Transcript Drug * Herb Interactions

Does it Effect the Older Adult
Wadie Najm, MD, MEd
UC Irvine- Geriatric Division
Supported by a Reynolds Grant
Retrieved September 29, 2011, from http://opinionforum.com/index/2009/07/overmedicating-children/
 Medication use by older adults
 Dietary Supplements –
 Regulations
 Quality Assurance
 How to Choose a Dietary Supplement
 Drug-herb interactions
 Resources
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 Passed by unanimous consent of House and
Senate
 Signed into law by President Bill Clinton
 Amended the Food Drug & Cosmetic Act
 Recognized a new category of regulated
products—”Dietary Supplements”(DS)
 Treats DS in many respect as food (i.e. does not
require premarket approval)
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 Definition:
 A product (other than tobacco) intended to
supplement the diet that bears or contains one or
more of the following dietary ingredients
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Vitamins
Minerals
Herbs or other botanicals
Amino acids
Concentrate, metabolite, constituent, extract or
combination of above listed ingredients
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 Manufacturer responsible for safety evaluation
 FDA has burden of proving DS is unsafe once
product is marketed
 Label must include:
 Name of each ingredient
 Quantity of each ingredient
 Total weight of all ingredient if a blend
 Identity of part of plant derived from
 Term “Dietary Supplement”
 Must contain nutritional labeling information
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 DSHEA authorized use of FDA approved
“Health claims” on label
 Describe the connection between a nutrient
or food substance and a disease or healthrelated condition
 Statements may be included on the label that
give the manufacturers description of the role of
the D/S
 Must be accompanied by disclaimer
 “This statement has not been evaluated by the
FDA. This product is not intended to diagnose,
treat, cure or prevent any disease”
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 Requires proper controls to ensure that DS are
processed in a consistent manner and meet
quality standards.
 cGMP apply to all domestic and foreign
companies involved in the US market
 Requires that DS are manufactured
consistently as to identity, purity, strength and
composition.
 Staggered 3 year phase for small business;
effective June 2008 for large companies.
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U.S.P. notation!
GMP or cGMP notation!
Consumer Lab seal!
Consider manufacturer /
distributor
 Look at brand used in studies
reporting positive outcome.
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FDA. (2010). TaintedDietarySupplements_1210. [pdf]. Retrieved September 29, 2011 from: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm236774.htm
 FDA has identified an emerging trend where
several over-the-counter products, frequently
represented as dietary supplements, contain
hidden active ingredients that could be harmful
 List of Supplements:
http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=tainted_suppl
ements_cder
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 Major delinquents:
 Weight loss supplements
 70 + reports of contamination (2010)
 Sibutramine (Meredia®)
 Erectile function/Sexual enhancement
 80 + reports of contamination (2010)
 Sildenafil (Viagra®), Tadalafil (Cialis®)
 Body building supplements
 80 + reports of contamination (2010)
 Anabolic steroids or steroid analogs
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Usually > 1 active ingredient per supplement
Variation in potency by season, region, etc.
Lack of clinical trials
Lack of full understanding of pharmacology of
herbs
 Presence of multiple ingredients not yet
characterized.
 Formulations using concentrated plant extracts
 Use of multiple supplements at one time
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HerbalGram. 2011
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HerbalGram. 2011
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Ann Intern Med. 2002;136:596-603
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 Ginkgo Evaluation of Memory (GEM) Study
cohort
 82.5% used at least 1 dietary supplement, with
54.5% using 3+.
 The overall mean number of prescription drugs
was 3.5 ± 2.7 and dietary supplements were
and 3.4 ± 3.0
 83% of prescription drug users also used dietary
supplements, and 90% of supplement users also
used prescription drugs
JAGS 57:1197–1205, 2009
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Look for available quality clinical research
(Efficacy)
Check for long tradition of use (Safety)
Check that active ingredient(s) are identified
Review mechanism of action determined
Verify that Supplement is commercially available
from a reliable source
 Ingredients and potency documented
 Quality assurance documented with seal of approval
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 Two types of interactions exist:
 Pharmacokinetic:
 herb–drug interactions are caused by one drug
interfering with the elimination, metabolism, or
absorption of another drug;
 Pharmacodynamic:
 Herb/supplement interaction due to pharmacological
properties similar or opposite to conventional
medications.
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 Induction of hepatic and intestinal drugmetabolism enzyme (Cytochrome P450
{CYP450}): important for Phase I drug
metabolism.
