Transcript Slide 1

COMMONWEALTH OF AUSTRALIA
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PHAR3811
Herbal Medicines
CVD Drug-Herb Interactions
George Li
University of Sydney
Faculty of Pharmacy
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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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Safety
and Drug-Herb 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
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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
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NS
Ginkgo biloba
- ADR: Bleeding
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20
0.004
- Interaction: Warfarin
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<0.001
Glucosamine
- Interaction: Warfarin
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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/
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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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Dose-effect relationship for drugs or
herbs
Probability
Effect
Toxicity
Drug or herb dose
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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
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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
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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
• Pharmacokinetic
• Pharmacodynamic
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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
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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
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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
Michalets,
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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
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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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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
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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)
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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
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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
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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?
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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
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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)
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Thank
Thankyou!
you!
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