drug interactions of warfarin

Drug Interactions of Anticoagulants – Part 1

(Drug Interactions of Warfarin (Coumarins)

Dr. P.NAINA MOHAMED PhDPharmacologist

Introduction

Anticoagulants are the drugs used to prevent harmful blood clots which can cause serious conditions like Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), or a Stroke, by affecting blood coagulation factors.

Interaction between one or more coadministered medications leading to change in their effectiveness or toxicity, is termed as “Adverse drug interaction”.

Anticoagulants can interact with prescription drugs, Over-the-counter (OTC) medications, Herbal products, Dietary supplements, Vitamins, Foods, Diseases, and Genetics (family history).

Anticoagulants Coumarins (Oral) Warfarin, Acenocoumarol, Dicoumarol, Ethyl biscoumacetate, Phenprocoumon Indandiones (Oral) Phenindione, Fluindione Factor Xa inhibitors Fondaparinux sodium, Rivaroxaban (Oral) Heparin Low Molecular Weight Heparins (LMWH) Enoxaparin, Dalteparin, Tinzaparin, Bemiparin, Certoparin, Nadroparin, Parnoparin, Reviparin Heparinoids Danaparoid, Dermatan sulphate, Pentosan polysulfate, Suleparoid, Sulodexide Direct Thrombin inhibitors Hirudins - Bivalirudin, Desirudin, Lepirudin Synthetic Thrombin Inhibitors – Argotroban Dabigatran etexilate (Oral)

Warfarin

Warfarin is used to treat patients with Deep Vein Thrombosis (DVT) or Pulmonary Embolism.

Warfarin is also used to prevent thrombosis in high risk patients with Atrial Fibrillation, Heart attack and knee or hip surgeries.

Warfarin can cause serious interactions with many commonly used medicines and it also can interact with certain foods.

Regular blood monitoring of INR (International Normalized Ratio) is recommended to check for effectiveness and safety.

Warfarin

Inhibition of vitamin K epoxide

reductase (VKOR) enzyme

Decreased availability of vitamin K in

tissues

Inhibition of Glutamyl

carboxylase

Blockade of carboxylation of

Coagulation factors II, VII, IX and

X

Coagulation factors unable to bind to

the endothelial surface of blood

vessels

Coagulation factors become

biologically inactive

Prevention of clotting

Warfarin & Tamoxifen

Consider using lower warfarin doses and closely monitor the INR (International Normalized Ratio) when Tamoxifen and Warfarin use is necessary.

http://journals.sagepub.com/doi/pdf/10.1345/aph.1M176

Warfarin + Tamoxifen

Tamoxifen may inhibit CYP2C9-

mediated warfarin metabolism

Elevated risk of bleeding




Warfarin & Simvastatin

Concurrent use of Warfarin and Simvastatin warrants the monitoring of Prothrombin time ratio or International normalized ratio (INR).

Monitor the patients also for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness, or weakness).

http://journals.sagepub.com/doi/pdf/10.1345/aph.1K167

Warfarin + Simvastatin

Warfarin and Simvastatin

compete for CYP3A4 mediated

metabolism

Increased risk of Bleeding and

Rhabdomyolysis




Warfarin & Penicillins

More frequent monitoring of INR is recommended, if concomitant use is necessary.

Substitute Penicillins with an antibiotic with a low-risk profile for bleeding, such as clindamycin and cephalexin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712345/

Warfarin + Penicillins (Amoxicillin, Cloxacillin, Ticarcillin,

Methicillin, etc)

Penicillins alter the intestinal flora

that synthesize vitamin K





Warfarin & Cephalosporins


Substitute Cephalosporins with an antibiotic with a low-risk profile for bleeding, such as clindamycin and cephalexin.


Warfarin + Cephalosporins

(Cefixime, Cefepime,

Ceftazidime, etc)

Cephalosporins alter the intestinal

flora that synthesize vitamin K





Warfarin & Macrolide Antibiotics


Substitute Macrolides with an antibiotic with a low-risk profile for bleeding, such as clindamycin and cephalexin.


Warfarin + Macrolide Antibiotics

(Azithromycin, Clarithromycin,

Roxithromycin, etc)

Macrolide Antibiotics alter the intestinal flora

that synthesize vitamin K





Warfarin & Fluoroquinolones

More frequent monitoring of the patient's INR is recommended, if concomitant use is required.


Warfarin + Fluoroquinolones (Ciprofloxacin,

Levofloxacin, Moxifloxacin, etc)

Fluoroquinolones alter the intestinal

flora that synthesize vitamin

K





Warfarin & Sulphonamides


Substitute Sulphonamides with an antibiotic with a low-risk profile for bleeding, such as clindamycin and cephalexin.

https://www.ncbi.nlm.nih.gov/pubmed/20386005/

Warfarin + Sulphonamides

(Sulfamethoxazole, Sulfisoxazole, etc)

Sulphonamides alter the intestinal flora that synthesize vitamin K &

Inhibit CYP2C9-mediated metabolism

of warfarin




Warfarin & Azole Antifungals



Warfarin + Azole Antifungals

(Fluconazole, Ketoconazole, Posaconazole, Miconazole,

Itraconazole, etc)

Azole antifungals alter the intestinal flora that synthesize vitamin K &

Inhibit CYP3A4-mediated metabolism of warfarin





Warfarin & Chemotherapeutic

Agents

Warfarin may not be the optimal anticoagulant for cancer patients for any indication, especially during treatment with chemotherapy.

