Chinese Traditional Medicine Journal Guideline based ... · Wong, et al.:Guideline based approach...

CTMJ | traditionalmedicinejournals.com Chinese Traditional Medicine Journal | 2020 | Vol 3 | Issue 3 1

Guideline based approach for the management of essential hypertension and hypertensive Crises via Traditional Chinese

Medicine: a systematic review

Lin ho Wong1,2, MB BCh BAo, Louisa Tay1, TCM student, Pang ong Wong2,3, Phd1Singapore College of Traditional Chinese Medicine, Singapore, 2Ong Fujian Chinese Physician Hall, Singapore,

3Changchun University of Chinese Medicine, China

BACKGRound

Hypertension, caused by multifactorial factors, is one of the leading causes of cardiovascular diseases and mortality worldwide.1 It usually results in a wide range of complications such as Chronic Kidney Disease, stroke, cardiovascular and peripheral vascular diseases.2 These complications are usually preceded by pressure induced end-organ injury such as left ventricular injury, proteinuria or renal insuffi ciencies.3 Studies have shown that patients who experience a reversal of night time blood pressure dipping frequently results in a poorer

outcome than those of normal dipping status. The dipping status is in turn affected by seasonal variations and racial profi le of the patients.4,5 It is therefore of paramount importance to ensure that patients receive adequate and appropriate management for their blood pressure individualised according to their age, location and racial profi le.

Management of hypertension for Western Medicine has been well established by the National Institute for Health and Care Excellence (NICE) guidelines which is based on a stepwise approach taking into account the age, comorbidities and race of the patients to provide individualised care, thus improving outcomes and reducing mortality.6 The NICE guideline was recently updated in August 2019, little has however changed as the guidelines maintain the threshold of management of blood pressure to

ABsTRACT

Background: Hypertension is a medical condition characterised by an elevation of blood pressure which frequently affects organs like the kidney, heart, and brain. Despite the presence of well-defi ned western medical guidelines for managing hypertension, Traditional Chinese Medicine (TCM) has yet to establish a similar standardized approach. The aim of this paper is to review existing data regarding known mechanisms of action (MOA) of TCM, through that assist in the understanding of possible drug-herb interactions and propose the standardization of clinical prescriptions and management to improve patient safety and possible synergism in the long term. search strategy: We searched through 4 databases (EMBASE, Pubmed, Wanfang and China National Knowledge Infrastructure (CNKI)) for commonly prescribed herbs for hypertension to identify possible antihypertensive effects, regardless of pharmacological mechanism. eligibility Criteria: We included studies that stated the MOA of individual herbs when used for treating Essential Hypertension, excluding them if they are described as part of a formula. Results: We identifi ed 29 commonly prescribed herbs for hypertension, of which 19 had previous research on MOA, and categorized them according to their MOA. Herbs prescribed by TCM clinicians consist of similar MOA as drugs for managing hypertension. Through the understanding of MOA, a 4 steps approach based on the National Institute for Health and Care Excellence (NICE) guidelines was proposed for the management of Essential Hypertension considering the patient’s age and race. Subsequently, the management of Hypertensive urgency/emergency was suggested. Direct vasodilating (e.g. Ligusticum chuanxiong hort) or beta blocker mimetics (e.g. Pueraria montana) were considered for critically ill patients, Angina and Pulmonary Edema whereas Calcium Channel Blocker mimetics (e.g. Senna obtusifolia and Panax notoginseng) were considered for neurological emergencies. Beta blocker or direct vasodilating mimetics were also considered for patients with Hypertensive urgency. Conclusion: The standardization of approach for management of hypertension will reduce prescription ambiguity, improve patient safety and likely outcome.

