PAPER OF HERB PROBLEM BASED LEARNING (PBL)

CELERY (APIUM GRAVEOLANS)

KELOMPOK 1 :
1. ZAHROH NUR LAILY 1808062161
2. NADYA AMALIA 1808062162
3. NOVIA ARIANI DEWI 1808062163
4. AKMAL MAULANA 1808062164
5. ASPRILLA RESTU S.W 1808062181
6. RISKA SYAFRITA NINGSIH 1808062188
7. MESRI WINDA 1808062190
8. IMA YUSHEILA C.D.D 1808062204
9. NURRAHMI 1808062210

KELAS : B PROFESI APOTEKER XXXVII

DOSEN PENGAMPU : ZAINAB M.Si.,Apt

PROGRAM PROFESI APOTEKER

FAKULTAS FARMASI UNIVERSITAS AHMAD DAHLAN
YOGYAKARTA
2019
SCENARIO

Mr. Agus 55 years old came to clinic herbal with headache, pain, and pounding

sensation in the neck. After being checked throroughly blood pressure was 160/90

mmHg. The pharmacist in the clinic give herbal medicine containing celery

extract, after 3 days of treatment the symptom were relieved.

LEARNING OUTCOME

1. Students can explain about definition and unfamiliar terms in the scenario

2. Students can explain about disesase’s pathophysiology and the

terminology

3. Students can determine EBM’s level of the plant and three other plant that

have similar effect

4. Students can explain about the active compunds, the group classified,

structure, and physicochemical properties (polarity, solubility, stability,

ect) of active compoud in plants

5. Student can explain the general mechanism of action and the active

compound’s mechanism of action

6. Strudents can explain and determine empirical, pre-clinical, and clinical

dose of the plant, and example of herb dosage form and their dose

7. Students can explain about indication, contraindication, interaction, side

effects, and toxicity of the plant.

 CHAPTER I
INTRODUCTION

A. Background

Nowadays, high blood pressure, also called hypertension, is one of the most

common cause of early death in symptoms-free adults. Uncontrolled hypertension

increases the risk of serious health problems and is considered a major risk factor

for stoke, heart attack, or myocardial infarction, ischrmia or brain atrophy,

blidness, and kidney disesase (Zimmet et al., 2001). The increase in blood pumps

from the heart and the narrowing of the arteries normally lead to hypertension.

Moreover, there is a direct relationship between systelic blood pressure and

hemorrhagic storoke (Kanter et al., 2004). In fact, the risk hemorrhagic stroke and

heart attack is higher when SBP increases by more than 175 mmHg. Controlling

hypertension can also improve exertional dyspnea, nocturia, and possibly even

erectile dysfunction caused by endothelial dysfunction. A health-promoting

lifestyle, weight loss, and decreased dietary NaCl have been shown to lower the

risk of developing hyoertension. Drug therapy will be necessary is these

intervensions are not efficient in decreasing blood pressure (Moghadam, 2013).

Medication are recommended for hypertensive with blood pressure more

than 140/90 mmHg. To achieve ideal blood pressure, the majority of

hypertensives will required threatment more than one drug. Appropriate

combinations of these drugs at lower doses may have additive effects on blood

pressure with lower incidence of side effects. Taking blood pressure medication

can cause side effects such as headache, dizziness, tachycardia, feeling tired, and

sexual dysfunction (Moghadam, 2013).

 There are many herbal medicines for management of hypertension, for

example, garlic, hawhorn, and cayenne papper. There are some ingridients in the

herbs that synergistically produce beneficial effect. Apium graveolens, commonly

known as celery, is a plant species in the family Apiaceae. Celery grows up to 1-

m height and has odd-pinnate coompound leaves with dentate leaflets on a central

stem (Zhou et al, 2009). In recent pharmacological studies, celery has

demonstrated antioxidant, hypolipidemic, and anti-inflamantory activities (Iyer

and patil, 2011). It was also administrated as an antihypertensive agent in folk

medicine (Gharouni et al., 2000). There are three active compounds in celery that

known as antihipertensive agent such as n-butylphthalide (NBP), apigenin and

apiin. So we need to know about it’s effectiveness and the mechanism of action as

anti-hypertensive.

