Pharmacology Unit 1 Page 1 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Learning goals for this file:

1) FDA involvement 2) Consumer issues 3) Professional issues 4) Herbals in “mainstream” (traditional) medicine 5) Commonly used herbals

a. Focus on toxicity of commonly used herbals b. Focus on drug interaction potential for commonly used herbals

Note: as we progress through the term, herbal and other alternative remedies for different conditions will additionally be discussed for that content. Note: this is not intended as a complete compendium of herbal and nutritional supplement therapy information; this is an introduction to the topic, with major/common agents discussed to highlight the importance of taking a good OTC history and considering these products as clinically relevant in various healthcare settings.

Pharmacology Unit 1 Page 2 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

COMPLEMENTARY & ALTERNATIVE MEDICINE (CAM): • CAM is a group of diverse medical and health care systems, practices, and products that

are not generally considered part of conventional medicine. • Definitions:

o Complementary medicine is used together with conventional medicine, usually with different providers

o Alternative medicine is used in place of conventional medicine. o Integrative medicine combines conventional and CAM treatments for which there is

evidence of safety and effectiveness, usually from the same provider. CAM for what diseases/conditions?

• See: http://www.nih.gov/news-events/news-releases/nationwide-study-reports-shifts-americans-use-natural-products

• Fish oil was the top for adults & children

See: https://nccih.nih.gov/research/statistics/2007/camsurvey_fs1.htm#therapy

Pharmacology Unit 1 Page 3 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

NUTRACEUTICALS – NUTRITIONAL SUPPLEMENTS & FOODS: • Food, or parts of food, that provide medical or health benefits, including the

prevention and treatment of disease. o may include herbals (plant derived), vitamins, other supplements

• NIH has the Office of Dietary Supplements: http://ods.od.nih.gov/ • NIH has the Dietary Supplement Label Database (DSLD):

http://www.dsld.nlm.nih.gov/dsld/ Examples of Dietary Supplements including botanicals (herbals): • Vitamins, minerals, co-enzyme Q, carnitine • Ginseng, Ginkgo Biloba, Saint John's Wort, Saw Palmetto WHAT ARE “MEDICAL FOODS”?? These are NOT considered food supplements • Read about it at this link:

http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/MedicalFoods/ucm054048.htm

o A medical food, as defined in section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)), is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”

o A medical food is prescribed by a physician when a patient has special nutrient needs in order to manage a disease or health condition, and the patient is under the physician's ongoing care. The label must clearly state that the product is intended to be used to manage a specific medical disorder or condition.

o An example of a medical food is a food for use by persons with phenylketonuria, i.e., foods formulated to be free of the amino acid phenylalanine

o Medical foods are not those foods included within a healthy diet intended to decrease the risk of disease, such as reduced-fat foods or low-sodium foods, nor are they weight loss products.

• Now being marketed more aggressively – they have an advantage over dietary supplements

o Dietary supplements CANNOT claim to treat a medical condition o Medical foods CAN claim to treat a medical condition

• Examples: o flavocoxid (Limbrel) for arthritis (sounds like a COX-2 inhibitor but it isn’t) o Phenyl-free-1 for PKU babies o Pro-Phree for celiac disease o Ketonex-1 for maple syrup disease o Transgenic plants (genes from another species have been placed in the plant

food source) such as vaccine manufactured in the plant to provide oral vaccination

o • Note that these products actually have their own NDC number (unique drug identifier

number assigned by the FDA), like any other drug

Pharmacology Unit 1 Page 4 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

NUTRITION AS PART OF THE THERAPEUTIC REGIMEN: • Preventive nutrition maintains a healthy body & prevents illness. • Prescribed nutrition is designed to help cure illness and alleviate symptoms

o If you PRESCRIBE nutrition, this is written down for charting (& also insurance reimbursement purposes) as Medical Nutrition Therapy (MNT)

“FUNCTIONAL FOODS”: examples of some functional foods Omega-3 fish oil: Useful in prevention of heart disease May slow rate of visual acuity decline in retinitis pigmentosa (see:

http://www.ncbi.nlm.nih.gov/pubmed/15364709 ) If taken prenatally may reduce asthma/wheezing in offspring (see:

http://www.nejm.org/doi/full/10.1056/NEJMoa1503734 ) BUT no benefit in cognitive decline (see: http://www.nih.gov/news-events/news-

releases/nih-study-shows-no-benefit-omega-3-or-other-nutritional-supplements-cognitive-decline )

Canola oil: may lower triglycerides Plant Stanols: • Available as product (Benecol) • This is “plant cholesterol” and may compete with absorption of animal cholesterol

when eaten with animal sources of food • Thus beneficial in reduction of cholesterol adsorption Dark chocolate:

• possible reduction in CVD and hypertension (see: http://www.bmj.com/content/344/bmj.e3657 )

Cinnamon:

• Dose of 1, 3, or 6 gm daily to reduce glucose, triglycerides, LDL-C and TC • Note – this is a LOT of cinnamon! • Caveat – may reduce blood sugar in insulin-treated diabetics causing hypoglycemia

Soluble fiber:

• Inlcudes oats, bran, psyllium, lignin • May have benefits in preventing heart disease & colon cancer • Benefits in managing irritable bowel syndrome

Pharmacology Unit 1 Page 5 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Prebiotics: Nondigestible nutrients that are used as an energy source by certain beneficial bacteria

that live in human intestines – sometimes called “fermentable fiber” Example:

o Fructo-oligosaccharides (FOS), often used as artificial sweetener since has sweetness levels between 30-5-% of commercial sugar syrups

o called oligofructose or oligofructan o may cause flatulence, but generally recognized as safe (GRAS) 5-10gm/day o Natural Plant Sources of FOS:

Inulin: polyfructose (many plants) bananas, onions, chicory root, garlic, asparagus, barley, wheat, jicama, tomatoes, leeks, Jerusalem artichoke & related Yacon root

Yacon Root: from Peru, claimed to prevent cancer, help gut absorption of vitamins & calcium

Probiotics:

• Naturally occurring bacteria, Lactobacillus & Saccharomyces • Found in active-culture yogurt, buttermilk as well as supplements • Should not be used in those who are immunosuppressed • Common uses:

o Take 2 hours after antibiotic dose to prevent diarrhea o May prevent yeast vaginitis from antibiotics, may benefit gastroenteritis

symptoms, may be of benefit in Non-alcoholic fatty liver disease (NAFLD), may lower LDL-cholesterol similarly to many plant products (e.g., psyllium seed)

WHAT IS A “QUALIFIED HEALTH CLAIM” FOR FOODS? • The FDA has rules regarding the claims that can be made for foods http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/default.htm • Examples of current foods that have such claims are green tea, tomatoes, etc. • List of foods with qualified health claim:

http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073992.htm • Examples:

o Tomatoes & tomato sauce may reduce the risk of some cancers (due to the lycopene)

o Barley at 0.75 gm of fat-soluble fiber or walnuts at 1.5 ounces/day & “part of a low saturated-fat and low cholesterol diet” may reduce cardiovascular disease (see: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108543.htm )

o Omega-3 fatty acids at 2 gm/day can protect against heart disease (see: http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073992.htm#cardio )

Pharmacology Unit 1 Page 6 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

HERBAL MEDICINE – PHYTOMEDICINE (PLANT MEDICINE): • botanicals recognized for medicinal effect – “phyto” means “plant” • may be ingested, inhaled, or massaged into skin • usually differentiate between culinary herbs and medicinal herbs.

o Medicinal herbs are usually considered to be any "useful" plant, that causes recognizable physiologic changes with accompanying symptoms and signs.

• History supports the use of herbs: remember, almost every drug in the traditional, allopathic pharmacopeia was originally derived from a botanical.

• Pharmacologic progress caused less use of herbs: usually, purification & chemical alteration of the original substance achieved the desired physiological outcome without the adverse effects seen with the unmodified botanical.

• Current thinking returns the use of herbs: since most botanicals are mixtures of many (sometimes unidentifiable) substances, this purification and modification may cause a reduction in the range of usefulness of the final product.

