Download Herbs and Alternative Therapies in the Hypertension Clinic

AJH
2001; 14:971–975
Review
Herbs and Alternative Therapies
in the Hypertension Clinic
George A. Mansoor
The use of alternative therapies, herbs, and supplements
occurs at a very high rate among patients attending a
variety of health care settings. Such therapy may cause
significant interactions or effects on hypertension and
other cardiovascular disorders and needs to be considered
by clinicians. In this brief review, we highlight several
commonly used alternative therapies that may have a
clinical impact in the hypertensive patient. Several problems hinder our complete awareness of these effects.
These problems include patients not informing physicians
about alternative treatment or herbal use, the lack of consistent scientific standards for the bioactivity of many
T
herbals or supplements, and the multiple names that each
bioactive substance is sold under. Specific questioning
regarding herbals and alternative therapies in the hypertension clinic is therefore needed. Herbals including ma
huang, St. John’s wort, yohimbine, garlic, and licorice all
may cause important consequences in the hypertensive
patient. Added care is needed in monitoring the use and
effects of herbal and alternative therapies in the hypertensive population. Am J Hypertens 2001;14:971–975
© 2001 American Journal of Hypertension, Ltd.
Key Words: Hypertension, alternative medicines,
ephedra, licorice, St. John’s wort.
he large number of patients taking herbals or alternative therapies suggests a likelihood that interactions of these agents with cardiovascular drugs
will occur. The usage of herbal and nutritional supplements is widespread in the United States with up to 90%
of patients taking either over-the-counter medications or
supplements depending on the definitions used.1 In a recent survey performed in a primary care setting in Alabama,2 41% of patients were taking nutritional supplements and 26% were taking herbal products. The
combined rate of herbal and supplement use and home
remedies (excluding calcium and vitamin supplements)
was 48%. Consistent with other studies, persons with a
higher income and more education were more likely to be
takers of herbal products.2 Studies in other patient populations3–5 have also shown a significant prevalence of
supplement, herb, and other alternative therapy use. It is,
therefore, commonplace for patients attending a medical
care setting to use supplements or herbs. Unfortunately,
most patients do not reveal the use of such treatments to
their health care providers.3 Although there are no data on
the prevalence of use in hypertension clinic populations, it
is likely that such treatments are also widely used in this
population. Therefore, it is important for the physician
treating hypertension and its comorbidities to be aware
of the possibility that patients are taking such therapies
and consider their possible effects on therapeutic goals
and drug–herb interactions. Clinicians should have a
comprehensive source of information detailing herbals,
supplements and their potential uses, side effects and
interactions.
Patients with cardiovascular disease including hypertension deserve special attention with regard to this issue.
Hypertension is very prevalent with some 50 million
Americans diagnosed with hypertension6 and the majority
is taking antihypertensive drugs. Furthermore, there are
now at least six classes of antihypertensive drugs with
their unique mechanisms of action and potential for interactions with supplement and herbal use. Also, because of
the fact that tighter goals for the treatment of hypertension,
hyperlipidemia, and hyperglycemia have been recommended, multidrug therapy is routine for these disorders.
In the case of hypertension, the achievement of goal blood
pressure (BP) especially in high-risk patients with diabetes
or renal disease routinely requires multiple drugs.7 Therefore, not only is it likely that drug– drug interactions will
occur as the number of drugs increases in an individual
patient but also the likelihood that drug–supplement or
drug– herb interactions will occur.
Traditional drug– drug interactions have been described
based on drug absorption, metabolism, elimination, and on
the pharmacodynamic effects and many of these mecha-
Received March 23, 2001. Accepted April 18, 2001.
Address correspondence and reprint requests to Dr. George A. Mansoor, MD, MRCP (UK), Section of Hypertension and Vascular Diseases,
263 Farmington Avenue, Farmington, CT 06030-3940; e-mail:
[email protected]
From the Section of Hypertension and Vascular Diseases, Farmington, Connecticut.
© 2001 by the American Journal of Hypertension, Ltd.
Published by Elsevier Science Inc.
0895-7061/01/$20.00
PII S0895-7061(01)02172-0
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HERBS IN THE HYPERTENSION CLINIC
nisms have been identified and studied. The pharmacokinetic drug interactions are easier to predict and explain,
but multiple factors affect pharmacodynamic interactions.
It is likely also that interactions of herbals and supplements with these agents will also affect the pharmacokinetic or pharmacodynamic properties of antihypertensive
drugs.
