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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 herbals or supplements, and the multiple names that each
occurs at a very high rate among patients attending a bioactive substance is sold under. Specific questioning
variety of health care settings. Such therapy may cause regarding herbals and alternative therapies in the hyper-
significant interactions or effects on hypertension and tension clinic is therefore needed. Herbals including ma
other cardiovascular disorders and needs to be considered huang, St. John’s wort, yohimbine, garlic, and licorice all
by clinicians. In this brief review, we highlight several may cause important consequences in the hypertensive
commonly used alternative therapies that may have a patient. Added care is needed in monitoring the use and
clinical impact in the hypertensive patient. Several prob- effects of herbal and alternative therapies in the hyperten-
lems hinder our complete awareness of these effects. sive population. Am J Hypertens 2001;14:971–975
These problems include patients not informing physicians © 2001 American Journal of Hypertension, Ltd.
about alternative treatment or herbal use, the lack of con- Key Words: Hypertension, alternative medicines,
sistent scientific standards for the bioactivity of many ephedra, licorice, St. John’s wort.

T
he large number of patients taking herbals or al- and consider their possible effects on therapeutic goals
ternative therapies suggests a likelihood that inter- and drug–herb interactions. Clinicians should have a
actions of these agents with cardiovascular drugs comprehensive source of information detailing herbals,
will occur. The usage of herbal and nutritional supple- supplements and their potential uses, side effects and
ments is widespread in the United States with up to 90% interactions.
of patients taking either over-the-counter medications or Patients with cardiovascular disease including hyper-
supplements depending on the definitions used.1 In a re- tension deserve special attention with regard to this issue.
cent survey performed in a primary care setting in Ala- Hypertension is very prevalent with some 50 million
bama,2 41% of patients were taking nutritional supple- Americans diagnosed with hypertension6 and the majority
ments and 26% were taking herbal products. The is taking antihypertensive drugs. Furthermore, there are
combined rate of herbal and supplement use and home now at least six classes of antihypertensive drugs with
remedies (excluding calcium and vitamin supplements) their unique mechanisms of action and potential for inter-
was 48%. Consistent with other studies, persons with a actions with supplement and herbal use. Also, because of
higher income and more education were more likely to be the fact that tighter goals for the treatment of hypertension,
takers of herbal products.2 Studies in other patient popu- hyperlipidemia, and hyperglycemia have been recom-
lations3–5 have also shown a significant prevalence of mended, multidrug therapy is routine for these disorders.
supplement, herb, and other alternative therapy use. It is, In the case of hypertension, the achievement of goal blood
therefore, commonplace for patients attending a medical pressure (BP) especially in high-risk patients with diabetes
care setting to use supplements or herbs. Unfortunately, or renal disease routinely requires multiple drugs.7 There-
most patients do not reveal the use of such treatments to fore, not only is it likely that drug– drug interactions will
their health care providers.3 Although there are no data on occur as the number of drugs increases in an individual
the prevalence of use in hypertension clinic populations, it patient but also the likelihood that drug–supplement or
is likely that such treatments are also widely used in this drug– herb interactions will occur.
population. Therefore, it is important for the physician Traditional drug– drug interactions have been described
treating hypertension and its comorbidities to be aware based on drug absorption, metabolism, elimination, and on
of the possibility that patients are taking such therapies 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. Man-
soor, MD, MRCP (UK), Section of Hypertension and Vascular Diseases,
From the Section of Hypertension and Vascular Diseases, Farming- 263 Farmington Avenue, Farmington, CT 06030-3940; e-mail:
ton, Connecticut. mansoor@nso1.uchc.edu

© 2001 by the American Journal of Hypertension, Ltd. 0895-7061/01/$20.00


Published by Elsevier Science Inc. PII S0895-7061(01)02172-0
972 HERBS IN THE HYPERTENSION CLINIC AJH–September 2001–VOL. 14, NO. 9, PART 1

