• It is Contraindicated to use Fibrinolytics and Defibrotide concomitantly. • Drugs increasing the risk of Fibrinolytics associated Bleeding include… o Anticoagulants (Warfarin, Heparin, Enoxaparin, Dabigatran, etc) o Antiplatelet agents (Aspirin, Clopidogrel, etc) o Pentosan Polysulfate Sodium • Herbs increasing the risk of Fibrinolytics associated Bleeding include… o Fenugreek o Garlic o Ginkgo o Evening Primrose Oil o Clove Oil o Anise o Turmeric (Curcumin) o Licorice o Asafetida o Capsicum (Capsaicin) o Celery o Kava o Cat's claw o Medowsweet o Feverfew o Tan-shen

1. D R U G
I N T E R A C T I O N S
O F
F I B R I N O LY T I C S
( P A R T 3 )
( D R U G I N T E R A C T I O N S O F
U R O K I N A S E )
D r P. N a i n a M o h a m e d P h D
P h a r m a c o l o g i s t

2. INTRODUCTION
• Urokinase is a Fibrinolytic agent and it was originally isolated from
human urine.
• Urokinase is also present in the blood and in the extracellular matrix of
many tissues.
• Urokinase used to treat Deep Venous Thrombosis (DVT), Pulmonary
Embolism (PE) and Myocardial Infarction (MI).
• Interaction between one or more coadministered medications leading
change in their effectiveness or toxicity, is termed as “Adverse drug
interaction”.
• Fibrinolytic agents can interact with prescription drugs, Over-the-
counter (OTC) medications, Herbal products, Dietary supplements,
etc.

3. MECHANISM OF ACTION OF FIBRINOLYTICS
• Ideally, thrombolytic drugs should be given within the first 2 hours of Ischemic Stroke
and Acute Myocardial Infarction.
Fibrinolytics
Bind to fibrin on the
surface of the clot
Activation of fibrin-
bound Plasminogen
Plasmin is cleaved
from fibrin-bound
Plasminogen
Plasmin breaks
cross-links between
fibrin molecules
Dissolution of clot

4. FIBRINOLYTICS
• Fibrinolytics include…
Recombinant Tissue Plasminogen Activators (tPA)
Alteplase
Reteplase
Tenecteplase
Streptokinase
Urokinase

5. FIBRINOLYTICS & DEFIBROTIDE
• Use of Fibrinolytic agents should be discontinued before initiating Defibrotide.
http://reference.medscape.com/drug/activase-tpa-alteplase-342287#3
Fibrinolytics +
Defibrotide
Defibrotide increases
tissue plasminogen
activator (tPA)
function, and
decreases the activity
of tissue plasminogen
activator inhibitor
Increased risk of
bleeding
Contraindicated

6. FIBRINOLYTICS & ANTICOAGULANTS
• 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
Fibrinolytics +
Anticoagulants (Warfarin,
Heparin, Enoxaparin,
Dabigatran, etc)
Additive
anticoagulation
Increased risk of
bleeding

7. FIBRINOLYTICS
& ANTIPLATELET AGENTS
• Close monitoring for bleeding is recommended, if concomitant use of Fibrinolytics and
Antiplatelet agents such as Aspirin, Clopidogrel, etc. is required.
http://www.neurology.org/content/79/13_Supplement_1/S68.long
Fibrinolytics + Antiplatelet
agents (Aspirin,
Dipyridamole, Clopidogrel,
etc)
Additive effects Increased risk of bleeding

8. FIBRINOLYTICS & PENTOSAN
POLYSULFATE SODIUM
• Monitor the patient closely for bleeding complications, if Fibrinolytics and Pentosan
polysulfate sodium are used concomitantly.
https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8930#sect
ion-9

9. THROMBOLYTICS & FENUGREEK
• Caution is advised if fenugreek and thrombolytic agents are used concomitantly.
• Monitor the patients for signs and symptoms of excessive bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949941/
Thrombolytics +
Fenugreek
Coumarins of
Fenugreek may affect
blood coagulation
Increased risk of
bleeding

10. THROMBOLYTICS & GARLIC
• Monitor for signs and symptoms of excessive bleeding, if excessive garlic is consumed
with concomitant use of thrombolytic agents.
• Garlic supplements should be discontinued at least 10 days prior to elective surgery.
http://ijpho.ssu.ac.ir/article-1-32-en.pdf
Thrombolytics +
Garlic
Garlic may reduce
thromboxane B2
Inhibition of platelet
aggregation
Increased risk of
bleeding

11. THROMBOLYTICS & GINKGO
• If both agents are taken together, monitor bleeding time and signs and symptoms of
excessive bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490168/
Thrombolytics + Ginkgo
Ginkgolide B of Ginkgo may
inhibit Platelet Activating
Factor (PAF) induced Platelet
aggregation
Increased risk of bleeding

12. THROMBOLYTICS & EVENING PRIMROSE
OIL
• Caution is advised if evening primrose oil and thrombolytic agents are used
concomitantly.
• Monitor the patients for signs and symptoms of excessive bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2541068/pdf/bmj00459-0008.pdf
Thrombolytics + Evening
Primrose Oil
Gamma-linolenic acid of
Evening primrose oil inhibits
Thromboxane B2 synthesis and
increases Prostacyclin synthesis
Additive anticoagulant effect Increased risk of bleeding

