Keywords

Medicinal plants; Hypertension; Interactions of medicinal plants

Introduction

Systemic arterial hypertension is a multifactorial clinical condition characterized by sustained high levels of blood pressure, and is often associated with functional and/or structural changes in target organs, and metabolic changes with consequent increased risk of cardiovascular events [1].

The circulatory system is endowed with a complex mechanism for controlling the blood pressure, which is determined approximately by the ratio between the volume of total flow and systolic arterial distensibility tree. Any condition that affects the movement either of these two factors will also affect blood pressure [2,3].

Initially, systemic arterial hypertension is asymptomatic in almost all patients, yet its chronic and largely silent nature affects patient’s quality of life, bringing consequences such as admissions for technical procedures of high complexity, deaths and early retirements [3].

According to the Ministério da Saúde (Brazil), hypertensive patients are defined by asystolic blood pressure equal or superior to 140 mmHg, and a diastolic blood pressure greater than or equal to 90 mmHg; these values being found in at least in two measurements taken within the same clinic visit and within close proximity of each other [4].

Treatment for hypertension includes, besides the use of drugs, modification of lifestyle [5] and the main objective is not to reduce symptoms, since almost all patients are asymptomatic, but to prevent cardiovascular complications [6]. The main classes of drugs available for treatment of hypertension are diuretics, sympatholytics, vasodilators, and calcium channel blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor II blockers and direct renin inhibitors [7].

Despite the recognition of hypertension as a public health problem, its adequate control is far from being achieved. This is mainly due to failure of prescribed treatments, including noncompliance, and also associated with other factors such as side effects and cost, prompting the patient, in many cases, to make use of complementary and alternative therapies. Among them, phytotherapy is considered a strategy of low cost and free of side effects. However, in many cases, it can further compromise blood pressure control [8].

Herbal medicine is characterized by the use of medicinal plants or plant parts containing substances or classes of substances responsible for their therapeutic action after collection processes, stabilization when applicable, and drying, and may exist in full form, grodd and chopped [4]. Co-administration of medicinal plants along with prescription medications can cause unexpected interactions [9] through carelessness in relation to their use, often driven by philosophies of life, personal and cultural customs. Some of these factors derive from patients, but may also arise through health professionals without expertise in this area [10].

Therefore, this study aimed to review the literature on medicinal plants that may cause changes in blood pressure and crossreference established knowledge concerning interactions resulting from concomitant use of these plants with antihypertensive medications, trying to understand and classify these interactions and identify the compounds responsible for them.

Materials and Methods

This work included a literature search through articles, magazines, periodicals, monographs, dissertations and theses, published in the last 16 years (1998-2014). In some situations this time frame was expanded due to a lack of information.

For this work, the identification of medicinal plants that can cause changes in BP was achieved through literature listed in Instruction No. 5 of 2010 [4] and from other sources available in the Professor Eurico Back Library - UNESC, using the search terms ‘hypertensive’, ‘hypotensive’, ‘anti-hypertensive’ and ‘blood pressure’, and their appropriate translations. To survey plant/ drug interactions, research was also carried out using Medline, PubMed, Science Direct, academic Google and Scielo, using the terms ‘antihypertensive drugs’ (antihypertensives), ‘high blood pressure’ (hypertension) and ‘drug interactions’, associated with the scientific name of plants identified as causing blood pressure alterations.

Results and Discussion

Fifty-six different literature sources were consulted and out of these, 31 (55.3%) contained information on medicinal plants affecting blood pressure, including 138 individual species. Among these, 84 (60.9%) were reports of popular use and 78 (56.5%) detailing scientific studies performed in vitro, in vivo or in humans (Table 1). In the Tables, medicinal plants that have a documented effect on blood pressure as reported through popular use are indicated with an asterisk (*).

Table 1: Medicinal plants with documented ability to effect changes in blood pressure.

The literature review was conducted using the scientific name (Latin binomial) avoiding unreliable information, since the same plant can have many common names in different regions and the same popular name may be used for different species. For medicinal plants with more than one scientific name, a search was performed for all synonymies.

In this work, a plant's effect on blood pressure was classified as hypotensive when it causes a reduction in blood pressure and hypertensive when it causes a blood pressure increase. For plants identified through popular use, hypotensive actions have been reported in 82 (97.6%), and hypertensive actions in 2 (2.4%), whereas for those identified through scientific studies, hypotensive actions have been reported in 68 (87.2%) and hypertensive actions in 10 (12.8%).

The effects of medicinal plants on blood pressure are due to the presence of diverse secondary metabolites. Secondary metabolites are substances that the plant synthesizes and stores during its growth, and usually in any given plant comprise several active components, of which one or a group determines the main action or pharmacological activity [11].