Availability: • OTC (over the counter) • Many are culture specific botanicals used by various cultures for specific cures and

results • European availability is extensive

o one of the first compendiums of herbals was “Commission E” (Germany, 1994) o Many herbals are now prohibited in Europe from OTC availability and must be

prescribed Standardization guidelines: • consistency of batches and individual pills/capsules. • Use reputable manufacturers. • Bottle/container states their name & address, batch/lot number & date of manufacture &

expiration, plant scientific name & plant parts used, processing information (e.g. alcohol extract).

• Standardized extract should be tested to insure the proper plant and plant part was used, and also tested for consistency so that label amounts are verified per batch.

• Removal of impurities (known contaminants such as pesticides, heavy metals, infectious microbes) should be removed during standardization.

• Terms: o USP means there is at least 80% of the amount stated in each cap/tab, &

minimal variability. o GMP (Good Manufactured Product) indicates higher quality standards. FDA

has issued final rule that manufacturing processes must meet this standard • Some Herbalists may not endorse standardization:

o Many herbalists feel that purified product with only one chemical is less helpful than an extract of whole herb.

o Herbalists often feel that the plant source contains therapeutic substances that act synergistically to provide increased benefit to the primary ingredient.

Pharmacology Unit 1 Page 7 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

“Taste Doesn’t Lie” • Many herbs that taste similar, although the plants may be unrelated, contain similar

substances and may be recommended for use in similar ways. • Example:

o licorice (Glycyrrhiza glabra), fennel (Foenicululm vulgare) and anise (Pimpinella anisum) all taste very similar.

o Most of these are used in the area of women's gynecological health & illness (including as abortifacents).

USA:

• USA availability based on classification as a “supplement” and not as drugs o these agents are sold as dietary supplements, under the 1994 Dietary

Supplement Health and Education Act o therefore NOT under complete Food and Drug Administration (FDA)

control • Nutritional supplements only need to "promote" or "maintain" the normal structure

and/or functions of the body – normally, the only claims allowed by law (with some exceptions)

• Governmental agency: o National Institutes of Health (NIH) National Center for Complementary and

Alternative Medicine (NCCAM) underwent a NAME CHANGE to the National Center for Complementary and Integrative Health (NCCIH)

o This was mainly started as a research area, now starting to provide some information directly applicable to consumers – focus is still on research

o https://nccih.nih.gov/ • FDA Consumer Information for Foods & Dietary Supplements:

o to encourage makers of foods and dietary supplements to make science-based health claims about their products.

o Fraudulent product list: http://www.accessdata.fda.gov/scripts/cderworld/index.cfm?action=compliance:main&unit=5&lesson=2&topic=5

o The Center for Food Safety and Applied Nutrition (CFSAN) is part of the FDA: http://www.fda.gov/Food/DietarySupplements/default.htm

Why do US adults use herbal supplements and products? Nice overview article in JAMA (2013): http://archinte.jamanetwork.com/article.aspx?articleid=1568520

Pharmacology Unit 1 Page 8 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

National Center for Complementary and Integrative Health (NCCIH)(formerly NCCAM): • National Center for Complementary and Alternative Medicine (NCCAM) and the National

Center for Health Statistics (part of the Centers for Disease Control and Prevention) • Findings are from the 2007 National Health Interview Survey (NHIS), an annual in-person

survey of Americans regarding their health- and illness-related experiences • Information on 23,393 adults aged 18 yo or older and 9,417 children aged 17 yo and

under

2007 data is the most current: https://nccih.nih.gov/research/statistics/2007/camsurvey_fs1.htm • CAM use among adults is greater

among women and those with higher levels of education and higher incomes.

• Nonvitamin, nonmineral natural products are the most commonly used CAM therapy among adults.

• Use has increased for several therapies, including deep breathing exercises, meditation, massage therapy, and yoga.

Pharmacology Unit 1 Page 9 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

What FDA “oversight” (regulation) exists over these nutraceuticals? • Dietary supplements are a subset of “foods” under the Dietary Supplement Health &

Education Act (DSHEA, 1994) http://ods.od.nih.gov/about/dshea_wording.aspx • The FDA determines if a product is “GRAS“ (Generally Recognized As Safe)

o Named in the Federal Food, Drug, and Cosmetic Act which covers substances subject to premarket review and approval by FDA

o The substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use

• Possible contamination (FDA can pull product from the market) o Example: ginseng warning due to pesticide contamination (FDA pulled product

from market) http://www.fda.gov/Food/FoodborneIllnessContaminants/Pesticides/ucm125185.htm Active drug ingredients in herbal preparations (that were removed from market by FDA)

o Example: Cholestin from Chinese red yeast (600 mg qid), actual drug here is lovastatin (same as the drug Mevacor; note that three of the marketed statins are natural derivatives of yeast); lowers TC & LDL-C. Consider that this has the same same liver effects as statin drugs, possibly similar interactions.

o Example: Vinarol marketed as a sexual stimulant. Included sildenafil (Viagra) and thus posed a potentially life-threatening risk to those taking nitrate medications.

o Example: Nature’s Youth hGH destroyed product due to false claims on label (claimed to stimulate the body’s natural production of Human Growth Factors and Insulin-Like Growth Factor-1).

o example: Actra-Rx or Yilishen, two products promoted and offered for sale on Web sites as "dietary supplements" for treating erectile dysfunction and enhancing sexual performance for men…contained an active prescription drug ingredient…sildenafil (Viagra)

o example: Liqiang 4 sold as a dietary supplement – contained glyburide (oral hypoglycemic)

o example: Snurf (promoted as a “pleasure herb”) contained high doses of dextromethorphan (DXM)

• Concern over undue toxicity o Example: Ma Huang (Ephedra) is natural ephedrine from plants & promoted for

weight loss, as an ergogenic aid (enhance athletic performance), increased energy. Banned for sale in USA due to unreasonable risk of injury or illness.

• Non-allowed advertising o Law specifies the language used in advertising of herbals and supplements o Many manufacturers use their brand-name recognition factor to emphasize

safety and standards o The FDA will allow language like “supports” or “promotes”

Example: "tension & mood" remedy containing St. John's wort. o Recently, the FDA has allowed some herbals and supplements to make claims

for actual risk reduction or treatment of illness Example: whole grain barley and barley-containing products that

contain at least 0.75 grams of soluble fiber per serving qualify for the health claim on their labels as being able to reduce the risk of coronary heart disease (CHD).

Pharmacology Unit 1 Page 10 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

What are “homeopathic” medications? • NCCIH overview: https://nccih.nih.gov/health/homeopathy • regulated by FDA similar to OTC drugs – no prescription needed • the label must list ingredients, dilutions, and instructions for safe use • the manufacturer can make claims regarding treatment benefit (unlike herbals) • From NCCIH:

o “The term homeopathy comes from the Greek words homeo, meaning similar, and pathos, meaning suffering or disease. Homeopathy seeks to stimulate the body's ability to heal itself by giving very small doses of highly diluted substances. This therapeutic method was developed by German physician Samuel Christian Hahnemann at the end of the 18th century. Hahnemann articulated two main principles:

o The principle of similars (or "like cures like") states that a disease can be cured by a substance that produces similar symptoms in healthy people. This idea, which can be traced back to Hippocrates, was further developed by Hahnemann after he repeatedly ingested cinchona bark, a popular treatment for malaria, and found that he developed the symptoms of the disease. Hahnemann theorized that if a substance could cause disease symptoms in a healthy person, small amounts could cure a sick person who had similar symptoms.

o The principle of dilutions (or "law of minimum dose") states that the lower the dose of the medication, the greater its effectiveness. In homeopathy, substances are diluted in a stepwise fashion and shaken vigorously between each dilution. This process, referred to as "potentization," is believed to transmit some form of information or energy from the original substance to the final diluted remedy. Most homeopathic remedies are so dilute that no molecules of the healing substance remain; however, in homeopathy, it is believed that the substance has left its imprint or "essence," which stimulates the body to heal itself (this theory is called the "memory of water").”