B. Formulation of The Problem

1. What is definition and unfamiliar terms we need to know?

2. What is the pathophysiology of hipertension?

3. What is the evidence level of celery and three other plants as anti-

hipertensive?

4. What is the active compounds, the group classified, structure, and

physicochemical properties of the celery?

5. What is the general and the each active compound’s mechanism of action?

6. How much empirical, preclinical, and clinical dose that used to decrease

blood pressure?

7. What is their indication, contraindication, side effects, and toxicity?

C. Research Objective

This study intended to:

1. To understanding definition, and the unfamiliar terminology.

2. To undertanding pathophysiology of hypertension.

3. To know the evidence level of celery and three other plants as anti-

hypertensive.

4. To know the active compounds, the group classified, structure, and

physicochemical properties of the celery.

5. To understanding the general and the each active compound’s mechanism of

action.

6. To know empirical, preclinical, and clinical dose that used to decrease blood

pressure.

7. To know indication, contraindication, side effects, and toxicity of celery.

 CHAPTER II
DISCUSSION
A. Definition of Hypertension
Definition of hypertension or high blood pressure is an increase in systolic

blood pressuremore than 140 mmHg and diastolic blood pressure more than 90

mmHg twicemeasurement with an interval of five minutes in a state of adequate

rest / calm.Long-term (persistent) increase in blood pressurecan cause damage to

the kidneys (kidney failure), heart (heart diseasecoronary) and brain (causing

strokes) if it is not detected early and getsadequate treatment. Many hypertensive

patients with blood pressure do notcontrolled and the number continues to

increase (Datin et.al, 2014)

According to AHA (2017), the Risk Factors for Hypertension are namely;

age, stress, gender (< 64 years old for man; > 64 years old for women), diabetes,

genetic, sleep apnea, high cholesterole, life style (alcohol intake, high sodium

intake, lack of physical activity), obesity

Manifestations that can arise in patients with hypertension are wakefulness

headaches which are sometimes accompanied by nausea and vomiting due to

increased intracranial blood pressure, blurred vision due to retinal damage,

unsteady swinging of steps due to damage to nerves, nocturia (increased urination

at night) due to increased renal blood flow and glomerular filtration (Corwin,

2001). Other symptoms, irritability, buzzing ears, heavy feeling in the nape of the

neck, difficulty sleeping and dizzy eyes (Mansoer, 2001).

 There is also a classification of hypertension divided into:

Based on causes

a. Primary Hypertension / Essential Hypertension

Hypertension whose cause is unknown (idiopathic), thoughassociated with a

combination of force factors such as lack of movement(inactivity) and diet. It

occurs in about 90% of patientshypertension.

b. Secondary Hypertension / Non Essential Hypertension

Hypertension that is known to cause. In about 5-10% of

sufferershypertension, the cause is kidney disease. At around 1-2%,the cause is

hormonal abnormalities or the use of certain drugs(for example birth control

pills).

B. Pathophysiology of hypertension

(Hermann dan Textor, 2017)

Angiotensinogen by renin is converted to angiotensin I. Angiotensin I by

ACE (Angiotensin Converting Enzyme) is converted to angiotensin II.

Angiotensin II is what has a key role in raising blood pressure.

C. Evidence Level of Celery and Three Plants That Have Anti
Hypertensive Activity
Based on the literature search obtained several journals that examined plants

that are efficacious as anti-hypertensive, including Apium graveolens, Allium

sativum, Beta vulgaris and Hibiscus sabdariffa.

