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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

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 5

GPs Knowledge of Adverse Drug Reactions

Potential side effects/interactions IM GP (%) Non-IM GP (%)

Black cohosh

- ADR: Liver toxicity

Ginkgo biloba

- ADR: Bleeding

42 37 28 20

P-value

0.004

- Interaction: Warfarin

Glucosamine

- Interaction: Warfarin

45 34

<0.001

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.

Dose-effect relationship for drugs or herbs

Effect Probability Toxicity Drug or herb dose

Basic Concepts in Pharmaco/Phytotherapy

Dose of drug or herbal product Concentration of drug, metabolite or constituent in plasma Pharmacological effect

PHARMACOKINETICS 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

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 pectin and natural resins) 15

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 range of drugs

Michalets, 1998 21

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 22

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 23

HERB-DRUG INTERACTION STUDIES WHICH ONE AND WHEN?

TYPE Cells or microsomes Mechanism COST Clinical Relevance Ethical Issues Animals Healthy subjects Patients

Recommendation and significance

Depends on the level of evidence and the risk: • Avoid combination • Caution: monitor effects 25

CVD: Herb Interaction

Herbal Medicine

Devil’s Claw Ginger

Interacting Drugs*

Warfarin Warfarin Antacids

Evidence and Mechanism Significance and Recommendation

Case report: bruising has been reported with combined use Caution: Monitor for signs of bleeding and possible increase in INR Suspected: possible increased anticoagulant effects due to antiplatelet activity 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

Ginkgo

Interacting Drugs*

Warfarin Ginseng (Asian, Korean or Siberian) Aspirin Warfarin

Evidence and Mechanism

Suspected: increased risk of bleeding via PAF inhibition. Suspected interaction: direct effects of ginkgo on platelet aggregation Case report: decreased INR Animal study: suggests no interaction

Significance and Recommendation

Avoid combination: monitor for signs of bleeding and possible increase in INR Caution: possible additive effect and risk of bleeding Caution: monitor for signs of lack of effect 27

CVD: Herb Interaction

Herbal Medicine

Hawthorn

Interacting Drugs*

Digoxin Antihyperten sives and nitrates

Evidence and Mechanism

Suspected: excessive reduction in blood pressure via vasodilation actions

Significance and Recommendation

Suspected: additive effects on heart rhythm because hawthorn contains digitalis-like constituents Avoid combination: monitor digoxin adverse effects.

Caution: monitor blood pressure and signs of hypotension 28

CVD: Herb Interaction

Interacting Drugs Herbal Medicine

Warfarin Warfarin Ginkgo Bilberry Garlic Ginger Korean ginseng St John’s wort Devils Claw Guarana

Evidence and Mechanism

Various

Significance and Recommendation

Avoid combination: monitor for signs of bleeding and possible increase in INR Caution 29

CVD: Herb Interaction

Drug

Beta blockers Thiazide Diuretics Digoxin

Herb

Goldenseal Liquorice Guarana Hawthorn Liquorice Liquorice St John’s wort Hawthorn

Interaction

Dec effect drug Dec Dec Increase Dec

Action

Avoid Avoid Caution Caution Avoid Dec Dec Increase Avoid Avoid 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, 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.

Drugs

CVS:

Crataegus monogyna

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

Effect/evidence /comments Drugs

Anti hypertensive Anti-diabetic Doxorubicin Additive effects (monitor BP) 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

Effect/evidence /comments Drugs

Anticoagulants CNS sedatives CNS stimulants Diuretics Hypoglycaemic agents Iron Reduced drug effect due to vitamin K with large doses of green tea (check INR if on warfarin) Reduced effect with large doses of green tea Additive effects (observe patient) Additive effects especially with high dose of herb Additive effects (observe patient) Proteasome inhibitor eg. Bortezomib, velcade Reduced absorption (separate dosing by at least 2 hours) Reduced drug effects (avoid combination) Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia.

CVS:

Allium sativium

Effect/evidence /comments Drugs

Anticoagulants Antihypertensive s Antiplatelet Helicobacter pylori triple therapy Increased bruising and bleeding (check INR if using large doses) Additive effects Increased bruising and bleeding especially with doses >4 grams Additive effects Hepatotoxic drugs Reduced side effects Braun L. & Cohen M (2007) Herbs & Natural Supplements: An Evidence Based Approach. Elsevier, Australia.

CVS:

Allium sativium

Effect/evidence /comments Drugs

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 Antiplatelet Additive drug effects when using improperly prepared extracts (check APTT, PTT and INR) Additive drug effects when using improperly prepared extracts (observe patient) Hypoglycaemi c 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.

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)