nisms have been identified and studied. The pharmacoki- loss products. Depending on the manufacturer, the label
netic drug interactions are easier to predict and explain, may indicate either individual amounts of the various
but multiple factors affect pharmacodynamic interactions. alkaloids or total amounts, or both. After careful quanti-
It is likely also that interactions of herbals and supple- tative analysis of the various alkaloids, these researchers
ments with these agents will also affect the pharmacoki- found considerable variability in the content of ephedra.
netic or pharmacodynamic properties of antihypertensive The amounts of ephedrine varied from 1.09 mg per cap-
drugs. sule to 15.33 mg per capsule and pseudoephedrine varied
This brief review focuses on known and potential herb– from 0.16 mg per capsule to 9.45 mg per capsule. Lot-to-
drug interactions of relevance to the physician treating lot variability was seen in several samples with some
hypertension. Although the focus is on agents affecting the being as high as 1000%. No correlation was found be-
treatment of hypertension, reference will be made to other tween the claimed amount of ephedra and the actual
cardiovascular drugs that are commonly taken by hyper- amounts found by analysis. These results and other find-
tensive patients. The content is not meant to be exhaustive ings11 show that there is suboptimal quality control and
but to be illustrative and to sharpen awareness of these consistency with some products. In addition, these prod-
possible interactions. ucts may contain multiple ephedra alkaloids that may
cause summation adverse effects by acting through similar
Lack of Regulation of Dietary mechanisms of action. The authors of this article also point
and Herbal Supplements out that the Food and Drug administration has not ap-
proved any product with multiple ephedra-like alkaloids
Dietary supplements including vitamins, amino acids, bo- because of fear of synergistic side effects. In addition,
tanicals, and other substances such as pyruvate and steroid many herbals also contain caffeine that may increase the
precursors are regulated as foods.8 This stems directly toxicity of ephedra alkaloids. Consumers should consider
from the Dietary Supplement Health and Education Act buying from manufacturers that have obtained Pharmaco-
that does not require governmental oversight of these peia standards for product purity and content reliability,
products and relies on self-regulation. Only when a spe- thus at least ensuring some standards are used in
cific disease treatment claim is made, Food and Drug manufacture.
Administration approval is needed. Therefore, manufac-
turers are mainly responsible for safety and accuracy of
the labeling of such products. Where there has been a
Patient Interview
pattern of human use of a substance, safety has been Because many patients do not consider supplements,
essentially assumed and no studies before marketing are herbs, or alternative treatments as relevant to medical
needed. This has led to de facto self-regulation in the practice, they may either intentionally or unintentionally
industry. not tell the physician about their use. For example, in a
The industry continues to grow at an amazing pace and recent survey completed in an emergency room in a sub-
sales were estimated in 1999 at some 10 billion dollars.9 urban area of New York, 24% of a consecutive sample of
The largest chunk of this expenditure is for vitamins 139 patients reported using herbs.3 Most of the patients
(48%), and herbals and botanicals (28%). Among herbals, who had taken alternative therapies did not inform their
garlic and ginseng each account for about 29% of the physicians about such use. Similarly, among 755 patients
market share with gingko biloba taking 14%. 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
Difficulties With
on their medical assessment.4 This makes it very important
Product Identification to ask patients specifically about alternative medicine use
There are some very basic problems with some herbals in a nonjudgmental way and after establishing patient
and supplements. The active product of a particular herb confidence. Inquiry should not only include items bought
may not be known or if known may not be on the label. over the counter but also items from another country or
Furthermore, the amount of the active substance stated bought over the internet or through mail order. An appre-
may not be accurate. Quality control measures vary from ciation of the cultural background and beliefs of the pa-
company to company and from product to product. tient regarding herbal dietary supplements may help in
For example, Gurley and colleagues10 compared ephe- establishing trust with the patient. Such history taking is
dra amounts on the product label to actual assayed also important in the hypertension clinic.
amounts in 20 ephedra-containing supplements. Ephedra
contains several alkaloids including ephedrine, pseudo- Specific Herbs or Supplements
ephedrine, methyl-ephedrine, nor-pseudoephedrine, and
Ephedra or Ma Huang
norephedrine. These substances are sympathomimetic
agents with an amphetamine-like action with varying po- This is one of the most commonly taken supplements and
tencies and are marketed as energy enhancers and weight is called by a variety of names including ma huang,
AJH–September 2001–VOL. 14, NO. 9, PART 1 HERBS IN THE HYPERTENSION CLINIC 973