Monitor the INR (International Normalized Ratio) closely and monitor for signs of bleeding when warfarin is used concomitantly with chemotherapeutic agents.


Warfarin + Chemotherapeutic

Agents (Cyclophosphamide,

Methotrexate, Doxorubicin)

Increased risk for elevated INR Bleeding




Warfarin & Amiodarone

Coadministration of Warfarin and Amiodarone increases the prothrombin time by 100% after 3 to 4 days.

Decrease the warfarin dose by one-third to one-half and monitor the prothrombin time, if concurrent use is required.

http://www.sciencedirect.com/science/article/pii/S0012369215346365

Warfarin + Amiodaro

ne

Decreased warfarin

metabolism Serious

Bleeding




Warfarin & Enoxaparin

If coadministration of Warfarin and Enoxaparin is required, closely monitor the patient for signs and symptoms of bleeding, and neurological impairment in patients who are receiving neuraxial anesthesia or undergoing spinal puncture.

Prothrombin time/INR should also be monitored closely if enoxaparin and warfarin are taken concomitantly, especially during medication initiation or discontinuation.


Warfarin + Enoxaparin

Additive anticoagulatio

n Increased risk of bleeding



Warfarin & Danaparoid

More frequent monitoring of Prothrombin time/INR is recommended, When concomitant use is required.

Warfarin + Danaparoid

Additive anticoagulation


Warfarin & Antiplatelet agents

Monitor patients closely for signs or symptoms of bleeding.http://www.onlinejacc.org/content/54/2/95

Warfarin + Antiplatelet

agents (Aspirin, Clopidogrel, etc)

Additive effects Increased risk of bleeding

http://www.onlinejacc.org/content/54/2/95

http://www.onlinejacc.org/content/54/2/95

Warfarin & Fish oil

Warfarin patients should be educated about and monitored for possible drug-supplement interactions.

https://www.ncbi.nlm.nih.gov/pubmed/14742793

Warfarin + Fish oil (Omega 3 Fatty Acids) supplements

EicosaPentaenoic Acid (EPA) of fish oil decreases the

availability of the Thromboxane

precursor in the phospholipids of the

cell membrane

Decreased Thromboxane A2 levels

Decreased platelet

aggregation

Elevated risk of Bleeding



Warfarin & Vitamin K rich

Foods

Large changes in dietary consumption of foods high in vitamin K should be avoided or accompanied by careful monitoring of the international normalized ratio (INR).


Warfarin + Vitamin K rich Foods (Kale,

Spinach, Brussels sprouts, Collard greens, Mustard greens,

etc)

Antagonism of warfarin

Altered anticoagulant effectiveness



Warfarin & Green tea

It is recommended to question Warfarin Patients routinely about their intake of vitamin K-containing foods and beverages.


Warfarin + Green tea

Vitamin K content of Green tea

antagonize warfarin action

Reduced anticoagulant effectiveness




Warfarin & Pomegranate

It is recommended to instruct the patient to avoid pomegranate, before initiating Warfarin.


Warfarin + Pomegranate

Pomegranate inhibits CYP3A4/ CYP2C9

mediated metabolism of warfarin

Increased plasma concentrations of

warfarinIncreased risk of bleeding



Anticoagulants & NSAIDs

If used concomitantly, monitor for signs of bleeding.http://www.aafp.org/afp/2009/1215/p1371.html

Anticoagulants + NSAIDs (Ibuprofen,

Diclofenac, Naproxen, etc)

NSAIDs possess antiplatelet effects

Increased risk of bleeding

http://www.aafp.org/afp/2009/1215/p1371.html

http://www.aafp.org/afp/2009/1215/p1371.html

Anticoagulants & SSRIs

Serotonin is essential in initiating the hemostatic response of platelets to vascular injury. Monitor patient for signs of increased bleeding When SSRIs and an anticoagulant are

given concurrently. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728939/

Anticoagulants + Selective serotonin reuptake inhibitors

(SSRIs) (Fluvoxamine, Paroxetine,

Vortioxetine, Escitalopram, Sertraline, Nefazodone, vilazodone)

SSRIs block the uptake of serotonin by platelets

Decreased function of platelets

Increased risk of Bleeding




Anticoagulants & SNRIs

Serotonin is essential in initiating the hemostatic response of platelets to vascular injury. Monitor patient for signs of increased bleeding When SNRIs and an anticoagulant are

given concurrently. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728939/

Anticoagulants + Selective Serotonin and

Norepinephrine Reuptake Inhibitors (SNRIs)

(Venlafaxine, Desvenlafaxine,

Duloxetine, Milnacipran, Levomilnacipran,

Sibutramine)

