+ Hibiscus as an

Alternative Treatment for Hypertension

Cara Montesano, Coral Rudie, Esther Lee, Helaine Krasner

December 17, 2012

++

Mahan, L.K. & Stump, S. (2008) Krause’s food & nutrition therapy. (12th ed.) St. Louis, MO.: Saunders/Elsevier.

Systolic BP Diastolic BP

Normal < 120 And < 80 Pre-Hypertensive

120-139 Or 80-89

Stage 1 HTN 140-159 Or 90-99 Stage 2 HTN > 160 Or > 100

Hypertension

++ Importance of Controlling Hypertension

  Avoid disease progression

  Prevent cardiovascular complications

  Untreated HTN leads to degenerative diseases such as HF, ESRD, PVD, and Stroke

  To maintain a good quality of life

  Reduce the mortality associated with this disease

Mahan, L.K. & Stump, S. (2008) Krause’s food & nutrition therapy. (12th ed.) St. Louis, MO.: Saunders/Elsevier.

++ Blood Pressure Homeostasis

 Body regulates BP via Sympathetic nervous system (short term) and the kidneys (long term control)

 Sympathetic nervous system can stimulate both vasoconstriction and vasodilatation

 Kidney regulates BP by controlling extracellular fluid volume and secreting renin which initiates the renin-angiotensin system system

Mahan, L.K. & Stump, S. (2008) Krause’s food & nutrition therapy. (12th ed.) St. Louis, MO.: Saunders/Elsevie

++ Physiological Mechanisms Involved in the Development of Essential Hypertension

  Cardiac Output

  Peripheral Resistance

  Renin-Angiotesin-Aldosterone System

  Autonomic Nervous System

  Other Factors: Bradykinin, Endothelin, Endothelial derived relaxing factor (EDRF) or nitric oxide, Atrial Natriuretic peptide (ANP), Ouabain

Beevers, G., Lip, G., & O'Brien, E. (2001). ABC of Hypertension- The pathophysiology of hypertension . British Medical Journal, 322(7291), 912-916..

++ Cardiac Output and Peripheral Resistance

 BP is a function of cardiac output and peripheral resistance  BP= CO x PR

 Most patients with essential HTN will have normal cardiac output, but increased peripheral resistance

Mahan, L.K. & Stump, S. (2008) Krause’s food & nutrition therapy. (12th ed.) St. Louis, MO.: Saunders/Elsevie Beevers, G., Lip, G., & O'Brien, E. (2001). ABC of Hypertension- The pathophysiology of hypertension . British Medical Journal, 322(7291), 912-916..

++

Mahan, L.K. & Stump, S. (2008) Krause’s food & nutrition therapy. (12th ed.) St. Louis, MO.: Saunders/Elsevier. Beevers, G., Lip, G., & O'Brien, E. (2001). ABC of Hypertension- The pathophysiology of hypertension . British Medical Journal, 322(7291), 912-916. Image: http://en.wikipedia.org/wiki/File:Renin-angiotensin-aldosterone_system.png

++ Autonomic Nervous System

  Patients with hypertension have an enhanced peripheral sensitivity to, and release of norepinephrine. As well as a increased response to stressful stimuli

  There is little evidence to suggest that norepinephrine and epinephrine play definite roles in the development of hypertension. But there effects are still important.

  Drugs that target the sympathetic nervous system are effective at lowering blood pressure, thus the ANS likely has some role in hypertension development.

Beevers, G., Lip, G., & O'Brien, E. (2001). ABC of Hypertension- The pathophysiology of hypertension . British Medical Journal, 322(7291), 912-916. Sear, J., & Dphil, P. F. (2004). Hypertension: pathophysiology and treatment. Continuing education in Anaesthesia, Critical Care, and Pain, 4(3), 71-74. .

++ Conventional Treatments

  Lifestyle Modifications

  Drug Therapy   Diuretics

  Beta- Blockers

  Calcium Channel Blockers

  Angiotensin Converting Enzyme (ACE) Inhibitors

  Angiotensin II Receptor Blockers

  Alpha-1 Andrenergic blockers

  Direct Vasodilators

  Central Adrenergic Inhibitors

  Natriuretic Peptides

Sear, J., & Dphil, P. F. (2004). Hypertension: pathophysiology and treatment. Continuing education in Anaesthesia, Critical Care, and Pain, 4(3), 71-74.