No Plant EBM (Grade)

1 Celery (Apium Graveolens L)
2 Garlic (Allium Sativum)
3 Rosella (Hibiscus Sabdariffa)
4 Beetroot (Betavulgaris)
1 RCT; 2 Pre-clinic; (B)
1 MA (11 RCT), 1 MA (7 MA, 7 RCT); 1
MA (3 MA, 2RCT); (A)
2 RCT; 1 MA (7RCT, 5 MA); (A)
2 RCT; 1 MA (15 MA); (A)

The Journal of celery was chosen because the journal has grade B, with 1

RCT and preclinical test of 2 articles with the following titles:

 A pilot study to evaluate the anti-hypertensive effect of a celery extract in

mild to moderate hypertensive patient (Madhavi et al, 2013)

Result: There was statusfically significant decrease in both sistol blood

pressure and diastolic blood pressure at week 3 and week 6 compared to

baseline the change at week 6 for the SBP was 8,2 mmHg and for the DBP

was 8,5 mmHg.

 Hypertensive effect of celery seed on rat blood pressure in chronic

administration (Maghadam et al, 2013)

Result: extract decrease blood pressure and increase the HR in

hypertensive rats, but had no effect on normositive rats. The data showed

that administration of 300mg/Kg of hexanic, metanolic, and aqueous

 etanolic (20/80, v/v) extract of celery seed caused 38, 24, and 23 mmHg

reduction in BP and 60, 25 and 27 beats perminute increase in the HR,

respectively.

 Vasorelaxant activity of extracts obtained from Apium graveolens posible

source for vasorelaxant molecules isolution with potensial anti-

hypertensive effect (Jorge et al, 2013)

Result: all extract caused consentration – dependenst relaxation in

precontracted aortic rings with and without endothelium the most active

extract were dichloromethane and ethyl acetat extract from Apium

graveolens.

The Journal of garlic was chosen because the journal has grade A, with 1

MA (11 RCT), 1 MA (7 MA, 7 RCT); 1 MA (3 MA, 2RCT) with the following

titles:

 Garlic for hypertension: A systematic review and meta-anlysis of

randomized controlled trial (Wang et al, 2015)

Result: significant lowering effect of garlic on both systolic blood pressure

and diastolic blood pressure.

 Effect of garlic on blood pressure: A systematic review and meta analysis (

Ried, 2008)

Result: While the mean decrease in the hypertensive systolic and diastolic

blood pressure

 Garlic lower blood pressure in hypertensive individuals, regulates serum

cholesterol and stimulated immunity: an update meta analysis and review

(Ried, 2016)
 Result: show decrease in systolic blood pressure and diastolic blood

pressure

The Journal of rosella was chosen because the journal has grade A, with 2

RCT; 1 MA (7RCT, 5 MA) with the following titles:

 Effect of sour tea (Hibiscus sabdariffa) on arterial hypertension a systemic

review and meta-analysis of randomized controlled trial (Serban et al,

2015)

Result: Aqueous extracts of Hibiscus sabdariffa were effective in

decreasing blood pressure. There has been no evidence of hepatic or renal

toxicity due to Hibiscus sabdariffa extract compsumtion

 Clinical efficacy of african tradisional medicines in hypertension a

randomized controlled trial with Combretum micranthum and Hibiscus

sabdariffa (Seck et al, 2017)

Result: efficacy of Hibiscus sabdariffa with mean reduction ranging from -

5,5 to -9,7 mmHg for systolic blood pressure and from -1,9 to -5,2 mmHg

for diastolic blood pressure.

 Effectiveness and tolerability of astandardized extract from Hibiscus

sabdariffa in patient with mild to moderate hypertension a controlled an

randomized clinical trial (Arellano et al, 2004)

Result: Hibiscus sabdariffa was able to decrease the systolic blood

pressure and diastolic blood pressure.