ephedra extract, ephedra sinica, ephedra equisetina, ephe- St. John’s Wort
dra intermedia, ephedra geradiana, ephedra herb powder,
This is a derivative of the plant Hypericum perforatum
epitonin, or ephedrine. All these names indicate the pres-
used for the treatment of mild depression. It can be ob-
ence of ephedrine. Ephedra is sold as treatment for asthma,
tained as a tea, capsule, or oil. St. John’s wort contains
cold and flu symptoms, and weight loss. Combinations of
several active ingredients that have a variety of effects on
other herbals and ephedra are also sold. For example,
neurochemical signals in the central nervous system. It has
herbal phen-fen is marketed as a weight loss supplement
undergone significant scientific testing including double
and contains St. John’s wort along with ma huang. It is
blind clinical trials and is widely used in Germany.20 In a
very common for caffeine to also be present in these
meta-analysis of 23 randomized trials with St. John’s wort,
supplements along with ephedra. Ephedrine stimulates
it appears to show similar response rates in the treatment
adrenergic receptors and can increase heart rate and pe-
of depression as tricyclic antidepressants and was also
ripheral vascular resistance. It can also act on the central
better tolerated.21
nervous system giving the individual a feeling of tremen-
The main concern regarding St. John’s wort of partic-
dous well-being.
ular interest to the hypertension physician is the reported
There is due cause for concern about ingestion of
interaction with several medications including cyclo-
ephedra-containing supplements in persons with hyperten-
sion and heart disease. In a recent report, Haller and sporin, protease inhibitors, and some cardiovascular drugs.
Benowitz12 independently reviewed 140 adverse events St. John’s wort has been shown to induce both liver and
related to dietary supplements containing ephedra. These intestinal CYP3A.22 This may have clinical consequences
represented reported cases between June 1, 1997 and and in a recent report,23 two patients experienced acute
March 31, 1999, in the FDA Medwatch report. The reports rejection of a heart transplant suggested to be due to
involved persons of all age groups including children. lowering of cyclosporin levels in patients taking St. John’s
Thirty-one percent were believed by the independent re- wort. Other expected interactions based on the CYP3A
viewers to be definitely or probably related to ephedra use, induction would include with digoxin24 and possibly cal-
with another 31% possibly related to ephedra use. In 17%, cium channel blockers.25 Close monitoring is appropriate
the reviewers believed that the event was unrelated to if St. John’s wort is taken with substrates of the CYP3A
ephedra use and in another 21%, no opinion could be system.
rendered due to lack of clinical information. Most of the
events considered possibly, probably, or definitely related Garlic
to ephedra use were cardiovascular in nature. Hyperten-
sion, tachycardia, or palpitations were the most common Garlic is commonly used among hypertensive patients
adverse effect in 30% and cardiac arrest in 8% of the total because of its reputed benefit in reducing cardiovascular
reports. Strokes also occurred in 10% and seizures in 7% disease and lowering BP. Other claims for the benefits of
of all the reports. In 26% of patients, these adverse events garlic have included cancer prevention and anti-inflamma-
resulted in death or permanent disability. Similarly, in a tion. Studies have suggested a multitude of physiologic
2-year period in Texas, some 5000 reports of adverse effects including inhibition of platelet activity and in-
effects of dietary supplements containing ephedra were creased levels of antioxidant enzymes. There are probably
reported.13 several active ingredients in garlic preparations.
It makes good sense to specifically instruct patients Not surprisingly, several studies have been done to
with hypertension, diabetes mellitus, thyroid disease, car- examine its utility in treating hypertension and hyperlip-
diac rhythm disorders, and seizures not to take herbals idemia. In its evidence report, on garlic, the Agency for
with ephedra. Drug interactions expected for ephedrine are Health Care Research and Quality reviewed 37 random-
also likely with ma huang. In normotensive subjects, the ized trials and found that garlic preparations did indeed
effects of ma huang on BP and heart rate appear unpre- lower total cholesterol by small amounts in the short term
dictable,14 but it undoubtedly can precipitate a hyperten- but no reduction was observed at 6 months.26 In the
sive crisis in certain individuals when combined with treatment of high BP, 27 small randomized placebo con-
caffeine.15 trolled trials of short duration were reviewed. Various
An additional cause of concern for clinicians treating doses of garlic were used providing about 3 to 6 mg of
hypertension is the reported association of kidney stones allicin per day. The majority of these studies found that
with ephedra ingestion.16 Chemical analysis has revealed garlic did not reduce BP compared to placebo, but the
these concretions to contain ephedrine and its metabolites. studies were small. Interestingly, in one cross-sectional
Renal calculi containing ephedrine have also been found observation study of older patients, garlic intake was
in patients consuming large amounts of guaifenesin and found to reduce age-related increases in aortic stiffness.27
ephedrine in over-the-counter preparations.17 It should be Garlic has been reported to increase the risk of bleeding,28
noted that ephedra has also been linked to cases of psy- probably due to its antiplatelet action, but this is not well
choses,18 mood disorders,18 and myocarditis.19 studied.
974 HERBS IN THE HYPERTENSION CLINIC AJH–September 2001–VOL. 14, NO. 9, PART 1

