herbal and natural medicines: what you should know mandy leonard, r.ph., pharm.d., bcps drug...

Herbal and Natural Medicines:What You Should Know

Mandy Leonard, R.Ph., Pharm.D., BCPS

Drug Information Specialist

Department of Pharmacy

The Cleveland Clinic Foundation

April 2004

Objectives• Review the reasons why people are using herbal/

alternative medicines.• Describe risks from the consumption of herbal/

alternative medicines.• Describe briefly changes in law regarding dietary

supplements.• Discuss commonly used dietary supplements, including

herbal medicines.• Review reputable sources of information regarding

herbal/alternative medicines.

Introduction

• Definitions– Food and Drug Administration (FDA)– World Health Organization (WHO)

• Homeopathy

• Over 20,000 herbal and other natural products available in the United States.

• Economics

• Widespread use

Top-Selling Herbs in Mainstream Market in U.S. 2001

• Gingko ($46)• Echinacea ($40)• Garlic ($39)• Ginseng ($31)• Soy ($28)• Saw Palmetto ($25)• St. John’s wort ($24)• Valerian ($12)

• Cranberry ($11)

• Black cohosh ($10)• Kava kava ($ 9)• Milk thistle ($ 7)• Evening primrose ($ 6)• Grape seed ($ 4)• Bilberry ($ 4)• Yohimbe ($ 2)

($ in millions; Herbalgram 2002;55:60.)

Top-Selling Herbs in Mainstream Market in U.S. 2002 ( 13.9%)

• Garlic ($34)• Ginkgo ($32)• Echinacea ($32)• Soy ($28)• Saw Palmetto ($23)• Ginseng ($21)• St. John’s wort ($15)• Black cohosh ($12)

• Cranberry ($11)

• Valerian ($ 8)• Milk thistle ($ 7)• Evening primrose ($ 7)• Kava kava ($ 6)• Bilberry ($ 3)• Grape seed ($ 3)• Yohimbe ($ 2)

($ in millions; Herbalgram 2003;58:71.)

Herbal versusConventional Medication

• Disappointment with current conventional therapies

• Fear of safety and long-term effects

• Lack of effective treatments/cures

Herbal versusConventional Medication

• Belief that herbal products are safe because derived from nature

• Peer influence

• Desire to have control of one’s own health

• False claims from manufacturers

Safety Considerations

• Forty to 70% of patients do not inform physicians about use of alternative therapies

• Adverse reactions

– One or more chemical component of the plant

– Inappropriate or incorrect manufacturing process

– FDA does not require reporting of adverse reactions from alternative therapies (MedWatch and SN/AEMS)

– Examples: L-tryptophan, ephedra (ma haung)

Safety Considerations

• Standardization– Nomenclature and chemical constituents vary– Mixtures are NOT standardized

• Lack of Good Manufacturing Practices (GMPs)

• Examples: ginseng, ephedra

– Difficult to identify ingredients– Lack of active ingredient– Contamination

Unsafe Herbal TherapiesUnsafe Herbal Therapies

• Licorice– Glycyrrhiza glabra

– Peptic ulcers

– High doses

(pseudoaldosteronism)

– Use no longer than 6 weeks

– Contraindications

– Drug interactions• Digoxin, furosemide

• Ephedra (ma haung)– Ephedra sinica– Anorexiant, decongestant– 1% ephedrine– Palpitations, MIs, death– Maximum recommended

dose: 100 mg/24 hours– Contraindications– Drug interactions

• Theophylline, digoxin, caffeine

Ephedra• Products containing ephedra account for 64% of

all adverse reactions to herbs in the US

• Less than 1% of herbal product sales

• FDA announced ban on 12/30/2003

• After Mid-March 2004, illegal to manufacture or sell dietary supplements that contain ephedrine and related alkaloids

• Does not include teas

Kava (Piper methysticum)

• Anxiety, stress, sleep disorders (kavapyrones)• May be effective for short-term treatment of anxiety

(similar to Valium® and Ativan®)• Hepatoxicity: liver failure and liver transplantation

– FDA warning; Canada and some European countries- market removal

– Kava dermopathy

• Use no > 4 weeks; no alcohol/sedating medications; caution when driving or operating heavy machinery

FDA Proposed Labeling and Manufacturing Standards

• Designing/construction of physical plants• Establishing quality control procedures• Testing manufactured dietary ingredients and

supplements– Five out of 18 soy or red clover-containing products

• Only 50 to 80% of declared isoflavones

– Niacin

• Almost 10 times more niacin

– Folic acid

• Only 35% of what was stated on label

United States Pharmacopeia (USP) Dietary Supplement

Verification Program (DSVP)

ConsumerLab.com

NSF International

Potential Warfarin-Herb Interactions

• Ginger– Additive effect

– Avoid supplements, but small amount in diet should not be problematic

• Garlic– Additive effect

– Avoid supplements, but small amount in diet should not be problematic

• Feverfew– Additive effect

– Monitor or avoid

• St. John’s Wort– Increased metabolism &

decreased effect of warfarin

– Monitor or avoid

Consumer Survey• Herbal use, products, and willingness to inform health care

practitioners

• 794/1300 surveys returned

– 42% (n=330): Herbal product use

– Common herbal products (aloe, garlic, ginseng, echinacea, and St. John’s wort)