D. Active Coumpound, the group classified, structure, and

physicochemical properties of the celery
 Active compound of celery are apiin, apigenin, and NBP

 Structure and phycochemical of apiin, apigenin, and NBP

 Apiin :

Structure =

Molecular formula = C26H28O14

Molecular Weight = 564,4 g/mol

Melting Point = 230 °C

Soluility = Soluble in ethanol, Methanol and acetone

Polarity = Semi polar (Pubchem, 2019)

 Apigenin :

Structure =

Molecular formula = C15H10O5

Molecular Weight = 270,23 g/mol

Group = Flavonoid Group

Melting Point = 345-350°C

Solubility = Soluble in ethanol, Pyridine, very soluble in dilute

of alkalies, moderate soluble in hot alcohol,

soluble in dilute KOH

Polarity = Polar (Pubchem, 2019)

  NBP (n-buthylpthalide):

Structure =

Molecular formula = C12H14O2

Molecular Weight = 190,242 g/mol

Boiling Point = 313°C

Solubility = DMSO

Group = Benzofuran

Non Polar (Pubchem, 2019)

E. The general and the each active compound’s mechanism of action

 Mechanism of action of celery in general is vasodilatasi and vasorelaxant

(Sabzevar et al, 2016)

 Apiin is inhibiting angiotesin converting enzyme (Zhu et al, 2015)

 Apigenin and NBP contained in celery is vasorelaxator or vasodilator

(dilates blood vessels) with a contraction inhibition mechanism caused by

the release of calcium (working mechanism such as calcium antagonists).

Calcium antagonists work by lowering blood pressure by blocking the

entry of calcium into the blood. If calcium enters muscle cells, it will

contract. By inhibiting the contraction of muscles that surround blood

vessels, blood vessels will expand so that blood flows smoothly and

blood pressure will decrease (Saputra et al, 2016)

 APIIN

Apigenin

NBP
F. Dossage, indication, contraindication, side effect, interaction and
toxicity
 Dossage
 Preclinical Test:

Infusion of celery leaves 20; 40% of the dose of 8 mL / head in white rats with

a comparison of furosemide dose of 1.4 mg / head, can increase urine

significantly. Giving celery leaf juice lowers cat blood pressure by 13-17

mmHg. In another studyCelery leaf extract lowers cat blood pressure by 10-30

mmHg.

 Clinical tests:

Those involving 49 hypertensive patients are given a tincture (equivalent to 2 g

/ mL of celery herb extract) 30-45 drops 3 times a day. The results gave

therapeutic effects at 26.5%, moderate effects at 44.9% and did not have an

effect on 28.6%. Addition of honey and syrup to fresh herbal juice doses of 40

mL / 3 times daily showed treatment effectiveness in 14 of 16 cases of

hypertension while 2 cases were ineffective.

2 x 1 capsules (75 mg extract of celery seed) daily (Madhavi, 2013)

 Posology 3 x 1 tablet (2 g seed powder) / day. 3 x 1 capsule (100 mg herbal

extract) / day (Formularium Herbal Indonesia, 2016)

 Product = Tensigard (Apium graviolens and Orthosiphon stamines bent)= 3 x

250 mg (Supari, 2002)

 Indication

Indications for Anti Hypertension

 Contraindications
 Contraindications Because strong diuretics are not used in acute kidney

disorders, kidney infections, breast feeding, low blood pressure, surgery and

pregnancy. Celery contains fuanokumarin which has a phototoxic effect and can

trigger allergic reactions. (Permenkes, 2016)

 Warning

Warning Fresh celery herbs more than 200 g once a drink can cause a sharp

drop in blood pressure resulting in shock. A dose of 200 g also causes a diuretic

effect. Celery seeds cause photosensitization, need to use sunscreen when exposed

to sunlight.

 Side Effects

Side Effects for Hypertension Patiens is :

● Sensitive to Apiaceae can cause allergic dermatitis

● Some coumarin compounds may have a tranquilizer effect

● Hypersensitive reaction

● Prolonged sedation

● Photosensitivity

● Uterine stimulation

 Interaction

Interaction Increases the effect of antihypertensive drugs and diuretics. Celery

seeds can thin the blood, so it is not used in people who use blood thinners,

including aspirin, and Warfarin. Patients using diuretics may not consume celery

seeds (Incombination with anti coagulant, incombination with other anti

hypertension drugs).

