Drug-Supplement
Interactions — A New Concern for Dietitians
Today’s Dietitan
By Annette M. Kobriger, RD, CD, MPH, MPA
Vol. 6, No. 9, p. 22
Alternative therapies, often based at least partly
on ancient systems of belief and practice, have had to fight for
respect. That battle has been won, for the most part, as complementary
and alternative medicine (CAM)—which can include therapies
as varied as acupuncture and hypnosis—has achieved widespread
use even in countries where state-of-the-art medical care is established.
In traditional or folk societies, it never went away. Estimates
are that more than 80% of the world’s population use CAM.
A recent survey by the National Center for Complementary
and Alternative Medicine (NCCAM) found that 36% of those over the
age of 18 used CAM. When prayer was included, the number increased
to 62%. The study used a representative sample of 31,000 U.S. adults.1
Some 60 million Americans choose alternative medicine.
Their reasons varied. Fifty-five percent believed
CAM would complement their current traditional healthcare. Twenty-six
percent used CAM when suggested by their traditional healthcare
provider. Thirteen percent used nontraditional therapies due to
cost of healthcare. Twenty-eight percent of those surveyed felt
traditional healthcare could not help them.1 Some believe natural
treatments are safer and superior to allopathic remedies such as
surgery and drugs.
For dietitians, these beliefs affect a crucial area:
dietary supplements, which are believed to be less invasive and
more holistic. Deregulatory government practices, especially since
1994, have allowed questionable supplements into the marketplace,
supported by massive media and marketing efforts. Sometimes, misleading
or inaccurate information is put forth.2,3
The use of dietary supplements varies with age.
By the age of 33, approximately 30% have used dietary supplements;
by the age of 50, one-half have tried dietary supplements; and after
the age of 50, up to 70% have used alternative medicine.2 Most—up
to 70%—do not tell their physician.3
Even if the supplements are pure and not harmful
by themselves, widespread use in the older population creates potential
problems. Dietary supplements may bind at receptors designated for
prescription drugs or compete for metabolism and elimination with
other drugs and cause toxicity or treatment failure. Thirty percent
to 40% of calls received by poison control centers are related to
dietary supplements.4
Most supplements are not harmful in and of themselves;
problems arise in combination with drugs and in the recent explosion
in herbal preparation use.
Prescription Drug-Herb Interactions
An estimated 4 million people are at risk for herbal-prescription
drug interactions.4 As people age, they use more supplements. Drugs
widely used by older people are affected by herb use. Some drugs
have a narrow therapeutic index and low range of therapeutic benefit.
Changes in the drug level—either up or down—cause therapeutic
failure or toxicity. The drugs known to be most at risk are warfarin,
digoxin, insulin, phenytoin, and St. John’s wort.
• Warfarin. Warfarin (Coumadin) is
used to prevent blood clotting for those at risk for deep vein thrombosis,
heart attack, or stroke. Herbal interactions have been reported
for this drug. Case reports have demonstrated elevated international
normalized ratio (INR) levels with the use of herbal supplements,
especially danshen, dong quai, garlic, and ginseng. An INR of 6
suggests a high level of bleeding. (Normal for anticoagulant therapy
is 2 to 3.)5
Some herbs contain varying amounts of vitamin K,
which can promote bleeding with those on warfarin. Examples are
alfalfa, nonbrewed black and green tea, and spring onions.6
Other herbs contain coumadin and coumadinlike components—including
alfalfa, chamomile, feverfew, garlic, willow bark, and ginseng—and
increase the bleeding with warfarin. Ginger is believed to inhibit
thromboxane synthetase, also increasing bleeding risk. Flaxseed,
fish oil supplements, goldenseal, and saw palmetto increase INR
levels.4,7,8,9
• Digoxin. Another cardiac drug used
that has a narrow therapeutic index is digoxin. Normal therapeutic
range is 0.9 to 2.0 micrograms per milliliter.5
Ginseng has been noted to falsely elevate the plasma
digoxin level.10 Some herbs have a diuretic action, causing depletion
of potassium, and some potentiate cardiac arrhythmias due to altered
fluid and electrolyte levels. These herbs include aloe, buckhorn,
licorice, dandelion, rhubarb, cascara, castor oil, and senna.6
Other herbs have cardioactive components, such as
hawthorn, fig wort, black hellebore, motherwort, oleander leaf,
and squill. Additional herbs contain cardiac glycosides, which have
a digoxinlike effect. They are often used as “heart tonic.”