Keywords: Traditional Chinese Medicine, Mechanism of Action, Hypertension, Hypertensive urgency, Guidelines

Chinese Traditional Medicine Journal

*Correspondence to:Lin Ho Wong, 259 Joo Chiat Road, Singapore 427513. E-mail: [email protected]

Wong, et al.: Guideline based approach for management of hypertension


be 140/90 mmHg despite a lowering of criteria by American Heart Association (AHA).7

Despite readily available guidelines for western medicine, there has been no standardization of management in Traditional Chinese Medicine (TCM) as it has been based traditionally on a “Syndrome based” approach which frequently results in varying efficacy. It can potentially be dangerous in an event of acute hypertensive crises where immediate reduction of blood pressure or management of other complications are required to prevent a further deterioration of the condition. This review aims to elucidate the underlying mechanism of action (MOA) for commonly used TCM herbs for the management of hypertension along with their side effects and possible contraindications based on their MOA. Through the understanding of commonly used herbs, we will attempt to establish a proper guideline-based approach based on NICE guidelines for the management of hypertension as well as Hypertensive urgency and emergencies via the use of TCM. Through the establishment of proper guidelines, we aim to provide TCM clinicians with a standardized management protocol and ensure the safety profile for patients undergoing treatment. This will also ensure that patients receive an adequate and appropriate management during acute hypertensive crises, thus reducing the possibility of any adverse outcome.

MeThods

Criteria for Considering studies for this Review

Types of studies

All studies eliciting the mechanism of action of a specific herb for the management of essential hypertension, regardless of model. Studies which involved the use of multiple herbs simultaneously (i.e. formulas) or management of secondary or gestational hypertension were excluded.

Search Methods for Identification of Studies

Electronic searches

For this review we searched EMBASE, Pubmed, Wanfang and China National Knowledge Infrastructure (CNKI).

Identifying the herbs

We first conducted a search to identify herbs which are currently commonly prescribed by TCM clinicians by identifying systematic reviews on frequently used herbs or formulas and extracted the relevant herbs from the formulas, using the terms “Hypertension AND TCM OR Traditional Chinese Medicine OR alternative medicine” in EMBASE, Pubmed, CENTRAL, Wanfang and CNKI (Figure 1).

We then extracted the latin and Mandarin names of the herbs used and identified those used primarily for the treatment of Essential Hypertension, before searching electronic databases for their mechanisms of action (Figure 2). Herbs prescribed for supportive treatment were excluded.

Pubmed And eMBAse

CNKI (overseas CNKI) And Wanfang (based on the translations of the keywords used in English medium)

1 “Uncaria rhynchophylla” AND “Hypertension” 2 “Eucommia ulmoides” AND “Hypertension” 3 “Prunella vulgaris” AND “Hypertension” 4 “Chrysanthemum indicum” AND “Hypertension”5 “Senna obtusifolia” AND “Hypertension” 6 “Gastrodia elata” AND “Hypertension” 7 “Crataegus pinnatifida” AND “Hypertension” 8 “Salvia miltiorrhiza” AND “Hypertension” 9 “Ligusticum chuanxiong hort” AND “Hypertension” 10 “Achyranthes bidentata” AND “Hypertension” 11 “Pueraria montana” AND “Hypertension” 12 “Apocynum venetum” AND “Hypertension” 13 “Paeonia sterniana” AND “Hypertension” 14 “Panax notoginseng” AND “Hypertension” 15 “Ast raga lus propinquus Schischkin” AND

“Hypertension” 16 “Codonopsis pilosula” AND “Hypertension” 17 “Alisma orientalis(Sam.) Juzep” AND “Hypertension” 18 “Scutellaria baicalensis Georgi” AND “Hypertension” 19 “Taxillus chinensis” AND “Hypertension” 20 “Angelica sinensis” AND “Hypertension” 21 “Haliotis discus hannai” AND “Hypertension” 22 “Poria cocos” AND “Hypertension”23 “Paeonia suffruticosa Andr.” AND “Hypertension” 24 “Fallopia multiflora” AND “Hypertension” 25 “Carthamus tinctorius L.” AND “Hypertension” 26 “Concha Ostreae” AND “Hypertension” 27 “Glycyrrhiza Uralensis” OR “licorice root” AND

“Hypertension” 28 “Pheretima aspergillum” AND “Hypertension” 29 “Alpinia oxyphylla Miq” AND “Hypertension”

We did not impose any language or publication restrictions.

data Collection and Analysis

Selection of studies

The authors (LH, L) reviewed the titles, abstracts and keywords of all records retrieved to determine the studies to be assessed. We retrieved full articles for further assessment if the information given suggested that the study: 1. Discussed essential hypertension,2. And administered any of 29 Chinese herbs identified

through the initial search.