++ Alternatives to Medication

 Good evidence to support hibiscus as an integrative therapy for hypertension.

 Hibiscus has antioxidant properties and can be an effective treatment for hypertension.

 Treatment of hypertension with hibiscus tea has roots in Ayurvedic, Chinese, and folk medicine.

Natural Standard: The authority on integrative medicine (2012). Hypertension.

++ Hibiscus

 Hibiscus sabdariffa Linn. (HS) belongs to the Malvaceae family

 Syn: Roselle, Indian sorrel, Sour tea and Karkade, Jamaica or Flor de Jamaica

 Annual shrub that grows to 8 ft in height and typically consists of a red calyx with five large sepals.

 Tropical plant native to India and Malaysia  Naturalized in many parts of the Americas

Deyanira Ojeda, (8 January 2010). Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa Journal of Ethnopharmacology, Volume 127, Issue 1, Pages 7–10 Francisco J. Alarcon-Aguilar, (8 October 2007,). Effect of Hibiscus sabdariffa on obesity in MSG mice Journal of Ethnopharmacology, Volume 114, Issue 1, Pages 66–71

++ Hibiscus (cont.)

  Hibiscus has been used for centuries in indigenous medicine   Diuretic   Treatment for gastrointestinal disorders, liver disease,

fever, hypercholesterolemia, and hypertension

  What’s in Hibiscus?   Phenolics, organic acids, sterols, terpenoids,

polysaccharides and some minerals.

  The extracts of HS exert potent antioxidant effects in vitro, achieved via the presence of several active constituents chief among which are flavonoids and vitamins.   *Active compounds: Anthocyanins (delphini- din 3-

sambubioside and cyanidin 3-sambubioside)*

M. Ajay, H.J. Chai, A.M. Mustafa, A.H. Gilani, M.R. Mustafa. (February 2007). Mechanisms of the anti-hypertensive effect of Hibiscus sabdariffa L. calyces. Journal of Ethnopharmacology, Volume 109, Issue 3, 12 Pages 388–393,

++ Mechanism of Action

  Vasodilator/Vasorelaxant   Relaxes aortic rings through endothelium-dependent and

independent vasodilator pathways.

  Endothelium-dependent vasodilator component results through activation of endothelium-derived nitric oxide/cGMP-relaxant pathway   Endothelium-independent component could be due to inhibition of

Ca2+ influx into vascular smooth muscle cells.

  Diuretic   Aldosterone antagonist

  Inhibits Angiotensin-converting enzyme (ACE)   ACE inhibitory effect attributed to anthocyanins, delphinidin-3-O-

sambubioside (Compound 1) and cyanidin-3-O-sambubioside (Compound 2)

++ Mechanism of Action

Aldosterone antagonist

Inhibits ACE activity

+ 15 Hibiscus  sabdariffa  L.  tea  (1sane)  

lowers  blood  pressure  in  prehypertensive  and  mildly  

hypertensive  adults  

Diane L. Mckay, C-Y Oliver Chen, Edward Saltzman, Jeffery B. Blumberg

++ Study Details

 Purpose of study: examine antihypertensive effects of H. sabdariffa tisane (hibiscus tea) consumption in humans.

 Study design: randomized, double-blind, placebo-controlled clinical trial

 Objective: determine if hibiscus tea reduced HTN in pre-mildly hypertensive adults > placebo

++ Materials & Methods

 Standardized method was used to measure BP at baseline and at weekly intervals while consuming test beverage and placebo.

 Sixty-five pre-mildly hypertensive adults age 30-70 yrs, not on HTN meds, consumed either 3 (240 mL) svgs/day of hibiscus tea or placebo beverage for 6 weeks.

