Herb drug interactions Charlotte Gyllenhaal Ph D Department of Medicinal Chemistry and Pharmacognosy Block Center for Integrative Cancer Treatment 6 1870 gyllenha uic edu Objectives Recognize level of evidence for herb drug interactions Distinguish pharmacokinetic PK versus pharmacodynamic PD interactions important in supplement drug interactions Outline interactions for St John s wort and warfarin Explain the potential for herb drug interactions in surgical dental procedures Use computer databases to analyze clinical questions involving herb drug interactions 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 coumarin 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 Know principles for clinical coping with herb drug interactions Evidence for herb drug interactions Case reports Underreported 70 don t ask don t tell Lab studies Define mechanisms Recent Not interest in CYP450 induction 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 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 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 effects Prevalence Canadian seniors Canadian seniors with osteoarthritis Survey n 191 Average 2 8 prescriptions 1 9 selfcare 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 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 St John s wort Hypericum perforatum Mild moderate depression multiple clinical trials fewer AEs than conventional drugs Case reports suggesting PK interactions most important of SWJ interactions Lab and clinical studies indicate PK interactions CYP450 3A4 mechanism short term inhibition 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 Long term 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 thus removes drugs from cells 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 Other drugs affected Blood levels of active metabolite were reduced 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 not major activity 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 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 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 a relatively weak anticoagulant Warfarin and G herbs Garlic Allium sativum 2 case reports Continuing ingestion of high levels of garlic or garlic oil can decrease platelet aggregation Ginger Zingiber officinalis Inconclusive results in studies in 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 a case report suggests
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