12 Safety of Herbal Medicine - Dr Rul

8/12/2019 12 Safety of Herbal Medicine - Dr Rul

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Rul Afiyah Syarif

Pharmacology and Therapy Depart.

School of Medicine UGM

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1. Know the side effect of herbal medicine/

phytopharmaca

2. Understand the risk of interaction between

modern drug and herbal medicine/phytopharmaca

3. Know mechanism pharmacokinetic and

pharmacodinamic interaction between

modern drug and herbal medicine/phytopharmaca

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mixtures of morethan one active

ingredient

the likelihood of herbdrug interactions istheoretically higher

than that of drugdruginteractions

Herbs and drugs mayinteract either

pharmacokineticallyor

pharmacodynamically.

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Skin: hypersensitivity reaction

Liver: hepatotoxic effect, elevation of

hepatic enzyme

GI tract: nausea, vomiting, diarrheaNeurologic: dizzines, headache, insomnia

Cardiovascular: syncope, hypotension

Renal: failure, K-Na retention, urinary

retention

Pulmo: bronkhiolitis

etc

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The risk and severity, depend on:

Patients age

Genetic constitution: G6PD defisiensi (anemi

hemolitik)Nutritional state

Concomitant diseases

Concurrent medication

Consumption of large amounts

Consumption of wide variety

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1. Intrinsic

a. Type A reactions: dose-dependent, predictable toxicity,

over dosage, interaction with pharmaceuticals

b. Type B reactions: unpredictable, idiosyncratic reactions

(e.g. allergy, anaphylaxis), no dose-dependent

2. Extrinsic

Failure of Good Manufacturing Practice

a. Misidentification

b. Lack of standardizationc. Contamination

d. Substitution

e. Adulteration

(Source: Drew and Myers, 1997)

f. Incorrect preparation

and/or dosageg. Inappropriate labeling

and/or advertising

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Yohimbine (an alkaloid found in Pausynistalia

yohimbebark)

Has 2-adrenoreceptor antagonist activity,

for male impotence Type A reaction: hypertension, anxiety

Type B reaction; bronchospasm, increased

mucus production when taken in normal

doses by a patient with severe allergicdermatitis

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1. Misidentification

Use binomial Latin names for genus and species for

plants

occur when other names are used

2. Lack of standardisation

examination in 50 commercial brands of ginseng sold

in 11 countries,1in 44 of these products, the

concentration of ginsenoside ranged from 1.9% to 9%

w/w; six products contained no ginsenoside

3. Contamination contaminated by pesticide residues, microorganisms,

aflatoxins, radioactive substances and heavy metals;

lead, cadmium, mercury, arsenic

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http://e/INTERNET/herbal%20medicine/Herbal%20safety/drew%20and%20Myers%2011997%20Safety%20of%20Herbal%20Medicine%20nplications%20for%20the%20health%20profesionals.htmlhttp://e/INTERNET/herbal%20medicine/Herbal%20safety/drew%20and%20Myers%2011997%20Safety%20of%20Herbal%20Medicine%20nplications%20for%20the%20health%20profesionals.htmlhttp://e/INTERNET/herbal%20medicine/Herbal%20safety/drew%20and%20Myers%2011997%20Safety%20of%20Herbal%20Medicine%20nplications%20for%20the%20health%20profesionals.htmlhttp://e/INTERNET/herbal%20medicine/Herbal%20safety/drew%20and%20Myers%2011997%20Safety%20of%20Herbal%20Medicine%20nplications%20for%20the%20health%20profesionals.htmlhttp://e/INTERNET/herbal%20medicine/Herbal%20safety/drew%20and%20Myers%2011997%20Safety%20of%20Herbal%20Medicine%20nplications%20for%20the%20health%20profesionals.htmlhttp://e/INTERNET/herbal%20medicine/Herbal%20safety/drew%20and%20Myers%2011997%20Safety%20of%20Herbal%20Medicine%20nplications%20for%20the%20health%20profesionals.html


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4. Substitution A Belgian slimming treatment, Stephania tetrandra

was replaced withAristolochia fangchi, containing

the nephrotoxic component aristolochic acid, caused

severe kidney damage

5. Adulteration

Herbal products contain steroids (e.g. prednisolone,

dexamethasone), pain killer (aminopyrine,acetaminophen), skeletal muscle relaxant (e.g.

chlorzoxazone), minor tranquilizer (e.g. diazepam)

and glybenclamide.

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6. Incorrect preparation/dosage

7. Inappropriate labelling/advertising

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16% of prescription users consume herbal

suplements (Izzo, 2005)

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potential interaction of alternative medicine

products with prescription medications.

especially important to drugs with narrow

therapeutic indices, such as warfarin.


