special considerations for complementary alternative medicine

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California

Special Considerations for Complementary and Alternative

Medicine Use in Older AdultsMarina Shkayeva, PharmD

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Meet the Speaker – Marina Shkayeva

• Assistant Clinical Editor for Natural Medicines, TRC Healthcare• Doctorate of Pharmacy at University of

Pittsburgh• 2-year residency in drug information and

natural medicine research• Hepatotoxicity-ADME Working Group,

Botanical Safety Consortium• Long Term Care Council, Right Care Alliance

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Disclosure

• No conflicts of interest to disclose.

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Learning Objectives

• Describe common reasons why older adults try complementary or alternative medicines.• Discuss safety concerns with the use of complementary or alternative

medicines in older adults.• List drug-supplement interactions of concern for older adults.• Identify complementary or alternative medicines that are safe and

might be beneficial for older adults.

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Tracking Supplements and Their Use

• Dietary Supplement Label Database (DSLD)• Records dietary information and supplement label claims for over 120,000+

dietary supplements in the United States

• National Health and Nutrition Examination Survey (NHANES)• A national survey program of studies characterizing the health and

nutritional status of adults and children in the United States

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Prevalence of Supplement Use in Adults Ages 60+

SOURCE: National Center for Health Statistics, National Health and Nutrition Examination Survey, 2017–2018.

62%67%

74%80%

67%

74%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

200 7-20 08 201 7-20 18

Male

Female

Total

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SOURCE: National Center for Health Statistics, National Health and Nutrition Examination Survey, 2017–2018.

Poly-Supplement Use Increases with Age

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Supplements Most Commonly Used by Adults 60+ (2017-2018)

SOURCE: NHANES, 2017–2018.Gahche et al. J Nutr. 2017 Oct; 147(10): 1968–1976.Vanoh et al. Clin Interv Aging. 2021;16:161-175.

39%37%

22%19%

12% 11%9%

MVM Vit D Omega-3s Calcium Vit B12 Vit C Herbals0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

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Why are Dietary Supplements Used?

Dickinson, MacKay. Nutr J. 13, 14. 2014.Gahche et al. J Nutr. 2017;147(10):1968-1976.

41%37%

22% 22%

14%

Improve health

Bone health

Nutrient gaps

Heart health

Immunity

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Dietary Supplement Market Size

• Effect of COVID-19 pandemic on the supplement market size the US• From $34.6 billion 2019 to $37.1 billion in 2020 the dietary supplement

market size in the US jumped by about 2.5 billion to 37 billion total worth

• Herbal product sales (American Botanical Council) • Normal growth in sales is 8-9% yearly• In 2020, the growth rate was 17.3% ($1.7 billion)

https://www.ibisworld.com/

https://www.herbalgram.org/resources/herbalgram/issues/131/

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Supplements Marketed to Older Adults

Key-term search of the Dietary Supplement Label Database (DSLD):• “senior” and “seniors”; filter “on market”

• ~1320 labels (<1% of database)

• “50 plus” and “50+”• >78,000 labels (60% of database)

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Natural Medicineswith Safety Concerns in Older Adults

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Safety Concerns in Older Adults• Natural medicines have pharmacologic effects to which older

individuals may be especially vulnerable• Biological activity similar to concerns highlighted by the BEERS criteria, such

as anticholinergic, sedative, and antiplatelet effects

• Some might increase the risk of hepatotoxicity or nephrotoxicity

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Safety: A Focus on Quality

• In the US, dietary supplements are regulated similarly to foods• Safety and quality not confirmed by FDA before marketing

• Safety and quality are regulated retroactively• FDA pulls unsafe products off the market AFTER reports of adverse effects• Adulteration and contamination are discovered AFTER a product has been on the market

for some time• Violation of Good Manufacturing Practices is discovered during facility spot checks

• Certain third-party programs provide prospective certification of quality• United States Pharmacopeia (USP), National Sanitation Foundation (NSF), others

https://www.nsf.org/https://www.usp.org/

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Safety of Multivitamins• Older adults using dietary supplements, 40% take MVMs

• MVMs often contain supra-therapeutic doses of vitamins and minerals • Not all vitamins and minerals are safe in high doses

• MVMs may contain non-vitamin and non-mineral ingredients• Additive biological effects• Increased risk of interactions

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Multivitamins Marketed to Older Adults• Which ingredients could be problematic in this MVM?

