phenindione

Actions and Spectrum: 

phenindione is an oral anticoagulant medication that is used to prevent blood clots. It belongs to the class of medications known as vitamin K antagonists (VKAs). VKAs work by inhibiting the action of vitamin K, which is necessary to produce specific proteins in the blood clotting process. By interfering with the production of these clotting factors, phenindione, and other VKAs help prevent blood clots’ formation. 

The action of phenindione involves inhibiting the synthesis of clotting factors II, VII, IX, and X, as well as anticoagulant proteins C and S. These factors are essential for the typical blood clotting cascade. By reducing the levels of these clotting factors, phenindione prolongs the time it takes for blood to clot.

This property makes phenindione helpful in preventing the formation of unwanted blood clots, which can lead to severe conditions like deep vein thrombosis, pulmonary embolism, and stroke. 

DRUG INTERACTION

Contraindicated  

Serious Use Alternative  

Monitor Closely  

Minor  

Frequency not defined 

Bleeding  

Hair loss 

Bruising 

Skin rash  

Diarrhea 

Black Box Warning: 

None 

Contraindication/Caution: 

Contraindication 

• Known Hypersensitivity: Individuals with a known hypersensitivity or allergic reaction to phenindione or related compounds should not use the medication. 
• Active Bleeding: phenindione is contraindicated in individuals with active bleeding or conditions that significantly increase the risk of bleeding, such as gastrointestinal ulcers, intracranial bleeding, or recent surgery. 
• Blood Disorders: Patients with certain blood disorders, such as hemophilia or other bleeding disorders, should avoid phenindione due to the increased risk of bleeding complications. 
• Pregnancy and Breastfeeding: phenindione is generally contraindicated during pregnancy, especially during the 1st trimester, as it can potentially harm the developing fetus. It may also be excreted in breast milk and pose a risk to nursing infants. 
• Severe Liver Disease: phenindione metabolism occurs primarily in the liver. Individuals with severe liver impairment may have altered drug metabolism, which can affect the safety and efficacy of phenindione. 
• Severe Kidney Disease: While phenindione’s elimination is not primarily through the kidneys, individuals with severe kidney impairment should be cautious when using this drug due to potential interactions and effects on coagulation. 
• Uncontrolled Hypertension: Elevated blood pressure can increase the risk of bleeding complications, and phenindione should be used cautiously in individuals with uncontrolled hypertension. 
• Alcohol Abuse: Chronic alcohol abuse can affect liver function and metabolism, potentially altering how phenindione is processed. This may increase the risk of bleeding complications. 
• Interactions with Medications: phenindione interacts with numerous medications, including those that affect its metabolism, clotting factors, and platelet function. 
• Elderly Patients: They may be more susceptible to bleeding complications due to age-related changes in physiology and an increased likelihood of having comorbidities and interacting medications. 

Caution 

• Bleeding Risk: The primary concern when using phenindione is the increased risk of bleeding. It’s essential to monitor for signs of bleeding, such as easy bruising, nosebleeds, bleeding gums, and prolonged bleeding from cuts. If any unusual bleeding occurs, medical attention should be sought promptly. 
• Regular Monitoring: phenindione’s anticoagulant effect can vary among individuals, so regular monitoring of blood clotting parameters, usually measured as the International Normalized Ratio (INR), is essential. This helps ensure that the dosage of phenindione is adjusted to maintain a therapeutic and safe anticoagulation level. 
• Dosage Adjustments: phenindione dosing can be complex due to age, weight, liver function, and interactions with other medications. Dose adjustments should be made under the supervision of a healthcare provider based on INR measurements. 
• Interactions with Other Medications: phenindione interacts with numerous medications, including other anticoagulants, antibiotics, antiplatelet drugs, and medications that affect liver enzymes. Always inform your healthcare provider about all your medications, supplements, and herbal products before starting phenindione. 
• Dietary Vitamin K: phenindione works by inhibiting vitamin K-dependent clotting factors. Consistently changing your intake of vitamin K-rich foods (such as leafy greens) can affect the medication’s effectiveness. Maintaining a consistent diet and informing your healthcare provider of significant dietary changes is essential. 
• Risk of Overdose: An excessive dose of phenindione can lead to an enhanced risk of bleeding. It’s essential to take the medication exactly as prescribed and not to make any adjustments to the dose without consulting a healthcare provider. 
• Elderly Patients: Elderly individuals may be more sensitive to the effects of phenindione, and their dosages may need to be adjusted accordingly. They are also more likely to have comorbidities and take multiple medications, which can enhance the risk of interactions. 
• Kidney and Liver Impairment: Individuals with impaired kidney or liver function may require careful monitoring and dosage adjustments when using phenindione, as these organs play a role in metabolizing and excreting the drug. 
• Hypothyroidism: Hypothyroidism (underactive thyroid) can affect the response to phenindione. Monitoring thyroid function and adjusting the dose of phenindione accordingly may be necessary. 
• Dental Procedures and Surgeries: Since phenindione increases the risk of bleeding, individuals undergoing dental procedures or surgeries should inform their healthcare providers about their medication regimen. Temporary discontinuation or dose adjustment may be needed before the procedure. 
• Travel and Lifestyle: Consult your healthcare provider if you’re traveling or making significant lifestyle changes. Changes in time zones, diet, and activity levels can influence phenindione’s effectiveness. 