Latin name Mandarin name Mechanism of actionUncaria rhynchophylla

Gou Teng Murine Model:1) Regulation of RAAS and SNS by regulating vascular endothelium

contraction, Angiotensin II, Endothelin-1 (ET-1) and Nitric Oxide. Promotes expression of ACE-Ang1-7-mas-AKT signaling pathway and enhances Kallikrein gene.

2) Regulation of vascular remodeling reduces serum CRP, MCP-1 and MMP-9 protein.

3) Acts on NO/sGC/cGMP and PGI2 (endothelium-derived relaxing factors), G protein-coupled M3- and β2 receptors, regulation of membrane potential through VG Ca2+channel, intracellular Ca2+ released from IP3R, and all potassium channels except the Kca channel.

Eucommia ulmoides

Du Zhong Murine Model:1) Regulates endothelin-1, EDGF, PGI2, Angiotensin II and ET-12) Increases serum NO and ET levels, SOD activity and reduces serum MDA level.3) Effects produced by 30, 60 mg/kg reduced blood pressures by 37±9, 57±4

mmHg respectivelyHuman Model:

1) Reduces eNOS and ET-12) Reduces BP via beta-adrenergic blocking activity.

Prunella vulgaris Xia Gu Cao Murine Model:1) Reduces Angiotensin II, Noradrenaline, ET, Thromboxane B22) Reduces BP duration: 2-7h depending on dosage.

Effects produced by 10g/kg: 3.26/2.08 mmHg, 5g/kg: 7.2/2.76 mmHg and 2.5g/kg: 4.28/3.4 mmHg respectively.

Human Model:Lowers ET-1, increases NO

Senna obtusifolia

Jue Ming Zi Murine Model:1) Reduces aldosterone, Renin and Angiotensin II2) Inhibits Voltage Gated Calcium Channels and increases NO

Gastrodia elata Tian Ma Murine Model:1) Reduces angiotensin II and expression of Angiotensinogen mRNA2) Inhibits Calcium influx and release and significantly enhances production of Nitric oxide and activities of NO synthase.

Human Model:Reduces ET and ATII 2.

Crataegus pinnatifida

Shan Zha Murine Model:1) Inhibits ACE2) Reduces the synthesis and release of ET and enhancing NOS activity

Human model:1) Reduces ET, Angiotensin II2) Decreases homocysteine

Salvia miltiorrhiza

Dan Shen In vitro:1) Decreases cytosolic free Calcium 2) Decreases TGF-B1, Angiotensin II, increases SOD

Ligusticum chuanxiong hort

Chuan Xiong Human Model:Decreases ET-1, increases NO

Pueraria montana

Ge Gen Human Model:1) Beta blocker like effect2) Reduces ET

Apocynum venetum

Luo Bu Ma Murine Model:1) Acts as diuretic, natriuretic and kaliuretic2) Increases Na, K, Cl secretion, time to effect 5-8h, reduces BP 15mmhg3) Releases NO and protects from the scavenging actions of the SOA.4) Inhibits Angiotensin II via SOA scavenging properties and Nitric oxide

releasing effect.

Table 1: Summary of mechanism of actions of commonly used herbs for hypertension

(Contd...)



Latin name Mandarin name Mechanism of actionPanax notoginseng

San Qi In vivoActs on Ginsenoside Rb1 and Rg1, activating NO by modulating PI3K/Akt/eNOS pathway and l-arginine transport in endothelial cells.Vasodilatory effect of PN95 was elicited via the NO/sGC/cGMP and β2-adrenergic receptors pathways.Murine Model:

1) Reduces ET-1 and improves vascular cell function2) Increases NO and SOD in kidneys and inhibits inflow of Calcium causing

vasodilationIn vitro

1) Lowers the cell proliferation by Noradrenaline and lowers Intracellular Calcium

2) Inhibits Calcium influx of platelets from essential hypertension and blocks Voltage Gated Calcium channels

3) Ginsenoside-Rd concentration-dependently inhibited endothelin-1 induced BAVSMC proliferation and Mn(2+) quenching rate within the same concentration range as required for inhibition of increased SOCC- or ROCC-mediated Ca(2+) entries during hypertension.