• Safety of homeopathics: o Due to the HIGH dilutions, thus actually very small amounts of product being

administred, usually there are no adverse reactions o However, may still contain toxix; o Example: 2010 FDA recall of Hyland’s Teething Tablets due to belladonna

toxicity http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230761.htm

Pharmacology Unit 1 Page 11 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Common provider concerns regarding CAM: • Herb-drug interactions: these are active chemical substances, with their own

pharmacokinetics – thus, potential for herb-drug interactions o POTENTIATION OF WARFARIN (ANTICOAGULANT EFFECT) with increased

INR and bleeding risk o reduced levels of co-administered therapeutic drugs (if the herbal is a CYP

inducer) o increased levels of co-administered therapeutic drugs (if the herbal is a CYP

inhibitor) • Unwanted toxicity.

o pleiotropic effects confuse their efficacy and prevent reliable prediction of toxicity. They may have effects on the nervous system, hematopoietic system, CNS, etc., as well as numerous drug-drug interactions.

o Example: in some Latino cultures, anise tea has been used to induce abortion in unwanted pregnancy (abortifacient). But, the therapeutic dose also causes renal failure.

• Issues of purity, contents, dose-to-dose variability, contaminants, labeling: o No guarantee of purity, dosage, sterility, or even contents as labeled o both US & Indian Ayurvedic medicines contain lead, mercury & arsenic o Example: One brand of Dolomite, a calcium supplement, was found to have

arsenic impurities on testing, since other metals are often found when gathering calcium from earth sources

• Knowledge deficit: lack of provider knowledge regarding herbals • Evidence base:

o scientific rationale for use of drugs usually rests with results of placebo-controlled, double-blind, population matched clinical trials.

o However, many (most) of the clinical trials that have tested herbal and other "natural" or "supplement" products use a different kind of trial, called open-label, in which the patient and the research team are aware of what drug/product they are receiving which may confound results by an enhanced placebo effect.

o Also, these “herbal trials” are often conducted with very small subject samples (poorly powered), reducing the statistical validity of conclusions.

• Other: o inconsistent effects in treated individuals. o usually, the therapeutic effect takes longer to develop than with traditional drug

therapy.

Pharmacology Unit 1 Page 12 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Provider responsibilities concerning CAM: • Part of the Clinical Drug History:

o Using herbs and all other OTC products? o Using prescribed medications (Rx by whom? Why? For how long?)? o What medications are you SUPPOSED to be taking (adherence)? o Check for safety and drug-drug interactions with ALL

• Continuing Pharmacology education: o awareness of commonly used products/herbs, ability to evaluate standard

herbal supplements (see below) • Common scenarios:

o Expert advice: patients seek our recommendations regarding use. o Drug interactions: we may be prescribing or administering drugs that interact

with the herbal (e.g., chamomile tea may interact with cyclosporine) o Unusual clinical presentations may alert us to the use of herbal and other

OTC products. Examples include clinical presentations such as urticaria (hives), asthma, other allergic phenomena, HTN, CNS changes.

o Food allergies may be exacerbated due to cross reactions with herbals (more in this Unit – example is Chamomile tea causing allergic reaction in those allergic to daisies, ragweed, etc.).

o Pregnant or Nursing women and children: • Most herbs have not had their safety established for women who are

pregnant or nursing, or in children • Especially worrisome (due to known toxicities): aloe (ingested), black

cohosh, dong quai, feverfew, ginseng, kava kava, saw palmetto, garlic, ginger (even though used extensively worldwide for emesis gravidarum), St. John's wort, valerian.

• Remember to check NCCIH o Example for chamomile as mentioned above:

https://nccih.nih.gov/health/chamomile/ataglance.htm o (I’m not “picking on” chamomile – I use it myself sometimes… but I don’t have

hayfever and I don’t take cyclosporine for an organ transplant)

Pharmacology Unit 1 Page 13 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

HERBS THAT MAY HAVE COAGULATION EFFECTS: 1. Anticoagulants:

• Those with Coumarin-like Compounds: Angelica (root of the Holy Ghost), Anise, Asafoetida, Dong Quai, alfalfa, arnica (wolf's bane), boldo, feugreek, horseradish, licorice, toothache bark (northern prickly ash), passionflower, quassia (bitterwood), red clover, roman chamomile, sweet clover, sweet vernalgrass, tonka bean, wild carrot, wild lettuce.

• Those with anti-platelet action: willow bark, onion, papain, poplar, safflower, clove, danshen, feverfew, licorice, meadowsweet, black cohosh, aspen, borage seed oil, bromelain, capsicum, celery. Also Vitamin E (alpha-tocopherol)

2. Coagulants:

• Those with Vitamin K activity: agrimony, alfalfa (both coagulant and anticoaguant !), plaintain, stinging nettle.

• Those with other coagulant acitivity: yarrow (wound wort), goldenseal, mistletoe.

3. This is one of the MOST common issues with herbals!!

• Some sort of coagulation effect (causing bleeding or clotting) • Or, interaction with coumadin, affecting coumadin dosage needs

GOLDENSEAL — THE URBAN LEGEND!! • Weak antiseptic properties due to alkaloids hydrastine, berberine • Claimed usefulness:

o To treat just about everything — infections in the sinuses & bladder, cholecystitis, cirrhosis, skin & eye irritations

o May be able to treat Chlamydia, Giardia, and Trichomonad infections o It may keep Strep A from adhering to epithelial cells o Most studies indicate these actions are very weak

• URBAN Legend: o people believe that this herb will mask a positive urine test for illicit drugs – this

is NOT true o may be why herb remains so popular!!

• Toxicities: o hyperreflexia, hypertension, convulsions, death from respiratory failure o AND it is an abortifacient

Pharmacology Unit 1 Page 14 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

SOME HERBALS & SUPPLEMENTS COMMONLY USED IN TRADITIONAL MEDICINE: • accepted use of herbal components in mainstream medical prescribing • some with FDA approval. Medical Uses of Nicotine: • Smoking cessation: patches, gums & nasal sprays. • ?? Beneficial effects:

o There is an inverse relationship of smoking & the development of uterine fibroids, uterine cancer, & endometriosis.

o But not Alzheimer’s disease, as previously thought • Possible treatment indications:

o Helpful in managing cocaine withdrawal: modulation of the dopamine/reward system (brain) helps relieve cocaine cravings.

o MAY be helpful in improving attentional focus (cognition) in ADD/ADHD, bipolar disorder (manic depression), schizophrenia, and autism

o MAY control Tourette's symptoms o MAY be helpful in treatment of Crohn’s disease.

Cranberry & Blueberry (Vaccinium species): • Mechanism:

o Theorized to reduce bacterial adhesion (the bacteria can't "hold on" to the urethral or bladder mucosa as well, reducing both UTI & pyelonephritis progression) by preventing the expression of adhesion molecules in bacteria.

• Usefulness: o UTI prevention – but recent trials have been disappointing in preventing pyuria o Blueberry is similarly effective; both these plants require the same growing

conditions (bogs), are often found growing together & belong to the same plant genus (Vaccinium).

• Potential concern: o cranberry contains oxalates, which in some individuals who form oxalate renal

stones, may increase the formation of such stones. o These people should avoid especially the concentrated supplements

• Cranberry juice/fruit or tablets? o Current evidence favors using cranberry juice or fruit, has best effectiveness data

Botulinum Toxin A (Botox and other formulations): • induces muscle paralysis via blockade of Acetylcholine release. • Anal fissure therapy: injection with botulinum toxin helps heal chronic anal fissure &

prevent recurrence. • Cosmetic dermatology: injection into the forehead reduces frown lines • Hyperhidrosis: also indicated for axillary hyperhidrosis (excessive sweating) • Other:

o injection to prevent head & voice tremors o relief of contractures (e.g. in stroke and multiple sclerosis patients) o relief of hyperhidrosis (excesssive sweating) with intradermal injections o treatment of blepharospasm o treatment of cervical dystonia

Pharmacology Unit 1 Page 15 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Analgesics & Opiates: • Aspirin:

o from white willow bark as well as meadowsweet (Spirea) o Spirea = gave us the name aspirin from the "spir" of "spirea"