Pregnancy consideration:  

US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

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

phenindione is a vitamin K antagonist that functions as an oral anticoagulant by interfering with synthesis of vitamin K-dependent clotting factors in liver. It inhibits the enzyme vitamin K epoxide reductase, which is a key for the activation of clotting factors like factors II, VII, IX, and X, and proteins C and S.

By reducing the production of these clotting factors and anticoagulant proteins; phenindione prolongs the time which it takes for blood to clot, effectively preventing the formation of blood clots. However, its use requires careful monitoring of the International Normalized Ratio (INR) to maintain the desired anticoagulation level and minimize the risk of bleeding complications. 

Pharmacodynamics: 

Mechanism of action: phenindione is an oral anticoagulant medication that inhibits the synthesis of certain blood clotting factors in the liver. It belongs to the class of medications known as vitamin K antagonists (VKAs).  

• Vitamin K-Dependent Clotting Factors: The blood clotting process involves a series of proteins called clotting factors that work together to form a stable blood clot at the injury site. Many of these clotting factors, such as factors II (prothrombin), VII, IX, and X, require the presence of vitamin K for their activation. Vitamin K is crucial in converting these factors into active forms. 
• Inhibition of Vitamin K Recycling: phenindione interferes with the action of vitamin K by inhibiting an enzyme called vitamin K epoxide reductase (VKOR). VKOR is responsible for recycling oxidized vitamin K back to its active form, which is essential for activating clotting factors. By inhibiting VKOR, phenindione prevents the recycling of vitamin K, reducing the availability of active vitamin K. 
• Decreased Activation of Clotting Factors: Due to the inhibition of VKOR, the levels of active vitamin K decrease in the body. This, in turn, leads to decreased activation of vitamin K-dependent clotting factors. The inactive forms of these factors cannot participate effectively in the blood clotting process. 
• Prolonged Blood Clotting Time: The blood’s ability to form clots is impaired with reduced levels of active clotting factors. This leads to a prolonged blood clotting time, meaning it takes longer for the blood to form a stable clot. As a result, phenindione reduces the risk of unwanted blood clots forming within blood vessels. 

Pharmacokinetics: 

Absorption 

phenindione is well-absorbed from the gastrointestinal tract after oral administration. Its absorption can be influenced by factors like food intake and presence of other drugs. Peak plasma concentrations are usually reached within a few hours after ingestion. 

Distribution 

phenindione is extensively bound to plasma proteins, primarily albumin. This binding limits its distribution into tissues and organs. The degree of binding can also be influenced by other medications that compete for protein binding sites. 

Metabolism 

phenindione undergoes extensive metabolism in the liver, primarily through hydroxylation. The major metabolite formed is 4′-hydroxyphenindione, which retains some anticoagulant activity. Enzymes in the liver, particularly cytochrome P450 enzymes, are involved in the metabolism of phenindione. 