++ Treatment

 Tea bag contained 1.25 g H. sabdariffa (ground dried calyces)

 Participants were instructed to steep bag in 240 mL boiled water for 6 minutes

 Placebo group received an artificial hibiscus flavor concentrate to be added to 240 mL water via 16-18 drops (1.2 mL)

 Participants could consume either beverage hot or cold, but had to consume within 12 hrs of prep

++ Participants

 65 non-smoking males and females age 30-70 yrs w/ BMI 18.5-35.0

 SBP 120-150 mmHg and DBP < 95 mmHg

 Excluded if: taking meds known to affect BP active CVD, RD, endocrine or GI disease, RA bw chg > 5% or preg w/in last 6 mos caffeine intake > 425 mg/d, ethanol > 28g/d vit C supp > 500 mg/d, illegal drug use high intensity aerobic exercise >30 min/d, abnormal EKG or std labs

++

++

++ Results

 Hibiscus tea significantly lowered SBP compared to placebo (-7.2 ± 11.4 vs - 0.3 ± 10mmHg; P=0.03).

 Diastolic BP was lower for both tea and placebo, but not significant.

 Participants w/higher SBP at baseline had better response to tx (r = -0.421; P=0.01)

 No effects based on age, gender, suppl use

++ Results

++ Change in SBP relative to baseline

Figure 1A

++ Mean BP over time

++ Study Conclusion

 Daily consumption of 3 svgs Hibiscus sabdariffa tea in an amt easily and readily incorporated into the diet reduced BP in pre-mildly hypertensive adults

 BP lowering effects were similar to those reported in previous large dietary intervention studies (DASH, PREMIER)

+ 27 Effec1veness  and  tolerability  of  a  standardized  extract  from  Hibiscus  sabdariffa  in  pa1ents  with  mild  to  

moderate  hypertension:  a  controlled  and  randomized  

clinical  trial    

A. Herrera-Arellanoa, S. Flores-Romerob, M.A. Cha!vez-Sotoc, J. Tortorielloa

++ Purpose

 The aim of the present study was to compare the antihypertensive effectiveness and tolerability of the dry calyx from H. sabdariffa (standardized on 9.6 mg of anthocyanins/ dose) with captopril.

  As well as to determine the modifications on the urinary electrolytes induced by the experimental treatment.

++ Materials and Methods

 Subjects:  90 participants  Both sexes  Between 30 and 80 years of age  Diagnosed with mild to moderate hypertension  Have not received antihypertensive treatment in

the last month  Granted consent

++ Preparation of Treatments

 Hibiscus sabdariffa  Collected from a controlled crop  Dried under dark conditions at room

temperature  Ground in an electric mill to obtain particles  10g given to the patient in powder form with

instructions

 Captopril  25mg  Administered every 12 hr for 4 weeks

++ Measurements

 Therapeutic tolerability

 Hypotensive effect

 Urine test to determine urine electrolyte

 Statistical analysis  ANOVA

++ Procedure

 Experimental group- 53 patients

 Control group- 37 patients

 Basal blood pressure

 Oral and written instructions given

++

++ Results

  70 subjects completed the study

++

++ Therapeutic Effectiveness/ Failure

Therapeutic Effectiveness:  78.95% from experimental group  84.38% from the control group

Therapeutic Failure:  23.08% from experimental group   25% from the control group

++ Conclusion

 The study contributes further evidence of the acceptance of the short- and long-term administration of aqueous extract from H. sabdariffa, because no side-effects or intolerability was detected.

+ 38 Clinical  Effects  Produced  by  a  Standardized  Herbal  Medicinal  Product  of  Hibiscus  sabdariffa  on  Pa1ents  with  Hypertension.  A  

Randomized,  Double-­‐blind,  Lisinopril-­‐Controlled  Clinical  Trial.    

Armando Herrera-Arellano, Judith Miranda-Sánchez, Pedro Ávila-Castro, Sara Herrera-Álvarez, Jesús Enrique Jiménez-Ferrer, Alejandro Zamilpa, Rubén Román-Ramos, Héctor Ponce-Monter, Jaime Tortoriello

++ Purpose of the Study

 “The aim of this project was to compare the antihypertensive effectiveness, tolerability, and safety, as well as the effect on serum electrolytes and the ACE inhibitory effect of a herbal medicinal product prepared from H. sabdariffa extract with lisinopril in patients with stage 1 or 2 HT.”