Alisma orientalis(Sam.)Juzep

Ze Xie Murine Model:Downregulates AT1R and AT2R mRNA expressionIn vitro:Reduces blood pressure by downregulating Angiotensin II-NADPH-ROS signaling pathway.Review:

1) Inhibits aldosterone regulated sodium absorption, Renin-angiotensin system and NO signal transduction.

2) Downregulates the RAAS system, regulates K+/NA pumps, causing potassium sparing diuresis.

Scutellaria baicalensis Georgi

Huang Qin In vivo:Attenuates angiotensin II and KCL induced vasoconstriction.

Angelica sinensis

Dang Gui Murine Model:1) Up regulates the expression of miR1222) Reduces the level of Renin and Angiotensin II.

Haliotis discus hannai

Shi Jue Ming Murine Model:Reduces Noradrenaline, Adrenaline, Angiotensin II and Aldosterone levels.

Carthamus tinctorius L.

Hong Hua Human Model1) Reduces Aldosterone, Angiotensin I and II.2) Reduces ET and Thromboxane A2 while increasing NO, 6-keto-PGF 1a.

Concha Ostreae Mu Li Murine Model:Exerts anti-hypertensive effect via ACE inhibition.

Glycyrrhiza Uralensis

Gan Cao Murine Model:Increases systolic blood pressure significantly. Causes the hyperplasia of smooth muscle cells and hypertrophy in arterioles. Inhibits the expression of 11HSD2and CYP11B2 mRNA.Review

1) Increases blood pressure via the inhibition of glucocorticoid inactivation,excitement of mineralocorticoid receptors,reduction of vasodilator release,and promotion of vasoconstriction

2) Induces psuedohyperaldosteronism. Pheretima aspergillum

Di Long Murine Model:1) Reduces level of renin, angiotensin II, aldosterone, Angiotensin I Receptor

mRNA, TGF-B1 and VEGF protein expression.2) Inhibits AngII-TLR4/NF-κB pathway and increasing IL-103) Reduces catecholamine and renalase.

Table 1: (Continued)



Figure 1: Study flow diagram for the identification of commonly used herbs for Essential Hypertension

A third review author (PO) acted as arbiter and resolved any differences in opinion.

data Analysis

We first identified the herbs that are frequently prescribed by TCM clinicians for treating hypertension. We then categorised the herbs according to their mechanisms of action, (Table 1) and plotted a schematic representation of them based on their clinical pharmacology. (Figure 3) We subsequently proposed a guideline for the management of Essential Hypertension (EH), Hypertensive urgencies and emergencies based on existing guidelines (e.g. NICE guidelines). (Figures 4 and 5)

ResuLTs

Results of the search to Identify herbs of Interest

Our initial searches in online databases identified 8126 studies, of which 123 systematic reviews were relevant to our topic, yielding 29 herbs. (Figure 1)

Included herbs

Herbs included Uncaria rhynchophylla,8-11 Eucommia ulmoides,12-15 Prunella vulgaris,16-18 Senna obtusifolia,19,20 Gastrodia elata,21-23 Crataegus pinnatifida,24-27 Salvia miltiorrhiza,28-32 Ligusticum chuanxiong hort,33 Pueraria montana,34-37 Apocynum venetum,38-41 Panax notoginseng,42-49



Table 2: Classification of herbs based on known mechanisms of action for the management of

hypertension.direct Mechanisms of Action targeting blood pressure

Latin names of herbs

Angiotensin Converting Enzyme Inhibitor(ACEI)/Angiotensin II Receptor Blocker (ARB) mimetics

Prunella vulgarisCrataegus pinnatifidaScutellaria baicalensis GeorgiAngelica sinensis ‎Haliotis discus hannaiCarthamus tinctorius L.Concha OstreaePheretima aspergillum

Diuretics mimetics (Thiazide/Loop)

Apocynum venetum

Potassium sparing diuretic mimetics (Spironolactone-like)