Elimination and Excretion 

The elimination of phenindione and its metabolites occurs primarily by the urine and, to a lesser extent, in the feces. Renal excretion is an important route, as unchanged phenindione and its metabolites can be found in the urine. The elimination half-life of phenindione can vary but is generally within several hours. 

Administration: 

Like other medications, phenindione should be taken exactly as your healthcare provider prescribes.  

• Dosage: Follow your healthcare provider’s instructions regarding the dosage of phenindione. The dosage can vary based on your medical condition, age, weight, and other factors. It’s important not to change the dosage without consulting your healthcare provider. 
• Timing: phenindione is usually taken once a day. Taking it simultaneously daily is essential to maintain consistent medication levels in your bloodstream. 
• Route: phenindione is typically available in tablet form and is taken orally with a glass of water. Swallow the tablet whole; do not crush, break, or chew it unless specifically instructed by your healthcare provider. 
• Food and Vitamin K: dietary vitamin K intake can influence phenindione’s effectiveness. While you don’t need to avoid vitamin K-rich foods entirely, it’s essential to maintain a consistent intake to avoid fluctuations in the medication’s effectiveness. Your healthcare provider can guide you in managing your diet while on phenindione. 
• Missed Dose: If a dose is missed, taking it as soon as possible is generally recommended. However, if the next scheduled dose is missed, it should be skipped and the following dose should be taken at the appropriate time. It is key to avoid taking a double dose of the drug in order to compensate for the missed dose. 
• INR Monitoring: Regular monitoring of your International Normalized Ratio (INR) is crucial to ensure that the anticoagulant effect of phenindione is within the therapeutic range. 
• Healthcare Provider Communication: Keep your healthcare provider informed about changes in your health, medications, or lifestyle. Inform them about any new medications, supplements, or herbal products you plan to take while on phenindione. 
• Medical Procedures: If you are scheduled for any medical or dental procedures, surgeries, or other interventions, inform your healthcare provider and the medical professionals involved about your use of phenindione. They may need to adjust your dosage or temporarily discontinue the medication to minimize bleeding risks. 
• Emergency Information: Wear a medical alert bracelet or carry a card that indicates you are taking an anticoagulant like phenindione. This information is essential in case of accidents or emergencies. 
• Consultation: Consult your healthcare provider if you have any questions or concerns about phenindione, its administration, or its potential interactions with other medications or health conditions. 

Patient information leaflet 

Generic Name: phenindione 

Why do we use phenindione? 

phenindione is a medication that belongs to the class of vitamin K antagonists (VKAs), which are used primarily as anticoagulants to prevent the formation of blood clots.  

• Thrombosis Prevention: phenindione is often prescribed to avert the formation of the blood clots in individuals who are generally at risk of developing venous thrombosis, which includes conditions like deep vein thrombosis (DVT) and pulmonary embolism (PE).  
• Atrial Fibrillation: phenindione may be used in individuals with atrial fibrillation (a heart rhythm disorder) at risk of stroke because of blood clots forming in the heart and traveling to the brain. The anticoagulant effect of phenindione reduces the risk of stroke associated with atrial fibrillation. 
• Heart Valve Replacement: After the implantation of mechanical heart valves, there is an increased risk of blood clot formation on the valve surfaces. phenindione may be prescribed to prevent clot formation on these valves. 
• Post-Surgery or Immobilization: After specific surgical procedures or when an individual is immobilized for extended periods (such as orthopedic surgery or prolonged bed rest), the risk of the blood clots forming in the legs or pelvis can increase. phenindione may be used to mitigate this risk. 
• Hypercoagulable States: Certain medical conditions and genetic factors can predispose individuals to excessive blood clotting. phenindione may be considered in individuals with hypercoagulable states to reduce the risk of clots. 
• Systemic Embolism Prevention: Individuals at risk of systemic embolism (blood clots traveling to different body parts, such as the brain) due to conditions like valvular heart disease or certain types of cardiomyopathy may benefit from phenindione therapy. 
• Recurrent Venous Thromboembolism: Individuals who have experienced previous venous thromboembolism (VTE) may be prescribed phenindione to prevent recurrent episodes.