++ Research Question

  How does the effectiveness, tolerability, and safety of H. sabdariffa extract compare to that of lisinopril in people with stage 1 and 2 Hypertension?

++ Study Background

  Study Design: Randomized, controlled, double-blind clinical trial

  Study Selection Criteria:   Inclusion:

  Males and Females   25 ± 61 years of age   Stages 1 or 2 Hypertension classification   Without antihypertensive treatment (at least during the previous 30

days)   Exclusion:

  Subjects with nephropathy, heart or hepatic diseases, cancer, non-controlled diabetes mellitus

  Pregnant or breast-feeding women   Subjects with evidence of secondary hypertension   Known hypersenstivity or intolerance to ACE inhibitors or to Hibiscus

sabdariffa

  Study Duration: 4 weeks   Study occurred between August 2004 to March 2005

++ Study Intervention

 Experimental Group:  Hibiscus sabdariffa calyxes (HsHMP), 250mg of

total anthocyanins per dose

 Control Group:  Lisinopril (USP, 10 mg) mixed with artificial

flavor and color

 The treatments were dissolved in 250 ml of water

 Treated daily for 4 weeks

++ Study Outcomes

 Effectiveness: diastolic blood pressure (DBP) reduction, >10 mmHg

 Tolerability: absence of intensive or severe side effects

 Safety: absence of pathological modifications in bio-chemical tests for hepatic and renal function (ALT, AST, ALP, urea, and creatinine).

 Effect on serum electrolytes (Na, K, Cl)

 Effect on ACE activity

++ Data Collection & Analysis

  At the initial interview, measurement of basal conditions was conducted

  Clinical evaluation, variables outcome, and treatment adherence were evaluated weekly.

  Blood samples for biochemical analysis were obtained at the beginning and the end of treatment.

  Statistical Analysis:   Differences between mean pairs of data with normal

distribution   The hypothesis test with analysis of variance (ANOVA)   The X2 test was used for comparing two groups of

proportions.   Stratified analysis was used for dichotomized confounding

variables.   Values of p < 0.05 were considered for rejecting the nullity

hypothesis.

++ Study Population

  193 subjects participated in the study

  100 in the experimental group and 93 in the control

  22 were eliminated due to lack of treatment adherence

  171 were included in the analysis

  No differences found between groups in the analyzed parameters (p >0.11)

  56.99% of the subjects were Stage 1 Hypertensive

++ Results – Effectiveness

17.14 mmHg

decrease in SBP

(11.7% ↓)

11.97 mmHg

decrease in DBP

(12.2% ↓)

SBP

DBP

++ Main Outcome Variables

++ Effect on Serum Electrolytes

Increased Cl by 3.42 meq/L & decrease in Na by 2.04 meq/L Increased Cl by 2.87 meq/L

++ Effect on ACE Activity

++ Summary

 The data showed that Hibiscus was effective, tolerable, and safe means to reduce blood pressure

 Unlike many diuretics, hibiscus does not modify serum potassium levels

 While Hibiscus was effective, Lisiprol was more effective at reducing blood pressure in Stage 1 & 2 hypertensive adults

+ 51

Okechukwu O. Ndu, Chukwuemeka S. Nworu, Chinwendu O. Ehiemere, Nichola C. Ndukwe, and Izuchukwu S. Ochiogu

Herb–Drug  Interac1on  Between  the  Extract  of  Hibiscus  sabdariffa  L.  

and  Hydrochlorothiazide  in  Experimental  Animals.  

++ Purpose of Study

 To examine the possibility of herb-drug interaction with concomitant use of Hibsicus sabdariffa (HSE) and hydroclorothiazide (HCT), a diuretic.

 Investigate any potential dangers and consequences of concomitant HSE and HCT usage

++ Research Question & Hypothesis

 Question: Will concomitant use of Hibiscus sabdariffa alter the pharmacologic effects of HCT?

