1

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.

2

CVD Drug-Herb InteractionsGeorge Li

University of Sydney

Faculty of Pharmacy

PHAR3811

Herbal Medicines

3

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

4

Safety and Drug-Herb Interactions

5

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

6

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

28

45

20

34

0.004

<0.001

Glucosamine- Interaction: Warfarin 34 29 NS

http://www.nps.org.au/research_and_evaluation/

7

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.

8

Dose-effect relationship for drugs or herbs

Probability

Drug or herb dose

Effect

Toxicity

9

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

10

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

11

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)

12

Mechanisms and Drug-Herb Interactions

13

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

14

Mechanisms of drug-herb interactions

• Physicochemical

• Pharmacokinetic

• Pharmacodynamic

15

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)

16

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

17

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

18

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

19

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

20

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

21

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

22

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

23

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

24

HERB-DRUG INTERACTION STUDIES WHICH ONE AND WHEN?

TYPE

Cells or microsomes

Animals

Healthysubjects

Patients

Mechanism COST Clinical Relevance

Ethical Issues

25

Recommendation and significance

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

26

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

27

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

28

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

29

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.

37

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

40

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

41

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

42

Thank you!Thank you!