Balloon cotton, dogbane, foxglove, frangipani, King’s crown,
lily of the valley, goldenseal, hawthorn, and Adonis are in this
category. Guar gum and other fibrous herbs decrease digoxin absorption.4,6,9,10
In one case, oleander seed poisoning caused a patient to be admitted
to a coronary care unit with severe cardiac arrhythmias.4,6,9,10
Calcium and vitamin D supplements given with digoxin
can increase the risk of arrhythmias. Take digoxin separately from
antacids by two hours.11
• Phenytoin. Another commonly used
drug with a narrow therapeutic index is phenytoin, which is used
for seizures. Almost 2 million people suffer from seizures. Seizures
are caused by an abnormal burst of energy from the brain. They occur
primarily in those over the age of 60 due to a stroke, neurodegeneration,
or brain injury.
The drugs used to decrease seizures usually depress
abnormal brain activity. Drugs often cause drowsiness, confusion,
and impaired walk and can trigger personality changes. Some individuals
may require more than one drug. The normal blood level for phenytoin
is 10 to 20 milligrams per liter.5
Dietitians are familiar with the need for folate
supplementation for patients taking phenytoin, usually in the range
of 0.8 to 1 milligram per day. Excess folate causes breakdown of
the anticonvulsant. Inadequate folate leads to birth defects in
infants and elevated homocysteine levels in adults. Elevated homocysteine
levels have been linked to cardiac disease.
Calcium and vitamin D supplements are also recommended
to decrease the risk of osteoporosis. Some studies suggest a decrease
in absorption when phenytoin is taken at the same time as calcium.
The recommendation is that these drugs be taken two hours apart.
Others suggest a supplement of vitamin K. During pregnancy, women
should discuss the use of these supplements with their physicians.
Herbal supplements for seizures are usually nerve
relaxants. Use of herbal supplements with traditional anticonvulsants
can increase confusion, fatigue, and risk of falls. Traditional
herbs used for seizures are skull cap, lobelia, lady’s slipper,
valerian root, Kava, passion flower, and lemon balm. The safety
of using herbs and traditional anticonvulsants at the same time
is a concern. Some herbs known to potentiate seizures are ginkgo,
glutamate, iprifavone, and white willow. White willow is of special
concern because its action can cause dangerously high blood levels
of phenytoin. Case reports have established a decrease in phenytoin
levels when taken with the syrup of shankhapushpi.10,12,13,14
• Insulin. Insulin can cause blood
sugar to drop dramatically. Inadequate insulin causes dangerously
high blood sugar levels. The body tightly regulates blood sugar
levels in the absence of diabetes.
Chromium, or brewer’s yeast, has been tested
since 1853 on ability to improve glucose tolerance. Studies vary
on the impact of chromium on blood glucose levels. Since chromium
can enhance the effect of insulin and cause hypoglycemia, it should
be used with medical supervision. Glucomannan is a water-soluble
dietary fiber that is believed to slow stomach emptying. The delayed
stomach emptying decreases carbohydrate absorption, thus lowering
the blood glucose level.
Some herbs have been shown to decrease blood sugar.
These are Coenzyme Q10, onion bulbs, garlic cloves, bitter melon
fruit, prickly pear, burdock, cumin seed, Chinese and Siberian ginseng,
fenugreek seeds, and stinging nettle. Celery seed, burpleurum, rosemary,
and gota kola raise blood sugar levels. There is also some minor
research on cinnamon to decrease insulin needs in those with diabetes.