– Women (majority)

– Higher education (75%)

– Herbal users = more prescription medications

– Herbal users = negative perception of prescription medications

Pharmacother 2000;20(1):83-7

Laws and Regulations

• 1994- Dietary Supplement Health and Education Act (DSHEA)– Definition (dietary supplements not categorized

as food additives) • Premarketing approval

– Burden of proof that product is adulterated or unsafe rests on the FDA (e.g., ephedra)

– “Third-party Literature” • Balanced view of available data

– Structure/Function Statements

Structure/Function Statements

• “This product is not intended to diagnose, treat, cure or prevent a disease.”

• Change in definition of disease

• Examples: – Absentmindedness and hair loss associated with

aging – Hot flashes– Premenstrual syndrome

Herbalgram 2000;48:32-8

Ginkgo (Ginkgo biloba)

– Leaves of the ginkgo biloba tree– Distinct chemical components

• Work synergistically

– Improves blood flow (brain and heart)– Protects against oxidative damage from free

radicals (antioxidant)– Inhibits effects of platelet activating factor (PAF)

Ginkgo: Efficacy• Data demonstrate ginkgo leaf extract can

stabilize or improve some measures of cognitive function and social functioning in patients with multiple types of dementia.

• No direct comparisons to conventional medications for dementia.

• Modestly improve visual memory and speed of cognitive processing in non-demented patients with age-related memory impairment.

Ginkgo: Adverse Effects &Drug Interactions

• Adverse Effects:– Hypersensitivity reactions, gastrointestinal

disturbances– Spontaneous bleeding (few case reports)

• Drug Interactions:– Anticoagulants (Coumadin®)– Antiplatelets (aspirin, Plavix®, Ticlid®)– Insulin

Ginkgo: Dose and Administration

• Standardized: 24% flavone glycosides and 6% terpenoids (leaf extract)

• Dementia:– 120 to 240 mg ginkgo leaf extract administered

orally in two or three divided doses

Ginkgo: Summary

• Mild-to-moderate vasoactive agent

• Data promising in Alzheimer’s Disease

• Used extensively in Germany

• No comparison to standard of care

• Well-tolerated (weeks to 1 year)

• Potential drug-herb interactions with anticoagulants, antiplatelets, and insulin

Ginseng• Each type of ginseng is unique

– Asian or Oriental ginseng (Panax ginseng)– Siberian ginseng (Eleutherococcus senticosus)– American ginseng (Panax quinquefolius)

• Active ingredients: Root (panaxosides)• Ginsenoside Rb-1

– Central nervous system depressant– Lowers blood pressure

• Ginsenoside Rg-1– Central nervous system stimulant– Raises blood pressure

Panax Ginseng: Efficacy

• Data demonstrate possibly effective:– Improving abstract thinking, selective memory, and

mental arithmetic skills (more effective in conjunction with ginkgo biloba leaf extract)

– Improving resistance to stress– Controlling blood glucose levels in people with

non-insulin dependent diabetes (Type 2)

• Possibly ineffective for enhancing athletic performance in healthy, young adults

Panax Ginseng: Adverse Effects & Drug Interactions

• Adverse Effects:– Nervousness, insomnia, excitation, palpitations,

affects blood pressure, lowers blood glucose, alters immune functiom

– Ginseng abuse syndrome? (long-term use)

• Drug Interactions:– Antidiabetic agents– Warfarin (Coumadin®)

St. John’s Wort (Hypericum perforatum)

• Common forms: capsules, tablets, tinctures

• Source:– Flowering tops– Naphthodianthrones (one of many potential active components)

• Hypericin - Inhibits MAOA > MAOB

• Hyperforin: Modulates effects of serotonin

– Serotonin inhibition at high concentrations– Norepinephrine inhibition– Catechol-O-methyl-transferase (COMT) inhibition

St. John’s Wort: Efficacy

• For the treatment of mild-to-moderate depression, data demonstrate that St. John’s wort is:– Superior to placebo– As effective as low-dose tricyclic antidepressants

(TCAs; Elavil® and Pamelor®),– Possibly as effective as selective serotonin

reuptake inhibitors (SSRIs; Prozac®, Zoloft®, Celexa®, and Lexapro®)

St. John’s Wort: Adverse Effects & Drug Interactions

• Adverse Effects:– Sun-exposure: Photosensitivity/Phototoxicity (hypericin

component; watch if taking antibiotics)

– Insomnia, vivid dreams, headache, dizziness

• Drug Interactions:– MAOIs, selective serotonin reuptake inhibitors (SSRIs), Imitrex®,

tramadol (Ultram®): Increased serotonin

– Cyclosporine (Neoral®): Decreased levels

– Warfarin (Coumadin®): Decreased INR (lab test)

– Oral contraceptives or hormone replacement therapy: Breakthrough bleeding

St. John’s Wort: Dose and Administration

• Standardized extract– 0.3% hypericin– 5% hyperforin

• Mild-to-moderate depression:– 300 mg

• Administed orally three times a day

– Doses of 1200 mg/day have also been used

Echinacea (Echinacea angustifolia, pallida, purpurea)

• Common Forms: tablet, juice, tea

• Purple coneflower

• Source: Applicable parts are the roots and above ground parts.

