Drug Interactions of Anticoagulants – Part 2

(Drug Interactions of Heparin)

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)

Defibrotide & Antithrombotics

Concomitant use of defibrotide and a systemic antithrombotic agent is contraindicated.

http://www.bloodjournal.org/content/120/21/3411?sso-checked=true

Antithrombotics + Defibrotide

Additive antithrombotic

effectsIncreased risk of bleeding

Contraindicated

Heparin & Telavancin or Oritavancin

If coadministration is required, collect blood samples prior to the next dose of Telavancin or Oritavancin.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm429767.htm

Heparin + Telavancin or Oritavancin

Telavancin or Oritavancin bind to the artificial phospholipid surfaces added to common anticoagulation

tests

Artificial prolongation of activated Partial Thromboplastin Time (aPTT) test

resultsContraindicated

Heparin & Other

Anticoagulants

If coadministration is required, closely monitor the patient for signs and symptoms of bleeding.

Heparin + Other Anticoagulants

(Enoxaparin, Dalteparin, Bivalirudin,

Danaparoid, Rivaroxaban, Apixaban,

Dabigatran)

Additive anticoagulation

Increased risk of bleeding

Anticoagulants & Fibrinolytics

Observe patients for external bleeding and be alert for signs and symptoms of internal bleeding, if concomitant use of an anticoagulant and a fibrinolytic agent is required.

https://www.ncbi.nlm.nih.gov/pubmed/11085346

Anticoagulants + Fibrinolytics

(Alteplase, Retaplase, Tenecteplase, Streptokinase,

Urokinase)

Additive anticoagulation

Increased risk of bleeding

Anticoagulants & Antiplatelet agents

Concomitant use warrants close monitoring.http://circ.ahajournals.org/content/116/3/305

Anticoagulants + Antiplatelet

agents (Aspirin, Clopidogrel,

Ticagrelor, etc)

Additive anticoagulation

Increased risk of bleeding

Anticoagulants & Fenofibrate

Reduce the dose of the anticoagulant by about one-third at the start of treatment, if concomitant use is required.

Then gradually adjust the dose based on the results of INR monitoring.https://www.ncbi.nlm.nih.gov/pubmed/12549950

Anticoagulants +

Fenofibrate

Additive effects on

anticoagulation

Enhanced bleeding risk

Anticoagulants & Orlistat

Caution should be exercised when Anticoagulants and Orlistat are used concurrently.

https://www.ncbi.nlm.nih.gov/pubmed/12659605

Anticoagulants + Orlistat

Orlistat may reduce the absorption of

fat-soluble vitamins, including

vitamin K

Increased risk of bleeding

Heparin & Alprostadil

Careful monitoring of antithrombolytic control is recommended in patients receiving Heparin and Alprostadil concurrently.

https://www.ncbi.nlm.nih.gov/pubmed/9671370

Heparin + Alprostadil

(Prostaglandin E1)

Inhibition of platelet reactivity

Increased risk of bleeding

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 & 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

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

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

Increased risk of bleeding

Anticoagulants & Garlic

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

http://onlinelibrary.wiley.com/doi/10.1002/mnfr.200700072/epdf

Anticoagulants + Garlic

Garlic has Anti-platelet,

Antithrombotic and Fibrinolytic activities

Increased risk of bleeding

Anticoagulants + Papaya

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025393/

Anticoagulants + Papaya

Papain of Papaya may damage the mucous membranes of the

gastrointestinal tract

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

Increased risk of bleeding

Anticoagulants & Coenzyme Q10

Caution is advised if coenzyme Q10 and Anticoagulants are taken together. Monitor the INR to determine continued therapeutic effect.https://www.ncbi.nlm.nih.gov/pubmed/9621803

Anticoagulants + Coenzyme

Q10

Coenzyme Q10 is chemically

similar to Vitamin K2

Reduced anticoagulant effectiveness

Anticoagulants & Ginger

Caution is advised if ginger and an anticoagulant are taken concomitantly.

https://www.ncbi.nlm.nih.gov/pubmed/11144706

Anticoagulants + Ginger

Ginger may inhibit thromboxane B2 formation & may

increase prostacyclin levels

Increased risk of bleeding

Anticoagulants & Fenugreek

Monitor bleeding time and signs and symptoms of excessive bleeding, if fenugreek and anticoagulants are used concomitantly.

http://onlinelibrary.wiley.com/doi/10.1592/phco.21.5.509.34492/epdf

Anticoagulants + Fenugreek

Coumarin content of

fenugreek may add to the effect of

anticoagulants

Increased risk of bleeding

Anticoagulants & Anise

Caution is advised if anise is taken with an anticoagulant. Monitor for signs and symptoms of increased excessive bleeding.

http://www.ajhp.org/content/57/13/1221.long

Anticoagulants + Anise

Coumarin content of Anise may add to the

effect of anticoagulants

Increased risk of bleeding

Anticoagulants & Clove Oil

Monitor the patient closely for signs and symptoms of bleeding, if both are taken together.

http://www.ajhp.org/content/57/13/1221.long

Anticoagulants + Clove Oil

Eugenol and Acetyl eugenol in clove oil

inhibit platelet aggregation

Increased risk of bleeding

Anticoagulants & Asafetida

Monitor the patient closely for signs and symptoms of bleeding.http://www.ajhp.org/content/57/13/1221.long

Anticoagulants + Asafetida

Asafetida contains free

ferulic acid and coumarin

derivatives

Increased risk of bleeding

Anticoagulants & Capsaicin

Signs and symptoms of excessive bleeding should be monitored closely if capsaicin (or large amounts of red pepper) and anticoagulants are taken concomitantly.

http://article.sciencepublishinggroup.com/pdf/10.11648.j.cmr.20140305.17.pdf

Anticoagulants + Capsaicin

Capsaicin may inhibit platelet

aggregation and enhance fibrinolytic

activity

Increased risk of bleeding

Anticoagulants & Evening primrose

oil

Monitor for signs and symptoms of excessive bleeding.https://www.ncbi.nlm.nih.gov/pubmed/19783511

Anticoagulants + Evening primrose oil

Gamma-linolenic acid from Evening primrose oil may inhibit thromboxane

B2 production and increase prostacyclin

production

Increased risk of bleeding

Anticoagulants & Licorice

Monitor for signs and symptoms of excessive bleeding, if licorice is taken with an anticoagulant.

https://www.ncbi.nlm.nih.gov/pubmed/23671711

Anticoagulants + Licorice

Inhibition of thrombin and platelet aggregation by

licorice Increased risk

of bleeding

Anticoagulants & Celery

Monitor the patient closely for signs and symptoms of bleeding, if both are taken together.

http://naturaldatabase.therapeuticresearch.com/nd/PrintVersion.aspx?id=882&AspxAutoDetectCookieSupport=1

Anticoagulants + Celery

Apigenin content of Celery, may inhibit thromboxane A2

formation leading to reduced platelet

aggregation & Celery contains coumarin

derivatives, which may produce additional

anticoagulant effects

Increased risk of bleeding

TIPS for Patients on Anticoagulants

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

Anticoagulant prior to any surgery. Talk to your Physician or Pharmacist before taking any other medications,

including prescription and OTC (Over-The-Counter) medicines. 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 Anticoagulant.

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/