This has yet to be proven in clinical trials.
Bitter melon is known to decrease blood sugar. There
have been no significant studies. This food is often eaten by people
of Asian origin as a food and medicine.7,10,15,16
The official viewpoint on herbal use in diabetes
was summarized by Michael J. Quon, MD, PhD, chief of the diabetes
unit at the NCCAM. He believes there is little evidence to show
support or safety of dietary supplements to prove current therapies.17
However, there are those in the supplement industry
who disagree and believe “there are claims that can be proven
for diabetes management.”17
• St. John’s wort. Another example
of potential harm from a commonly used herb is St. John’s
wort. St. John’s wort is taken by 7.5 million Americans as
a depression remedy and can cause serious consequences when taken
with selective serotonin reuptake inhibitors (SSRIs) such as Prozac,
Zoloft, or Paxil. It can also cause “serotonin syndrome”:
dizziness, nausea, vomiting, headache, epigastric pain, confusion,
restlessness, and irritability. This herb may also interact with
digoxin, chemotherapy drugs, and other drugs, causing treatment
failure. St. John’s wort induces liver enzymes to increase
metabolism of warfarin, cyclosporin, indiavar, and oral contraceptives.
Two case reports show acute organ rejection due to the interaction
of cyclosporin and St. John’s wort.2,4,9,10
Drug-herb interactions like these are serious. If
the offending herb were a drug, the government would normally restrict
marketing, make it a prescription-only item, and/or require warnings.
It is important to understand why this isn’t happening and
appreciate the dilemmas all practitioners, including dietitians,
encounter.
Regulatory Limbo
Herbal and plant-based medications have always been used for self-treatment.
This does not prove safety or effectiveness, however.18 In the United
States, there are more than 16,000 dietary supplements and 2,000
botanical species. In 2002, $76 million was spent for just three
dietary supplements: androstenedione, kava, and yohimbe.19
Herbal products are not tested for purity, effectiveness,
and safety as drugs are. In an interesting twist of logic, herbs
are considered “dietary supplements” even though they
are touted as medicinal. The FDA defines dietary supplements as
vitamins, minerals, herbs, additional plant products, amino acids,
enzymes, and extracts from plants and organs.2,3,4
The Federal Food, Drug, and Cosmetic Act of 1938
“grandfathered in” many drugs and herbal products in
common use. In the 1990s, Congress acted to give the FDA the ability
to regulate health claims. At this time, the Federal Trade Commission
planned to ban all nutritional or therapeutic claims on supplement
labels—a shotgun approach to the abuses it perceived.
Rise of the Supplement Industry
The supplement industry urged customers to fight for their right
to continue to self-medicate with dietary supplements as well as
the industry’s right to advertise medicinal benefits.
Congress largely backed down. The Dietary Supplement
Health and Education Act (DSHEA) of 1994 required the FDA to prove
beyond any doubt that a supplement is unsafe before removing it
from the market.
The burden of proof lies with the government. Congress
assumed herbal supplements were safe due to their long use—mostly
in other countries. Issues of purity, concentration, variations
in quality, and potency from species to species were not addressed,
nor were the potential drug-herb interactions.
Congress did, however, establish the Office of Dietary
Supplements (ODS) at the National Institutes of Health in 1995.
This office is charged with obtaining knowledge and understanding
of dietary supplements, evaluating scientific data, conducting research,
and educating the public. The ODS has 60 staff members and a budget
of $10 million to monitor a $19.4 billion industry.19
The FDA regulates supplement labeling in an attempt
to mitigate the worst of the problems. Manufacturers now cannot
claim a supplement diagnoses, prevents, mitigates, or cures illness
but can state only structural effects. A product “may maintain
bone health during adulthood,” “supports the immune
system,” or “helps reduce harmful free radicals in cells.”