• Pharmacologic action [constituent(s)?]

• Indirect antiviral activity

• Immune system stimulatory effects– Cytokines, monocytes, natural killer cells

Echinacea: Efficacy• Echinacea is possibly effective for

– Reducing symptoms associated with influenza-like upper respiratory infections such as the common cold and flu.

– Evidence suggests reduction in duration and severity of symptoms if started when symptoms are first noticed and used for 7 to 10 days.

• Possibly ineffective for preventing the common cold or influenza when taken prophylactically.

Echinacea: Adverse Effects & Drug Interactions

• Adverse Effects:– Allergic reactions

• ragweed, daisies, marigolds

– Fever, nausea, vomiting, unpleasant taste, and dizziness

– Atopy; more likely to experience allergic reaction

• Drug Interactions:– Immunosuppressants: Interfere with therapy

– Medications used for transplant patients, cancer patients, and patients with multiple sclerosis

Echinacea: Dose and Administration

• Wide variety of doses depending on formulation• Difficulty in standardization (echinacoside, alkamide

content)• Purpurea herb juice: 6 to 9 mL for 8 weeks• Purpurea crude extract: 2 tablets administered orally

three times a day• Tea: 5 to 6 cups on day 1 of symptoms, then 1 cup/day

for 5 days

Echinacea: Summary

• Formulation/species that offer most benefit is unclear.

• E. purpurea pressed juice or E. pallida root extracts at first sign of cold

• If taken greater than 8 weeks– Reduced immunostimulatory effects?– One week drug holiday (not substantiated)

• Well-tolerated (up to 12 weeks)

Dietary Supplements:Immune-Stimulating Properties• Alfalfa• Panax ginseng• Astragalus• Cat’s claw• Coenzyme Q10• DHEA• Echinacea• Garlic

• Goldenseal• Grape seed extract• Melatonin• Siberian ginseng

Dietary Supplements-Potential Interaction with Steroids

• Aloe• Asian (Panax) ginseng• Bayberry• Licorice

Herbal Use in Patients Undergoing Surgery

• Approimately 26% of patients scheduled for surgery use herbal products– Cardiovascular instability– Prolongation of anesthesia/sedation– Bleeding– Electrolyte disturbances– Immunosuppression

Anaesthesia 2002;57:889-99

Discontinuation of Use Before Surgery• Echinacea

– No data

– Immunosuppression

• Ephedra (ma huang)– 24 hours

– Cardiac cautions

• Garlic– 7 days

– Bleeding

• Gingko– 36 hours

– Bleeding

• Ginseng– 7 days

– Hypoglycemia; Bleeding

• Kava– 24 hours

– Sedation

• St. John’s Wort– 5 days

– Drug-herb interactions

• Valerian– No data

– SedationJAMA 2001;286(2):213

Herbal References

• Natural Medicines Comprehensive Database– $92/year (book or web version)– $132/year (book and web version)

• The Review of Natural Products– $160/year (bimonthly updates)

• The Professional’s Handbook of Complimentary and Alternative Medicine– $40/edition

Natural Medicines Comprehensive Database

The Review of Natural Products

Herbal Medicine: Expanded Commission E Monographs

PDR for Herbal Medicines

American Botanical Council (ABC)

Herbal References

• The United States Pharmacopeia and The National Formulary (USP-NF)– $526/edition– 21 botanical monographs (since 1995)

• Internet Reference– The Natural Pharmacist (www.tnp.com)

• Conditions

• Drug Interactions

• Review of published articles

• Search

Herbal References

• The Herbal Internet Companion – Herbs and Herbal Medicine Online– $20 (ISBN 0-7890-1052-6)

IBIDS Database

• International Bibliographic Information on Dietary Supplements– Office of Dietary Supplements (ODS) at the NIH– Published, international, scientific literature

• Vitamins, minerals, and botanicals

– Over 676,000 unique scientific citations abstracts– Three databases

• Full IBIDS database

• Peer-Reviewed Citations Only database

• IBIDS Consumer database

CARDS Database

• Computer Access to Research on Dietary Supplements– Office of Dietary Supplements (ODS) at the NIH– Specific mandates from the DSHEA– Federally funded research projects pertaining to

dietary supplements– Free of charge– www.ods.od.nih.gov

Summary• Tell physician, nurse, and pharmacist about

herbal therapy use (documentation)

• “Natural” does not mean safe

• Herbal-pharmaceutical interactions do occur

• Lack of standardization (variability in herbal content and efficacy among manufacturers)

• Lack of quality control and regulation (contamination and misidentification)

Conclusions• Because of lack of efficacy and toxicity

information, patients and clinicians should be aware that advice about herbal therapies is not absolute and is a matter of judgment.

• Base advice on available knowledge that is congruent with your needs and the clinician’s best judgment

• Majority of recommendations are NOT evidence-based