Alisma orientalis(Sam.)Juzep

Calcium Channel Blocker (CCB) mimetics

Senna obtusifoliaPanax notoginseng

Beta-blocker mimetics Pueraria montanaACEI/ARB and CCB mimetics

Uncaria rhynchophyllaGastrodia elataSalvia miltiorrhiza

ACEI/ARB and Beta-blocker mimetics

Eucommia ulmoides

Direct vasodilator (acting on Nitric Oxide) mimetics

Ligusticum chuanxiong hort

Alisma orientalis(Sam.) Juzep,50-53 Scutellaria baicalensis Georgi,54 Angelica sinensis,55,56 Haliotis discus hannai,57 Carthamus tinctorius L.,58,59 Concha Ostreae,60,61 Glycyrrhiza Uralensis62-64 and Pheretima aspergillum.65-67

Results of the search for herb Mechanisms of Action

Included studies

Searching online databases yielded 10114 studies, of which 174 met the inclusion criteria. (Figure 2) No studies were found for the herbs Chrysanthemum indicum, Achyranthes bidentata, Paeonia sterniana, Astragalus propinquus Schischkin, Codonopsis pilosula, Taxillus chinensis, Poria cocos(Schw.)Wolf, Paeonia suffruticosa Andr., Fallopia multiflora and Alpinia oxyphylla Miq.

Excluded studies

We excluded studies which: 1. Do not include the mechanism of action of herbs; 2. Included the herbs as a part of a formula; 3. Discussed management of secondary or gestational hypertension.

Mechanisms of Action

We first extracted the proposed mechanisms of action of the herbs (Table 1) and categorised them according to the known mechanisms of action of Western medicines utilized for the treatment of hypertension. Based on known mechanisms, the herbs were categorised into Angiotensin Converting Enzyme Inhibitor(ACEI)/ Angiotensin II Receptor Blocker (ARB) mimetics, Diuretics mimetics (Thiazide/Loop), Potassium sparing diuretic mimetics (Spironolactone-like), Calcium Channel Blocker (CCB) mimetics, Beta-blocker mimetics, and Direct vasodilator (acting on Nitric Oxide) mimetics (Table 2). The schematic representation on how herbs act on the pathophysiology pathways of hypertension is depicted in Figure 3. The herbs act mainly as CCB mimetics in blocking the entry of calcium into myocytes in arterial walls, ACEI/ ARB mimetics in inhibiting ACE in converting Angiotensin I to Angiotensin II, Beta blocker mimetics in reducing heart rate and by antagonizing the activation of Angiotensin II receptors, which ultimately allows for vasodilation.

dIsCussIon

Mechanism of Actions of Commonly used herbs

TCM has traditionally adopted a “Syndrome based” approach for the management of diseases unlike the disease based models for western medicine.68 Despite the difference in approach between the two fields, herbs have been shown to exhibit a similar mechanism of action as that of drugs commonly used for the management of hypertension (Table 1). Herbs in general exerts its effects on the Renin-Angiotensin-Aldosterone System (RAAS), free/cytosolic calcium, produces b-adrenergic blockade or diuretic-like effect, or acts to increase or decrease Nitric Oxide (NO) and Endothelin-1 (ET-1) respectively. These mechanisms of actions (Figure 3) have been well established to reduce blood pressure either by vasodilation, increasing renal output or reducing the heart rate.69 The herbs also act via other MOA which have not been used by western medications such as 1) Promoting the expression of ACE-Ang1-7-mas-AKT signaling pathway 2) Regulation of vascular remodeling 3) reduction of Noradrenaline, thromboxane B2 and TGF-B1 4) Increasing SOD and Interleukin-10 5) Upregulation of miR122 (Table 1). These additional pathways might result in further reduction of blood pressure as opposed to western medications which traditionally acts on a linear pathway.

However, unlike drugs, majority of the herbs which act on the RAAS system have not clearly demonstrated to either inhibit Angiotensin Converting Enzyme (ACEI) or Angiotensin II Receptor (ARB) except for Crataegus pinnatifida and Concha Ostreae. There was also a lack of differentiation of the type of diuretic mimetics (loop or thiazide diuretic) e.g Apocynum venetum. Further analysis (Table 1) showed that Apocynum venetum, results in the increase of urinary excretion of