• Opiates: o Opium poppy yields opiates. o The culinary poppy seed will cause a positive drug screen (Jewish hamentashen

cookies!!). Contraceptives: • the Mexican yam (Dioscorea villosa) yielded the initial hormonal components of the first

tested oral contraceptives. • This is NOT the food yam sold in the USA (what your grocery store calls a “yam” is really

a sweet potato) Chemotherapy for Cancer: look out your window. • Vinca (periwinkle): vincristine & vinblastine (breast cancer treatment). • Yew tree: taxol (both the rare Pacific yew and the more common hedge yew). Foxglove (Digitalis): "cardiac tonic" for heart failure (in the past) & cardiac arrhythmias. Chili (Cayenne) peppers (Capsaicin)(Zostrix cream): • naturally derived plant product depletes substance P from skin nerve endings, causing

reduced pain & inflammation. • Usefulness:

o small areas of inflammation in small joints. o Other applications include post-herpetic neuralgia (PHN), RA, DJD, diabetic

neuropathy. • Dose:

o Must be used TID - QID o may need to be used for weeks before effect is noted o can cause severe burning sensation with initial use (resolves with continued use)

Podophyllin (from mandrake, May apple)(podophyllum resin): • from mandrake ( May apple) • MOA: podophyllotoxin (podofilox) binds to cellular microtubules, causing mitotic arrest &

preventing cell replication • Usefulness:

o treat anogenital warts o NOT over large surfaces (systemic toxic absorption) o NOT in the mouth, NOT in pregnancy

• Dosing: o 5% strength for self use at home (Condylox BID x 3 days in weekly cycles o Clinican applied 10-40% directly to wart (do NOT get on skin) o wait 2 hours, then wash WELL; then use HC cream if prone to irritation

• Warning: If taken internally, highly toxic (especially to the CNS & GI systems)

Pharmacology Unit 1 Page 16 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Cantharidin (Cantharone): dried blister beetles (Spanish fly) poisons mitochondria. • from dried blister beetles (Spanish fly) • MOA: poisons mitochondria • Usefulness:

o periungual warts, molluscum contagiosum, verruca vulgaris o Can cause SEVERE BLISTERS

• Dosing: o Paint on digital wart, put ring of petrolatum around medication, & cover with

nonporous plastic tape o Wart involutes in 2 weeks o Re-treat by paring wart and reapplying o GREAT in kids (no needles, no scarring) o But, ring of warts at periphery may develop & may need to re-treat

Evening Primrose Oil (EPO)(black currant seed oil)(borage seed oil): • Also called black currant seed oil & borage seed oil

o low-growing weed o yellow flowers open at night thru the next day

• Claimed usefulness: o fibrocystic mastitis (mastalgia), atopic dermatitis, rheumatoid arthritis, PMS, hot

flashes (rubbed on the skin) o Disappointing clinical trials, although probably beneficial in some dermatoligic

conditions • Active ingredient: essential fatty acids (EFAs) linoleic & gamalinolenic

o Usual Dose: adult (10-12 caps/day), child (4 caps/day) Laxatives: • internally taken aloe, cascara, senna, and ground psyllium seed • Recently, FDA determined that aloe, cascara, & senna are NO longer recognized as

safe for OTC use either alone or in combination products • Final rule: http://www.fda.gov/ohrms/dockets/98fr/050902a.htm • However, sennosides are still sold as laxatives

https://www.drugs.com/cdi/sennosides.html Astringent:

• FDA approved witch hazel for topical use Kratom: (pronounced KRAY-tum)

• Supplement from a tropical tree in the coffee family, active ingredient is mitragynine • MOA: opioid, serotonergic, adrenergic, dopaminergic pathways • Use: for stimulant OR sedative OR euphoria (getting high) – or preventing opioid

withdrawal • Does not show up on toxicology screens for opioids • Many of the same side effects as opioids – constipation, nausea & withdrawal

syndrome • DEA may classify as SCHEDULE I (illicit)

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Zinc Lozenges & the Common Cold: also a nasal gel • nasal gel & oral lozenges; usually combined with Vitamin C • Usefulness:

o RCTs have proven that zinc can reduce the duration & severity of URI symptoms

o also effective when used prophylactically • Dose:

o approx 12 - 13 mg lozenge q 2 - 3 h while awake (80 mg daily) for only 5 days & stop if no improvement after 3 days

• Note: RDA of zinc is 15 mg/day • Warning:

o may cause copper deficiency if taken long-term o Long-term use may also lower HDL-C (the "good" cholesterol) o Excessive intake may raise prostate cancer risk o Loss of sense of smell (intranasal products) o Excessive zinc given to children may cause anemia (sideroblastic and copper

deficiency)

Aloe Vera Gel: inner leaf gel of aloe vera contain polysaccharides. • Internal usefulness claims:

o internal use includes treatment of peptic ulcer, irritable bowel syndrome (IBS), and as a laxative

o previously FDA approved as a laxative, no longer considered safe for OTC use). • Topical usefulness: treatment of burns and dermatitis. • Dosing: 100 mg of solid extract of inner leaf gel with at least 8 oz of water, qd - tid.

o FDA previous approval as a laxative has been revoked o it is approved as a natural food flavoring

• Warning: o do NOT use the outer leaf gel — causes serious cathartic (laxative) effects and

many other adverse effects in higher doses. o Recently in the news – being sold to cancer patients as a bogus cancer cure.

Pharmacology Unit 1 Page 18 of 33

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Green Tea (Camellia Sinensis): • Dried fresh leaf contains theophylline, theobromine, catechins, phenolic acids, terpenoids,

tannins (tannic acid), kunacatechins • MOA unknown – assumed due to anti-oxidant and anti-neoplastic qualities of green tea

catechins • WHEN USED TOPICALLY: tooth extraction and genital warts

o Postop tooth extraction place a moistened teabag on the surgical site to help stop bleeding and organize clot for healing

o FDA-approved two drugs for genital warts o Polyphenon E (15% ointment) & kunacatechins (Veregen 15% ointment) o Apply directly to the genital warts three times daily up to 16 weeks (or stop

when the warts are gone) • When taken internally – claimed usefulness:

o Lowers cholesterol & BP, is anti-platelet, promotes diuresis o Reduces risk of stroke o "Anti-" everything (cancer, caries, bacterial) o Dietary intake of tea may reduce risk of ovarian cancer

• Potential adverse effects: o GI upset and hyperacidity, diarrhea, vomiting, anorexia o Renal damage o Muscle spasm o Anxiety attacks, panic, tremor, palpitations, vertigo, insomnia o May bind to alkaline drugs and prevent their absorption

• Dose: < 5 cups of tea daily as a beverage (< 300 mg caffeine) Medical uses of honey: • Herpes simplex labialis (cold sore):

• Yes, this is the food from bees! • topical application is effective and safe in recurrent herpes labialis and genital

herpes. • Compared to topical acyclovir cream, just as good.

• Medi-honey brand name: • approved by the FDA as a “medical device” dressing for wound healing • from manuka honey • antibacterial and helps with debridement & pain • See: http://www.dermasciences.com/medihoney

Pharmacology Unit 1 Page 19 of 33

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SOME COMMON WESTERN HERBALISM HERBALS & SUPPLEMENTS: • These are often found on store shelves and/or recommended by herbalists for specific

complaints • Some have also reached mainstream medicine (e.g. chondroitin recommended by

orthpedists) Coffee & Tea & Caffeine: • Wakes you up! (methylated xanthine) • Good:

o Lowers coronary disease risk (but tea is better!): http://atvb.ahajournals.org/content/30/8/1665.abstract

o Coffee intake inversely associated with mortality in one study and positively associated with mortality in another study (may be a dose relationship – more than 7 cups per week seemed to increase mortality: http://www.nejm.org/doi/full/10.1056/NEJMoa1112010 VS. http://www.mayoclinicproceedings.org/article/S0025-6196%2813%2900578-8/abstract

o Coffee lowers risk of developing Type 2 DM: http://www.ncbi.nlm.nih.gov/pubmed/19727658 and and http://www.ncbi.nlm.nih.gov/pubmed/24150256 and improved glucose sensitivity in those with T2DM http://www.ncbi.nlm.nih.gov/pubmed/23331476

o Protective against stroke in women? http://stroke.ahajournals.org/content/early/2011/03/10/STROKEAHA.110.603787.abstract

o Improves liver disease: http://onlinelibrary.wiley.com/doi/10.1111/liv.12304/abstract

o Protective against gastric cancer: http://www.ncbi.nlm.nih.gov/pubmed/24608187

o Protective against prostate cancer: http://www.ncbi.nlm.nih.gov/pubmed/24343360

o Improved mortality rate in colon cancer: http://www.dana-farber.org/Newsroom/News-Releases/Drinking-coffee-daily-may-improve-survival-in-colon-cancer-patients.aspx