 Toxicity
 Toxicity: High dose caused hepatotoxic, There is no systemic toxicity would

appear to be 5000 mg/µg per day.

 CHAPTER III
CONCLUSION
Based on the completion of the scenario, it can be concluded that:
1. The patient suffers from stage II hypertension (blood pressure 160/90 mmHg)
with clinical manifestations of a throbbing headache and nape feels stiff.
2. The right herbs to treat hypertension based on the analysis to use celery. the
recommended dosage is 3 x 1 tablet (2 g seed powder) / day, 3 x 1 capsule (100
mg herbal extract) / day.
 CHAPTER IV
Quenstions and Answers
The Questions :
1. What’s the non-pharmacology therapy for hypertension ?
2. Did celery extract can be consumed with other antihypertension drugs?
3. What’s the normal value for blood pressure ?
4. Are there other indications of celery?
5. What is the lifestyle of people with hypertension?
6. Are there journals that compare with ARB groups?
7. Can you explain about the stage of hypertension?
8. What will be caused if patient take celery combination with the captopril?
9. How stress can causes an increase the blood pressure?
10. Can you explain the group of 3 active compounds from celery?
11. How the side effect and the active compound of celery can cause allergy
reaction?
12. Does celery can use in stage 2 hypertension?
13. What compund can cause the interaction of celery with anticoagulant drug?
14. Why celery can causeb bleeding if we take together with anti coagulant?
15. Which part of celery is used to reduce blood pressure?
16. How does celery’s work as a vasorelaxant?
The Answers :
1. - limited of sodium intake
- Excerise minimum 30 minutes
- Quitting smoking and limited alcohol
- Diet (fruits, vegetable, and low fat)
- Lossing weight if obesity
2. It’s better to avoid to consume with anti hypertension agent especially diuretic
agent because it can make hypotension
3. Normal value of blood pressure is 120/80 mmHg, but in the case the patient
has hypertension stage II so the target blood pressure is 140/90 mmHg
4. one possible advantage of celery extract over conventional drugs use in high
blood pressure is that beta-blocker, ACEI, CCB tend to significantly lower
cerebral blood flow. While this effect is helpful in reducing the likehood of
stroke. As appetite
enhancer, helpful in rheumatism and gout.
5. Diet and behavioural modifications to control hypertension:
a. Stop smoking
b. Reduce total and saturated fat, red meat, sugary drinks, refined
carbohydrates, salt, alcohol, weight
c. Increase fruit, vegetables, whole grains, fish and poultry, low fat dairy
products, olives and olive oil, garlic, and aerobic exercise
6. Not found yet
7. According to JNC 7 for adults >18 years
Systolic BP Diastolic BP
Normal <120 <80
Prehypertension 120-139 80-89
Stage I 140-159 90-99
Stage II >160 >100

8. The combination of celery and captopril might be beneficial for the treatment
of hypertension, as celery causes an increase in the plasma level of captopril,
which an enchane its efficacy. But the combination can also causes a
hypotension.
9. Stress can cause hypertension by stimulation of the nervous system to produce
large amounts of vasoconstictring hormones that can increase the blood
pressure.
10. Apiin is flavonoid, apigenin is glycoside, and NBP is benzofuran.
11. The active compound is fuanokumarin cause phototoxic and triggered allergy
reaction.
12. Can use in hypertension stage 2 , but should consultation with doctor or
combination with synthetic drug example nifedipin.
13. NBP (N-buthylphtalide) incombination with anticoagulant can cause risk of
bleeding.
14. Cause in celery theres’s NBP, NBP has antiplatelet, agregation and anti
trombolitic effect. So it can rise the risk of bleeding
15. Based on journals that are found to be the most effective part of celery used to
reduce blood pressure are celery leaves.
16. Vasorelaxant effect is related to blokade of Ca channel. The active compounds
in celery inhibit the Ca influx through voltage and ligand calcium channels
thus can cause reduction in vascular smooth muscle tone, avoid periphenak
pressure increase, so that blood pressure decreases.
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