 Hypothesis: Given Hibiscus sabdariffa’s antihypertensive properties, concomitant administration will alter HCT’s pharmacologic effect

++ Study Design

 Two Phases  Phase 1: Determination of the toxic range  Phase 2: Co-administration of HSE and HCT and

effect in diuresis & effect of HSE on Pharmacokinetics and Pharmacodynamics of HCT

 Materials and Methods:  Plant Material  Drug  Animals

++ Study Design --Phase 1--

Group 1 1,600 mg/kg

Group 2 2,900 mg/kg

Group 3 3,600 mg/kg

Group 4 5,000 mg/kg

Acute Toxicity Test of Extract

**LD50= >5,000 mg/kg

++ Study Design --Phase 2--

Effect of Co-Administration of HSE and HCT on Diuresis

Group 1

Group 3

Group II

Group 4

Group 5

HCT (10 mg/kg)

Distilled water

HSE (40mg/kg)

HCT(10mg/kg)+ HSE (40 mg/kg)

HCT (10 mg/kg) + Distilled Water

++

Effects of HSE on Pharmacokinetics of HCT Group 3

Group 2

Group 1

HCT 10 mg/kg

HCT 10 mg/kg + HSE 20 mg/kg

HCT 10 mg/kg + HSE 40 mg/kg

Study Design --Phase 3--

++ Data Collected

++ Data Collected

++ Data Collected

++ Data Collected

++ Results

 Physiochemical Effect on Urine  Administration of HSE alone  Did not cause increase in urinary excretion of

Na +, Cl-, and HCO3-  Decreased chance of dilutional hyponatremia

 Co-adminstration of HSE and HCT  Decrease in urinary pH, Na+, HCO3-, Cl-

concentrations  Possibility of metabolic acidosis with

prolonged use

++ Results

  Pharmacokinetic Effects:

  HCT + HSE   Decreased CL (volume of blood cleared of drug per unit

time)   Increased AUC (total amount of drug achieved in body

  Maximum AUC obtained when administered 40 mg/kg HSE

  What does this mean?   Co-administration possibly increases retention of HCT

elimination from the body   Less HCT will be cleared from the body with increasing

dose of co-administered HSE   HSE slows rate HCT is eliminated from the body

++ Summary

 HSE significantly altered both pharmacodynamics and pharmacokinetic indices of HCT  Increased diuretic effect  Decreased pH, HCO3-, Cl- in urine  Increased retention in the body

 HSE is reasonably safe without evidence of acute toxicities.

 Concomitant usage of H. sabdariffa and HCT diuretics in the management of hypertension should be avoided!

++ Recap of the Studies

 Herbal hibiscus tea containing 21 mg anthocyanins consumed daily reduced SBP by 5.6% from baseline in pre-mildly hypertensive adults. MAP was reduced by 4.7% and DBP was reduced 3.9%.

 Hibiscus supplement containing 9.6 mg anthocyanins taken daily reduced SBP by 11% and DBP by 12.4% in mild to moderate hypertensive adults.

 Hibiscus supplement containing 250 mg anthocyanins taken daily in mild to moderately hypertensive adults, reduced SBP by 11.7%, and DBP by 12.2%.

 Co-administration of HSE (40mg/kg) and HCT resulted in increased diuretic effect, decrease in pH, and electrolytes in urine.

++ Risk reduction analysis

 5 mm Hg reduction in SBP  14% overall reduction in mortality due to stroke  9% reduction in mortality due to coronary heart

disease  7% reduction in all cause mortality

 3mm Hg reduction in SBP  8% overall reduction of mortality due to stroke  5% overall reduction in mortality due to CHD

++ Conclusion

 Daily consumption of hibiscus, both in the form of a tea and a capsule dissolved in water, can be an effective lifestyle intervention to reduce blood pressure in pre-moderately hypertensive adults.

 Mechanism of action include function as an ACE inhibitor, K-sparing diuretic, and a vasorelaxant.

 The level of blood pressure lowering effects of hibiscus are similar to those reported for studies using the DASH intervention and certain medications.

 Consuming hibiscus tea can be considered a safe and effective lifestyle change to reduce risks associated with HTN.

++ Concerns/ Cautions

 Caution with diuretic medications

 Avoid if allergic or hypersensitive to hibiscus, or members of the Malvaceae family

 Hibiscus rosa-sinensis has exhibited infertility activity.