This brief review focuses on known and potential herb–
drug interactions of relevance to the physician treating
hypertension. Although the focus is on agents affecting the
treatment of hypertension, reference will be made to other
cardiovascular drugs that are commonly taken by hypertensive patients. The content is not meant to be exhaustive
but to be illustrative and to sharpen awareness of these
possible interactions.
Lack of Regulation of Dietary
and Herbal Supplements
Dietary supplements including vitamins, amino acids, botanicals, and other substances such as pyruvate and steroid
precursors are regulated as foods.8 This stems directly
from the Dietary Supplement Health and Education Act
that does not require governmental oversight of these
products and relies on self-regulation. Only when a specific disease treatment claim is made, Food and Drug
Administration approval is needed. Therefore, manufacturers are mainly responsible for safety and accuracy of
the labeling of such products. Where there has been a
pattern of human use of a substance, safety has been
essentially assumed and no studies before marketing are
needed. This has led to de facto self-regulation in the
industry.
The industry continues to grow at an amazing pace and
sales were estimated in 1999 at some 10 billion dollars.9
The largest chunk of this expenditure is for vitamins
(48%), and herbals and botanicals (28%). Among herbals,
garlic and ginseng each account for about 29% of the
market share with gingko biloba taking 14%.
Difficulties With
Product Identification
There are some very basic problems with some herbals
and supplements. The active product of a particular herb
may not be known or if known may not be on the label.
Furthermore, the amount of the active substance stated
may not be accurate. Quality control measures vary from
company to company and from product to product.
For example, Gurley and colleagues10 compared ephedra amounts on the product label to actual assayed
amounts in 20 ephedra-containing supplements. Ephedra
contains several alkaloids including ephedrine, pseudoephedrine, methyl-ephedrine, nor-pseudoephedrine, and
norephedrine. These substances are sympathomimetic
agents with an amphetamine-like action with varying potencies and are marketed as energy enhancers and weight
AJH–September 2001–VOL. 14, NO. 9, PART 1
loss products. Depending on the manufacturer, the label
may indicate either individual amounts of the various
alkaloids or total amounts, or both. After careful quantitative analysis of the various alkaloids, these researchers
found considerable variability in the content of ephedra.
The amounts of ephedrine varied from 1.09 mg per capsule to 15.33 mg per capsule and pseudoephedrine varied
from 0.16 mg per capsule to 9.45 mg per capsule. Lot-tolot variability was seen in several samples with some
being as high as 1000%. No correlation was found between the claimed amount of ephedra and the actual
amounts found by analysis. These results and other findings11 show that there is suboptimal quality control and
consistency with some products. In addition, these products may contain multiple ephedra alkaloids that may
cause summation adverse effects by acting through similar
mechanisms of action. The authors of this article also point
out that the Food and Drug administration has not approved any product with multiple ephedra-like alkaloids
because of fear of synergistic side effects. In addition,
many herbals also contain caffeine that may increase the
toxicity of ephedra alkaloids. Consumers should consider
buying from manufacturers that have obtained Pharmacopeia standards for product purity and content reliability,
thus at least ensuring some standards are used in
manufacture.
Patient Interview
Because many patients do not consider supplements,
herbs, or alternative treatments as relevant to medical
practice, they may either intentionally or unintentionally
not tell the physician about their use. For example, in a
recent survey completed in an emergency room in a suburban area of New York, 24% of a consecutive sample of
139 patients reported using herbs.3 Most of the patients
who had taken alternative therapies did not inform their
physicians about such use. Similarly, among 755 patients
undergoing preanesthetic evaluation, about one third were
self administering one or more herbs or related compounds
and 70% of these patients did not report this information
on their medical assessment.4 This makes it very important
to ask patients specifically about alternative medicine use
in a nonjudgmental way and after establishing patient
confidence. Inquiry should not only include items bought
over the counter but also items from another country or
bought over the internet or through mail order. An appreciation of the cultural background and beliefs of the patient regarding herbal dietary supplements may help in
establishing trust with the patient. Such history taking is
also important in the hypertension clinic.
Specific Herbs or Supplements
Ephedra or Ma Huang
This is one of the most commonly taken supplements and
is called by a variety of names including ma huang,
AJH–September 2001–VOL. 14, NO. 9, PART 1
ephedra extract, ephedra sinica, ephedra equisetina, ephedra intermedia, ephedra geradiana, ephedra herb powder,
epitonin, or ephedrine. All these names indicate the presence of ephedrine. Ephedra is sold as treatment for asthma,
cold and flu symptoms, and weight loss. Combinations of
other herbals and ephedra are also sold. For example,
herbal phen-fen is marketed as a weight loss supplement
and contains St. John’s wort along with ma huang. It is
very common for caffeine to also be present in these
supplements along with ephedra. Ephedrine stimulates
adrenergic receptors and can increase heart rate and peripheral vascular resistance. It can also act on the central
nervous system giving the individual a feeling of tremendous well-being.
