clotting initiation.

Acenocoumarol is approved for use in the following clinical indications

• Prevention and treatment of thromboembolism

Acenocoumarol is used in the treatment and prevention of thromboembolism that may occur after an acute myocardial infarction, post-cardiac stent implant, and cardiac valve replacement. It can also be used as a prophylaxis for Deep Vein Thrombosis (DVT), in preventing thromboembolism during a prolonged hospitalization after a critical illness, and in non-valvular atrial fibrillation.

• Prevention and treatment of thromboembolism

Oral Dose

Initial: 8 to 12 mg on day 1, followed by 4 to 8 mg on day 2. Subsequent dosage should be based on INR measurements.

The usual range of maintenance doses: is 1 to 10 mg/day. Tapering of dosage is recommended prior to discontinuation.

Acenocoumarol is available in various strengths as 0.5mg, 1mg, 2mg, 3mg, and 4mg.

Acenocoumarol is available in the form of an Oral Tablet.

Avoid herbs and supplements with anticoagulant/antiplatelet activity (eg., include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba).

Avoid food containing a high levels of Vitamin K (e.g., beef and pork liver, green tea, green leafy vegetables) it may reverse the anticoagulant effect.

Acenocoumarol is contraindicated in patients with

• Hemorrhagic diathesis and blood dyscrasia (e.g. hemophilia, thrombocytopenic purpura, leukemia), peptic ulcer or hemorrhage of the GI tract, urogenital tract or resp system; cerebrovascular hemorrhage, acute pericarditis, pericardial effusion, infective endocarditis, severe HTN.
• Recent or potential surgery of the eyes/CNS. Recent surgery resulting in increased fibrinolytic activity (e.g. surgery of the lung, prostate, and uterus).
• Uncooperative patient (e.g. unsupervised senile, alcoholic, psychotic, w/ dementia).
• Severe hepatic and renal impairment.
• Pregnancy.

• Anaphylaxis/hypersensitivity

May cause hypersensitivity reactions, including anaphylaxis; use with caution in patients with anaphylactic disorders. Cross-reactivity among coumarin anticoagulants has been described.

• Bleeding

May cause major or fatal bleeding. Risk factors for bleeding include high-intensity anticoagulation (INR >4), age (>65 years), variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, severe diabetes, malignancy, trauma, renal insufficiency, polycythemia vera, vasculitis, open wound, history of PUD, indwelling catheters, menstruating and postpartum women, and long duration of therapy or known genetic deficiency in CYP2C9 activity. Patients must be instructed to report bleeding, accidents, or falls as well as any new or discontinued medications, herbal or alternative products used, significant changes in smoking or dietary habits. Unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation. Treatment should be withdrawn at the earliest signs of bleeding.

• Skin necrosis/gangrene

Necrosis or gangrene of the skin and other tissues can occur (rarely) due to early hypercoagulability; risk is increased in patients with protein C or S deficiency. Onset is usually within the first few days of therapy and is frequently localized to the limbs, breasts, or penis.

• "Purple toe” syndrome

"Purple toe” syndrome, due to cholesterol microembolization, has been described with coumarin-type anticoagulants.

Avoid the consumption of alcohol with Acenocoumarol as it may increase the risk of bleeding.

Very small quantities of Acenocoumarol can be detected in breast milk and undesirable effects in nursing infants are not anticipated. The manufacturer recommends prophylaxis therapy with phytonadione (1 mg administered once weekly) and monitoring of the infant for signs of bleeding. The American College of Chest Physicians (ACCP) considers Acenocoumarol to be safe to use in breastfeeding women.

Teratogenic effects have been reported with coumarin derivative anticoagulants following first-trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Acenocoumarol crosses the placenta. Adverse events to the fetus have also been observed following second and third-trimester exposure with coumarin derivative anticoagulants and may include CNS abnormalities (including ventral midline dysplasia, and dorsal midline dysplasia). Fatal hemorrhage in the fetus has been reported even when the mother’s Acenocoumarol levels were in the therapeutic range. Acenocoumarol should not be used during pregnancy because of significant risks.

Avoid herbs and supplements with anticoagulant/antiplatelet activity (eg., include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba).

Avoid food containing high levels of Vitamin K (e.g., beef and pork liver, green tea, green leafy vegetables) it may reverse the anticoagulant effect.

• Skin necrosis, Priapism, and Hemorrhage may occur at virtually any site that may be predisposed to bleeding. Includes cerebral hemorrhage, gallbladder hemorrhage, hematuria, hemophthalmos, hepatic hemorrhage, melena, menorrhagia, metrorrhagia, and Hepatotoxicity.

