1Herb-drug interactionsCharlotte Gyllenhaal, Ph.D.1,3Gail Mahady, Ph.D.2Departments of Medicinal Chemistry and Pharmacognosy,1Pharmacy Practice2Block Center for Integrative Cancer Treatment36-1870, [email protected]▶ Evidence for herb-drug interactions▶ Pharmacokinetic (PK) versus pharmacodynamic(PD) interactions▶ St. John’s wort▶ Warfarin▶ Miscellaneous▶ Herb-drug interactions and surgical/dentalprocedures▶ Use of computer databases for clinical questions2Evidence 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 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 therapy3PK vs PD▶ 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: unknown but underinvestigation▶ 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; 52:340-454St. John’s wort (Hypericumperforatum)▶ Mild-moderate depression -> long-term treatment;multiple clinical trials, fewer AEs than conventionaldrugs▶ Case reports suggesting PK interactions (mostimportant of SWJ interactions)▶ Lab 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 this orphan nuclear receptor Also regulates MDR-1 (multidrug resistancegene) and other drug transportersChavez, Life Sci 2006; 78:2146-575St. 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 reduce OCexposure and breakthrough bleeding. 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 CYP2D6Murphy 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▶ Photosensitivity Active constituent hypericin is photosensitizing butgenerally not a problem with healthy persons.Potential interaction with other photosensitizing drugs6Clinical 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) “Green drinks” – clinical interactions with oncologypatients. Case reports with cranberry juice also. Multivitamins 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; 87:1075-67Warfarin-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▶ PD herbs that decrease platelet aggregation Decreased thromboxane synthesis Herbs with coumarin content (though this is a relativelyweak anticoagulant)Warfarin and Chinese herbs▶ Dan-shen (Salvia miltiorrhiza) – animal studies, casereports▶ Dong quai (Angelica sinensis) – animal studies, casereports▶ Asian ginseng (Panax ginseng) – ginsenosides may inhibitplatelet aggregation (anticoagulant). 2 case reports oflowered or unsteady INR (procoagulant) RCT in healthy volunteers showed no effect of Asian ginseng onINR, platelet aggregation. Vitamin K in extracts? Monitor closely.▶ American ginseng (Panax quinquefolius) – RCT in healthyvolunteers indicated moderately reduced INR, warfarinlevels, AUC. Avoid with warfarin.Chavez, Life Sci 2006; 78:2146-57Jiang, Br J Clin Pharm 2004; 57:592-9Yuan, Ann Intern Med 2004; 141:23-78Warfarin and “G” herbs▶ Garlic (Allium sativum) – 2 case reports. Continuingingestion of high levels of garlic or garlic oil can decreaseplatelet aggregation▶ Ginger (Zingiber officinalis) – Inconclusive results in studiesin healthy volunteers but case reports exist.▶ Ginkgo (Ginkgo biloba) – Ginkgolide B decreases PAF,extract inhibits thromboxane and prostacyclin in diabetics.Preliminary human study indicates no effect on INR, but acase report suggests interaction▶ Green tea (Camellia sinensis) – Inhibits
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