• Bad: o emerging evidence that it raises the risk of first-trimester spontaneous abortion

and stillbirth http://www.bmj.com/content/326/7386/420.full o coffee, cola, anger, sex, vigorous exercise, nose blowing raise risk of stroke in

those with untreated brain aneurysm: http://stroke.ahajournals.org/content/early/2011/05/05/STROKEAHA.110.606558.abstract

o Coffee intake inversely associated with mortality in one study and positively associated with mortality in another study (may be a dose relationship – more than 7 cups per week seemed to increase mortality: http://www.nejm.org/doi/full/10.1056/NEJMoa1112010 VS. http://www.mayoclinicproceedings.org/article/S0025-6196%2813%2900578-8/abstract

Pharmacology Unit 1 Page 20 of 33

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Echinacea (Purple coneflower, a type of daisy): • Claimed usefulness:

o may stimulate immune function (possibly by helping macrophages). o The root is used to help fight viral infections (& for flu prophylaxis); the leaf is used

for UTI, URI, GI upset. o Polyphenols are supposed to be the active constituent.

• Warnings: o Longterm use of echinacea (> 8 weeks) use may affect the hematopoietic system,

and those persons with autoimmune disease shouldn't take it — may activate or reactivate such illnesses by stimulating the immune system (examples: those with lupus, RA, myasthenia gravis, etc.).

o Potential for cross-reaction hypersensitivity allergic reaction in those persons with daisy or ragweed allergies.

• Dosing: varies (175 mg, bid - tid, or 15-20 drops qid in water). Taken with food. o Most herbalists recommend temporary use when exposed to viral or bacterial

infection, but not taken for more than two months. o Recent evidence that echinacea provides NO benefit in treating common URI

viral illness • Drug interactions:

o may inhibit CYP3A4 raising levels of other drugs and increasing their toxic potential.

Soy Isoflavones: • not just helpful in menopausal management. • Genistein is one of the more common isoflavones, found in soy. More on this in the

Endocrine section. • Skin cancer: found to also be helpful in conditions like skin cancer (photo-aging and UV-

induced skin cancers (genistein applied topically). • Breast cancer prevention?? anti-oxidants may also be anti-mutagenic. • Other isoflavones: studies ongoing.

o One recent with red clover (Promensil) failed to show significant benefit to reducing menopausal symptoms.

• Menopausal management: current ACOG guidelines support the use of soy isoflavones in the management of menopausal vasomotor syndrome (hot flushes) and possibly in protection against menopausal osteoporosis. However, a recent study (HALT) by the NIH failed to show a benefit with soy or any other popular herbals for hot flushes. See: https://www.nih.gov/news-events/news-releases/herbal-supplement-fails-relieve-hot-flashes-large-nih-trial

• Prostate cancer recurrence: no benefit

Pharmacology Unit 1 Page 21 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

DHEA (dehydroepiandrosterone): • This is an adrenal androgen marketed as an "anti-aging" hormone to increase energy,

muscle strength/mass, bone density. • Physiology:

o DHEA is a steroid precursor of both androgens & estrogens; peaks at age 20 y/o, then declines.

o One study indicated greater CV death rates in men with lower DHEA/DHEAS levels.

o May have both immuno-modulating effects as well. • Investigational use:

o Therapy for wasting illnesses, MS, lupus, muscle strength & LBM (lean body mass), extending lifespan

• Approved uses: o Prasterone (Fidelin) approved as orphan drug for Addison’s Disease o Prasterone (Intrarosa) approved as intravaginal treatment for

postmenopausal dyspareunia due to vaginal atrophy • Alternative & Complementary therapy:

o Studies restoring the physiologic level to that of age 20 y/o (50 mg/day) yields results of improved psychologic, sexual, physical well-being & increased IGFs.

o However, other more recent studies refute this benefit • Toxicity & Side effects:

o androgenic effects, possibly irreversible o include hirsutism, voice deepening, adverse lipid impact, gynecomastia in men o lowering of HDL levels o mania may develop

• Drug interactions: o Inhibits CYP3A4, thus increasing levels of other drugs that use this

biotransformation pathway o Examples of interactions: raising levels of carbamazepine (Tegretol), some

statins, some anxiolytics, some H2-blockers. What are “Superfoods”? • Some juices, herbs and algae are sometimes marketed as “superfoods” • Examples:

o JUICES: Noni (morinda, mulberry), acai (pronounced ah-sah-EE, mangosteen (xango), goji, pomegranate

o HERBS: Chia (the same as in “Chia pets”) – mint family (pronounced “chee-ah” o ALGAE: blue-green algae

• Potential benefits: o fiber, calcium magnesium, alpha-linolenic acid (an omega-3), vitamin C

• Some specific concerns: o High in potassium – HOWEVER worrisome if on ACEI, ARB, spironolactone, Yaz

(drospirenone OCP) – or any potassium sparing drug o Possible liver toxicity o Warfarin drug interaction (increased bleeding) o CYP3A4 drug interaction (grapefruit & pomegranate juice) o Alpha-linolenic acid (ALA) can cause worsened triglycerides and possibly increase

prostate cancer risk in some men

Pharmacology Unit 1 Page 22 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

Milk Thistle: active component is silybin (silymarin). • Claimed usefulness: Used in liver illnesses, including hepatitis and cirrhosis. May

protect against liver-toxic drugs. • Dosing: extract standardized for 80% silymarin, take 320 mg qd. One of the few herbs

with no AEs of clinical importance. • Recent trials: disappointing results (no benefit) at

http://www.ncbi.nlm.nih.gov/pubmed/22797645 Glucosamine & Chondroitin: • glucosamine sulfate (from crab shells) & chondroitin sulfate (from cow cartilage) • these chemicals are needed by the body to make cartilage. • Claimed usefulness:

o Used for arthritis to protect cartilage & help rebuild it,also improving pain symptoms and joint damage in DJD (osteoarthritis).

o Often said to require combination with manganese for full effectiveness, although recent trials have not included manganese, and are using glucosamine alone without the chondroitin.

• Warnings: o most products are impure, and dose is controversial

• SPECIAL WARNING: o MADE FROM OYSTER AND CRAB SHELLS o ANAPHYLACTOID REACTION IF ALLERGIC TO SHELLFISH/IODINE

• Current information: o Several controlled clinical trials indicate that glucosamine alone is sufficient to treat

arthritis pain o both glucosamine & chondroitin are probably safe in the short term. o There are other herbals that sound and are spelled very much like this product, and

are more toxic – consumer beware o 2008 Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) did not find any

benefit of either glucosamine or chondroitin in slowing cartilage loss: https://nccih.nih.gov/news/2008/092908.htm

o Additional studies in 2010 confirmed lack of benefit in low back pain and lumbar DJD: http://jama.ama-assn.org/content/304/1/45.short?rss=1

• DIABETIC, LIPID & HYPERTENSION interaction: o Potential diabetic and lipid interactions. o May raise blood insulin levels and cause hypoglycemia, hypertension, fluid

retention, and rise in lipids. o Other trials have indicated that the opposite effect may occur after long-term use

(development of HYPERGLYCEMIA & diabetes due to worsening insulin resistance over time).

o In the short term, greatest concern now is for the development of the lipid dysfunction along with possible insulinemia.

o Recommendation: increased glucose/lipid monitoring.