SOURCE: https://dsld.od.nih.gov/dsld/docs/230990.pdf

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Anticholinergic Effects• Many herbs have anticholinergic activity• These are not common in dietary supplements but may be found in

homeopathic products or Traditional Chinese Medicine (TCM) preparations. • Examples include:

Hung DZ., Hung YH. Clinical Toxicology. doi.org/10.1007/978-94-007-6288-6_44-1.

ü Angel’s trumpetü Belladonnaü Bitter yamü Jimson weedü Knotweedü Scopolia

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Sedative Effects• Many herbs have sedative effects. Many of these herbs can be found

in combination products, increasing the risk for additive effects.• Examples include:

Podadzki et al. Clin Med (Lond). 2013 Feb;13(1):7-12.

ü California Poppyü Kavaü Passionflowerü St. John’s wortü Valerian root

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Antiplatelet Effects

• Many natural medicines have been shown to have antiplatelet effects. • Examples include:

Di Minno, et al. Blood Rev. 2017 Jul;31(4):193-203.Kim et al. Evid Based Complement Alternat Med. 2019;2019:7125162.

ü Garlicü Gingerü Ginkgoü Panax ginsengü Turmeric

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Possible Hepatotoxic Effects

• Some natural medicines have been linked to cases of liver toxicity.• Examples include:

Frenzel, et al. Int J Mol Sci. 2016 Apr 27;17(5):588.Teschke. Front Pharmacol. 2015 Apr 23;6:72.

ü Green tea extractü Herbs containing pyrrolizidine alkaloids (PAs, hepatotoxic

constituents) such as Borage, Butterbur, Coltsfoot, Comfreyü Kavaü Kratom

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Possible Nephrotoxic Effects

• Certain natural medicines have been linked to cases of acute kidney injury. • Examples include:

Komarnytsky. Int J Mol Sci. 2021 Apr; 22(8): 4132.Naufall, et al. Blood Purif. 2016;41(1-3):123-9.

ü Aloeü Aristolochiaü Licoriceü Willow barkü Wormwood oilü Yohimbe

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Q: Which natural medicine might have antiplatelet effects? • A) Aloe• B) Comfrey• C) Ginkgo• D) Kava

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Natural Medicinesand Drug Interactions Important to Older Adults

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Interactions with Fruit and Juice

• Grapefruit juice inhibits CYP3A4 and OATP1A2• Effects of grapefruit juice may last at least 48 hours

• Seville orange and pomelo juices might inhibit CYP3A4 • Studied drugs: cyclosporine, felodipine• Low certainty

Chen et al. J Food Drug Anal. 2018;26(2S):S61-S71.Bailey. Br J Clin Pharmacol. 2010;70(5):645-55.

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Other Fruit and Juice Interactions• Apple and orange juice inhibit intestinal absorption via OATP2B1

• Studied drugs: aliskiren, atenolol, celiprolol, fexofenadine

• Early research suggests grape juice induces CYP3A4 and CYP1A2• Studied drugs: cyclosporine, phenacetin• More evidence is needed to confirm

Chen et al. J Food Drug Anal. 2018;26(2S):S61-S71. Grimstein and Huang. J Food Drug Anal. 2018;26(2S):S12-S25.

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Focus on: Cranberry Fruit and Juice• Does cranberry interact with warfarin?

• 15+ case reports of warfarin with cranberry juice resulting in elevated INR and sometimes bleeding

• Many studies show that dietary amounts of cranberry juice have no effect on warfarin metabolism and do not inhibit CYP2C9 and CYP3A4

• It is possible that only certain cranberry products taken in high doses can increase warfarin levels and effects

Chen et al. J Food Drug Anal. 2018;26(2S):S61-S71.Bailey. Br J Clin Pharmacol. 2010;70(5):645-55..

