Complementary and Alternative Medicine Drug - Herb Interactions

7/30/2019 Complementary and Alternative Medicine Drug - Herb Interactions

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Wadie Najm, MD, MEd

Retrieved September 29, 2011, from http://opinion-forum.com/index/2009/07/overmedicating-children/

Does it Effect the Older Adult

UC Irvine- Geriatric DivisionSupported by a Reynolds Grant



Medication use by older adultsDietary Supplements –

Regulations

Quality AssuranceHow to Choose a Dietary Supplement

Drug-herb interactions

Resources

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UC Irvine- Reynolds Grant 7



Passed by unanimous consent of House andSenateSigned into law by President Bill Clinton

Amended the Food Drug & Cosmetic ActRecognized a new category of regulatedproducts —‖Dietary Supplements‖(DS)

Treats DS in many respect as food (i.e. does notrequire premarket approval)




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Definition: A product (other than tobacco) intended tosupplement the diet that bears or contains one or more of the following dietary ingredients

VitaminsMineralsHerbs or other botanicalsAmino acids

Concentrate, metabolite, constituent, extract orcombination of above listed ingredients

UC Irvine - Reynolds Grant



Manufacturer responsible for safety evaluationFDA 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 fromTerm “ Dietary Supplement ”

Must contain nutritional labeling information




DSHEA authorized use of FDA approved ―Health claims‖ on label Describe the connection between a nutrientor food substance and a disease or health-related condition Statements may be included on the label thatgive the manufacturers description of the role of the D/S

Must be accompanied by disclaimer “ This statement has not been evaluated by theFDA. This product is not intended to diagnose,treat, cure or prevent any disease”




Requires proper controls to ensure that DS areprocessed in a consistent manner and meetquality standards.

cGMP apply to all domestic and foreigncompanies involved in the US marketRequires that DS are manufacturedconsistently as to identity, purity, strength and

composition.Staggered 3 year phase for small business;effective June 2008 for large companies.




U.S.P. notation!GMP or cGMP notation!

Consumer Lab seal!Consider manufacturer /distributor

Look at brand used in studiesreporting positive outcome.




UC Irvine - Reynolds Grant 14FDA. (2010). TaintedDietarySupplements_1210. [pdf]. Retrieved September 29, 2011 from: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm236774.htm



FDA has identified an emerging trend whereseveral over-the-counter products, frequentlyrepresented as dietary supplements, contain

hidden active ingredients that could be harmfulList of Supplements:

http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=tainted_supplements_cder








Major delinquents:Weight loss supplements

70 + reports of contamination (2010)Sibutramine (Meredia®)

Erectile function/Sexual enhancement80 + reports of contamination (2010)Sildenafil (Viagra®), Tadalafil (Cialis®)

Body building supplements80 + reports of contamination (2010) Anabolic steroids or steroid analogs




Usually > 1 active ingredient per supplementVariation in potency by season, region, etc.Lack of clinical trials

Lack of full understanding of pharmacology of herbsPresence of multiple ingredients not yetcharacterized.

Formulations using concentrated plant extractsUse of multiple supplements at one time




18UC Irvine - Reynolds GrantHerbalGram . 2011



UC Irvine - Reynolds Grant 19HerbalGram . 2011



20UC Irvine - Reynolds Grant Ann Intern Med. 2002;136:596-603



Ginkgo Evaluation of Memory (GEM) Studycohort82.5% used at least 1 dietary supplement, with54.5% using 3+.The overall mean number of prescription drugswas 3.5 ± 2.7 and dietary supplements wereand 3.4 ± 3.083% of prescription drug users also used dietarysupplements, and 90% of supplement users alsoused prescription drugs

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JAGS 57:1197 – 1205, 2009UC Irvine-Reynolds Grant









Look for available quality clinical research(Efficacy)Check for long tradition of use (Safety)

Check that active ingredient(s) are identifiedReview mechanism of action determinedVerify that Supplement is commercially available

from a reliable sourceIngredients and potency documentedQuality assurance documented with seal of approval




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 pharmacologicalproperties similar or opposite to conventionalmedications.

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Induction of hepatic and intestinal drug-metabolism enzyme (Cytochrome P450{CYP450}): important for Phase I drug

metabolism.Induction of drug transporters (intestines, liver,kidney) i.e. P-glycoprotein, plays important role:

AbsorptionDistributionExcretion




Over 80 dietary supplements have some effecton a Cytochrome (CYP) enzyme,The potential to interact with drugs metabolized

by these enzymes is high.The majority of the research is based onlaboratory work ( in vitro or in animals).

The clinical significance of these remainsquestionable.




Role of CYP450 system is the metabolismand detoxification of endogenouscompounds 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



http://pharmacistsletter.therapeuticresearch.com/pl/DD_pu.aspx?cs=ce&pt=3&fpt=28&dd=-1&pb=PL&s=PL









0

50

100

150

200

250

300

0 12 24 36 48 62 72 84

Time

Induction Neutral Inhibition


Dr ug

Plasma

Conc



Used commonly alone or in combination with

other supplements.Indications: Depression; anxiety; stress;insomniaEfficacy: good scientific evidence for mild tomoderate depression.Standardized ingredient: Hyperforin; Hypericin

Other phytochemicals are present.




SJW is a complex mixture of over 24constituents: flavonols, flavonol glycosides,biflavones, naphthodianthrones,acylphloroglucinols, and phenylpropanesHyperforin is believed to be the major constituent responsible for its antidepressantactivity, as it inhibits the reuptake of neurotransmitters in synapsesProposed action: inhibits 5-HT, NE, DA uptake;GABA receptor ligand;




In vitro studies have demonstrated that SJWextract is a potent inducer of CYP3A4 and 2B6,and the responsible component was hyperforin.