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Feverfew: significant side effects & drug interactions; disappointing clinical trials • Claimed usefulness: preventive for migraine headaches (plus associated nausea &

vertigo), takes several weeks to work. Some claim useful in treating joing pain. • Active ingredient: parthenolide is a serotonin antagonist that inhibits leukotriene &

prostaglandin production (really an NSAID ??) – inhibits inflammatory mediators • Drug-drug interaction: warfarin (need dose adjustment). • Allergic potential: If allergic to daisies, will cause allergic reaction. • Pregnancy: If pregnant, may act as an abortifacient • Dose & Side Effects:

o chewing a few leaves every day, or taking herb in doses of 150 mg capsules qd. o SIDE EFFECT is mouth ulcers, loss of taste, and swelling of mouth/lips/tongue. o Even using the capsules won't eliminate the side effects.

Ginkgo biloba (Egb): most popular herb in Europe. • Claimed usefulness: treatment/prevention of Alzheimer's disease & other dementias,

treatment of tinnitus, CAD/angina, PVD, vertigo, impotence. Really, any condition caused by poor blood flow has been claimed as a condition that will be helped with this herb. Older studies showed possible benefit, but the studies were not constructed properly in terms of blindedness and matched cohort. Recent studies (2009 Ginkgo Evaluation of Memory trial, GEM) failed to show any benefit in preventing dementia. See: https://www.nih.gov/news-events/news-releases/ginkgo-evaluation-memory-gem-study-fails-show-benefit-preventing-dementia-elderly

• Cultural: No other plant like gingko; rotted fruit smells like dog feces & is not planted in the USA (although used as a food in China).

• Mechanism: vasodilator (?), possibly due to its autonomic nervous system action. • Dosing: 60-80 mg tid of standardized 25% gingko; drug is obained from the leaves. • Interaction: warfarin (need dose adjustment) due to anti-platelet effects. Jimsonweed: • Claimed usefulness: used as a cheap alternative to synthetic hallucinogens, especially in

the Southwest USA. • Warning: Multiple nervous system effects — hallucinogenic, atropinic, intoxication,

ataxia, blurred vision. Pokeweed: • Claimed usefulness: has been used as an anodyne (pain reliever) and cathartic. • Toxicity: Poorly prepared, it is highly poisonous, especially towards children. Hawthorn: contain vitexin flavonoids. • Claimed usefulness: Used in Europe to treat heart failure, angina, ASHD, HTN,

dyslipidemia. Considered to be an antioxidant. • Warning: potentiates digoxin. • Dosing: 360 mg qd of standardized extract 2% vitexin.

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Comfrey (blackwort): • Claimed usefulness: dysentery, cough, bleeding, bronchitis, peptic ulcer, everything!! • Highly toxic — don't use!! • Warning: may cause veno-occlusive disease, liver failure or liver cancer Sassafras: from the bark of the sassafras. • Claimed usefulness: used in the past as a "tonic," as an antiseptic topical, and as a

diuretic. Not enough information to recommend. • Warning: may be a hepatic carcinogen. Resveratrol: • one of the polyphenol flavonoids • found in the skin of red grapes, and thus in red wine

o grapes may provide just as much protection • MOA:

o may increase sirtuin enzme activity o this is associated with increased lifespan in lab animals and lower life-forms o no proof as yet in humans, although studies are ongoing

Ginseng: • a tonic depending on cultural traditions and the type of ginseng. • Two common types are Panax (contain ginsenoisides) and Siberian (contains

eleutherosides). • Claimed usefulness: prevention of cancer, boost energy, and counteract fatigue & stress,

menopausal management (phytoestrogen) and prevention of the common cold. • New claims:

o Diabetes Benefit ? Improved glycemic control with 3 gm/day of Panax. o Prevention of the common cold (brand sold as Cold-fx in Canada)

• Warning: o raises the blood pressure, do not take with caffeine. o Phytoestrogen, so may cause abnormal bleeding on postmenopausal women,

and may reactivate estrogen-dependent tumors. o Panax ginseng can interfere with digoxin. o High doses of ginseng may cause arrhythmias, headache, depression,

insomnia. o Possibly teratogenic in pregnant women. o Lastly risk of hypoglycemia in treated diabetics

• Dosing: o Use cyclically (qd x 2 months, then off x 2 weeks). o For Panax, 7% ginsenoisides use 75-150 mg qd. o For Siberian, 8% eleutherosides, 150-300 mg qd.

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St. John's wort: • Claimed usefulness: a mild SSRI antidepressant, and for PMS. • Active ingredient & drug category: Active ingredient is removed by alcohol extraction of

the above-ground part of the plant (just before or during flowering) to obtain USP Hypericum perforatum L; active ingredient is hypericin. This has SSRI effects, thus is a serotonergic agent. Doses of USP preps: 300 mg TID (½ this dose for children). Some companies provide USP prep in USA (Solaray, Enzymatic therapy, Nature's resources). In order to insure USP quality, it should say "USP guaranteed potency."

• Considerations: sold as a food supplement, no FDA quality assurance or label approval for use.

• Recent information: no benefit in AD/HD • Warnings: This is a good example of drug-drug concern.

o Possibility of serotonin syndrome: Excessive activation of serotonin receptors due to combination of two serotonergic drugs (e.g. St. John’s wort plus SSRI med or other serotonergic agent). DO NOT use with MAO inhibitors or othr SSRI agents and also some

TCA antidepressants. o Induction of CYP3A4 pathway & reduced efficacy of other drugs:

Reduced efficacy of other drugs such as protease inhibitors (for HIV), oral contraceptives (OCs, OCPs — unplanned pregnancy), cyclosporine (transplant rejection), theophylline, reduced digoxin & warfarin levels.

Reports of HIV patients failing their anti-retroviral therapy and women on OCP becoming pregnant because they took OTC St. John’s wort.

o Glycoprotein transporter interactions: Affects the GP transporter, needed to absorb many drugs and also affects hepatic absorption of many drugs. Many drug interaction possibilities.

• Other Cautions: o Photosensitivity – recommend sunblock & avoid UVR o Cataracts – recommend avoid UVR & wear dark sunglasses.

SAMe (S-adenosyl-L-methionine): • usually used as an herbal antidepressant, for osteoarthritis, fibromyalgia & pruritus from

hepatic cholestasis • Mechanism: both serotonergic & adrenergic

o Claimed to help neurons make more neurotransmitter from methionine & ATP o Considered to be a “methyl donor” to synthesize serotonin (5HT) &

catecholamines (NE) o Also some anti-inflammatory properties

• Availability: o osteoarthritis preparations (Flexium, contains glucosamine and SAMe) o for depression (dose 1600 mg/day oral as 800 mg bid or 200 mg/day IM)

• Potential AEs: unmask hypomania/mania in depressed patients.

Pharmacology Unit 1 Page 26 of 33

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Ma Huang (Ephedra) & Bitter Orange: • Ma Huang (Ephedra) has been off the market in USA since 2004 • Now being replaced in many herbal preparations with Bitter Orange • Usual claim: weight loss (“burns fat” “energy buzz”) • Chemicals: ephedra had ephedrine, bitter orange has synephrine • Warnings for both:

o insomnia, HTN, MI, angina, anxiety, insomnia, etc. o Very dangerous, especially if comorbid conditions include DM, angina, HTN,

glaucoma, hyperthyroidism. o Increased risk of MI, stroke, arrhythmia, syncope

Sweet wormwood (quing hao, Sweet Annie): Active component is called artemisinin. • Claimed clinical usefulness: treat different parasites, including malaria. • Other uses: A type of wormwood, Artemesia absinthium, was used to flavor absinthe,

causing illness to many in the 1800's (now outlawed). Another form of wormwood is used to flavor vermouth now.

• Warning: may cause CNS toxicity (hallucinations). Horse Chestnut: the seeds contain aescin. • Claimed usefulness: may help varicose veins & nocturnal leg cramps. Evidence not

convincing, although probably not very toxic, either. • Dosing: 150 mg bid of 15% aescin extract. • Warning: GI upset. Bromelain: • an enzyme from pineapple. • Used to reduce pain and swelling from inflammation. Chaparral (in Herp-eeze): associated with acute toxic hepatitis, very TOXIC !! • Claimed usefulness: for genital warts. • Marketed: to kill the virus that causes genital herpes. They claim to have produced an

extract without large amounts of the toxic substance NDGA. • Active (toxic) ingredient: NDGA (nordihydroguairetic acid & lignins) from the leaf of the

chaparral or creosote bush (SW United States & Mexico). This is so toxic that herbivores won't eat the bush.

