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COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been copied and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968. (The Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. 1 PHAR3811 Herbal Medicines CVD Drug-Herb Interactions George Li University of Sydney Faculty of Pharmacy 2 At the completion of this lecture you will • Have an understanding of the mechanism of different drug interactions • Appreciate the levels of evidence supporting different drug-herb interactions • Be able to compare scientific information to assess the significance of potential drug-herb interactions, in particularly cardiovascular drugs – herbs interactions 3 Safety and Drug-Herb Interactions 4 Herbal Safety • Traditional use is NOT a substitute for safety assessment • As toxicological studies improve, new data is constantly emerging e.g. aristolochic acids • Long term and safe therapeutic use of a herb/formula will be taken into account in evaluating safety of a product • Information on pharmacological activity of ingredients and their components should be provided where available • Where data documenting traditional use is insufficient or there are suspicions of toxicity, safety evaluation will need 5 to be supported by other studies GPs Knowledge of Adverse Drug Reactions Potential side effects/interactions IM GP (%) Non-IM GP (%) P-value Black cohosh - ADR: Liver toxicity 42 37 NS Ginkgo biloba - ADR: Bleeding 28 20 0.004 - Interaction: Warfarin 45 34 <0.001 Glucosamine - Interaction: Warfarin 34 29 NS • TGA and numerous journals have warned of the association between black cohosh and hepatotoxicity • February 2008 ADRAC bulletin warned of the potential interaction between glucosamine and warfarin • February 2005 ADRAC bulletin warned of the potential interaction between ginkgo biloba and warfarin http://www.nps.org.au/research_and_evaluation/ 6 Herbal Safety Safety is dependent on: • Formulation of the product overall • Intended therapeutic purpose • Dosage and duration of use • Method (or route) of administration • Patient group (such as children, the elderly, and pregnant and lactating women, associated disease states) • Drug/herb interaction. 7 Dose-effect relationship for drugs or herbs Probability Effect Toxicity Drug or herb dose 8 Basic Concepts in Pharmaco/Phytotherapy Dose of drug or herbal product Concentration of drug, metabolite or constituent in plasma PHARMACOKINETICS Pharmacological effect PHARMACODYNAMICS Pharmacokinetics what the body does to the drug or herb Pharmacodynamics what the drug or herb does to the body 9 Drugs with a narrow safety margin • Dose that leads to efficacy is close to the dose that may cause toxicity For example • Warfarin • Digoxin and amiodarone • Cyclosporine and immunosuppressants • Some antidepressants 10 Who are the patients at risk from drug-herb interactions? • elderly and very young • • • • • multiple medications or herbal products multiple prescribers or practitioners multiple disease states chronic and serious illness change in organ function (eg renal or hepatic failure) 11 Mechanisms and Drug-Herb Interactions 12 Mechanisms and drug-herb interactions Understanding the mechanism of a drug interaction allows • the prediction of other interactions and • the assessment of the clinical significance 13 Mechanisms of drug-herb interactions • Physicochemical • Pharmacokinetic • Pharmacodynamic 14 Mechanisms of drug-herb interactions Physicochemical Interactions • physical or chemical interaction between a drug and a herb • referred to as incompatibility • favourable (may aid absorption eg Iron supplements absorbed better when ingested with citrus juice) • unfavourable (reduce extend of absorption eg 15 pectin and natural resins) Mechanisms of drug-herb interactions Pharmacokinetic Interactions • Absorption of a drug or herb • Distribution including protein binding drug transporters (p-glycoprotein) • Metabolism cytochrome P450 • Renal elimination competition for active carriers 16 Mechanisms of drug-herb interactions: Examples Pharmacokinetic Interactions Altered p-glycoprotein transport in gut lumen by St Johns wort affecting cyclosporine and digoxin Induction of metabolism by St John’s wort reducing concentration of antiretroviral drugs 17 Mechanisms of drug-herb interactions Pharmacodynamic Interactions • Additive or opposing effects – contains structurally similar ingredients • Interaction of constituents and drug at a receptor – Ubiquinone is structurally related to Vitamin K and can antagonise the effect of warfarin 18 Metabolic Drug-herb Interactions • Substrate - metabolised by and may compete for metabolic sites • Inhibitor - competes for metabolic site (not always a substrate) • Inducer - increases