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warfarin under the microscope

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Amber Suszek

on 5 September 2016

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Transcript of warfarin under the microscope

Warfarin
A Look Under the Microscope

A Review of the Mechanism of Action of Warfarin
Prothrombin Time (PT): 11-16 seconds
INR= International Normalized Ratio
For majority of patients of warfarin, INR goal will be 2-3. If the patient has for example a mechanical mitral valve, their goal would be 2.5-3.5. This is because we want the blood to be flowing easily to help prevent the build up of bacteria on the mechanical valve.
the INR is really just the standard unit used to report the result of a PT test
aPTT (activated Partial Thromboplastin Time): 20-25 to <35 seconds - this is what is normally used to monitor heparin
Foods
o Foods with vitamin K can alter anticoagulant effectiveness
alter the absorption of warfarin, direct antagonist of warfarin
• Examples of foods
high
in vitamin k: green tea, brussel sprouts, kale
• Examples foods with
moderate/high
levels: asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, lettuce, liver, soy products (soy milk, soybeans), lentils, peas, mustard greens, turnip greens, parsley, green scallions, and spinach.

Drugs
Herbal/ Natural Products
Bleeding Risk Assesment
When a patient's INR is extremely high, pharmacy uses this Bleeding Risk Assesment to help decide what the next course of action should be.

The patient is evaluated on a few different criteria and given points.

More points means higher risk of bleeding.
Warfarin is always entered as 1mg so that the pharmacists don’t have to change the order everyday when they are dosing it based on INRs
When the nurse goes to take the dose out—a matrix drawer opens with all of the different strengths available (1, 2, 2.5, 5mg)
The nurse then takes out the appropriate tablets to make the correct dose and types in the free-text space what the dose given was (in mg- not tablets) and the patient's INR
Warfarin Drawer Access @ NRH
The next day, the pharmacist compares an automatically generated report of doses pulled from the pyxis to the dose that was recommended to be given by pharmacy. If there are any discrepancies, they are investigated.
o Major Interactions
• Gingko
- often used for Alzheimer’s
recommended to avoid use together.
The onset of the interaction is delayed. Gingko may inhibit platelet activating factor (PAF) induced platelet aggregation thereby causing increased bleeding.
• Fish Oil
- lipids
Fish oil has an inhibitory effect on thromboxane A2 which causes decreased platelet aggregation. The onset of effect of this interaction is delayed.
• Lycium (Goji)
- traditionally used to support the kidneys and the liver, to protect the eyes, to enhance the immune system, to treat male infertility, and as an anti-aging tonic
• St. John's Wort
- depression
If a patient decides to take both, monitor the patient for symptoms of
decreased anticoagulant effect.
Only consider increasing the dose of warfarin if the patient takes St. John's Wort on a daily basis and the product has a consistent level of active ingredient. St. John's Wort is an
inducer
of warfarin's metabolism.
• Chamomile
- sleep disorders, anxiety, digestion/intestinal conditions, skin infections/inflammation
• Garlic
- Cardiovascular disease, hyperlipidemia, hypertension
Regular ingestion of food containing small amounts of garlic should be a problem. If excessive garlic is consumed with concomitant use of anticoagulants, monitor the INR and/or bleeding time and signs and symptoms of excessive bleeding


o
Pomegranate
may increase plasma concentration- ↑ risk of bleeding
inhibition of warfarin metabolism
o
Cranberry juice
- ↑ risk bleeding
data is somewhat conflicting, but it may be a good idea to avoid drinking large quantities
o
High protein food
- ↓ anticoagulant effectiveness
o
Noni juice
– may result in acquiring warfarin resistance
exact mechanism is unknown, but the Hawaiian product is possibly fortified with additional vitamin K
Most cause an increased bleeding risk
Warfarin is an anticoagulant that works by blocking the regeneration of vitamin K(1) epoxide, which thereby inhibits the synthesis of vitamin K-dependent clotting factors including factors 2, 7, 9 and 10, and the anticoagulant proteins C and S.
Amber Suszek
Massachusetts College of Pharmacy and Health Sciences
Doctor of Pharmacy Candidate- 2014

Facts about the start of therapy
It takes a few days to see the full effect of warfarin because the vitamin K dependent factors already present in the plasma must go through their half-lives before the effect of the drug is seen
What are the goal levels for patients on warfarin?