Grape Seed (Vitis Vinifera): • crushed red grapes contain OPCS (procyandins) that are anti-oxidants, anti-inflammatory,

and claime to be radio-protective. • Claimed usefulness: visual function, varicose veins, lymphedema, acrocyanosis,

telangiectases, capillary fragility, cancer, PMS, dental caries. • No literature supports claims. Consider usefulness of red grapes as part of preventive

management for ASHD (see later) due to its antioxidant effects.

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Bilberry (Vaccinium myrtillus): eaten as a dried fruit, or used as a tincture. • Claimed usefulness: multiple claims, including cataracts, poor vision, diabetic retinopathy,

macular degeneration, varicose veins, diabetes, capillary fragility, ulcers, stroke, angina, diarrhea, glaucoma, dysmenorrhea, rheumatoid artharitis, hemorrhoids. Most commonly used for diarrhea.

• Recommendation: no proven usefulness. Remember, if a whole host of claims is made, this makes it unlikely that it helps any of them very much.

• AEs: prolonged use causes intoxication and can be FATAL. Ginger: often recommended for motion sickness (vertigo) & nausea. • Rhizome (root) used for centuries, both as medicinal and culinary herb. • May be helpful for any cause of nausea (chemotherapy, pregnancy, motion sickness) but

caution in pregnancy advised (no data). • Warnings:

o anti-platelet activity may require warfarin adjustment o NO LONGER CONSIDERED SAFE IN PREGNANCY (cytotoxic in vitro)

• Dosing: 1 gram ½ hr before boarding ship, then 0.5-1 gram q4h, not > 4 gm/day. Licorice root: • licorice is a sweet flavoring used in many teas, but some candy licorice is actually flavored

with anise. • Claimed usefulness: an anti-inflammatory. Also, has been used in treating peptic ulcers.

Use the DGL type (see below). • Warning: metabolically interferes with adrenal gland synthesis of cortisol and

mineralocorticoids, so can cause HTN, hypokalemia, edema, cardiac arrest. Mostly due to the glycyrrhizinic acid component. Deglycyrrhizinated licorice (DGL) has less of these adverse effects, and may still have the effectiveness as a treatment herb.

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MENOPAUSAL HERBS: see Endocrine section. Remember – are they "phytoestrogens" (could reactivate breast tumors) or not, and are they known to have toxic potential (many do). MALE HEALTH: COMPLEMENTARY AND HERBAL THERAPIES: topics include erectile dysfunction, benign prostatic hypertrophy (BPH), prostate cancer. See Endocrine section in course notes. Examples of herbs used are saw palmetto. INTEGRATIVE MEDICINE AND ASTHMA: So far, no proven benefit from a variety of modalities; Ma Huang recommended, BUT UNSAFE (Ephedra product). (More in later Module) CARDIOVASCULAR ILLNESS — WESTERN HERBALISM APPROACHES: • recommendations must encompass overall health promotion, risk factor reduction,

lifespan issues, genetics, and lifestyle choices (including diet, nutrition, and risk behaviors)

• Obviously, phytochemicals that may be beneficial would be: anti-thrombotic, anti-platelet, anti-oxidants, improve the lipid profile, lower blood pressure (BP), and reduce/maintain to normal weight

• Some products also include soy and n-3 fatty acids (omega-3 PUFAs) • Also the issue of how much alcohol has cardiovascular benefit, and how binge-drinking is

dangerous to the heart • More in later Modules

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HERBAL MANAGEMENT ACCORDING TO THE HERBALISTS: NOTE – these are NOT necessarily SAFE to use, but this is a list of COMMON recommendations. • Anxiety & Insomnia: Kava kava, valerian, chamomile, passionflower, hops, linden

flower, hawthorn, skullcap • Cancer Prevention: Selenium, green tea, allium family (garlic, onion), ginseng (red &

white), sulforaphanes in foods (broccoli, cauliflower, brussel sprouts, turnips, kale), folic acid (colon cancer).

• Cancer Treatment: (all toxic & no efficacy proved) Astragalus, cat's claw, iscador, milk thistle, essiac, laetrile.

• Colds, Flu and Other Infections: Zinc gluconate, Echinacea, comfrey, Vitamin C (doses 1 gm/day)

• Antidepressant Therapy: St. John's Wort, Ma Huang, passion flower, Yohimbine • Fatigue and Stress: Ginseng, guarana, kola, ma Huang, yohimbine • Gastrointestinal Symptoms & Peptic Ulcers: Aloe vera gel, licorice, comfrey, slippery

elm, ginger (nausea) • Liver Disease: Milk Thistle • Migraine Headache: Feverfew (prevention), catnip tea (abortive therapy) • Memory Loss, Tinnitus, Hearing Loss: Ginkgo Biloba • Prostate Problems & Impotence: Saw Palmetto, Yohimbine, Gingko biloba, L-arginine • Varicose Veins: Horse Chestnut • Joint Pain: Feverfew, comfrey, bromelain, capsaicin, glucosamine with or without

chondroitin and/or manganese. • Parasitic Illness: Sweet wormwood • Diuretics: Alfalfa, dandelion, celery, chicory, wild carrot, marshmallow root • Easy Bruising: Bioflavonoids in citrus • Laxatives: Cascara, aloe, psyllium, senna • PMS: Evening primrose oil, Chaste Berry (Vitex), Calcium, St Johns wort, vitamin

combinations. • Anticoagulants: Alfalfa, cinchona bark, clove oil, ginkgo, garlic, ginger, ginseng,

feverfew • Motion sickness, nausea: Ginger • Cold Sores: Chaparral (topically) • Asthma: gingko biloba, Ma Huang, licorice root, green tea, forskolin. ****** REMEMBER: MANY OF THE ABOVE ARE HIGHLY TOXIC, SEE NEXT PAGE.

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HERBAL AGENTS WITH TOXIC POTENTIAL — BRIEF SUMMARY: • Ma Huang (Ephedra): sold as an "energy" & "weight loss" aid. Stimulates the

sympathetic nervous system, may raise HR & BP. • Dong Quai: remember the warnings listed above, especially — photosensitivity,

increased bleeding, interaction with coumadin, fever, reactivation of estrogen-dependent tumors.

• Yohimbine: sold as a cure for impotence (doesn't work that well). Can cause HTN, heart & CNS damage.

• Kava (Kava kava): extreme sedative effects and "hangover" possibility, and nausea, muscle weakness, HEPATOTOXICITY.

• Black Cohosh: remember the warnings listed above, especially — increased bleeding, sedation, headache, no long-term safety established beyond 6 months use, possible reactivation of estrogen-dependent tumors. Several reports of auto-immune hepatitis that is now required to be on the LABEL as causing liver damage.

• Ginseng: hypertension, irritability, skin rashes, insomnia. • Mercury: used by Puerto Ricans (practicing espiritismo) for good luck & protection; renal

failure (mercury poisoning). • Chamomile: may cause anaphylactic shock and contact dermatitis. • Comfrey: may cause veno-occlusive disease, liver failure or liver cancer. • Foxglove (Digitalis): malignant arrhythmias, cardiac arrest. • Jimsonweed: Multiple nervous system effects — hallucinogenic, atropinic, intoxication,

ataxia, blurred vision. • Mayapple (Mandrake): scopolaminic and anti-cholinergic effects. • Mate (Ilex) veno-occlusive disease, hepatic failure. • Pokeweed: saponin content (a natural soap) causes gastroenteritis, bloody diarrhea,

respiratory depression, mitogenic effects. • Sassafras: hepatic carcinogen. • Snakeroot (Bistort, Indian snakeroot, rauwolfia)): reserpine like action on CNS with

intoxication and withdrawal syndrome. • Jin Bin Huan: can cause liver damage and death. • Valerian: dystonic reaction, hepatotoxicity. Acute withdrawal reaction after long-term

use. • Chaparral: hepatic toxicity. • Gingko biloba: anti-platelet agent that may potentiate other forms of anticoagulation. • Saw palmetto: pancreatitis • Lavender & Tea Tree Oil: gynecomastia (estrogenic)

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File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

ORGAN SYSTEM TOXICITIES OF SELECTED MEDICINAL HERBS: • Liver damage: usually the pyrrolizidine alkaloid compounds cause liver toxicity, and are

found in many herbs. Herbs known to cause hepatotoxicity include: comfrey (European treatment for arthritis, skin, lung, GI conditions), chaparral, jin bu huan, germander, pennyroyal (sold now to control fleas in pets & for children's skin diseases; in ancient times used as an abortifacient), pokeroot, chaparral, coltsfoot, valerian, kava kava.

