Drug-supplement Drug-supplement interactionsinteractions

Charlotte Gyllenhaal, Ph.D.Charlotte Gyllenhaal, Ph.D.

Department of Medicinal Chemistry and Department of Medicinal Chemistry and PharmacognosyPharmacognosy

andandBlock Center for Integrative Cancer TreatmentBlock Center for Integrative Cancer Treatment

gyllenha@uic.edu

March 31, 2014March 31, 2014

Learning objectivesLearning objectives

► Use Natural Medicines Comprehensive Database to Use Natural Medicines Comprehensive Database to investigate drug-supplement interactions.investigate drug-supplement interactions.

► Know the principal pharmacokinetic and Know the principal pharmacokinetic and pharmacodynamic interactions of St John’s Wort.pharmacodynamic interactions of St John’s Wort.

► Know the main drug-supplement interactions with Know the main drug-supplement interactions with warfarin.warfarin.

► Recognize some other major drug-supplement Recognize some other major drug-supplement interactions. interactions.

► Know the main reasons for caution with Know the main reasons for caution with supplements and surgery or dental procedures.supplements and surgery or dental procedures.

► Know principles for clinical coping with drug-Know principles for clinical coping with drug-supplement interactions.supplement interactions.

Evidence for herb-drug Evidence for herb-drug interactionsinteractions

► Case reportsCase reports Underreported? 70% “don’t ask-don’t tell”Underreported? 70% “don’t ask-don’t tell”

► Lab studiesLab studies Define mechanismsDefine mechanisms

► Recent interest in CYP450 inductionRecent interest in CYP450 induction► Not necessarily borne out in trials Not necessarily borne out in trials

► Human studies Human studies – interpret with caution– interpret with caution Trials using probe drugsTrials using probe drugs May be too short or expensiveMay be too short or expensive May be done on healthy population (not always)May be done on healthy population (not always) Genetic polymorphismsGenetic polymorphisms Multiple drug/herb users, elderly patientsMultiple drug/herb users, elderly patients

De Smet, Br J Clin Pharm 2006; 63:258-67

PK vs PD: main issues with PK vs PD: main issues with herbsherbs

► PKPK: absorption, distribution, metabolism, : absorption, distribution, metabolism, eliminationelimination CYP450, PgPCYP450, PgP Absorption from GI tract (laxatives)Absorption from GI tract (laxatives)

► PDPD: pharmacological function: pharmacological function Anticoagulant drugs plus anticoagulant herbsAnticoagulant drugs plus anticoagulant herbs Sedative herbs plus anesthesiaSedative herbs plus anesthesia

► NegativeNegative MostMost

► Positive or synergisticPositive or synergistic Possible PD or PKPossible PD or PK Decrease side effectsDecrease side effects

Prevalence: Mayo ClinicPrevalence: Mayo Clinic

► 6 specialty areas 6 specialty areas Survey of 1795 patients; 39.6% used supplementsSurvey of 1795 patients; 39.6% used supplements

► Potential interactions Potential interactions detected using Lexi-detected using Lexi-Interact (available on PDA)Interact (available on PDA) 107 interactions with potential clinical significance107 interactions with potential clinical significance Garlic, valerian, kava, ginkgo and St. John’s wort Garlic, valerian, kava, ginkgo and St. John’s wort

accounted for most potential interactions – 68%accounted for most potential interactions – 68% Antithrombotics, sedatives, antidepressants, and Antithrombotics, sedatives, antidepressants, and

antidiabetics most involved in interactions – 94%antidiabetics most involved in interactions – 94% No patient was seriously harmed by herb-drug No patient was seriously harmed by herb-drug

interactioninteraction

Sood et al. 2008; 121(3):207-11

Natural Medicines Natural Medicines Comprehensive DatabaseComprehensive Database

uic.edu > Library > Databases A-uic.edu > Library > Databases A-Z >Z >

Natural Medicines Natural Medicines Comprehensive DatabaseComprehensive Database

Case History: a patient who Case History: a patient who uses multiple natural uses multiple natural

supplementssupplements► 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).

Episode 1Episode 1► The patient arrives at your office for a checkup and The patient arrives at your office for a checkup and

says that she would like to discuss a new problem says that she would like to discuss a new problem with you. She complains of feeling very depressed with you. She complains of feeling very depressed due to health problems being experienced by her due to health problems being experienced by her children and asks if it would be a good idea if she children and asks if it would be a good idea if she takes St John’s wort (Hypericum perforatum) as a takes St John’s wort (Hypericum perforatum) as a natural way to help her depressed feelings. Can natural way to help her depressed feelings. Can you recommend this to her?you recommend this to her?