 Induction of drug transporters (intestines, liver,
kidney) i.e. P-glycoprotein, plays important role:
 Absorption
 Distribution
 Excretion
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 Over 80 dietary supplements have some effect
on a Cytochrome (CYP) enzyme,
 The potential to interact with drugs metabolized
by these enzymes is high.
 The majority of the research is based on
laboratory work (in vitro or in animals).
 The clinical significance of these remains
questionable.
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 Role of CYP450 system is the metabolism
and detoxification of endogenous
compounds after they have been ingested.
 CYP 450 is found in high concentrations in
the liver and small intestine.
 Comprehensive list of drug interaction:
 Indiana University
http://medicine.iupui.edu/clinpharm/ddis/p450_Table_Oct_11_2009.pdf
 Prescriber’s letter:
http://pharmacistsletter.therapeuticresearch.com/pl/DD_pu.aspx?cs=ce
&pt=3&fpt=28&dd=-1&pb=PL&s=PL
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D
r 300
u
g 250
Induction
Neutral
Inhibition
P 200
l
a
150
s
m
a 100
C
o
n
c
50
0
0
12
24
36
48
62
72
84
Time
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 Used commonly alone or in combination with
other supplements.
 Indications: Depression; anxiety; stress;
insomnia
 Efficacy: good scientific evidence for mild to
moderate depression.
 Standardized ingredient: Hyperforin; Hypericin
 Other phytochemicals are present.
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 SJW is a complex mixture of over 24
constituents: flavonols, flavonol glycosides,
biflavones, naphthodianthrones,
acylphloroglucinols, and phenylpropanes
 Hyperforin is believed to be the major
constituent responsible for its antidepressant
activity, as it inhibits the reuptake of
neurotransmitters in synapses
 Proposed action: inhibits 5-HT, NE, DA uptake;
GABA receptor ligand;
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 In vitro studies have demonstrated that SJW
extract is a potent inducer of CYP3A4 and 2B6,
and the responsible component was hyperforin.
 Based on in vitro, in vivo animal and human
studies, SJW interacted with CYPs in two ways:
induction of CYP and modulation (inhibition or
stimulation) of enzyme activity, which may be the
underlying mechanism for the observed SJW–
drug interactions.
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7500-2.
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Comparison of pre-supplementation and post-supplementation phenotypic
ratios for CYP3A4. (A= St John’s wort (SJW); B = garlic oil);
Clin Pharmacol Ther 2002;72:276-87
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Apparent sex-related difference in St John’s wort (SJW)–mediated
CYP3A4 induction. Differences in pre-supplementation and postsupplementation) were significantly greater for female subjects.
Clin Pharmacol Ther 2002;72:276-87
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Transplantation. 2001 Jan 27;71(2):239-41.
1) Drug interaction between St. John's wort and cyclosporine. Barone GW, et
al. Ann Pharmacother. 2000 Sep;34(9):1013-6.
2) herb-drug interactions in renal transplant patients.. Nowack R, Nephrology
2008 Jun;13(4):337-47.
3) Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A
metabolism in a patient after liver transplantation. Karliova M, et al. J
Hepatol. 2000 Nov;33(5):853-5.
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 Grapefruit has the potential to interact with
numerous drugs.
 A number of organic compounds, identified as
furanocoumarin derivatives, interfere with the
hepatic and intestinal CYP3A4.
 Other bioactive compounds interfere with Pglycoprotein and organic anion transporting
polypeptides (OATPs) either increasing or
decreasing bioavailability of a number of drugs.
Clin Pharmacol Ther. 2007 May;81(5):631-3
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Concomitant ingestion of grapefruit juice and fexofenadine reduced
fexofenadine area under curve (AUC)0–8 h by 52%; Grapefruit
juice ingested 4 h before drug had no effect.
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NYTimes, March 20, 2006
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Br J Clin Pharmacol 2010;70(5);645–655
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 Approximately 60 -80% of levothyroxine is
absorbed after oral administration.
 This absorption occurs within the first 3 h of
ingestion and is localized mainly in the jejunum
and ileum.
 Absorption of levothyroxine is maximal when the
stomach is empty
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 Levothyroxine plus chromium picolinate 1000
mcg; decreases levothyroxine levels by 17%
 Calcium binds levothyroxine in the GI tract;
variably reduces absorption
 Levothyroxine taken with coffee decreases
levothyroxine levels by 27% to 36%.