Some patients experience a transient hyper-coagulable state (clot too much) early on in therapy.
Both proteins C and S are vitamin K-dependent
Protein C is an inhibitor of hemostasis and has a short half-life of ≤6 hours
Early in the course of warfarin anticoagulation, concentrations of carboxylated protein C may fall below a critical threshold, before the pro-coagulant factors reach a similar state
What can influence these levels?
What exactly is an INR, aPTT, or PT?
They all are measurements of how fast the blood is clotting.
For example, in a person who is not taking any "blood thinners", or does not have any bleeding disorders, if they test their INR it would be around 1.
An INR of 2 means that it takes the blood twice as long to form a clot (aka, is "thinner"). An INR of 3 correlates with taking three times as long to form a clot.
If the INR is less than 1, it means that the blood is "thicker" and can form a clot more easily
This is important to keep in mind when looking at goal levels for warfarin patients since we are trying to prevent clots, but do not
want to cause a serious bleed
Antifungals:
Fluconazole
If concomitant use of fluconazole and warfarin is required, more frequent monitoring of the patient's INR and prothrombin time is recommended, especially during initiation and discontinuation of fluconazole. Continue monitoring for 4 to 5 days after fluconazole discontinuation. Dose adjustments of warfarin may also be needed
Fluconazole disrupts the synthesis of vitamin K, and it also is a CYP3A4 inhibitor.
Miconazole
Mechanism of interaction- inhibition of warfarin metabolism resulting in an increased risk of bleeding. This interaction has a delayed effect.
INR and PT should be closely monitored when starting or stopping concomitant treatment
Amiodarone
Amiodarone decreases warfarin metabolism. This interaction is delayed
Co-administration increases the prothrombin time by 100% after 3 to 4 days
INR greater than 5 occurred most commonly during the first 12 weeks of concomitant warfarin and amiodarone therapy
If concurrent use is required, decrease the warfarin dose by one-third to one-half and monitor the PT
In patients on chronic warfarin, a prophylactic 35 to 65% reduction in the warfarin dosage is recommended at the initiation of therapy with amiodarone
Tamoxifen
Co-administration is contraindicated due to increased risk of bleeding. This is a delayed interaction.
In certain clinical situations where it may be necessary to give both drugs, consider using lower warfarin doses and closely monitor the INR.
(A) What is the interaction?
(B) When is the effect seen if the combo is given?
(C) How long is the residual effect once one drug is d/c'd?
Patient Case Examples
Introduction:
Review of the Clotting Cascade
Check in!
Is a patient with an INR of 3.8 more likely to experience a bleed or a clot?
A bleed
Antibiotics:
Bactrim
Increased risk of bleeding due to Bactrim inhibiting vitamin K synthesis and also inhibits CYP3A4 mediated metabolism.
Closely monitor a patient's INR when starting or discontinuing Bactrim. Preemptive warfarin dose reductions of 10% to 20% of the mean daily dose may be considered to prevent increased INR during coadministration
Macrolides
Macrolides such as azithromycin can cause an increased risk of bleeding. Onset of interaction is delayed. Mechanism of action of the interaction- disruption of vitamin K synthesis. Monitor the INR more frequently if concurrent use if necessary, especially during initiation and discontinuation.
Fluoroquinolones
Quinolones such as levofloxacin and ciprofloxacin can cause increased bleeding risk by disrupting vitamin K synthesis. More frequent monitoring of the INR is recommended.
Rifampin
Rifampin is an CYP450
INDUCER
which means increased metabolism and decreased effectiveness of warfarin. Closely monitor the patient's INR.
High warfarin doses may be necessary in order to maintain proper anticoagulation
A 50% reduction of the warfarin dose should be considered within 1 to 2 weeks after rifampin is discontinued with further reduction if necessary after that


o Moderate Interactions w/good documentation
• Coenzyme 10
- anti aging, Alzheimers, etc
Use caution is co-administer. Mechanism of interaction- coenzyme 10 has a similar chemical structure to vitamin K2
• Ginger
- used in digestive, antitussive, antiflatulent, laxative, and antacid preparations
Some studies suggest that over 4 grams of dried or 15 grams raw ginger root daily must be ingested in order to have any effect on blood coagulation (additive anti-platelet effect)
• Ginseng
- used for cold remedies, boost immune system, lower blood sugar.
Avoid concomitant use if possible. If given in combination, monitor INR/PT. Onset of interaction is delayed and the mechanism by which the risk of increased bleeding happens is currently unknown
o Interactions with Fair documentation
• Goldenseal/echinacea
- cold/flu remedies
• Willow
- contains salicin has been used to treat many different kinds of pain, including rheumatic pain, back pain, toothache, headache, and menstrual cramps. It is also used to relieve sore throat, fever, and headache associated with upper respiratory tract infections and influenza

References
Micromedex
Natural Standard
Peripheral Brain for the Pharmacist


There are two different pathways. These pathways have different clotting factors early on in the cascade which need to be activated in order to form a clot
Factor X (10) is a common factor in both pathways

Factor V (5) is a co-factor for factor X

Factor Xa (10a) converts prothrombin (factor IIa) into thrombin (*a very important enzyme*)

Thrombin converts fibrinogen into fibrin
Statins
increased risk of bleeding and rhabdomyolysis. Statins are competition for CYP3A4 mediated metabolism
Monitor the INR to check if adjustments in dose need to me made to maintain proper anticoagulation. Also monitor to signs of rhabdo (muscle aches, dark urine, etc)
Fibrin cross links to form a clot
o It is recommended that patients avoid large servings or frequent intake of foods that contain substantial amounts of vitamin K
• Patient don’t need to necessarily avoid/completely cut these foods out of your diet, just don’t drastically change the amount that you consume if you are started on warfarin therapy.
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