 Use cautiously if pregnant, trying to become pregnant or breastfeeding

Natural Standard: The authority on integrative medicine (2012). Hypertension.

++ References   Mahan, L.K. & Stump, S. (2008) Krause’s food & nutrition therapy. (12th ed.) St. Louis, MO.: Saunders/

Elsevier.

  McKay, D., Chen, C. Saltzman, E., Blumberg, J., Hibiscus sabdariffa L. tea (tisane) lowers blood pressure in prehypertensive and mildly hypertensive adults. The Journal of Nutrition. 2010;140(2)298-303.

  Natural Standard: The authority on integrative medicine (2012). Hypertension. Retrieved from: http://www.naturalstandard.com.ezproxy.hsclib.sunysb.edudatabases/conditions/

  Ndu, O. O., Nworu, C. S., Ehiemere, C. O., Ndukwe, N. C., & Ochiogu, I. S. (2011). Herb–Drug Interaction Between the Extract of Hibiscus sabdariffa L. and Hydrochlorothiazide in Experimental Animals. Journal of medicinal food,14(6), 640-644.

  Sear, J., & Dphil, P. F. (2004). Hypertension: pathophysiology and treatment. Continuing education in Anaesthesia, Critical Care, and Pain, 4(3), 71-74.

  Herrera-Arellano, A., Miranda-Sánchez, J., Ávila-Castro, P., Herrera-Álvarez, S., Jiménez-Ferrer, J. E., Zamilpa, A., et al. (2007). Clinical Effects Produced by a Standardized Herbal Medicinal Product of Hibiscus sabdariffa on Patients with Hypertension. A Randomized, Double-blind, Lisinopril-Controlled Clinical Trial. Planta Med, 73, 6-12.

  Herrera-Arellano, A., & Flores-Romero, S. (2004). Effectiveness and tolerability of a standardized extract from Hibiscus sabdariffa in patients with mild to moderate hypertension: a controlled and randomized clinical trial. Phytomedicine, 11, 375-382.

  Ojeda, D., Jiménez-Ferrer, E., Zamilpa, A., Herrera-Arellano, A., Tortoriello, J., & Alvarez, L. (2010). Inhibition of angiotensin converting enzyme (ACE) activity by the anthocyanins delphinidin-and cyanidin-3- O-sambubiosides from Hibiscus sabdariffa.. Journal of ethnopharmacology, 127(1), 7-10.

++ References (Continued)

  Sharma, J. N. (2009). Hypertension and the bradykinin system. Current Hypertension Reports , 11(3), 178-181. Retrieved December 9, 2012, from the SpringerLink database.

  Hynynen, M. M., & Khalil, R. A. (2006). The Vascular Endothelin System in Hypertension – Recent Patents and Discoveries. Recent Pat Cardiovasc Drug Discov, 1(1), 195-108. Retrieved December 9, 2012, from the PubMed database.

  Sodium Ions, Calcium Ions, Arterial Contractility and Ouabain Hypertension. (n.d.). University of Maryland School of Medicine. Retrieved December 9, 2012, from http://medschool.umaryland.edu/blaustein_ppg/overview.asp

  Francisco J. Alarcon-Aguilar, Alejandro Zamilpa, Ma. Dolores Perez-Garcia, Julio C. Almanza-Perez, Eunice Romero-Nuñez, Efrain A. Campos-Sepulveda, Laura I. Vazquez-Carrillo, Ruben Roman-Ramos (8 October 2007,). Effect of Hibiscus sabdariffa on obesity in MSG mice. Journal of Ethnopharmacology Volume 114, Issue 1, Pages 66–71

  M. Ajay, H.J. Chai, A.M. Mustafa, A.H. Gilani, M.R. Mustafa. (February 2007). Mechanisms of the anti-hypertensive effect of Hibiscus sabdariffa L. calyces. Journal of Ethnopharmacology, Volume 109, Issue 3, 12 Pages 388–393,

  Beevers, G., Lip, G., & O'Brien, E. (2001). ABC of Hypertension- The pathophysiology of hypertension . British Medical Journal, 322(7291), 912-916.