Herb-drug interactionsCharlotte Gyllenhaal, Ph.D.Department of Medicinal Chemistry and Pharmacognosy,Block Center for Integrative Cancer Treatment6-1870, [email protected]▶ Recognize level of evidence for herb-druginteractions▶ Distinguish pharmacokinetic (PK) versuspharmacodynamic (PD) interactions important insupplement-drug interactions▶ Outline interactions for St. John’s wort andwarfarin▶ Explain the potential for herb-drug interactions insurgical/dental procedures▶ Use computer databases to analyze clinicalquestions involving herb-drug interactionsLearning objectives▶ Distinguish between pharmacokinetic andpharmacodynamic interactions.▶ Know the principal pharmacokinetic and pharmacodynamicinteractions of St John’s Wort, i.e. induction of CYP4503A4, and serotonin syndrome/photosensitivity▶ Know the main reasons for herb-drug interactions withwarfarin, i.e. vitamin K activity; decreased GI absorption orCYP450 2C9 metabolism; and herbs that decrease plateletaggregation or thromboxane synthesis or have coumarincontent.▶ Know the main reasons for caution with herbs and surgeryor dental procedures, i.e., herbal anticoagulants (causebleeding), sedative or stimulant herbs (modify anesthesia).▶ Know principles for clinical coping with herb-druginteractionsEvidence 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 patientsDe Smet, Br J Clin Pharm 2006; 63:258-67Drug Interaction Resolution▶ Require dosage adjustments▶ Temporary or complete elimination of oneor the other agent to avoid seriousconsequences▶ Close monitoring of the subject▶ Total change of drug therapyPK vs PD review▶ 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 effectsPrevalence: Canadian seniors▶ Canadian seniors with osteoarthritis Survey, n = 191. Average 2.8 prescriptions, 1.9 self-care products▶ Potential interactions detected using standarddatabases 214 instances, 14% possible clinical significance 7 herbs/supplements, associated with 5 clinicallyinsignificant interactions 1 recommendation to stop medications (dilatiazem +atrorvastatin -> statin side effects intensified) Clinically significant interactions may be rare – but thuseasier to forget about and harder to monitor!Putnam, Can Fam Physician 2006; 52:340-45Prevalence: 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 wortaccounted for most potential interactions – 68% Antithrombotics, sedatives, antidepressants, andantidiabetics most involved in interactions – 94% No patient was seriously harmed by herb-druginteractionSood et al. 2008; 121(3):207-11St. John’s wort (Hypericumperforatum)▶ Mild-moderate depression; multiple clinical trials,fewer AEs than conventional drugs▶ Case reports suggesting PK interactions (mostimportant of SWJ interactions)▶ Lab and clinical studies indicate PK interactions:▶ CYP450 3A4 mechanism▶ short-term inhibition▶ Long-term induction; of most importance clinically▶ Reduces various drugs to subtherapeutic levels▶ Hyperforin, an active constituent, is a ligand for the xenobioticpregnane X receptor -> CYP450 3A4St John’s wort▶ Other PK interactions▶ P-glycoprotein (PgP): involved in multidrugresistance, acts as a pump to remove drugsfrom cells SJW induces; thus removes drugs from cells Also regulates MDR-1 (multidrug resistancegene) and other drug transportersChavez, Life Sci 2006; 78:2146-57St. John’s wort: PK interactions▶ Human trial with irinotecan (cancer) Blood levels of active metabolite were reduced▶ Other drugs affected Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib,alprazolam, midazolam, amitriptyline, digoxin, fexofenadine,methadone, omeprazole, theophylline, verapamil, etoposide. Human study with oral contraceptives indicating reduced OCexposure and breakthrough bleeding (pregnancies resulted). Case of delayed emergence from general anesthesia observed. Multiple potential interactions with oncology drugs (but rare useby oncology patients?).▶ Other CYP450s May inhibit CYP1A2, does not inhibit CYP2D6, hyperforin inhibitsCYP2C9Murphy Contraception 2005; 71:402-8St. John’s wort▶ 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)Clinical strategy▶ Avoid use with other medications unlesschecked out in an interaction database. Willhave similar interaction profile to otherCYP450 3A4 inducers. Major drug-drug interaction pathwayWarfarin-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 foundno effect on INR. Case reports suggest monitoring.Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5Engelsen, Throm Hemost 2002; 87:1075-6Warfarin-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 theactive S-enantiomer of warfarin (saw palmetto, kava,bromelain possible but only lab data)▶ PD Herbs that decrease platelet aggregation Decreased thromboxane synthesis Herbs with coumarin content (though coumarin is arelatively weak anticoagulant)Warfarin
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