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Focus on: Goji Berry Fruit

• 75-year-old female, history of mitral valve replacement, stabilized on flecainide and warfarin, presented to the ER with arrhythmia • Started drinking 1-2 glasses of concentrated goji tea daily x2 weeks to

prevent COVID-19 • Flecainide toxicity (CYP2D6 inhibition) • Elevated INR (CYP2C9 inhibition)

• Previous case reports: elevated INR and bleeding after use of goji berry juice, goji berry concentrated tea, or goji berry wine

Guzman, et al. Eur Heart J Case Rep. 2021;5(6):ytab204.

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CYP3A4 inhibitors

• Many natural medicines inhibit CYP3A4 • Examples include:

• Berberine and berberine-containing herbs: European barberry, goldenseal, Oregon grape, tree turmeric, others

• Piperine• Schisandra• Turmeric (limited evidence)

Grimstein and Huang. J Food Drug Anal. 2018;26(2S):S12-S25.Xin, et al. Br J Clin Pharmacol. 2007 Oct;64(4):469-75.

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CYP3A4 Inducers

• Many natural medicines induce CYP3A4 • Examples include:

• St. John’s wort (hyperforin)• Also induces CYP1A2, CYP2E1, CYP2C9, CYP2C19, P-glycoprotein

• Ginkgo • Conflicting research, might also induce CYP2C9, CYP2C19

Grimstein and Huang. J Food Drug Anal. 2018;26(2S):S12-S25.Robertson et al. Curr Med Res Opin. 2008;24(2):591-9.

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Conflicting CYP3A4 effects

• Many natural medicines have shown conflicting effects on CYP enzymes and other metabolic pathways• Variability in formulation and content of different natural products (plant part

used, extraction methods, etc.)• Different PK study designs (dosing regimen, ROA, population)

• For example, studies using different extracts of echinacea, milk thistle, and Panax ginseng report conflicting effects on CYP3A4 substrates

Choi, et al. Pharmaceutics. 2020 Dec 30;13(1):43. Rombola, et al. Life (Basel). 2020 Jul; 10(7): 106.

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Consequences of Herb-Drug Interactions

• Serious adverse events (bleeding, arrhythmia, stroke)• Reduced effects of drug therapy

• E.g. Transplant rejection due to reduced effectiveness of immunosuppressant tacrolimus (CYP3A4 induction)

• Drug toxicity • E.g. Excessive dizziness and increased fall risk (additive sedative effects)

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Q: Which fruit beverage might decrease the effects of atenolol? • A) Apple juice • B) Cranberry juice• C) Goji berry juice• D) Grape juice

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Multivitamins Marketed to Older Adults• Which ingredients could be problematic in this MVM?

SOURCE: https://dsld.od.nih.gov/dsld/docs/230990.pdf

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Natural Medicinesfor Physical Function in Older Adults

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Supplements for Age-Related Muscle Loss

• Endogenous molecule made of the amino acids L-arginine, glycine, and L-methionine and found in muscle• Doses of 0.1 grams/kg or 3-10 grams daily for 7-14 weeks, combined

with resistance training• Modestly improves muscle strength and performance in older adults

• To be consumed with plenty of water, to prevent dehydration• Caution in kidney disease

Candow, et al. Nutrients. 2021 Feb 26;13(3):745..

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• Hydroxymethylbutyrate (HMB)• Metabolite of the amino acid leucine • Calcium-HMB up to 3 grams daily for up to 24 weeks along with resistance

training• Modest or low benefit for muscle gain in adults aged 50 to 80 years

• No known interactions or safety concerns

Courel-Ibanez. Nutrients. 2019 Sep 3;11(9):2082.

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• Protein isolated from milk• Beneficial for muscle strength and function when used with exercise, but

unclear if adds benefit to exercise alone• 20-35 grams three times weekly for 12 weeks with resistance exercise• No known safety concerns• May interfere with absorption of certain drugs like levodopa and quinolones

Courel-Ibanez. Nutrients. 2019 Sep 3;11(9):2082.