Figure 2: Study flow diagram for the identification of articles of commonly used herbs

sodium, potassium and chloride which resembles to that of thiazide diuretics.70

Some herbs have also exhibited multiple known MOA used for the management of hypertension, e.g, Uncaria rhynchophylla, Gastrodia elata and Salvia miltiorrhiza have demonstrated ACEI/ARB and Calcium channel blocker (CCB) like activities while Eucommia ulmoides showed ACEI/ARB and beta-blocker like activities (Table 2). TCM clinicians should be cautious when prescribing such herbs to reduce incidents of hypotension and the prescription of such herbs in patients with absolute contraindications to either of the MOA, such as the use of beta blockers (Eucommia ulmoides) in asthmatic patients.71

side effects and Contraindications of herbs

As herbs exhibit similar MOA as that of drugs, TCM clinicians should be aware of the common side effects caused by the different categories of the anti-hypertensive herbs. Well established side effects include: 1) Non potassium sparing diuretics mimetics: headache, dizziness, hyperuricemia, hypoglycaemia, hyponatremia, hypomagnesemia, hypokalemia and ototoxicity. 2) Potassium sparing diuretics mimetics: headache, dizziness, gynecomastia, and hyperkalaemia 3) ACEI/ARB mimetics: dry cough

(ACEI), hyperkalaemia, hypotension, and angioedema 4) Beta-blockers mimetics: bradycardia, hypotension, hypoglycaemia and worsening of asthma. 5) CCB mimetics: hypotension, bradycardia, peripheral edema and constipation.72 In addition, most of the herbs also exhibit multiple MOA including some which are not commonly utilized in anti-hypertensive management. TCM clinicians should thus, also be able to identify the unexpected side effects when prescribing.

Given the similarity in the MOA, the prescription of the TCM herbs which fall under the same class to that of drugs should also be avoided if a contraindication for the particular class of drug arises, e.g. the use of beta-blockers mimetics in asthmatic patients or the use of ACEI mimetics in bilateral renal artery stenosis, pregnancy/breastfeeding or hypersensitivity to the drug. This would prevent any adverse event from happening should herbs with similar MOA be used.

use of Glycyrrhiza uralensis for hypertension and hypertensive Crises

Glycyrrhiza Uralensis (Gan Cao) has often been prescribed for the management of hypertension.73 Ironically, it has been shown to increase blood pressure tremendously due to



Figure 3: Pharmacology of Antihypertensive Therapy

the inhibition of glucocorticoid inactivation, excitement of mineralocorticoid receptors, reduction of vasodilator release and promotion of vasoconstriction (Table 1). Excessive use of Glycyrrhiza Uralensis would thus result in Cushing syndrome and pseudohyperaldosteronism due to increased glucocorticoid and mineralocorticoid activity. Both of these conditions will further deteriorate the existing condition of the patient, resulting in hypertensive crises.62-64 The use of Glycyrrhiza Uralensis or TCM formulas which contain Glycyrrhiza Uralensis such as “Gentiana Longdancao Decoction to Drain The Liver” and “Drain The Epigastrium Decoction” for the management of hypertension and/or hypertensive crises should therefore be avoided regardless of “Syndrome” diagnosed by TCM clinicians.

Proposed Guidelines for Managing essential hypertension Based on nICe Guideline

Through the identification of key MOAs of lowering blood pressure (Table 2), a 4 step guideline for the management of hypertension is proposed (Figure 4) based on existing NICE guidelines. As per NICE guideline, management is individualised according to the age, race, and comorbidities of the patients.

Herbs with ACEI/ARB (Group A) or CCB (Group C) like activities should be prescribed as first line therapy depending on patients’ age and race followed by a combination of Groups A and C or C and D (Diuretics mimetics). If the



Figure 4: Proposed guidelines for TCM management of Hypertension based on NICE guidelines

Figure 5: Proposed guidelines for the management of Hypertensive emergency and Urgency



blood pressure is still not managed, herbs in groups A, C and D should be combined. Herbs with multiple activities should only be used when the necessary criteria have been met, such as the use of herbs with Group A and C activities (e.g. Uncaria rhynchophylla, Gastrodia elata and Salvia miltiorrhiza) in step 2.