Yohimbine can increase the bioavailability of many substrates of


CYP3A, including immunosuppressive drugs, certain
This is a prescription drug that has been available for
HMG-Co-A reductase inhibitors, and most dihydropyri-
about 30 years and has long been known to be present in
dine calcium channel blockers.38 The effect is robust and
the bark of a West African tree. The bark product contains
quick in onset and lasts for up to 24 h after ingestion of the
several alkaloids including yohimbine that may be present
juice. One glass of 200 mL of juice can significantly
in varying amounts. Yohimbine is a presynaptic ␣2-adren-
inhibit intestinal CYP3A. The chemical content of grape-
ergic blocking agent and possibly a monoamine oxidase
fruit that causes this effect has been suggested to be
inhibitor. It also has other effects on the autonomic ner-
flavonoids and nonflavonoids, although this is by no
vous system. Although not available as an over-the-
means certain. The effect of grapefruit juice was first
counter product, it can be found in herbal and supplement
discovered with felodipine and other 1,4 dihydropyridine
stores and is promoted as treatment for erectile dysfunction.
calcium antagonists are also targets for this interaction.
It has been fairly well documented that yohimbine can
The effect is much less pronounced in the highly bioavail-
increase BP in humans and should be used with caution if
able drugs amlodipine and nifedipine. There is conflicting
at all in hypertensive patients.29 The pressor effect of
data regarding the non-dihydropyridine drugs, verapamil
yohimbine is seen at low (10 mg) and higher doses (22
and diltiazem.
mg).30,31 One case report implicates yohimbine as the
A more serious problem was reported in which a man-
cause of a hypertensive emergency in a 63-year-old man
ufacturing error resulted in a nephrotoxic and carcinogenic
taking yohimbine for erectile dysfunction.32 Of additional
herb (Aristolochia fangchi) being ingested by patients who
concern is the increase seen in norepinephrine with yo-
later developed interstitial fibrosis and rapid progression to
himbine use29; a particular concern for patients with cor-
end-stage renal failure.39 These patients were generally
onary artery disease or congestive heart failure. The drug
women who took these herbs to lose weight and some had
should also not be used in patients taking tricyclic
prolonged intake. Unfortunately, a substantial number of
antidepressants.
these patients developed urothelial carcinomas. This illus-
Licorice trates the serious and widespread problems that may arise
in the manufacture, distribution, and toxicities of herbal
Of course, physicians treating hypertension in the United preparations.
States should be aware of licorice. It is marketed for the
treatment of stomach disorders and is associated with a Conclusions
form of pseudoaldosteronism manifesting as weight gain,
It is essential for all physicians treating hypertension to
hypertension, hypokalemia, and metabolic alkalosis. The
obtain a history of any herbal, dietary, or supplement use
implicated substance is glycyrrhizic acid that inhibits 11-
from all patients. Because of the potency of the effect of
␤-hydroxysteroid dehydrogenase33 and hence increased
grapefruit juice on several drugs used in hypertensive
levels of cortisol that combine with the mineralocorticoid
patients, specific questioning is needed about this. The
receptor (an acquired apparent mineralocorticoid excess).
number and complexities of such substances and their
The disorder reverses within a few days on cessation of
possible interactions with cardiovascular drugs make it
intake of licorice but may be associated with hypertensive
imperative that a written or electronic reference source be
encephalopathy34 and chronic refractory hypertension.35,36
immediately available for consultation. Serious consider-
ation should be given to having all patients attending a
Interactions With Drugs hypertension clinic discuss use of any such products with
and Drug Metabolism their physician before intake. Case reports and case series
of hypertensive emergencies and serious cardiovascular
Many herbs can increase digoxin levels or potentiate the
complications illustrate the serious adverse effects that
effects of digitalis. This is because many herbs contain
may occur. More vigilance is needed in monitoring the use
digitalis-like glycosides.37 Many herbs and supplements
of herbals, supplements, and other nontraditional medica-
can also affect anticoagulation levels or bleeding times.28
tions in the hypertensive population.
Especially in the case of coumadin that has a narrow
therapeutic range, such interactions may be serious. In-
deed several case reports attest to this in patients taking References
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