Supplement labels must include the product’s identity, contents,
function, directions, a facts panel, ingredients in descending order,
and the manufacturer’s address. The label must also contain
the following statement: “This statement has not been evaluated
by the Food and Drug Administration. This product is not intended
to diagnose, treat, cure, or prevent any disease.”2,4
You’re forgiven if you can’t determine
a substantive difference between structural statements and health
claims—neither can your clients. Hardly anyone misses the
intended point of the structural claims that the supplement prevents
or cures a disease or condition or pays much attention to the disclaimer.
Supplement sales have soared, raising concerns that have caused
the government to inch closer to true regulation based on sound
scientific standards. The first outright banning of an herbal supplement
is in force. The manufacturing process is also under the microscope.
Disturbing studies have highlighted the need for
FDA guidelines for reviewing manufacturing processes.20 In 1998,
one of the first studies focused on the leading herbal supplements:
echinacea, St. John’s wort, ginkgo biloba, garlic, saw palmetto,
goldenseal, aloe, Siberian ginseng, and valerian. Researchers found
more than 880 formulations of these dietary supplements available
on store shelves. Analysis proved that the ingredient dosage correlated
with the label information less than one-half of the time. The labels
were accurate only 20% of the time, and more than one-third of the
labels were incomplete.20
The Internet provides valuable information for consumers
and dietitians. One site, www.consumerlab.com, was founded five
years ago by Todd Cooperman, MD, and William R. Obermeyer, PhD.
Obermeyer is internationally recognized as a natural chemist and
previously worked with the FDA. In three years of testing hundreds
of supplements, 25% were found to contain too little or none of
the primary ingredient advertised on the label. Dangerous levels
of contaminants were often found. Only dietary supplements that
pass their testing process are listed on the Web site.3
A study of 251 Asian patent medicines found in health
food stores in California found them to be contaminated with heavy
metals. Twenty-four contained lead at 1 part per million, 36 contained
arsenic, and 35 contained mercury.10
Attempts to regulate any medicinal compound face
several structural problems relating to the patent laws. Those with
an interest in and the ability to do the kind of rigorous testing
and research on herbs the public needs—pharmaceutical companies—will
not. Because they cannot patent herbal and plant compounds, which
are considered “foods” and have been used for centuries,
they cannot justify the expense of such testing.3 Kay notes that
the cost for drug companies to research, develop, and market a new
drug is $500 million.3
Those marketing herbs and other supplement products
save millions of dollars not spent on research and development—or
worse, are free to create their own “research,” which
often does not include rigorous controls. The supplement industry’s
position is that people should be free to choose their remedies,
and the drug testing and regulatory procedure takes too long and
costs too much, effectively condemning people to ill health for
legal and bureaucratic reasons.
Ephedra
Compiling negative information and spotlighting industry problems
has not made it easier for the FDA to prevent a dietary supplement
from being sold for safety reasons. The ephedra story is a case
in point.
For seven years, the FDA attempted to remove the
weight-loss product ephedra from the market, citing numerous anecdotal
reports of deaths from cardiac problems. In 1997, the agency was
forced to back down when the General Accounting Office advised Congress
that the FDA “did not establish a causal link” between
taking ephedra and deaths or injuries. The FDA was not aware until
later that Metabolife International, Inc., an ephedra manufacturer,
had received 14,648 complaints about the product. In December 2003,
following the 2002 death of professional baseball player Steve Bechler,
Congress demanded that the FDA enact a formal ban under the DSHEA,
and ephedra was finally removed from shelves in April. Side effects
of ephedra include seizures and heart attacks, and ephedra was implicated
in 155 deaths.19
The first day of the ban, a federal judge rejected
a petition for a temporary restraining order by supplement companies.