• 5-Aminosalicylic Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. 5-Aminosalicylic Acid Derivatives may diminish the anticoagulant effect of Vitamin K Antagonists.
• Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants.
• Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased prothrombin times (PT)/therapeutic effects of oral anticoagulants if allopurinol is initiated/dose increased, or decreased effects if allopurinol is discontinued/dose decreased. Reductions in coumarin dosage will likely be needed.
• Amiodarone: May enhance the anticoagulant effect of Vitamin K Antagonists. Amiodarone may increase the serum concentration of Vitamin K Antagonists. Management: Monitor patients extra closely for evidence of increased anticoagulant effects if amiodarone is started. Consider empiric reduction of 30% to 50% in warfarin dose, though no specific guidelines on dose adjustment have been published.
• Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased effects of vitamin K antagonists if an androgen is initiated/dose increased, or decreased effects if androgen is discontinued/dose decreased. Significant reductions in vitamin K antagonist dose are likely required.
• Anticoagulants: May enhance the anticoagulant effect of Vitamin K Antagonists.
• Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. Anticoagulant dose increases of 30% to 60% may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction.
• Carbamazepine: May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased INR and effects of vitamin K antagonists if carbamazepine is initiated/dose increased, or increased INR and effects if carbamazepine is discontinued/dose decreased. Vitamin K antagonist dose adjustments will likely be required.
• Cholestyramine Resin: May decrease the serum concentration of Vitamin K Antagonists. Management: Separate the administration of vitamin K antagonists and cholestyramine by at least 3 to 4 hours. Monitor patients closely for reduced vitamin K antagonist effects (eg, decreased INR, thrombosis) when these agents are combined.
• Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Avoid coadministration of cimetidine and vitamin K antagonists. If unavoidable, monitor for increased effects of vitamin K antagonists when cimetidine is initiated/dose increased, or decreased effects if cimetidine is discontinued/dose decreased.
• CYP2C9 Inducers (Moderate): May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased effects of vitamin K antagonists (eg, decreased INR, thrombosis) if combined with moderate CYP2C9 inducers. Vitamin K antagonist dose adjustments will likely be required.
• CYP2C9 Inducers (Weak): May decrease the serum concentration of Vitamin K Antagonists.
• CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Vitamin K Antagonists.
• CYP2C9 Inhibitors (Weak): May increase the serum concentration of Vitamin K Antagonists.
• Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation.
• Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider reducing the oral anticoagulant dose by 25% to 33% when initiating a fibric acid derivative. Monitor for toxic or reduced anticoagulant effects if a fibric acid derivative is initiated/dose increased, or discontinued/dose decreased, respectively.
• Fluconazole: May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives when possible. If combined, consider reducing the vitamin K antagonist dose by 10% to 20% if combined with fluconazole. Monitor for increased anticoagulant effects (ie, increased INR, bleeding) to guide further dose adjustments.
• Fosphenytoin-Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Fosphenytoin-Phenytoin may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin-Phenytoin.
• Fusidic Acid (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Vitamin K antagonist dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely for evidence of bleeding and to determine appropriate dose.
• Lornoxicam: May enhance the anticoagulant effect of Vitamin K Antagonists. Lornoxicam may increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising.
• Menatetrenone: May diminish the anticoagulant effect of Vitamin K Antagonists. Management: Coadministration is not recommended. If concomitant use of menatetrenone and vitamin K antagonists cannot be avoided, monitor coagulation parameters, such as PT/INR.
• Metronidazole (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding.
• Miconazole (Topical): May increase the serum concentration of Vitamin K Antagonists. Management: Avoid using any miconazole-containing preparation in patients who are taking warfarin. If coadministration is unavoidable, consider reducing warfarin dose 10% to 20% and monitor for increased warfarin effects (eg, INR, bleeding).
• Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants.
• Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising.
• Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants.
• Salicylates: May enhance the anticoagulant effect of Anticoagulants.
• Selective Serotonin Reuptake Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists.
• Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists.

The common side effects of Acenocoumarol include the following

• Common

Bleeding, Dizziness, Headache, Blood in urine, Blurred vision.

• Rare

Hypersensitivity, Loss of appetite, Nausea and vomiting, Liver injury, Alopecia.

• Pregnancy

Pregnancy Category

Teratogenic effects have been reported with coumarin derivative anticoagulants following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Acenocoumarol crosses the placenta. Adverse events to the fetus have also been observed following second and third trimester exposure with coumarin derivative anticoagulants and may include CNS abnormalities (including ventral midline dysplasia, dorsal midline dysplasia). Fatal hemorrhage in the fetus has been reported even when the mother’s Acenocoumarol levels were in the therapeutic range. Acenocoumarol should not be used during pregnancy because of significant risks.

• Nursing Mothers

Very small quantities of Acenocoumarol can be detected in breast milk and undesirable effects in nursing infants are not anticipated. The manufacturer recommends prophylaxis therapy with phytonadione (1 mg administered once weekly) and monitoring of the infant for signs of bleeding. The American College of Chest Physicians (ACCP) considers Acenocoumarol to be safe to use in breast-feeding women.

• Symptoms: Haemorrhage, haematemesis, haemoptysis, haematuria (w/ renal colic), haematoma, menorrhagia, GI and cutaneous haemorrhage, vaginal, gingival, joint, and nose bleeding; tachycardia, hypotension, peripheral circulatory disorder, nausea, vomiting, diarrhoea, abdominal pain, high PT/INR value, prolonged thromboplastin time.
• Management: Oral vit K1 (phytomenadione) may be given for moderate to severe haemorrhage. Administer fresh blood/frozen plasma, complex concentrate/recombinant factor VIIa supplemented w/ vit K1 for severe and life-threatening haemorrhage.

Pharmacodynamic

Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by Acenocoumarol.

Pharmacokinetics

• Absorption

Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration.

• Distribution

Approximately 98.7% is bound to protein, mainly to albumin. The volume of distribution at steady state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 mg/kg respectively.

• Metabolism and Excretion

Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active.

• https://www.uptodate.com/contents/acenocoumarol-united-states-not-available-drug-information#F52868689
• https://go.drugbank.com/drugs/DB01418
• https://www.drugs.com/international/acenocoumarol.html
• https://www.mims.com/malaysia/drug/info/acenocoumarol?mtype=generic
• https://www.practo.com/medicine-info/acenocoumarol-785-api
• https://www.apollopharmacy.in/salt/ACENOCOUMAROL