St. John’s wort: PK St. John’s wort: PK interactionsinteractions

► Human trial with irinotecan Human trial with irinotecan (cancer)(cancer) Blood levels of active metabolite were reducedBlood levels of active metabolite were reduced Strong CYP4503a4 Strong CYP4503a4 inducerinducer

► Other drugs affected by CYP450 3a4 inductionOther drugs affected by CYP450 3a4 induction Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib, Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib,

alprazolam, midazolam, amitriptyline, digoxin, alprazolam, midazolam, amitriptyline, digoxin, fexofenadine, methadone, omeprazole, theophylline, fexofenadine, methadone, omeprazole, theophylline, verapamil, etoposide. verapamil, etoposide.

Human study with oral contraceptives indicating Human study with oral contraceptives indicating reduced reduced OC exposureOC exposure and breakthrough bleeding (pregnancies and breakthrough bleeding (pregnancies resulted). resulted).

Delayed emergence from general anesthesia. Delayed emergence from general anesthesia. Multiple potential interactions with oncology drugsMultiple potential interactions with oncology drugs

► Other CYP450sOther CYP450s May inhibit CYP1A2, does not inhibit CYP2D6, hyperforin May inhibit CYP1A2, does not inhibit CYP2D6, hyperforin

inhibits CYP2C9inhibits CYP2C9Murphy Contraception 2005; 71:402-8

St. John’s wort: other St. John’s wort: other interactionsinteractions

► PK interactionsPK interactions: P-glycoprotein induction – : P-glycoprotein induction – remove drugs from cells (drug resistance)remove drugs from cells (drug resistance)

► PD interactionsPD interactions With other antidepressantsWith other antidepressants

► Serotonin syndromeSerotonin syndrome SJW has both SSRI and MAO inhibitor activitySJW has both SSRI and MAO inhibitor activity Restlessness, nausea, vomiting, tachycardia, Restlessness, nausea, vomiting, tachycardia,

hallucinations etc.hallucinations etc. Case reports with buspirone, loperamil, Case reports with buspirone, loperamil,

nefazodone, paroxetine, sertraline, venlafaxinenefazodone, paroxetine, sertraline, venlafaxine► Possible adrenergic crisisPossible adrenergic crisis

MAO inhibitor activity (not major activity)MAO inhibitor activity (not major activity)

GarlicGarlic

► Drug Interactions:Drug Interactions: Saquinavir (Fortovase) study-10 healthy volunteersSaquinavir (Fortovase) study-10 healthy volunteers AUC during the 8 hour dosing interval decreased by 51% AUC during the 8 hour dosing interval decreased by 51% 10 day wash out needed before Cmax, AUC levels returned 10 day wash out needed before Cmax, AUC levels returned

to 60-70% of normalto 60-70% of normal Ritonavir – possible interaction with garlic PK or PD, Ritonavir – possible interaction with garlic PK or PD,

resulting in garlic toxicity to GI tractresulting in garlic toxicity to GI tract Garlic and Protease Inhibitors should be avoidedGarlic and Protease Inhibitors should be avoided Mechanism questionable; some allicin-containing garlic Mechanism questionable; some allicin-containing garlic

extracts induce CYP3A4, probable mechanism, but other extracts induce CYP3A4, probable mechanism, but other garlic extracts do not show CYP3A4 induction.garlic extracts do not show CYP3A4 induction.

Clin Infect DisClin Infect Dis, 2002, 34:234-238., 2002, 34:234-238.

Episode 2Episode 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?

Warfarin-herb interactionsWarfarin-herb interactions► Numerous drug-drug interactions: Numerous drug-drug interactions:

macrolides, NSAIDs, COX2s, SSRIs, macrolides, NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc (variable quality of omeprazole, 5FU etc (variable quality of evidence).evidence).

► Possible pathways: Possible pathways: ►Vitamin K activity lowers INRVitamin K activity lowers INR Foods: leafy greens (healthy diet)Foods: leafy greens (healthy diet) Multivitamins (low vitamin K dose)Multivitamins (low vitamin K dose) CoQ10: similar structure to vitamin K, but RCT CoQ10: similar structure to vitamin K, but RCT

found no effect on INR. Case reports suggest found no effect on INR. Case reports suggest monitoring.monitoring.

Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5Engelsen, Throm Hemost 2002; 87:1075-6

Warfarin-herb interactionsWarfarin-herb interactions

► PKPK decreased absorption from GI tract due to decreased absorption from GI tract due to

mucilage (comfrey, Iceland moss) or laxative mucilage (comfrey, Iceland moss) or laxative herbs (senna, rhubarb etc)herbs (senna, rhubarb etc)

CYP450 2C9 inhibition/induction, which CYP450 2C9 inhibition/induction, which metabolizes the active form of warfarin (kava, metabolizes the active form of warfarin (kava, bromelain possible but only lab data)bromelain possible but only lab data)

► PDPD Herbs that decrease platelet aggregationHerbs that decrease platelet aggregation Decreased thromboxane synthesisDecreased thromboxane synthesis Very large number of herbs and supplements with Very large number of herbs and supplements with

potential interactions due to these mechanisms potential interactions due to these mechanisms (see Natural Medicines Comprehensive Database)(see Natural Medicines Comprehensive Database)

Herbal laxativesHerbal laxatives

►Decrease blood levels Decrease blood levels of drugs by of drugs by shortening gastrointestinal transit timeshortening gastrointestinal transit time

► Increase potassium lossIncrease potassium loss►Common herbal laxatives: aloe, cascara Common herbal laxatives: aloe, cascara

sagrada, rhubarb, sennasagrada, rhubarb, senna

Abebe W, 2003. J Dental Hygiene 77(1):37-46Abebe W, 2003. J Dental Hygiene 77(1):37-46

Episode 3Episode 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.

Other potential interactions: Other potential interactions: top 10 herbs + otherstop 10 herbs + others

CranberryCranberry – possible warfarin interaction, – possible warfarin interaction, unconfirmed in human trialsunconfirmed in human trials*Garlic *Garlic – saquinavir interaction, possibly due – saquinavir interaction, possibly due to CYP3a4 interaction. Possible anticoagulant to CYP3a4 interaction. Possible anticoagulant interactioninteraction*Saw palmetto *Saw palmetto – possible anticoagulant – possible anticoagulant interaction, possible antiestrogenic effectinteraction, possible antiestrogenic effectSoySoy – estrogenic effect may be seen with soy – estrogenic effect may be seen with soy isoflavones, not soy foods.isoflavones, not soy foods.*Ginkgo *Ginkgo – antiplatelet effect; caution with – antiplatelet effect; caution with anticoagulant drugs, some psychotropics alsoanticoagulant drugs, some psychotropics also

Other interactionsOther interactions

Milk thistle Milk thistle – possible CYP enzyme effect, – possible CYP enzyme effect, not confirmed in human trialsnot confirmed in human trials

Black cohosh Black cohosh – hepatotoxic effect, possibly – hepatotoxic effect, possibly due to adulteration and mostly case reportsdue to adulteration and mostly case reports

EchinaceaEchinacea – theoretical interaction with – theoretical interaction with immunosuppressantsimmunosuppressants

*American and Asian ginseng *American and Asian ginseng – Decreased – Decreased INR with warfarin; may lower blood glucose; INR with warfarin; may lower blood glucose; theoretical additive effect with stimulants theoretical additive effect with stimulants and interference with immunosuppressantsand interference with immunosuppressants

Other interactionsOther interactions

TurmericTurmeric – possible anticoagulant interaction – possible anticoagulant interaction

FlaxFlax – possible anticoagulant interaction, – possible anticoagulant interaction, also may interact with oral meds due to bulkalso may interact with oral meds due to bulk

ElderberryElderberry – none – none

*Green tea *Green tea – possible hepatotoxic effect in – possible hepatotoxic effect in high supplement doses; Interaction with high supplement doses; Interaction with sunitinib (anticancer), separate from sunitinib (anticancer), separate from bortezomib (anticancer) by 2-3 daysbortezomib (anticancer) by 2-3 days

*Mistletoe *Mistletoe – (intravenous anticancer) – – (intravenous anticancer) – hypovolemic shock, cardiotoxicityhypovolemic shock, cardiotoxicity