John-Kalarickal J, et al. Thyroid 2007;17:763-5. Benvega S, et al. Thyroid
2008;18:293-301.
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Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 781–792
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 Warfarin exerts its effect by interfering with the
cyclic interconversion of vitamin K and its 2,3
epoxide (vitamin K1 epoxide).
 Treatment with warfarin results in the hepatic
production of partially carboxylated &
decarboxylated proteins with reduced anticoagulant
activity.
 The anticoagulant effect of warfarin can be reversed
by the intake of vitamin K1 (phytonadione)
Expert Opin. Drug Saf. (2006) 5(3):433-451
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Factors that can
contribute to variability:
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age,
gender,
ethnicity,
vitamin K intake,
Body weight,
albumin level
Other medication(s)
Expert Opin. Drug Saf. (2006)
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 Older adults are more likely to eat vegetables,
therefore, have higher vitamin K intake. Vitamin
K intake among adults > 55 years is estimated to
range from 80 to 210 μg/day.
Expert Opin. Drug Saf. (2006) 5(3)
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 Absorption of warfarin may be inhibited by drugs that
affect the bioavailability of warfarin, such as
colestyramine or sucralfate.
 Warfarin also interacts with medications that are highly
protein-bound (salsalate, sulfasalazine).
 Warfarin is inhibited by medications that induce
cytochrome P450 liver enzymes (rifampin,
carbamazepine)
 Warfarin is enhanced by medications that inhibit CYP
liver enzymes (metronidazole, cimetidine).
 Pharmacodynamic interactions may occur with drugs
that affect platelet function and aggregation, causing
increased risk of bleeding (aspirin, clopidogrel, NSAIDs)
Expert Opin. Drug Saf. (2006) 5(3):433-451
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 Over 40 reports of interactions with warfarin
(Coumadin)
 Glucosamine alone or in combination with chondroitin
 Most reports involved typical doses,
 Glucosamine 1500 mg/day and chondroitin 1200
mg/day
 Effect: bruising, bleeding {increased INR)
Knudsen J et al., Pharmacotherapy 2008;28:540-8.
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J Thromb Thrombolysis 31:326
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Clinically significant drug interactions can occur when an interacting drug,
food or herbal supplement is added during warfarin therapy, discontinued
during warfarin treatment, or used intermittently during warfarin treatment.
J Thromb Thrombolysis (2011) 31:326–343
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Expert Opin. Drug Saf. (2006) 5(3)
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Expert Opin. Drug Saf. (2006) 5(3)
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 Bitter orange contains the stimulant “synephrine”
 QT-interval prolongation in case reports
 Combining with other QT-interval prolonging drugs
increases risk of arrhythmia:
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Amiodarone
Quinidine
Sotalol
Stimulants
Several others
Nasir JM, et al. Mayo Clin Proc 2004;79:1059-62.
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Caffeine
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Guaraná
Kola nut
Yerba maté
Green tea
Black tea
Cocoa
Ephedra
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Guaraná
Kola nut
Yerba maté
Green tea
Bitter orange
Combinations
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 Medical history should include information about
Herbal/Dietary supplements
 Consider Herbal – Drug interactions
 Physicians and patient must become better
educated about the potential for interactions.
 Elderly people are subject to higher risk for
Drug-Herb interactions
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 Herbal Supplements-Drug Interactions:
Scientific and Regulatory Perspectives Y.W.
Francis Lam, Shiew-Mei Huang, Stephen D. Hall
(2006)
 Herbal Supplements: Efficacy, Toxicity,
Interactions with Western Drugs, and Effects
on Clinical Laboratory Tests. Amitava Dasgupta
(2011)
 A-Z Guide to Drug-Herb-Vitamin Interactions
Revised and Expanded 2nd Edition: Alan R.
Gaby (2006)
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 Mandatory reporting for manufacturers
 Voluntary reporting for health professionals
 Report it to MedWatch http://www.fda.gov/medwatch/
 Report using Natural Medicines Comprehensive
Database: Natural Medicines Watch
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 Tips for Older Dietary Supplement Users
http://www.fda.gov/Food/DietarySupplements/ConsumerInformat
ion/ucm110493.htm
 My Dietary Supplements (MyDS) Mobile App
(ODS)
http://ods.od.nih.gov/About/mobile/AboutMyDS.aspx
 Zhou SF, et al. Clinically important drug interactions
potentially involving mechanism-based inhibition of
cytochrome P450 3A4 and the role of therapeutic drug
monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710.
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