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Natural Medicinesfor Cognitive Health in Older Adults

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Natural Medicines for Cognitive Health

• Derivative of the amino acid L-carnitine• Limited research suggests improved memory in older adults

• Unclear if helps to prevent cognitive decline or dementia • No known interactions, well tolerated up to 3 grams/daily

Pennisi et al. Nutrients. 2020 May 12;12(5):1389.

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• Potential acetylcholine precursors• Citicoline• Phosphatidylserine• Phosphatidylcholine

• Limited evidence of benefit • No notable safety concerns

Alvarez, et al. Methods Find Exp Clin Pharmacol. 1997 Apr;19(3):201-10.Crook, et al. Neurology. 1991 May;41(5):644-9.

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• Tree native to China• Ginkgo leaf extract (EGb761) 240 mg daily for up to 6 months modestly

improves cognition and physical function in patients with dementia• Ginkgo given for 2-3 weeks may inhibit platelet aggregation (conflicting

studies)• Frequently adulterated: use supplements verified by a third party (e.g.

USP, NSF)

Aruna et al. Br J Clin Pharmacol. 2007 Mar;63(3):333-8.Farina et al. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854.

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• Other examples of natural medicines marketed to prevent cognitive decline, with weak or negative evidence of benefit:

• Vitamin E• B vitamins• Green tea extract• Panax ginseng• Prevagen (apoaequorin)

McCleery, et al. Cochrane Database Syst Rev. 2018;11(11):CD011905.Moran, et al. Adv Mind Body Med. 2016;30(1):4-11.

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Natural Medicinesfor Heart Health in Older Adults

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Supplements for Heart Health

• No strong evidence for primary or secondary prevention of CVD• Effective for lowering triglyceride levels

• 2-4 grams of prescription fish oil• Fish oil supplements: inconsistent and low amounts of omega-3 fatty acids, need to

take up to 12 capsules daily to achieve Rx dose

• Well tolerated, mild GI effects• Higher doses (3-10 grams or more) rarely reported to increase bleeding risk

Skulas-Ray, et al. Circulation. 2019 Sep 17;140(12):e673-e691.

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• Endogenous cofactor for metabolism and energy• Limited evidence: CoQ10 30-300 mg daily for up to two years might

improve heart failure severity • No known safety concerns• Vitamin K-like activity may antagonize warfarin effects; further research

is needed to confirm

Ge et al. Evid Based Complement Alternat Med . 2014;2014:957362.Mortensen et al. JACC Heart Fail. 2014 Dec;2(6):641-9.

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• Other examples of natural medicines marketed for heart health, but no convincing evidence of benefit:

• Artichoke leaf extract• Garlic• Hawthorn berry extract• Niacin and derivatives (niacinamide, inositol nicotinate)• Pomegranate

Ge et al. Evid Based Complement Alternat Med . 2014;2014:957362.Mortensen et al. JACC Heart Fail. 2014 Dec;2(6):641-9.

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Which supplement is commonly used for heart health? • A. Creatine• B. Fish Oil• C. Ginkgo• D. HMB

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Summary

• Just because something is natural does not mean it is safe• Older adults may be especially vulnerable• Natural products have a broad range of biological activity• Product quality is often unknown

• Dietary supplements may benefit some populations, but the evidence is always changing• Evidence is often low-quality or may not exist

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Resources

• DSLD. https://ods.od.nih.gov/Research/Dietary_Supplement_Label_Database.aspx• Natural Medicines. https://naturalmedicines.therapeuticresearch.com/

• NHANES. https://www.cdc.gov/nchs/nhanes/index.htm

• ODS Supplement Fact Sheets. https://ods.od.nih.gov/factsheets/list-all/

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https://ods.od.nih.gov/Research/Dietary_Supplement_Label_Database.aspx

https://naturalmedicines.therapeuticresearch.com/

https://www.cdc.gov/nchs/nhanes/index.htm

https://ods.od.nih.gov/factsheets/list-all/

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