Surgery and Dental Surgery and Dental ProceduresProcedures

Drug interactions and physiological reactionsDrug interactions and physiological reactions::CNS herbs: potential PD interactions with CNS herbs: potential PD interactions with

anesthesiaanesthesia::Valerian, kava, St. John’s wort (PK interaction Valerian, kava, St. John’s wort (PK interaction also), lavender, passionflower, lemon balm, also), lavender, passionflower, lemon balm, ashwaganda, ginseng, ephedra. Midazolam – SJW, ashwaganda, ginseng, ephedra. Midazolam – SJW, goldenseal and possibly ginkgo PK effects but goldenseal and possibly ginkgo PK effects but ginkgo studies are contradictoryginkgo studies are contradictory

Blood glucose Blood glucose – ginseng, bitter melon, chromium, – ginseng, bitter melon, chromium, fenugreek, cinnamon. Patients may use these to fenugreek, cinnamon. Patients may use these to help control blood glucose levels but if they are help control blood glucose levels but if they are stopped before surgery, blood sugars may be stopped before surgery, blood sugars may be elevated.elevated.

Ang-Lee, JAMA 2001; 286:208-16

Surgery and Dental Surgery and Dental ProceduresProcedures

Anticoagulant herbsAnticoagulant herbs: post-op bleeding and : post-op bleeding and interaction with aspirin or other NSAIDs interaction with aspirin or other NSAIDs that may cause bleeding.that may cause bleeding.

Garlic, ginger, ginkgo, ginseng, feverfew.Garlic, ginger, ginkgo, ginseng, feverfew.Angelica, asafoetida, anise, astragalus, arnica, Angelica, asafoetida, anise, astragalus, arnica,

bogbean, bromelain, borage seed, capsicum, bogbean, bromelain, borage seed, capsicum, clove, curcumin, dong quai, fenugreek, fish oil, clove, curcumin, dong quai, fenugreek, fish oil, green tea, horsechestnut, juniper, licorice, green tea, horsechestnut, juniper, licorice, meadowsweet, onion, pau d’arco, parsley, meadowsweet, onion, pau d’arco, parsley, passionflower, quassia, red clover, reishi, passionflower, quassia, red clover, reishi, salvia, turmeric, willow.salvia, turmeric, willow.

Surgery and Dental Surgery and Dental ProceduresProcedures

Stop herb and supplement use 7-14 Stop herb and supplement use 7-14 days prior to surgerydays prior to surgery..

All pre-surgical patients should be All pre-surgical patients should be questioned about herb/supplement questioned about herb/supplement use to determine recent consumption use to determine recent consumption of anticoagulant or drug-interacting of anticoagulant or drug-interacting herbs.herbs.

Clinical copingClinical coping

► Counteract “don’t ask-don’t tellCounteract “don’t ask-don’t tell”” Open and nonjudgmental discussionOpen and nonjudgmental discussion Follow up herb use found in case historiesFollow up herb use found in case histories Explain importance of potential interactionsExplain importance of potential interactions

► Avoid SJW and warfarin interactionsAvoid SJW and warfarin interactions► Patients on complicated medical regimens should Patients on complicated medical regimens should

avoid herbs and supplements unless carefully avoid herbs and supplements unless carefully screened/supervised, but prioritize drugs with narrow screened/supervised, but prioritize drugs with narrow therapeutic index, ie: therapeutic index, ie: carbamazepine, cyclosporine, digoxin, ethosuximide, levothyroxine, phenytoin, procainamide, theophylline and warfarin

Drug Interaction ResolutionDrug Interaction Resolution

►Require dosage adjustmentsRequire dosage adjustments►Temporary or complete elimination of Temporary or complete elimination of

one or the other agent to avoid serious one or the other agent to avoid serious consequencesconsequences

►Close monitoring of the subjectClose monitoring of the subject►Total change of drug therapyTotal change of drug therapy

Checking for herb-drug Checking for herb-drug interactionsinteractions

► Natural Standard (Natural Standard (www.naturalstandard.com). ).

► Natural Medicines Comprehensive Database Natural Medicines Comprehensive Database ((www.naturaldatabase.com).).

► Lexi-Interact. Subscription service (Lexi-Interact. Subscription service (www.lexi-comp.com))

► MicroMedex – Altmedex. Subscription MicroMedex – Altmedex. Subscription service (service (www.micromedex.com))

► Some misleading information but generally Some misleading information but generally err on the side of pointing out interactions err on the side of pointing out interactions for which there is little to no evidence base, for which there is little to no evidence base, rather than missing interactions altogether.rather than missing interactions altogether.