Anticoagulation Overview: Vitamin-K Antagonists (Warfarin)

VITAMIN -K ANTAGONIST
Warfarin  (Coumadin®) tablets: (approved by FDA June 8, 1954)             
Mechanism: Vitamin K antagonist: produces its pharmacological effect by interfering with the interconversion of Vitamin-K and its 2,3 epoxide.  Leads to depletion of Factors: II, VII, IX and X (produced in liver) and anticoagulant proteins C & S. 
 
Dosage: at least 4 to 5 days are necessary before a patient is anti-coagulated.
Initial dose: 5mg / day in normal patients.  The INR should be 2 in four to five days. 

• 2.5 to 4mg for elderly or patients with liver disease 

• 7.5 to 10mg for young, healthy or obese patients 
• Most clinicians titrate warfarin doses by trial and error 
• Now the FDA is suggesting lower doses for patients with certain genetic variations. 

Genetic Variations in Warfarin:  

• CYP2C9 activity indicates a slow or fast metabolizer. A slow metabolizer may need a lower maintenance dose and take longer for their INR to get to steady state 

• Vitamin K epoxide reductase activity (VKORC1) tells whether a patient is sensitive or resistant to warfarin’s effects. 

 
Adverse effects: bleeding
Treatment: stop the drug 

• If minor bleeding progresses to major bleeding: Administer Vitamin-K 5 to 25mg parenterally. May cause prolonged resistance to warfarin. 
• If INR is between 5 to 9, a low dose of oral Vitamin K (2.5mg) is given 
• Greater than 9: give 5 mg orally.  Will reduce the INR within 12 to 24 hours. 

Contraindications: pregnancy Category X
 
Drug interactions: Warfarin is metabolized by the P450 enzyme system.  Lots of drug interactions.  

• P450 inhibitors (blockers): Azole-antifungals, some HMG CoA reductase drugs, erythromycins, etc. 
• P450 inducers: carbamazepine, barbiturates, phenytoin 
• Can be displaced from binding sites: loop diuretics, valproate 
• Platelet aggregation: NSAIDS can enhance warfarin’s effect. 

Drug monitoring:  

• Initial: INR should be done daily while in the hospital. 
• Every 2 or 3 days if not hospitalized 
• Once stabilized, monitor every 4 to 6 weeks 
• TARGET INR is between 2 and 3 for most conditions requiring anticoagulation therapy 

 
TEACHING POINTS FOR Warfarin  

1. Consult pharmacist or practitioner for recommendations for OTC medications  

1. Bleeding:  have lots of Band-Aids; use electric razors 

1. FOOD–drug interactions:  Be careful with diets and Vitamin K rich foods.   Patients are often told to avoid foods high in vitamin K because of warfarin antagonism. A diet too low in vitamin K makes it MORE difficult to manage INR, because any change in dietary vitamin K can cause large fluctuations in INR. Encourage patients to eat a well-balanced consistent diet. 

1. Note: Warfarin patients are at the goal INR only 55% of the time (yikes!) 

1. –BEFAST: teach your patients signs and symptoms of a stroke, pulmonary embolism, deep vein thrombosis and heart attack: 

 
Signs and symptoms of a Stroke—BE FAST!  

• B -Balance: sudden loss of balance, headache, or dizziness 
• E -Eyes: trouble seeing out of one or both eyes 
• F -Face: Uneven smile or expression, facial droop or numbness in the face 
• A -Arms: weakness, numbness, one arm drifts down 
• S -Speech: slurred, mute, inappropriate words or strange speech 
• T– Time: seek help immediately. Immediately call 9-1-1. 

 
Signs and Symptoms of Pulmonary Embolism (PE)  

• Dyspnea: Difficulty breathing or shortness of breath. Usually sudden and severe 
• Hemoptysis: Coughing up blood 
• Diaphoresis: Abnormal sweating 
• Cyanosis: Nails or lips turning blue 
• Tachycardia: Rapid heartbeat 
• Pain: Unexplained sharp, severe pain in the chest and/or back 
• Syncope: Loss of consciousness 

 
Signs and Symptom of Deep Vein Thrombus (DVT)  

• throbbing or cramping pain in 1 leg (rarely both legs), usually in the calf or thigh. 
• swelling in 1 leg (rarely both legs) 
• warm skin around the painful area. 
• red or darkened skin around the painful area. 
• swollen veins that are hard or sore to the touch 

 
Signs and symptoms of Heart Attack in WOMEN
Usually in female patients multiple symptoms may occur:  

• Chest pain: or fullness in the chest (an elephant sitting on my chest!) 
• Nausea or stomach pain: feeling like the need to vomit. More commonly seen in women 
• Anxiety: feeling like something is wrong, but cannot put your finger on it 
• Arm pain: pain in the arm, leg, or jaw. A woman may feel numbness radiating down the left arm, and this pain or sensation can pread elsewhere in the body, especially the shoulders 
• Dyspnea: shortness of breath or difficulty with breathing 
• Cold sweats: resulting in cold clammy skin  
• Dizziness: sudden onset of lightheadedness, room spinning is usually combined with other symptoms on this list 
• Extreme fatigue: unexpected sluggishness or exhaustion 
• Heart palpitations: heart skips a beat or fluttering sensation 

 
Signs and symptoms of Heart Attack in Men
Usually in male patients the following symptoms occur:  

• Pain or tingling in back, neck, shoulder, or jaw 
• Chest pain 
• Sweating 
• Shortness of breath