Herb drug interactions Charlotte Gyllenhaal Ph D 1 3 Gail Mahady Ph D 2 Departments of Medicinal Chemistry and Pharmacognosy 1 Pharmacy Practice2 Block Center for Integrative Cancer Treatment3 6 1870 gyllenha uic edu Outline Evidence for herb drug interactions Pharmacokinetic PK versus pharmacodynamic PD interactions St John s wort Warfarin Miscellaneous Herb drug interactions and surgical dental procedures Use of computer databases for clinical questions Learning objectives Distinguish between pharmacokinetic and pharmacodynamic interactions Know the principal pharmacokinetic and pharmacodynamic interactions of St John s Wort i e induction of CYP450 3A4 and serotonin syndrome photosensitivity Know the main reasons for herb drug interactions with warfarin i e vitamin K activity decreased GI absorption or CYP450 2C9 metabolism and herbs that decrease platelet aggregation or thromboxane synthesis or have coumadin content Know the main reasons for caution with herbs and surgery or dental procedures i e herbal anticoagulants cause bleeding sedative or stimulant herbs modify anesthesia 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 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 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 PK 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 effects Prevalence Canadian seniors Canadian seniors with osteoarthritis Survey n 191 Average 2 8 prescriptions 1 9 self care products Potential interactions detected using standard databases 214 instances 14 possible clinical significance 7 herbs supplements associated with 5 clinically insignificant interactions 1 recommendation to stop medications dilatiazem atrorvastatin statin side effects intensified Clinically significant interactions may be rare but thus easier to forget about and harder to monitor Putnam Can Fam Physician 2006 52 340 45 Prevalence Mayo Clinic 6 specialty areas Survey of 1795 patients 39 6 used supplements Potential interactions detected using LexiInteract available on PDA 107 interactions with potential clinical significance Garlic valerian kava ginkgo and St John s wort accounted for most 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 St John s wort Hypericum perforatum Mild moderate depression long term treatment multiple clinical trials fewer AEs than conventional drugs Case reports suggesting PK interactions most important 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 xenobiotic pregnane X receptor CYP450 3A4 St John s wort Other PK interactions P glycoprotein PgP involved in multidrug resistance acts as a pump to remove drugs from cells SJW induces this orphan nuclear receptor Also regulates MDR 1 multidrug resistance gene and other drug transporters Chavez Life Sci 2006 78 2146 57 St 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 OC exposure and breakthrough bleeding pregnancies resulted Case of delayed emergence from general anesthesia observed Multiple potential interactions with oncology drugs but rare use by oncology patients Other CYP450s May inhibit CYP1A2 does not inhibit CYP2D6 hyperforin inhibits CYP2C9 Murphy Contraception 2005 71 402 8 St 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 but generally not a problem with healthy persons Potential interaction with other photosensitizing drugs Clinical strategy Avoid use with other medications unless checked out in an interaction database Will have similar interaction profile to other CYP450 3A4 inducers Major drug drug interaction pathway 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 Green drinks clinical interactions with oncology patients Case reports with cranberry juice also 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 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 S enantiomer of warfarin PD herbs that decrease platelet aggregation Decreased thromboxane synthesis Herbs with coumarin content though coumarin is a relatively weak anticoagulant Warfarin and Chinese herbs Dan shen Salvia miltiorrhiza animal studies case reports Dong quai Angelica sinensis animal studies case reports Asian ginseng Panax ginseng ginsenosides may inhibit platelet aggregation anticoagulant 2 case reports of lowered or unsteady INR procoagulant RCT in healthy volunteers showed no effect of Asian ginseng on INR platelet aggregation Vitamin K in extracts Monitor closely American ginseng Panax quinquefolius RCT in
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