We have focused our discussion of the mechanism(s) of action of identified plants on blood pressure on those cited in more than three references. Relevant species in popular use include: Alpinia zerumbet, Cymbopogon citratus, Eugenia uniflora L. (12.9%), Cuphea carthagenensis (16.1%) and Allium sativum L. (29%). Those identified in scientific studies include: Pausinystalia johimbe (12.9%), Olea europaea L. (16.1%), Crataegus oxyacantha, Viscum album L. (19.3%), Rauvolfia serpentina (22.5%) and Allium sativum L. (45.1%).

In pharmacological tests, it has been shown that the antihypertensive action of Alpinia zerumbet is related to the presence of flavonoids and a vasodilatory action through the release of nitric oxide stimulated by bradykinin via the beta 2 receptors [12,13]. This same vasodilator effect has been used to justify the hypotensive effect attributed to the plant Cuphea carthagenensis [14].

For Eugenia uniflora L., one study suggests that its hypotensive effect is mediated by both a direct vasodilating action and a weak diuretic effect which could be related to an increase in renal blood flow [15]. Although these actions have been proven, the chemical compounds responsible have not yet been described [16].

Cymbopogon citratus has been reported to be responsible for changing blood pressure, and there are scientific studies on its hypotensive effects. This plant induces hypotension probably due to decreased vascular resistance which may be caused by inhibition of calcium influx. The compounds responsible for this have not been reported [17].

A vasodilatory effect through calcium channel blockade is also attributed to the hypotensive effect of Panax ginseng [18], whose vasodilation may also be mediated through nitric oxide release and a depressive action on the central nervous system due to its ginsenosides. This plant exhibits a peripheral vasoconstrictor effect at low doses and peripheral vasodilation at high doses. It seems that these effects are due to the presence of saponins [19].

The set of sulfur compounds, particularly allicin, which has vasodilatory effect, maybe responsible for the hypotensive effect of Allium sativum, the most cited plant in theliterature with activity on blood pressure. However, fructosans, through their diuretic effect, may act as adjuvants [20-24].

Oligomeric flavonoids, as procyanidins, present in plants such as Crataegus laevigata, exert vasodilatory effect with consequent reduction in blood pressure [25,26]. Crataegus laevigata also has its hypotensive activity justified by the presence of amines in their fresh flowers, as tyramine [20] and by angiotensin converting enzyme inhibition [27].

Pausinystalia johimbe contains the alkaloid yohimbine, known as an antagonist of the alpha 2-adrenoceptor [11,28,29]. Hypertension induced by this plant may be the result of increased activity of the sympathetic nervous system, changes in renal blood flow and retention of salt and water [30].

The alkaloid reserpine, among others, is present in Rauvolfia serpentina, which causes a reduction in blood pressure by interfering with the action of central neurotransmitters [20,23]. Reserpine lowers blood pressure by decreasing cardiac output, peripheral vascular resistance, heart rate and rennin [31].

Viscum album L. has hypotensive effects due to the presence of some flavonoids with diuretic action and vasodilator amines that act in the vasomotor centre, such as histamine, tyramine and choline, also present in Phytolacca Americana L. and Capsella bursa-pastori [20,25]. The vasodilatory effect of Viscum album can also be related to inhibition of calcium channels [8].

The hypotensive effect of an aqueous extract of Olea europaea L. is demonstrated by inhibition of angiotensin converting enzyme, an effect attributed to the metabolite oleacina [24]. Its metabolite oleoeuropeoside has demonstrated vasodilatory action [20].

Regarding the hypotensive action of Melissa officinalis and Lippia alba, it was assumed that hypotension occurs through vasodilatation, since it is known that a stressed state, heart rate, blood flow and consequently raising blood pressure [32].

Certain medicinal plants have differential effects on blood pressure depending on the part used and the method of preparation. As an example, Foeniculum vulgare has a hypotensive effect only when its extracts are subjected to boiling, suggesting that the active ingredient may be a metabolite produced upon heat transformation. Another such example is Uncaria sinensis, as researchers have shown that excessively long cooking reduces its antihypertensive potential, and also that the thorns on the branches do not possess pharmacological activity. This demonstrates the importance of retention of knowledge related to medicinal plant use [33].

Based on the literature, we found 22 (15.9%) medicinal plants with demonstrated interactions with antihypertensive drugs, interfering with the therapeutic efficacy of these drugs and consequently, in regulating blood pressure (Table 2). Among these, 1(4.6%) was reported through popular use only to have an effect on blood pressure, 5 (22.7%) were reported through both popular use and by scientific studies, while16 (72.7 %) were reported to have an effect on the blood pressure by scientific studies.