Lastly, if the blood pressure is still not contained, an Ambulatory Blood Pressure Monitoring (ABPM) should be employed and postural hypotension should be determined. The addition of a fourth herb is recommended based on serum potassium levels (K≤ 4.5mmol/l: Alisma orientalis (Sam.) Juzep, K≥4.5mmol: Pueraria montana). This is to reduce the likelihood of possible hyperkalemia secondary to spironolactone-like effects of Alisma orientalis (Sam.) Juzep. The advice of a specialist should also be considered at this point of time. The use of a stepwise approach to the management of hypertension will ensure treatments are individualised according to the severity of hypertension, increasing when the hypertension is not managed by initial therapy. It reduces any ambiguity in the management arising from the use of “Syndrome based” approach. The guideline-based approach is also more objective as it considers the renin levels based on patients’ age and race. In people of Chinese ethnicity, which form the bulk of intake of TCM herbs, they have been shown to react well with ACEI drugs.74,75 Thus, management of people of Chinese ethnicity is similar to those of white ethnicity and in people less than 55 years of age. In addition, a guideline-based approach allows TCM clinicians to better predict the likely side effects and avoid certain herbal therapies in situations where a contraindication arises as mentioned.

Management of hypertensive urgency and emergency

Hypertensive crises such as Hypertensive urgency and emergency are characterised by sudden acute elevation in blood pressure (>180/110 mm Hg) with/without end-organ dysfunction.76 Since 2000, there has been an increase in hospitalization due to hypertensive emergencies.77 The in-hospital mortality rate has remained around 2.5% with a 1 and 10 year survival rate of more than 90% and 70% respectively.77,78

The management for hypertensive crises differs between Hypertensive urgency and emergency (Figure 4). Hypertensive crises usually require urgent management especially in the case of hypertensive emergencies due to damage to end organs which might further progress to myocardial infarction, vision loss, renal failure, stroke and death.79 In patients experiencing Hypertensive emergency, management also differs based on the end-organ affected. For example, patients which are critically ill, experiencing Angina and Pulmonary Edema should consider Ligusticum chuanxiong hort due to its direct vasodilating effects. However, Pueraria montana (beta blocking mimetics) and Apocynum venetum (diuretic mimetic) can also be

considered for patients with Angina or Pulmonary Edema respectively. In an event of Neurological Emergency, Senna obtusifolia or panax notoginseng should be considered due to their CCB-like effects.

Patients with Hypertensive urgency should be managed with Intravenous Pueraria montana or Ligusticum chuanxiong hort if they are not actively treated for Acute Coronary Syndrome (ACS), Congestive Heart Failure (CHF) or intracranial hemorrhage. Through this approach it will ensure that in an emergency like hypertensive crises, patients will receive appropriate and adequate management via herbs with the right MOA and prevent further worsening of complications. This differs from the traditional “Syndrome based” management by TCM clinicians which might result in relatively different management for patients presenting with the same conditions. These measures can be used concurrently with western medications but has to be dose adjusted based on the patient’s age, body weight and the dosage of western medications being used. In addition, clinicians would have to take into account the other MOAs and the impurities of a herb which might result in a greater/lesser than expected fall in blood pressure. Subsequently, patients would have to be continually monitored for signs and symptoms of overdosage and side effects as mentioned previously.

ConCLusIon

Lifestyle advice such as reduction of salt intake, smoking cessation and exercise should be encouraged prior to the starting of medication/herbal therapies. The standardization and guideline-based management will ensure greater patient safety and likely outcome and ensure a systematic stepwise approach to the management of patients, thus reducing unnecessary herbs from being prescribed. The understanding of herbal MOA also allows clinicians to predict, monitor and prevent side effects and contraindications of herbs of different classes from occurring. In an unfortunate event where side effects were to occur, clinicians would also be able to rapidly identify which group of herbs are causing it, stop the use immediately or find appropriate antidotes via the reversal of mechanism.

Further research should be done on herbs without known MOA, differentiation of herbal effects e.g. if herbs reduce Angiotensin II by inhibiting ACE or blocking Angiotensin II receptor, duration of effect or half-life of the herbs as well as any additional side effects or contraindication of herbs as a result of miscellaneous MOA. In addition, unconventional MOA which herbs exhibit but has not been utilized by drugs can be considered for future research.

Author disclosure statement

No competing financial interests exist.



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