Drug-supplement interactions

1. Drug-supplement interactions Charlotte Gyllenhaal, Ph.D. Department of Medicinal Chemistry and Pharmacognosy and Block Center for Integrative Cancer Treatment gyllenha@uic.edu March 31, 2014

2. Learning objectives • Use Natural Medicines Comprehensive Database to investigate drug-supplement interactions. • Know the principal pharmacokinetic and pharmacodynamic interactions of St John’s Wort. • Know the main drug-supplement interactions with warfarin. • Recognize some other major drug-supplement interactions. • Know the main reasons for caution with supplements and surgery or dental procedures. • Know principles for clinical coping with drug-supplement interactions.

3. Evidence for herb-drug interactions • Case reports • Underreported? 70% “don’t ask-don’t tell” • Lab studies • Define mechanisms • Recent interest in CYP450 induction • Not necessarily borne out in trials • Human studies – interpret with caution • Trials using probe drugs • May be too short or expensive • May be done on healthy population (not always) • Genetic polymorphisms • Multiple drug/herb users, elderly patients De Smet, Br J Clin Pharm 2006; 63:258-67

4. PK vs PD: main issues with herbs • PK: absorption, distribution, metabolism, elimination • CYP450, PgP • Absorption from GI tract (laxatives) • PD: pharmacological function • Anticoagulant drugs plus anticoagulant herbs • Sedative herbs plus anesthesia • Negative • Most • Positive or synergistic • Possible PD or PK • Decrease side effects

5. Prevalence: Mayo Clinic • 6 specialty areas • Survey of 1795 patients; 39.6% used supplements • Potential interactions detected using Lexi-Interact (available on PDA) • 107 interactions with potential clinical significance • Garlic, valerian, kava, ginkgo and St. John’s wort accounted for most potential interactions – 68% • Antithrombotics, sedatives, antidepressants, and antidiabetics most involved in interactions – 94% • No patient was seriously harmed by herb-drug interaction Sood et al. 2008; 121(3):207-11

6. Natural Medicines Comprehensive Database uic.edu > Library > Databases A-Z > Natural Medicines Comprehensive Database

7. Case History: a patient who uses multiple natural supplements • Your patient in a primary care practice is a 76-year old female with hypercholesterolemia, osteoarthritis and hypertension, who had a stroke two years ago. She is also being treated for angina. Her medications are: acetaminophen, lovastatin (Mevacor), warfarin (Coumadin), and verapamil (Calan).

8. Episode 1 • The patient arrives at your office for a checkup and says that she would like to discuss a new problem with you. She complains of feeling very depressed due to health problems being experienced by her children and asks if it would be a good idea if she takes St John’s wort (Hypericumperforatum) as a natural way to help her depressed feelings. Can you recommend this to her?

9. St. John’s wort: PK interactions • Human trial with irinotecan(cancer) • Blood levels of active metabolite were reduced • Strong CYP4503a4 inducer • Other drugs affected by CYP450 3a4 induction • Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib, alprazolam, midazolam, amitriptyline, digoxin, fexofenadine, methadone, omeprazole, theophylline, verapamil, etoposide. • Human study with oral contraceptives indicating reduced OC exposure and breakthrough bleeding (pregnancies resulted). • Delayed emergence from general anesthesia. • Multiple potential interactions with oncology drugs • Other CYP450s • May inhibit CYP1A2, does not inhibit CYP2D6, hyperforin inhibits CYP2C9 Murphy Contraception 2005; 71:402-8

10. St. John’s wort: other interactions • PK interactions: P-glycoprotein induction – remove drugs from cells (drug resistance) • PD interactions • With other antidepressants • Serotonin syndrome • SJW has both SSRI and MAO inhibitor activity • Restlessness, nausea, vomiting, tachycardia, hallucinations etc. • Case reports with buspirone, loperamil, nefazodone, paroxetine, sertraline, venlafaxine • Possible adrenergic crisis • MAO inhibitor activity (not major activity)

11. Garlic • Drug Interactions: • Saquinavir (Fortovase) study-10 healthy volunteers • AUC during the 8 hour dosing interval decreased by 51% • 10 day wash out needed before Cmax, AUC levels returned to 60-70% of normal • Ritonavir – possible interaction with garlic PK or PD, resulting in garlic toxicity to GI tract • Garlic and Protease Inhibitors should be avoided • Mechanism questionable; some allicin-containing garlic extracts induce CYP3A4, probable mechanism, but other garlic extracts do not show CYP3A4 induction. Clin Infect Dis, 2002, 34:234-238.

12. Episode 2 • Since her stroke, your patient has periodic checks of INR due to her warfarin prescription, and her levels have always been within a therapeutic range. Then you learn that over the weekend, she has been seen at the emergency room with epistaxis, and an INR of 10. None of her other medications have changed and she is not using St John’s wort or other herbs. She does admit to eating large amounts of ginger root and drinking ginger tea over the past week because of “stomach troubles.” Ginger has an anti-nausea effect and is used by many people for mild digestive conditions. Is there an herb-drug interaction in this case?