There is due cause for concern about ingestion of
ephedra-containing supplements in persons with hypertension and heart disease. In a recent report, Haller and
Benowitz12 independently reviewed 140 adverse events
related to dietary supplements containing ephedra. These
represented reported cases between June 1, 1997 and
March 31, 1999, in the FDA Medwatch report. The reports
involved persons of all age groups including children.
Thirty-one percent were believed by the independent reviewers to be definitely or probably related to ephedra use,
with another 31% possibly related to ephedra use. In 17%,
the reviewers believed that the event was unrelated to
ephedra use and in another 21%, no opinion could be
rendered due to lack of clinical information. Most of the
events considered possibly, probably, or definitely related
to ephedra use were cardiovascular in nature. Hypertension, tachycardia, or palpitations were the most common
adverse effect in 30% and cardiac arrest in 8% of the total
reports. Strokes also occurred in 10% and seizures in 7%
of all the reports. In 26% of patients, these adverse events
resulted in death or permanent disability. Similarly, in a
2-year period in Texas, some 5000 reports of adverse
effects of dietary supplements containing ephedra were
reported.13
It makes good sense to specifically instruct patients
with hypertension, diabetes mellitus, thyroid disease, cardiac rhythm disorders, and seizures not to take herbals
with ephedra. Drug interactions expected for ephedrine are
also likely with ma huang. In normotensive subjects, the
effects of ma huang on BP and heart rate appear unpredictable,14 but it undoubtedly can precipitate a hypertensive crisis in certain individuals when combined with
caffeine.15
An additional cause of concern for clinicians treating
hypertension is the reported association of kidney stones
with ephedra ingestion.16 Chemical analysis has revealed
these concretions to contain ephedrine and its metabolites.
Renal calculi containing ephedrine have also been found
in patients consuming large amounts of guaifenesin and
ephedrine in over-the-counter preparations.17 It should be
noted that ephedra has also been linked to cases of psychoses,18 mood disorders,18 and myocarditis.19
HERBS IN THE HYPERTENSION CLINIC
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St. John’s Wort
This is a derivative of the plant Hypericum perforatum
used for the treatment of mild depression. It can be obtained as a tea, capsule, or oil. St. John’s wort contains
several active ingredients that have a variety of effects on
neurochemical signals in the central nervous system. It has
undergone significant scientific testing including double
blind clinical trials and is widely used in Germany.20 In a
meta-analysis of 23 randomized trials with St. John’s wort,
it appears to show similar response rates in the treatment
of depression as tricyclic antidepressants and was also
better tolerated.21
The main concern regarding St. John’s wort of particular interest to the hypertension physician is the reported
interaction with several medications including cyclosporin, protease inhibitors, and some cardiovascular drugs.
St. John’s wort has been shown to induce both liver and
intestinal CYP3A.22 This may have clinical consequences
and in a recent report,23 two patients experienced acute
rejection of a heart transplant suggested to be due to
lowering of cyclosporin levels in patients taking St. John’s
wort. Other expected interactions based on the CYP3A
induction would include with digoxin24 and possibly calcium channel blockers.25 Close monitoring is appropriate
if St. John’s wort is taken with substrates of the CYP3A
system.
Garlic
Garlic is commonly used among hypertensive patients
because of its reputed benefit in reducing cardiovascular
disease and lowering BP. Other claims for the benefits of
garlic have included cancer prevention and anti-inflammation. Studies have suggested a multitude of physiologic
effects including inhibition of platelet activity and increased levels of antioxidant enzymes. There are probably
several active ingredients in garlic preparations.
Not surprisingly, several studies have been done to
examine its utility in treating hypertension and hyperlipidemia. In its evidence report, on garlic, the Agency for
Health Care Research and Quality reviewed 37 randomized trials and found that garlic preparations did indeed
lower total cholesterol by small amounts in the short term
but no reduction was observed at 6 months.26 In the
treatment of high BP, 27 small randomized placebo controlled trials of short duration were reviewed. Various
doses of garlic were used providing about 3 to 6 mg of
allicin per day. The majority of these studies found that
garlic did not reduce BP compared to placebo, but the
studies were small. Interestingly, in one cross-sectional
observation study of older patients, garlic intake was
found to reduce age-related increases in aortic stiffness.27
Garlic has been reported to increase the risk of bleeding,28
probably due to its antiplatelet action, but this is not well
studied.