metabolic activity by increasing amount of enzyme 19 Cytochrome P450 (CYP450) heme-containing isoenzymes found in liver, small intestine (enterocytes), kidney, lungs and brain oxidative metabolism (Phase I) of – endogenous compounds (steroid hormones, postaglandins and fatty acids) – xenobiotics 20 Relevant CYPs • over 30 human CYP-450 isoenzymes relevant to drug metabolism • CYP3A4 • CYP2D6 • CYP1A2 • CYP2C subfamily • most isoenzymes can metabolise a Michalets, 21 range of drugs 1998 Check list for assessing the clinical significance of herb-drug interactions • • • • • • Quality of the herbs Dose of herb and drug Duration of use (acute or chronic) Frequency of administration (single or multiple) Route of administration Level of evidence Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD. Interaction or Over-reaction. 22 Journal of Complementary Medicine 2003; 60-61 Levels of evidence of herb-drug interactions Depends on study design…… • Controlled trials in patients • Controlled trials in healthy subjects • Case reports or series • • • • Animal studies In vitro studies Adverse event data Theoretical Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD. Interaction or Over-reaction. 23 Journal of Complementary Medicine 2003; 60-61 HERB-DRUG INTERACTION STUDIES WHICH ONE AND WHEN? TYPE Mechanism COST Clinical Relevance Ethical Issues Cells or microsomes Animals Healthy subjects Patients 24 Recommendation and significance Depends on the level of evidence and the risk: • Avoid combination • Caution: monitor effects 25 CVD: Herb Interaction Herbal Medicine Interacting Drugs* Evidence and Mechanism Significance and Recommendation Devil’s Claw Warfarin Case report: bruising has Caution: Monitor for been reported with signs of bleeding combined use and possible increase in INR Ginger Warfarin Suspected: possible increased anticoagulant effects due to antiplatelet activity Antacids Suspected: increased gastric secretions may reduce activity of antacids Caution: monitor for signs of bleeding and possible increase in INR 26 CVD: Herb Interaction Herbal Medicine Interacting Drugs* Evidence and Mechanism Significance and Recommendation Ginkgo Warfarin Suspected: increased risk of bleeding via PAF inhibition. Avoid combination: monitor for signs of bleeding and possible increase in INR Aspirin Suspected interaction: direct effects of ginkgo on platelet aggregation Caution: possible additive effect and risk of bleeding Case report: decreased INR Animal study: suggests no interaction Caution: monitor for signs of lack of effect Ginseng Warfarin (Asian, Korean or Siberian) 27 CVD: Herb Interaction Herbal Medicine Interacting Drugs* Evidence and Mechanism Hawthorn Digoxin Suspected: additive Avoid combination: effects on heart rhythm monitor digoxin adverse effects. because hawthorn contains digitalis-like constituents Antihyperten Suspected: excessive sives and reduction in blood nitrates pressure via vasodilation actions Significance and Recommendation Caution: monitor blood pressure and signs of hypotension 28 CVD: Herb Interaction Interacting Drugs Herbal Medicine Evidence and Mechanism Significance and Recommendation Warfarin Ginkgo Bilberry Garlic Ginger Korean ginseng St John’s wort Various Avoid combination: monitor for signs of bleeding and possible increase in INR Warfarin Devils Claw Guarana Caution 29 CVD: Herb Interaction Drug Herb Interaction Action Beta blockers Goldenseal Dec effect drug Avoid Liquorice Dec Avoid Guarana Dec Caution Hawthorn Increase Caution Thiazide Diuretics Liquorice Dec Avoid Digoxin Liquorice Dec Avoid St John’s wort Dec Avoid Hawthorn Increase Caution Barnes J, Anderson LA, and Phillipson JD (2007) Herbal Medicines. Third Edition. Pharmaceutical Press. London, UK. Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia. Brinker F (2001) Herb Contraindications and Drug Interactions, 3rd ed. Eclectic Medical Publications, Sandy, Oregon, USA. Gruenwald J, et al (2007) PDR for Herbal Medicines. Fourth Edition. Thomson Healthcare Inc. Montvale, NJ. CVS: Crataegus monogyna Drugs Effect/evidence /comments Anti-arrhythmic Additive effects (observe patient) Antihypertensive Additive effects (monitor BP) Cardiac glycosides Additive effects (monitor drug requirements) Nitroglycerin or glyceryl trinitrates Additive hypotensive effects (use combination with caution) Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia. CVS: Viscum album Drugs Effect/evidence /comments Antihypertensive Anti-diabetic Additive effects (monitor BP) Doxorubicin Additive effects (evidence from animal studies Synergism (evidence from in-vitro cell studies) Barnes, J, Anderson, LA, Phillipson, JD, Newall, CA (2007) Herbal Medicines. 