Table 2: Possible interactions between medicinal plants that may alter blood pressure and concomitant antihypertensive medication.

These highlighted interactions were based on results of research and studies conducted by experimental models and the potential interaction was classified as follows: enhanced when the plant: drug combination causes increased effect (↑), and antagonized when the plant: drug combination cause decreased effect of the drug (↓).

The interactions of medicinal plants with antihypertensive drugs identified to be most widely documented through this study were those involving Crataegus oxyacantha, Ginkgo biloba and Pausinystalia johimbe. However, other medicinal plants with effects on blood pressure, as evidenced by scientific studies, may also display the potential to interact with this drug class, and there is need for further studies related to this subject.

We can observe that an antihypertensive can have its effects antagonized (27.3%) when used with medicinal plants with hypertensive activity, thus leading to vasoconstriction and fluid retention, or, in some cases, potentiated, (72.7%) when used with plants with hypotensive activity, in turn leading to vasodilation and/or diuretic actions. For a more in depth understanding of these reports we cite as an example the interactions between antihypertensive medications and Allium sativum and Pausinystalia johimbe.

For Alexandre et al. [34] the possible interaction between Allium sativum and antihypertensive medication such as angiotensin converting enzyme inhibitors can be explained by the fact that the sulfur compounds in garlic may mediate nitric oxide release, enhancing the hypotensive effect of the drug when used concomitantly. This same mechanism of interaction maybe attributed to other medicinal plants with vasodilating action.

Pausinystalia johimbe has an alkaloid known as yohimbine that is antagonist alpha 2-adrenoceptor, so it causes interaction with antihypertensive drugs that actin the same place, antagonizing its effects and increasing blood pressure [28,29,35].

It can be seen that interactions between conventional drugs, in this case the antihypertensive, and the chemical components present in herbals, occur and can affect the absorption, distribution, metabolism and excretion of the drug, resulting in broadening or reducing the expected effects and the mechanisms [34].

The popular belief that herbal medicines do not cause negative health effects needs to be clarified with patients and a clear assessment of need on a cost versus benefit analysis of their use is always warranted, as with any other medication [36].

It is incumbent on a country's health authorities to provide for the means to ensure the correct use of safe and effective medicinal plants through supplementary measures to current pharmaceutical legislation, such as the regulation of registration, production and marketing of the herbal industry, from the application of standards at the plant selection level, through cultivation, correct use and development of quality control techniques [21].

Patients should be reminded to report all medications that they take, whether or not they are conventional or alternative, because the use of undeclared medication may result in public health problems such as leading to significant delays inappropriate care and selection of optimal therapy [28].

Given the prevalence of cardiovascular diseases, including hypertension, in the population, and the myriad of natural products that have pharmacological effects on cardiovascular parameters, this review highlights the need for caution in the combined and particularly undeclared use of such substances. Pharmacists are in an optimal position to advice on concomitant medications, and should always enquire as to all herbal and other supplements patients are taking as part of every consultation. As with any suspected case of drug interactions, those that occur between conventional drugs and herbs should be reported to the relevant authorities [28,37-64].

Conclusion

This study reviewed the risks of concomitant use of medicinal plants with anti-hypertensive drugs for patients with hypertension. Most plants that cause changes in blood pressure, both through reports of popular use and by scientific studies, have hypotensive action (97.6 and 87.2%) respectively, with the most reported species from both sources being Allium sativum (29 and 45.1%). Of those plants with the potential for interaction with antihypertensive drugs the most common effect of concomitant use was blood pressure elevation (72.7%). Among those medicinal plants that cause changes in blood pressure reported through the popular use, 24 (28.5%) has their hypotensive effects borne out by scientific studies, with 5 (20.8%) having demonstrable interaction with antihypertensive medication.

Based on these results, we suggest the need for further studies on popular medicinal plants that can cause blood pressure changes and their possible interactions with antihypertensive drugs, especially regarding the mechanistic aspects of such interactions. Another important recommendation is the development of further education resources for health professionals, so that they can guide the population of risk, since many patients ignore these issues when making concomitant use of drugs and medicinal plants.

A significant number of medicinal plants may cause changes in blood pressure, regardless of their therapeutic use, and although they may offer, depending on their chemical constituents, potential treatments for cardiovascular diseases including hypertension, they may also have unintended effects including serious consequences for users.

Acknowledgments

This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) and Conselho nacional de desenvolvimento científico e tecnológico (CNPq) and Fundação de Amparo à pesquisa de Santa Catarina (FAPESC).

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