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COMMONWEALTH OF AUSTRALIACopyright 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.
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CVD Drug-Herb InteractionsGeorge Li
University of Sydney
Faculty of Pharmacy
PHAR3811
Herbal Medicines
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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
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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 to be supported by other studies
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GPs Knowledge of Adverse Drug Reactions
• 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
Potential side effects/interactions
IM GP (%)
Non-IM GP (%)
P-value
Black cohosh- ADR: Liver toxicity 42 37 NS
Ginkgo biloba- ADR: Bleeding
- Interaction: Warfarin
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45
20
34
0.004
<0.001
Glucosamine- Interaction: Warfarin 34 29 NS
http://www.nps.org.au/research_and_evaluation/
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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.
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Basic Concepts in Pharmaco/PhytotherapyDose of drug or herbal product
Concentration of drug, metabolite or constituent in plasma
Pharmacological effect
PHARMACODYNAMICSPHARMACOKINETICS
Pharmacokinetics what the body does to the drug or herb
Pharmacodynamics what the drug or herb does to the body
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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
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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)
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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
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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 pectin and natural resins)
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Mechanisms of drug-herb interactions
Pharmacokinetic Interactions • Absorption of a drug or herb• Distribution
including protein bindingdrug transporters (p-glycoprotein)
• Metabolismcytochrome P450
• Renal eliminationcompetition for active carriers
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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
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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
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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
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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
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Relevant CYPs
• over 30 human CYP-450 isoenzymes
relevant to drug metabolism• CYP3A4• CYP2D6• CYP1A2• CYP2C subfamily• most isoenzymes can metabolise a range
of drugs Michalets, 1998
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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. Journal of Complementary Medicine 2003; 60-61
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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. Journal of Complementary Medicine 2003; 60-61
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HERB-DRUG INTERACTION STUDIES WHICH ONE AND WHEN?
TYPE
Cells or microsomes
Animals
Healthysubjects
Patients
Mechanism COST Clinical Relevance
Ethical Issues
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Recommendation and significance
Depends on the level of evidence and the risk:• Avoid combination• Caution: monitor effects
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Herbal Medicine
Interacting Drugs* Evidence and Mechanism Significance and Recommendation
Devil’s Claw
Warfarin Case report: bruising has been reported with combined use
Caution: Monitor for signs of bleeding and possible increase in INR
Ginger Warfarin Suspected: possible increased anticoagulant effects due to antiplatelet activity
Caution: monitor for signs of bleeding and possible increase in INR
Antacids Suspected: increased gastric secretions may reduce activity of antacids
CVD: Herb Interaction
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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
Ginseng (Asian, Korean or Siberian)
Warfarin Case report: decreased INR Animal study: suggests no interaction
Caution: monitor for signs of lack of effect
CVD: Herb Interaction
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Herbal Medicine
Interacting Drugs*
Evidence and Mechanism
Significance and Recommendation
Hawthorn Digoxin Suspected: additive effects on heart rhythm because hawthorn contains digitalis-like constituents
Avoid combination: monitor digoxin adverse effects.
Antihypertensives and nitrates
Suspected: excessive reduction in blood pressure via vasodilation actions
Caution: monitor blood pressure and signs of hypotension
CVD: Herb Interaction
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Interacting Drugs
Herbal Medicine Evidence and Mechanism Significance and Recommendation
Warfarin Ginkgo BilberryGarlicGingerKorean ginsengSt John’s wort
Various Avoid combination: monitor for signs of bleeding and possible increase in INR
Warfarin Devils ClawGuarana
Caution
CVD: Herb Interaction
CVD: Herb Interaction
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, 3 rd ed. Eclectic Medical Publications, Sandy, Oregon, USA.Gruenwald J, et al (2007) PDR for Herbal Medicines. Fourth Edition. Thomson Healthcare Inc. Montvale, NJ.
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
CVS: Crataegus monogynaDrugs 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 albumDrugs Effect/evidence /comments
Anti-hypertensive
Additive effects (monitor BP)
Anti-diabetic Additive effects (evidence from animal studies
Doxorubicin 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 inhibitor eg. Bortezomib, velcade
Reduced drug effects (avoid combination)
Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia.
CVS: Allium sativiumDrugs Effect/evidence /comments
Anticoagulants Increased bruising and bleeding (check INR if using large doses)
Antihypertensives
Additive effects
Antiplatelet Increased bruising and bleeding especially with doses >4 grams
Helicobacter pylori triple therapy
Additive effects
Hepatotoxic drugs
Reduced side effects
Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia.
CVS: Allium sativiumDrugs Effect/evidence /comments
Hypolipidaemic Additive effects
Immunosuppressant
Reduced drug effects (observe clinically)
Paclitaxel Reduced drug effects
paracetamol Reduced side effects
Saqinavir Reduced drug effects (avoid combination)
Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia .
CVS: Aesculus hippocastanumDrugs 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)
Hypoglycaemic
Additive effects (check BSL)
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, 3 rd ed. Eclectic Medical Publications, Sandy, Oregon, USA.Gruenwald J, et al (2007) PDR for Herbal Medicines. Fourth Edition. Thomson Healthcare Inc. Montvale, NJ.
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Traditional Chinese medicinesRational 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?
Cane Toad Venom - Recent controversial on herbal toxicity
Current Issues for TCM Internationalisation
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
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
Cane Toad Venom - Recent controversial on herbal toxicity
Current Issues for TCM Internationalisation
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.
AACMA Response - Herbs Not Lethal11 February, 2010 http://www.acupuncture.org.au/
TCM are regulated by TGA; Prescribed by practitioners rather than self medication
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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
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Acknowledgments
HMRECAndrew McLachlan
Jimmy Xuemin JiangDr Colin Duke
Prof Basil RoufogalisDr Alaina Ammit
Gray PengPeter Coxeter
Vincent Fairfax Family Foundation
The National Health and Medical Research Council (NHMRC)
Prof Ric Day
A/Prof Kenneth Williams
Dr Winston Liauw
St Vincent's Hospital
Sydney