13. Warfarin-herb interactions • Numerous drug-drug interactions: macrolides, NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc (variable quality of evidence). • Possible pathways: • Vitamin K activity lowers INR • Foods: leafy greens (healthy diet) • Multivitamins (low vitamin K dose) • CoQ10: similar structure to vitamin K, but RCT found no effect on INR. Case reports suggest monitoring. Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5 Engelsen, Throm Hemost 2002; 87:1075-6

14. Warfarin-herb interactions • PK • decreased absorption from GI tract due to mucilage (comfrey, Iceland moss) or laxative herbs (senna, rhubarb etc) • CYP450 2C9 inhibition/induction, which metabolizes the active form of warfarin (kava, bromelain possible but only lab data) • PD • Herbs that decrease platelet aggregation • Decreased thromboxane synthesis • Very large number of herbs and supplements with potential interactions due to these mechanisms (see Natural Medicines Comprehensive Database)

15. Herbal laxatives • Decrease blood levels of drugs by shortening gastrointestinal transit time • Increase potassium loss • Common herbal laxatives: aloe, cascara sagrada, rhubarb, senna Abebe W, 2003. J Dental Hygiene 77(1):37-46

16. Episode 3 • The patient has been stable since being treated for her stroke, but comes to your office one day with complains of moderately severe muscle pain that feels “different from my arthritis.” The pain sounds like myopathy associated with statin drugs but she has already been on lovastatin for 3 years without problems. On questioning, you learn that she recently started using red yeast rice “as a natural way to help lower her cholesterol more.” Is there an interaction? • Note: red yeast rice is sometimes used to lower cholesterol in statin-intolerant patients.

17. Other potential interactions: top 10 herbs + others Cranberry – possible warfarin interaction, unconfirmed in human trials *Garlic – saquinavir interaction, possibly due to CYP3a4 interaction. Possible anticoagulant interaction *Saw palmetto – possible anticoagulant interaction, possible antiestrogenic effect Soy – estrogenic effect may be seen with soy isoflavones, not soy foods. *Ginkgo – antiplatelet effect; caution with anticoagulant drugs, some psychotropics also

18. Other interactions Milk thistle – possible CYP enzyme effect, not confirmed in human trials Black cohosh – hepatotoxic effect, possibly due to adulteration and mostly case reports Echinacea – theoretical interaction with immunosuppressants *American and Asian ginseng – Decreased INR with warfarin; may lower blood glucose; theoretical additive effect with stimulants and interference with immunosuppressants

19. Other interactions Turmeric – possible anticoagulant interaction Flax – possible anticoagulant interaction, also may interact with oral meds due to bulk Elderberry – none *Green tea – possible hepatotoxic effect in high supplement doses; Interaction with sunitinib (anticancer), separate from bortezomib (anticancer) by 2-3 days *Mistletoe – (intravenous anticancer) – hypovolemic shock, cardiotoxicity

20. Surgery and Dental Procedures Drug interactions and physiological reactions: CNS herbs: potential PD interactions with anesthesia: Valerian, kava, St. John’s wort (PK interaction also), lavender, passionflower, lemon balm, ashwaganda, ginseng, ephedra. Midazolam – SJW, goldenseal and possibly ginkgo PK effects but ginkgo studies are contradictory Blood glucose – ginseng, bitter melon, chromium, fenugreek, cinnamon. Patients may use these to help control blood glucose levels but if they are stopped before surgery, blood sugars may be elevated. Ang-Lee, JAMA 2001; 286:208-16

21. Surgery and Dental Procedures Anticoagulant herbs: post-op bleeding and interaction with aspirin or other NSAIDs that may cause bleeding. Garlic, ginger, ginkgo, ginseng, feverfew. Angelica, asafoetida, anise, astragalus, arnica, bogbean, bromelain, borage seed, capsicum, clove, curcumin, dong quai, fenugreek, fish oil, green tea, horsechestnut, juniper, licorice, meadowsweet, onion, paud’arco, parsley, passionflower, quassia, red clover, reishi, salvia, turmeric, willow.

22. Surgery and Dental Procedures Stop herb and supplement use 7-14 days prior to surgery. All pre-surgical patients should be questioned about herb/supplement use to determine recent consumption of anticoagulant or drug-interacting herbs.

23. Clinical coping • Counteract “don’t ask-don’t tell” • Open and nonjudgmental discussion • Follow up herb use found in case histories • Explain importance of potential interactions • Avoid SJW and warfarin interactions • Patients on complicated medical regimens should avoid herbs and supplements unless carefully screened/supervised, but prioritize drugs with narrow therapeutic index, ie: carbamazepine, cyclosporine, digoxin, ethosuximide, levothyroxine, phenytoin, procainamide, theophylline and warfarin

24. Drug Interaction Resolution • Require dosage adjustments • Temporary or complete elimination of one or the other agent to avoid serious consequences • Close monitoring of the subject • Total change of drug therapy

25. Checking for herb-drug interactions • Natural Standard (www.naturalstandard.com). • Natural Medicines Comprehensive Database (www.naturaldatabase.com). • Lexi-Interact. Subscription service (www.lexi-comp.com) • MicroMedex – Altmedex. Subscription service (www.micromedex.com) • Some misleading information but generally err on the side of pointing out interactions for which there is little to no evidence base, rather than missing interactions altogether.