3rd edn. Pharmaceutical Press: London, UK. Eno AE et al (2008) Stimulation of insulin secretion by Viscum album (mistletoe) leaf extract in streptozotocin-induced diabetic rats. Afr J Med Med Sci.37(2):141-7. Orban DD et al (2005) Evaluation of the hypoglycemic effect and antioxidant activity of three Viscum album subspecies (European mistletoe) in streptozotocin-diabetic rats. J Ethnopharmacol. 98(1-2):95-102. Sabová L et al (2009) Cytotoxic effect of mistletoe (Viscum album L.) extract on Jurkat cells and its interaction with doxorubicin. Phytother Res. Jul 16. [Epub ahead of print] CNS: Camellia sinensis Drugs Effect/evidence /comments Anticoagulants Reduced drug effect due to vitamin K with large doses of green tea (check INR if on warfarin) CNS sedatives Reduced effect with large doses of green tea CNS stimulants Additive effects (observe patient) Diuretics Additive effects especially with high dose of herb Hypoglycaemic agents Additive effects (observe patient) Iron Reduced absorption (separate dosing by at least 2 hours) Proteasome Reduced drug effects (avoid combination) inhibitor eg. Bortezomib, velcade Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia. CVS: Allium sativium Drugs Effect/evidence /comments Anticoagulants Increased bruising and bleeding (check INR if using large doses) Antihypertensive Additive effects s Antiplatelet Increased bruising and bleeding especially with doses >4 grams Helicobacter Additive effects pylori triple therapy Hepatotoxic drugs Reduced side effects Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia. CVS: Allium sativium Drugs Effect/evidence /comments Hypolipidaemic Immunosuppressa nt Paclitaxel paracetamol Saqinavir Additive effects Reduced drug effects (observe clinically) Reduced drug effects Reduced side effects Reduced drug effects (avoid combination) Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia. CVS: Aesculus hippocastanum Drugs Effect/evidence /comments Anticoagulant Additive drug effects when using improperly prepared extracts (check APTT, PTT and INR) Antiplatelet Additive drug effects when using improperly prepared extracts (observe patient) Hypoglycaemi Additive effects (check BSL) c Barnes J, Anderson LA, and Phillipson JD (2007) Herbal Medicines. Third Edition. Pharmaceutical Press. London, UK. Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia. Brinker F (2001) Herb Contraindications and Drug Interactions, 3rd ed. Eclectic Medical Publications, Sandy, Oregon, USA. Gruenwald J, et al (2007) PDR for Herbal Medicines. Fourth Edition. Thomson Healthcare Inc. Montvale, NJ. Traditional Chinese medicines Rational of TCM theory and practice on formula and TCM plus pharmaceuticals: • Quality control • Efficacy: eg diabetes, cold formula with OTC • Safety • Positive and negative interaction with drug understood. • Integrative approach? 37 Current Issues for TCM Internationalisation Cane Toad Venom - Recent controversial on herbal toxicity Fri 9/02/2010 The Age| 'Natural' remedies can prove lethal: Professor Byard said his interest in the area was sparked by the 2006 death of a young South Australian man who had injected chan su, a traditional Chinese herbal remedy that contains toxic toad venom. http://www.theage.com.au/lifestyle/wellbeing/natural-remedies-can-prove-lethal-research-20100208-nnaf.html BBC NEWS, 26 Jan 2010|Chinese medicine market sought for cane toad poison Australia's most notorious pest, the pervasive and poisonous cane toad, could soon end up on dinner tables and in medicinal treatments in Asia. http://news.bbc.co.uk/2/hi/8480041.stm Current Issues for TCM Internationalisation Cane Toad Venom - Recent controversial on herbal toxicity AACMA Response - Herbs Not Lethal 11 February, 2010 http://www.acupuncture.org.au/ TCM are regulated by TGA; Prescribed by practitioners rather than self medication The venom contains cardiac glycosides as main components. It is used to treat sore throats, boils, and heart failure. It is among the ingredients of a common pill, Six Miracle Pills. Issue: Dosage (mg range); drug (CVD) TCM herb interaction. Sample questions • Which of the following statements about herb-drug interactions are correct? • Most herbal medicines are non-toxic and therefore drug interactions are unlikely • Hypericum is an inhibitor of CYP P450 • Herbal medicines may have additive or antagonistic effects on conventional medicines • Most clinically significant herb-drug interactions have been characterised in controlled clinical studies • None of the above 40 Acknowledgments HMREC Andrew McLachlan Jimmy Xuemin Jiang Dr Colin Duke Prof Basil Roufogalis Dr Alaina Ammit Gray Peng Peter Coxeter Prof Ric Day A/Prof Kenneth Williams Dr Winston Liauw St Vincent's Hospital Sydney Vincent Fairfax Family Foundation The National Health and Medical Research Council (NHMRC) 41 Thank Thankyou! you! 42