SNRIs block uptake of serotonin by platelets

Decreased function of platelets

Increased risk of Bleeding




Anticoagulants & St. John's Wort

Prothrombin time should be monitored closely. Patients should not discontinue St. John's Wort without notifying their

health care provider.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917631/

Anticoagulants + St.John's Wort

St. John's Wort induce CYP3A4 and CYP1A2

mediated metabolism of R-warfarin and CYP2C9

mediated S-warfarin metabolism

Decreased warfarin plasma concentrations

leading to Reduced anticoagulant effectiveness



Anticoagulants & Ginkgo

Extreme caution is advised, due to the severity of the bleeding cases reported.

http://onlinelibrary.wiley.com/doi/10.1002/mnfr.200700098/epdf

Anticoagulants + Ginkgo

Ginkgolide B of Ginkgo may inhibit Platelet Activating

Factor (PAF) induced platelet aggregation




Anticoagulants & Garlic

Monitor bleeding time and signs and symptoms of excessive bleeding, if garlic is taken with an anticoagulant.


Anticoagulants + Garlic

Garlic has Anti-platelet,

Antithrombotic and Fibrinolytic activities




Anticoagulants + Papaya

The patient should be monitored closely for symptoms of bleeding and the INR should be closely monitored, if taken concomitantly.


Anticoagulants + Papaya

Papain of Papaya may damage the

mucous membranes of the

gastrointestinal tract

Increased bleeding risk




Anticoagulants & Chamomile

Patients should be educated about the potential risk of using chamomile products, while being treated with warfarin.

Monitor the patient for signs and symptoms of excessive bleeding.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435958/

Anticoagulants + Chamomile (Matricaria

chamomilla)

Coumarins present in chamomile may

potentiate the effect of

anticoagulants




Warfarin & Tobacco Smoking

Close monitoring of warfarin therapy is recommended when there is a change in smoking status of patients.


Warfarin + Tobacco smoking (Polycyclic

aromatic hydrocarbons)

Induction of CYP1A2-mediated

metabolism of Warfarin

Decreased Warfarin efficacy




Warfarin & Alcohol

Patients on Warfarin should avoid large amounts of alcohol.http://circ.ahajournals.org/content/119/8/e220

Warfarin+ Alcohol

Alcohol possess

Antiplatelet activity


http://circ.ahajournals.org/content/119/8/e220



TIPS for Warfarin Patients

Limit the intake of Vitamin K rich foods kale, collards, broccoli, spinach and other green leafy vegetables.

Do not double the dose to compensate a missed one. Do not forget to discuss with your surgeon or dentist about the regular use of

Warfarin prior to any surgery. Contact your doctor if you develop severe diarrhea, an infection or a fever. Seek immediate medical advice if there is signs of bleeding such as blood in

your stools or urine, nose-bleeds, bleeding gums, excessive menstrual bleeding or excessive bruising.

Be careful with knives and try to minimize the risk of falling. Always adhere to the prescribed dosage schedule. Wear or carry an identification stating that You are on Warfarin. Stick with the same brand of warfarin to maintain INR levels stable.

Conclusion

Drug interactions can result in significant morbidity and mortality and thus minimizing the risk for drug interactions should be a goal in drug therapy.

The patients with clotting disorders should bring a list of all of the drugs they are taking including prescription drugs, over-the-counter drugs, and any supplements, herbal or otherwise, during their visit to the doctor or pharmacist.

The risk of adverse effects could be reduced by healthcare professionals through the screening, education, and follow up on suspected drug interactions.

If possible, the patients are recommended to fill all their prescriptions at one pharmacy.

Pharmacists can play a crucial role in identifying possible drug interactions by asking Warfarin patients about their herbal and other alternative medicine product use.

References

Stockley’s Drug Interactions, 9e Karen Baxter Goodman & Gilman's: The Pharmacological Basis of

Therapeutics, 12e Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann Basic & Clinical Pharmacology, 12e Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor A Manual of Adverse Drug Interactions J.P. Griffin, P.F. D'Arcy Clinical Manual of Drug Interaction Principles for Medical

Practice Gary H. Wynn, . Jessica R Oesterheld, . Kelly L Cozza, . Scott CArmstrong

References http://www.micromedexsolutions.com http://

reference.medscape.com/drug-interactionchecker https://www.drugs.com/drug_interactions.html http://www.webmd.com/interaction-checker/ http://

www.rxlist.com/drug-interaction-checker.htm http://

umm.edu/health/medical/drug-interaction-tool http://ukhealthcare.uky.edu/Library/DrugReferenc

e/Druginteractionchecker/

http://www.micromedexsolutions.com/

http://reference.medscape.com/drug-interactionchecker



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https://www.drugs.com/drug_interactions.html

http://www.webmd.com/interaction-checker/

http://www.webmd.com/interaction-checker/

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http://www.rxlist.com/drug-interaction-checker.htm

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http://umm.edu/health/medical/drug-interaction-tool

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drug interactions of warfarin

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