Based on in vitro, in vivo animal and humanstudies, SJW interacted with CYPs in two ways:induction of CYP and modulation (inhibition or stimulation) of enzyme activity, which may be theunderlying mechanism for the observed SJW –drug interactions.


Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7500-2.




Comparison of pre-supplementation and post-supplementation phenotypicratios for CYP3A4. (A= St John’s wort (SJW); B = garlic oil);

Clin Pharmacol Ther 2002;72:276-87




Apparent sex- related difference in St John’s wort (SJW) – mediatedCYP3A4 induction. Differences in pre-supplementation and post-supplementation) were significantly greater for female subjects.

Clin Pharmacol Ther 2002;72:276-87




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, Nephrology2008 Jun;13(4):337-47.

3) Interaction of Hypericum perforatum (St. John's wort) with cyclosporin Ametabolism in a patient after liver transplantation. Karliova M, et al. JHepatol. 2000 Nov;33(5):853-5.



Grapefruit has the potential to interact withnumerous drugs.

A number of organic compounds, identified as

furanocoumarin derivatives, interfere with thehepatic and intestinal CYP3A4.Other bioactive compounds interfere with P-glycoprotein 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




Concomitant ingestion of grapefruit juice and fexofenadine reducedfexofenadine area under curve (AUC)0 – 8 h by 52%; Grapefruit

juice ingested 4 h before drug had no effect.



38UC Irvine - Reynolds GrantNYTimes, March 20, 2006




Br J Clin Pharmacol 2010;70(5);645 – 655



Approximately 60 -80% of levothyroxine isabsorbed after oral administration.This absorption occurs within the first 3 h of

ingestion and is localized mainly in the jejunumand ileum.

Absorption of levothyroxine is maximal when thestomach is empty




Levothyroxine plus chromium picolinate 1000mcg; decreases levothyroxine levels by 17%Calcium binds levothyroxine in the GI tract;

variably reduces absorptionLevothyroxine taken with coffee decreaseslevothyroxine levels by 27% to 36%.

John-Kalarickal J, et al. Thyroid 2007;17:763-5. Benvega S, et al. Thyroid 2008;18:293-301.





Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 781 – 792



Warfarin exerts its effect by interfering with thecyclic interconversion of vitamin K and its 2,3epoxide (vitamin K1 epoxide).Treatment with warfarin results in the hepaticproduction of partially carboxylated &decarboxylated proteins with reduced anticoagulant activity.

The anticoagulant effect of warfarin can be reversedby the intake of vitamin K1 (phytonadione)


Expert Opin. Drug Saf. (2006) 5(3):433-451



Factors that cancontribute to variability:

age,gender,ethnicity,vitamin K intake,Body weight,

albumin levelOther medication(s)


Expert Opin. Drug Saf. (2006)



Older adults are more likely to eat vegetables,therefore, have higher vitamin K intake. Vitamin

K intake among adults > 55 years is estimated torange from 80 to 210 μg /day.


Expert Opin. Drug Saf. (2006) 5(3)



Absorption of warfarin may be inhibited by drugs thataffect the bioavailability of warfarin, such ascolestyramine or sucralfate.Warfarin also interacts with medications that are highlyprotein-bound (salsalate, sulfasalazine).Warfarin is inhibited by medications that inducecytochrome P450 liver enzymes (rifampin,carbamazepine)Warfarin is enhanced by medications that inhibit CYPliver enzymes (metronidazole, cimetidine).Pharmacodynamic interactions may occur with drugsthat affect platelet function and aggregation, causingincreased risk of bleeding (aspirin, clopidogrel, NSAIDs)


Expert Opin. Drug Saf. (2006) 5(3):433-451



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 1200mg/dayEffect: bruising, bleeding {increased INR)

Knudsen J et al., Pharmacotherapy 2008;28:540-8.








J Thromb Thrombolysis (2011) 31:326 – 343

Clinically significant drug interactions can occur when an interacting drug,food or herbal supplement is added during warfarin therapy, discontinuedduring warfarin treatment, or used intermittently during warfarin treatment.



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Expert Opin. Drug Saf. (2006) 5(3)






Bitter orange contains the stimulant ― synephrine ‖ QT-interval prolongation in case reportsCombining with other QT-interval prolonging drugsincreases risk of arrhythmia:

AmiodaroneQuinidineSotalolStimulantsSeveral others

Nasir JM, et al. Mayo Clin Proc 2004;79:1059-62. 53UC Irvine - Reynolds Grant



Caffeine Ephedra


GuaranáKola nut

Yerba matéGreen teaBlack teaCocoa

GuaranáKola nut

Yerba matéGreen teaBitter orangeCombinations



Medical history should include information aboutHerbal/Dietary supplementsConsider Herbal – Drug interactionsPhysicians and patient must become better educated about the potential for interactions.Elderly people are subject to higher risk for Drug-Herb interactions


































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 Effectson Clinical Laboratory Tests. Amitava Dasgupta(2011)

A-Z Guide to Drug-Herb-Vitamin InteractionsRevised and Expanded 2nd Edition: Alan R.Gaby (2006)




Mandatory reporting for manufacturers

Voluntary reporting for health professionals

Report it to MedWatch http://www.fda.gov/medwatch/

Report using Natural Medicines ComprehensiveDatabase: Natural Medicines Watch


http://www.fda.gov/medwatch/

http://www.fda.gov/medwatch/



Tips for Older Dietary Supplement Usershttp://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 interactionspotentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug

monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710.

http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/ucm110493.htm






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Complementary and Alternative Medicine Drug - Herb Interactions