• Cardiac toxicity: pheasant's eye, anemone (pasque flower), lily of the valley, thorn apple, foxglove (digitalis), male fern, yellow jasmine, false hellebore, mistletoe, Chinese caowu (chuanwu).

• GI (gastrointestinal) Toxicity: arnica, bryony, ipecac, mandrake (mayapple), squill. • CNS (Brain) Toxicity: deadly nightshade (belladonna), thorn apple, male fern, yellow

jasmine, henbane, rauwolfia (Indian snakeroot), squill, valerian. Common plants with anticholinergic properties can cause hallucinations (catnip, juniper, lobelia, jimsonweed, wormwood, nutmeg).

• Abortifacient potential: (may abort a pregnancy) devil's claw root (for arthritis), bilberry (for stomach problems), dong quai (menses), ruta, oregano, anise (as a tea), pennyroyal, feverfew. All are highly toxic when taken in doses that cause abortion, and if taken by a pregnant person who is unaware of her pregnancy, may result in miscarriage.

• Hematopoietic: Echinacea (if taken too long), Vitex (Chaste Tree berry), black cohosh, dong quai, vitamin E (excessive doses), fish oil (excessive doses), gingko biloba (anti-platelet effects on coagulation function).

• Reactivation of estrogen-dependent tumors and/or endometrial hyperplasia: ginseng, saw palmetto, garden sage, soy, black cohosh, dong quai, red clover.

• Reactivation or Exacerbation of auto-immune illnesses: Echinacea, garlic, onion. • Diabetes as a comorbid condition: be careful with garlic, ginger, ginseng, hawthorn,

ma huang, nettle and possibly glucosamine. • HTN as a comorbid condition: be careful with devil's claw, ginseng, goldenseal,

hawthorn, licorice, ma huang, squill, yohimbine, glucosamine. • Depression as a comorbid condition: be careful with valerian, kava kava. • Allergies as comorbid condition:

o Ragweed, daisy, aster, chrysanthemum — asteraceae family: be careful with chamomile, echinaceau, feverfew, yarrow.

o Other pollens: goldenrod, St. John's wort, slippery elm. • Dyslipidemia: glucosamine. • Pancreatitis: saw palmetto • HIV: garlic, St. Johns wort both induce CYP enzymes and lower levels of therapeutic

protease inhibitor (PI) drugs possibly resulting in FAILURE OF THERAPY. • Cancer: (increased risk of) prostate cancer & lung cancer (vitamin E), lung cancer (beta-

carotene in smokers), prostate cancer (alpha-linolenic acid, such as Chia herb)

Pharmacology Unit 1 Page 32 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

HOW HERBS ARE TYPICALLY PREPARED FOR MEDICINAL USE: • botanical factors in growing live plants contribute to potency. • Active herb depends on on climate, rainfall, soil conditions, growing time, the plant's

lifecycle at harvest, which parts of the plant are used (stem, seeds, flowers, leaves), and how the plant is finally processed and stored.

• Note that processing may not remove biological agents (bacteria) -- e.g. cold extract of kava-kava, commonly sold in the Pacific Islands as a recreational “alcohol alternative”

NO NEED TO MEMORIZE THESE TERMS – JUST READ FOR HISTORIAL INTEREST: Bulk herbs: usually thought of as culinary, and are provided without processing. Examples are cloves of garlic, ginger or ginseng root, peppermint leaves. Infusions: a tea made by steeping bulk herbs in boiling water. This is usually ½ to 1 oz combined with 1 pint of boiling water and then steeping. Herb is strained out and the fluid is drunk; oils and vitamins are brought out of the plant in this manner. Decoctions: the plant is boiled in the water for some time, and may include bark and fibrous roots. Boiling for 10 minutes, then steeping, then strain & drink. Thought that the "bitter" substances and minerals are brought out of the plant with this method. Cold Extract: soaking the plant in cold water for 8-12 hours removes oils & vitamins. Thought to preserve chemical activity better; but, a concern is that any biological contaminants are not deactivated through heat or alcohol. Juice: press water through chopped up plant and drink immediately. Powders: ground-up bulk herbs. Usually then placed into tablets or capsules. Usual amount is the amount of powder you can place on a dinner knife. Syrup: boiling raw or brown sugar, or honey, to produce a syrup to which medicinal substances are added. Often used to give medicine to children. Extracts: chemically concentrated whole herbs; commonly as medicinal herbs.

• Tinctures: least concentrated. Herb is soaked in a solvent (water or alcohol) for several weeks, and then pressed out of solution. Usually, tinctures are a 1:5 concentration (1 part herb to 5 parts solvent). Not as economical; in order to get significant dose of herb, lots must be taken. Last a long time.

• Fluid extracts: more concentrated. Evaporate the solvent from a tincture to obtain the usual ratio of 1:1.

• Solid extracts: most concentrated. Solvent is completely removed. Expressed as a ratio of "grams of crude herb to grams of extract" — thus, a 4:1 concentration means 4 gm of crude herb was used to make 1 gm of extract. More economical & chemically stable.

Essence: one ounce of herb's essential oil in one pint of alcohol. Good for preserving plant oils that may not be soluble in water. Poultice (cataplasm): herbs applied to the skin with moist heat. Herb is mashed up, heated, then mixed with moist flour/corn meal/bread & milk and applied to the skin. Moist warm cloth is applied over the poultice. If herb is irritating, it is placed between two cloths. Thought to soothe, irritate, or "draw out" impurities from the body.

Ointment: powder mixed with petroleum jelly, lard, beeswax. Fomentation: a cloth or towel is soaked in the infusion or decoction, and applied hot. Thought to be less effective than a poultice. Cold compress: infusion or decoction is used to soak a cloth, applied cold and left on for 15-20 minutes until warmed by body heat. Then, removed and redone/reapplied. Hydrotherapy: herbs added to bathwater to achieve both skin application and inhalation of aromas/vapors. Includes full bath, half-bath, Sitz baths, foot baths, eye baths, vapor baths, and any variety of body part immersion bath.

Pharmacology Unit 1 Page 33 of 33

File: advpharm_unit1_9herbal.pdf SOURCE: C. DECRISTOFARO, MD

SMALL GLOSSARY OF HERBAL TERMS: • Note that some of these terms are still in use today • Examples: antispasmodic, astringent, cathartic, purgative, styptic NO NEED TO MEMORIZE THESE TERMS – JUST READ FOR HISTORIAL INTEREST Adaptogen: increased resistance to stress, balancing effect on the body. Alterative: gradually and favorably alters the body's condition. Anodyne: action of pain relief. Anticatarrhal: eliminates or counteracts formation of mucous. Antilithic: removes or prevents formation of stones or gravel in the urinary system. Antispasmodic: relaxes nervous tension causing digestive colic. Aromatic: oils of aromatic herbs massaged into muscles to promote circulation. Astringent: constricting or binding effect to aid in breaking down secretions. Bitter: promotes appetite and aids digestion. Carminative: relieves intestinal gas. Cathartic: laxatives. Cholagogue: promotes flow of bile into small intestine. Demulcent: soothes inflamed mucous membranes. Diaphoretic: induce sweating. Emmenagogue: promotes menstruation. Glycerites: preparations extracted using glycerin. Hepatic: improves liver function. Maceration: strained cold-water extract (concern re: sterility). Nervine: ease anxiety and stress. Purgative: promote bowel movement and intestinal peristalsis. Rubefacient: applied to the skin to stimulate circulation in that area. Stomachic or Tonic: maintains or restores health. Styptic: cause capillaries to contract and stop superficial hemorrhage bleeding.