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HERBS IN THE HYPERTENSION CLINIC
Yohimbine
This is a prescription drug that has been available for
about 30 years and has long been known to be present in
the bark of a West African tree. The bark product contains
several alkaloids including yohimbine that may be present
in varying amounts. Yohimbine is a presynaptic ␣2-adrenergic blocking agent and possibly a monoamine oxidase
inhibitor. It also has other effects on the autonomic nervous system. Although not available as an over-thecounter product, it can be found in herbal and supplement
stores and is promoted as treatment for erectile dysfunction.
It has been fairly well documented that yohimbine can
increase BP in humans and should be used with caution if
at all in hypertensive patients.29 The pressor effect of
yohimbine is seen at low (10 mg) and higher doses (22
mg).30,31 One case report implicates yohimbine as the
cause of a hypertensive emergency in a 63-year-old man
taking yohimbine for erectile dysfunction.32 Of additional
concern is the increase seen in norepinephrine with yohimbine use29; a particular concern for patients with coronary artery disease or congestive heart failure. The drug
should also not be used in patients taking tricyclic
antidepressants.
Licorice
Of course, physicians treating hypertension in the United
States should be aware of licorice. It is marketed for the
treatment of stomach disorders and is associated with a
form of pseudoaldosteronism manifesting as weight gain,
hypertension, hypokalemia, and metabolic alkalosis. The
implicated substance is glycyrrhizic acid that inhibits 11␤-hydroxysteroid dehydrogenase33 and hence increased
levels of cortisol that combine with the mineralocorticoid
receptor (an acquired apparent mineralocorticoid excess).
The disorder reverses within a few days on cessation of
intake of licorice but may be associated with hypertensive
encephalopathy34 and chronic refractory hypertension.35,36
Interactions With Drugs
and Drug Metabolism
Many herbs can increase digoxin levels or potentiate the
effects of digitalis. This is because many herbs contain
digitalis-like glycosides.37 Many herbs and supplements
can also affect anticoagulation levels or bleeding times.28
Especially in the case of coumadin that has a narrow
therapeutic range, such interactions may be serious. Indeed several case reports attest to this in patients taking
certain supplements. Some drugs that may increase warfarin anticoagulation include vitamin E, dan-shen, dong
quai, and devils claw, whereas ginseng and coenzyme Q
may reduce its effect.28
Grapefruit juice, although not an herbal in the way it is
used in this article, is also of concern to the hypertension
physician because of its effect on the metabolism of many
cardiovascular drugs. By inhibiting intestinal CYP3A, it
AJH–September 2001–VOL. 14, NO. 9, PART 1
can increase the bioavailability of many substrates of
CYP3A, including immunosuppressive drugs, certain
HMG-Co-A reductase inhibitors, and most dihydropyridine calcium channel blockers.38 The effect is robust and
quick in onset and lasts for up to 24 h after ingestion of the
juice. One glass of 200 mL of juice can significantly
inhibit intestinal CYP3A. The chemical content of grapefruit that causes this effect has been suggested to be
flavonoids and nonflavonoids, although this is by no
means certain. The effect of grapefruit juice was first
discovered with felodipine and other 1,4 dihydropyridine
calcium antagonists are also targets for this interaction.
The effect is much less pronounced in the highly bioavailable drugs amlodipine and nifedipine. There is conflicting
data regarding the non-dihydropyridine drugs, verapamil
and diltiazem.
A more serious problem was reported in which a manufacturing error resulted in a nephrotoxic and carcinogenic
herb (Aristolochia fangchi) being ingested by patients who
later developed interstitial fibrosis and rapid progression to
end-stage renal failure.39 These patients were generally
women who took these herbs to lose weight and some had
prolonged intake. Unfortunately, a substantial number of
these patients developed urothelial carcinomas. This illustrates the serious and widespread problems that may arise
in the manufacture, distribution, and toxicities of herbal
preparations.
Conclusions
It is essential for all physicians treating hypertension to
obtain a history of any herbal, dietary, or supplement use
from all patients. Because of the potency of the effect of
grapefruit juice on several drugs used in hypertensive
patients, specific questioning is needed about this. The
number and complexities of such substances and their
possible interactions with cardiovascular drugs make it
imperative that a written or electronic reference source be
immediately available for consultation. Serious consideration should be given to having all patients attending a
hypertension clinic discuss use of any such products with
their physician before intake. Case reports and case series
of hypertensive emergencies and serious cardiovascular
complications illustrate the serious adverse effects that
may occur. More vigilance is needed in monitoring the use
of herbals, supplements, and other nontraditional medications in the hypertensive population.
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