The supplement industry replaced ephedra with other stimulant herbs,
such as bitter orange. In May, the Nutraceutical Corporation sued
the FDA, claiming that “ephedra has been consumed safely for
millennia” and that the FDA did not meet its burden of proof
that ephedra supplements present “a significant or unreasonable
risk of illness or injury at every dose level as labeled.”21
As the ephedra ban neared, a new diet herbal concoction,
Zentrex 3, hit the market and soared to the top of the sales charts,
providing supplement manufacturers with plenty of money to pursue
litigation.
Educational Void
With the government hamstrung, the pharmaceutical industry neutralized,
and supplement company lawyers armed and ready, how does the public
get good information about herbal supplements? Information flows
both ways. Most patients, as mentioned earlier, do not tell their
conventional healthcare providers about their use of CAM. Most fear
the provider will ridicule them or show disapproval in other ways.
On the other hand, many providers do not ask patients
about their use of CAM—even though they may be supplement
users as well. A study of 655 dietitians in Washington State found
that 60% took a supplement either daily or occasionally.5 In a survey
of 181 cardiologists, one-half were found to be taking antioxidant
vitamins. However, only 37% of the cardiologists recommended the
supplements to their patients.18
A study of 458 Veterans Administration general medicine
outpatients found 179 of 458 patients (43%) took a nutritional supplement.
There were 89 (45%) potential diet-drug interactions, and 6% of
these interactions had a potential for a severe reaction. The outpatients
took an average of three supplements with their prescription medications.
These were older patients with multiple chronic diseases. Some patients
took six or more supplements.
The most serious interactions included the following:
• A calcium supplement given with levofloxacin,
which decreased the effectiveness of the antibiotic.
• Interactions of warfarin with Coenzyme Q10
and ginseng, which decreased the anticoagulant effect of warfarin.
• Garlic and ginkgo biloba taken with warfarin.
Both these herbs have an antiplatelet effect and decrease the effectiveness
of warfarin.
• Digoxin was taken with pectin, which has
the potential to decrease the serum digoxin level.
• Another interaction was noted with St. John’s
wort, which has the potential to increase serotonin levels.22
The primary sources of information on herbal supplements
were relatives, friends, books, magazines, and television. Physicians
and pharmacists provided only roughly 25% of their information.
Until recently, most medical schools and colleges of pharmacy did
not provide education in plant-based medicine.
There’s an information gap here, and nutrition
professionals are right in the middle of it.
What Dietitians Can Do
Most nutrition professionals ask about prescribed drugs as part
of a nutrition assessment. Asking about herbal supplements is also
appropriate, but self-education comes first. Publications for health
practitioners of all disciplines are available: Table 1 lists publications
that can be used for self-study.
The American Dietetic Association (ADA) has been
interested in supplements for years but is newly interested as dietitians
see an opportunity and a challenge in the herbal revolution. In
2001, an ADA position statement expressed concern about the “insufficiently
regulated” food supplement industry. DSHEA expanded the definition
of dietary supplements beyond substances known to be needed for
adequate nutrition. This includes herbs and other plant-based products.
The argument raised by the ADA is, “Registered dietitians
must evaluate whether their academic preparation and scope of practice
… qualifies them to provide advice about advocating the use
of such products.”23
Apparently, the answer will be yes as the ADA is
working with pharmacology groups to create a credential in botanical
medicine.3
Addressing the use of herbal and dietary supplements can be included
in assessment of the client’s needs. Guidelines for herbal
or nutritional supplement assessment is provided in Table 2.
Even though the listing of herbs as “dietary
supplements” along with vitamins and minerals creates an uncomfortable
situation, we cannot simply say that most dietary supplements do
not fall into our scope of practice. Using the resources and information
cited here, nutrition professionals can provide useful information
to their clients about the safety of taking herbal supplements and
can direct the client back to his or her physician if indicated.
Dietitians can continue to learn about alternative medicines through
continuing education. There may also come a time when RDs can be
credentialed in botanical medicine.
— Annette M. Kobriger, RD, CD, MPH, MPA,
is president of Kobriger Presents, Inc., which provides seminars,
publications, and national consultation for the long-term care industry.
References
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