13. THROMBOLYTICS & CLOVE OIL
• Avoid concomitant use of clove oil with thrombolytic agents. If both are taken together
monitor the patient closely for signs and symptoms of bleeding.
http://jpma.org.pk/full_article_text.php?article_id=4757
Thrombolytics + Clove
oil
Clove oil inhibits Platelet
aggregation
Increased risk of
bleeding

14. THROMBOLYTICS & ANISE
• Concomitant use warrants monitoring of the patients for signs and symptoms of
increased bleeding.
http://www.ajhp.org/content/57/13/1221.long
Increased risk of
bleeding
Coumarin of Anise
may increase the
anticoagulant effect
Thrombolytics +
Anise

15. THROMBOLYTICS & TURMERIC
(CURCUMIN)
• Caution is advised if curcumin and thrombolytic agents are used concomitantly.
• Monitor for signs and symptoms of excessive bleeding.
http://www.sciencedirect.com/science/article/pii/0049384885902762?via%3Dihub
Thrombolytics +
Turmeric (Curcumin)
Curcumin inhibits
platelet aggregation
Increased risk of
bleeding

16. THROMBOLYTICS & LICORICE
• Monitor the patients for signs and symptoms of excessive bleeding.
http://www.sciencedirect.com/science/article/pii/S0049384803005425
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345862/
Thrombolytics +
Licorice
Licorice may inhibit
Thrombin and
Platelet aggregation
Increased risk of
bleeding

17. THROMBOLYTICS & ASAFETIDA
• Monitor the patient closely for signs and symptoms of bleeding.
http://www.ajhp.org/content/57/13/1221.long
Thrombolytics +
Asafetida
Additive
anticoagulant effects
increased risk of
bleeding

18. THROMBOLYTICS & CAPSICUM
(CAPSAICIN)
• Signs and symptoms of excessive bleeding should be monitored closely if capsaicin
and thrombolytic agents are taken concomitantly.
http://www.ajhp.org/content/57/13/1221.long
Increased risk of bleeding
Capsaicin may inhibit
platelet aggregation and
enhance fibrinolytic activity
Thrombolytics + Capsicum
(Capsaicin)

19. THROMBOLYTICS & CELERY
• Monitor the patient closely for signs and symptoms of bleeding.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064255
Thrombolytics +
Celery
Celery may inhibit
Platelet aggregation
Increased risk of
bleeding

20. THROMBOLYTICS & KAVA
• Monitor the patient closely for signs and symptoms of bleeding.
https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-2006-957597.pdf
Thrombolytics +
Kava
Kava may inhibit
Cyclooxygenase
(COX)
Inhibition of Platelet
aggregation
Increased risk of
bleeding

21. THROMBOLYTICS & CAT'S CLAW
• Monitor the patient closely for signs and symptoms of bleeding.
http://www.ajhp.org/content/66/11/992.long
Thrombolytics + Cat's claw
Rhynochophylline of Cat's
claw may inhibit Platelet
aggregation
Increased risk of bleeding

22. THROMBOLYTICS & MEADOWSWEET
• Monitor the patient closely for signs and symptoms of bleeding.
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2710.2002.00444.x/full
Increased risk of
bleeding
Salicylate content of
Meadowsweet Possess
Antiplatelet activity
Thrombolytics +
Meadowsweet

23. THROMBOLYTICS & FEVERFEW
• Caution is advised if feverfew is taken with thrombolytic agents. Monitor the patient
closely for signs and symptoms of bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210009/
Thrombolytics + Feverfew
Parthenolide of Feverfew
reduce Thromboxane A2
production
Inhibition of platelet
aggregation
Increased risk of bleeding

24. THROMBOLYTICS & TAN-SHEN
• Avoid concomitant administration of thrombolytic agents with Tan-shen.
http://www.sciencedirect.com/science/article/pii/S0003497598006249
Thrombolytics + Tan-
shen
Tan-shen may inhibit
cAMP
phosphodiesterase
Additive antiplatelet
effects
Increased risk of
bleeding

25. 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 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 patients on Fibrinolytics about their herbal and other alternative
medicine product use.

26. REFERENCES
o Stockley’s Drug Interactions, 9e
Karen Baxter
o Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e
Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann
o Basic & Clinical Pharmacology, 12e
Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor
o A Manual of Adverse Drug Interactions
J.P. Griffin, P.F. D'Arcy
o Clinical Manual of Drug Interaction Principles for Medical Practice
Gary H. Wynn, Jessica R. Oesterheld, Kelly L. Cozza, Scott C. Armstrong
o Handbook of Drug Interactions: A Clinical and Forensic Guide
Ashraf Mozayani, Lionel Raymon

27. REFERENCES
• http://www.micromedexsolutions.com
• https://link.springer.com/article/10.2165/00003088-199528040-
00004#enumeration
• https://www.ncbi.nlm.nih.gov/pubmed/8578491
• 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/DrugReference/Druginteractionchec
ker/