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Follow modern pharmacological principle

1. Pharmacokinetic interaction

a. Induction/inhibition of hepatic and intestinal

drug metabolizing enzymes (cytochrome P450)1) St Johns wort, echinacea, kava, garlic

2) Flavonoids, coumarins, furanocoumarins,

anthraquinon, caffeine, terpene

b. induction/inhibition of drug transporters, such

as P-glycoprotein :Curcumin, ginsenosides, piperines, sylimarin, catechins

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2. Pharmacodynamic interaction

a. Additive/synergistic:

HM potentiates the action of synthetic drugs :

anticoagulant warfarin interacts with antiplatelet

herbs

b. Antagonistic: HM reduces the efficacy of

synthetic drugs:

Kava (Piper methysticum) possesses dopaminergic

antagonist propertise, reduce the pharmacologicalactivity of levodopa

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keduanya berinteraksi dengan obat-obat

konvensional menyebabkan efek

berlawanan atau menghilangkan efek dari obat

kimia itu sendiri

1. Herba Hypericum perforatum

(St. John's wort)

2. Rhizoma Hydrastis canadensis (Golden seal)

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3. Piper methysticum (kava-kava) :

menyebabkan kerusakan hati

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4. Atropa belladonna: atropine, hyoscyamine,scopolamine

5. Digitalis sp.: digitoxin

6. Ephedra sp.: efedrine &pseudoefedrine

7. Rauwolfia serpentina:yohimbine,

reserpine, serpentinine

mengandung senyawa

berkhasiat amat toksik,

dikembangkan menjadi

obat dan digolongkansebagai obat keras

(tidak dijual bebas),

penggunaannya harus

diawasi dokter

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BPOM, 201118


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The possible interaction between conventional

drugs and popular herbal medicine :

1. Ginkgo (Ginkgo biloba)

2. St Johns wort (Hyperiicum perforatum)3. Ginseng (Panax sp)

4. Garlic (Allium SativumL.)

5. Echinacea,

6. Saw palmetto (Serenoa repens)

7. Kava (Piper methysticum)

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to improve cognitive functionAlzheimers disease and dementia

to improve blood flow

peripheral vascular disease, tinnitus, or memory

impairment Main constituents: ginkolides, flavonoid

Ginkgolide B inhibits platelet-activating factorby displacing it from its receptor-binding site,

resulting in reduced platelet aggregation. Several cases of bleedingthought to be

secondary to ginkgo ingestion

Ginkgo force, Ginkan, Ginokan, etc

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Drugs results Mechanism Comments

Aspirin Spontaneous

hyphema

additive effect on

platelet agregation

(ginkgolides are

potent inhibitors of

PAF or haveantiplatelet activity)

hyphema is a

clinical rare

problem

NSAID bleeding

Paracetamol

and

ergotamine/caffeine

Bilateral

subdural

hematoma

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Warfarin over-

anticoagulation

additive effect on

coagulation

mechanism

Intracerebral

hemorrhage

Thiazidediuretic

Hypertension This effect may be anunusual adverse

reaction to the drug or

herb;

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Main compounds: hypericine, hyperforin, flavonoids

management of depression.

as a MAO inhibitor

Result of research :1. acts as a selective serotonin reuptake inhibitor (SSRI)

Concurrent use of SSRIs with St Johns wort is

contraindicated.

2. may act in the cytochrome P-450 system of the liver.

3. Another research :unlikely to inhibit the CYP2D or

CYP3A4 liver enzyme systems. More research is needed.

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Drugs results mechanism CommentsDigoxin

(cardiac

inotropic)

decreased

plasma digoxin

concentration

St Johns Wort induces P-

glycoprotein involved in

digoxin absorption/

excretion

Digoxin has a

narrow

therapeutic index

warfarin decreased

anticoagulant

effect

Warfarin is metabolised

by CYP enzyme which are

induced by St Johns

Wort

potential

thrombotic

complications

Simvastatin decreased

plasmasimvastatin

concentration

Simvastatin is a substrate

P-glycoprotein and ismetabolized by CYP

enzymes

Both P-glycoprotein and

CYP enzymes are induced

by St Johns Wort

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Drugs results mechanism CommentsVerapamil Decreased

bioavailability

of verapamil

Induction of intestinal

CYP3A4 by St Johns

Wort

Theophylline Reduction

theophylline

concentration

in plasma

St Johns Wort induce

hepatic enzyme

Cyclosporin

(immunnosupres

sant)

Decreased

Cyclosporin

concentrationsin serum

St Johns Wort decrease

intestinal absorption and

increase metabolism ofCyclosporin

Combined oral

contraceptive

(ethinyloestradi

ol and

desogestrel)

Breakthrough

bleeding

Induction of intestinal

CYP3A4 by St Johns

Wort

Decreae plasma

level of

ethinyloestradi

ol and

desogestrel25


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Three ginseng species:

1. American ginseng (Panax quinquefolius) :polysacharides

2. Oriental ginseng (Panax ginseng):ginsenosides

3. Siberian ginseng (Eleutherococcussenticosus) : eleutherosides

have been promoted as energy enhancers,stress reducers, and mood improvers.

(Panax

quinquefo l ius)

(Panax gins eng

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marketed for a wide range of indications: erectile dysfunction, cancer prevention, enhanced

physical function and improved cognitive functions.

The active components : ginsenosides

The pharmacological activity of eachginsenoside appears to vary depending onwhere the plant grew and the extractiontechniques used.

Also, data suggest that the ginsenosidecomposition varies widely among commerciallyavailable ginseng products (1,9-9%).

This variability makes it difficult to evaluatethe safety and efficacy of ginseng products.

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Pharmacological effect of ginsenosides:

may increase adrenal hormone synthesis,

decrease blood glucose concentrations, and

promote immunomodulation.Oriental ginseng (Ginsana)

may antagonize the anticoagulant effects of

warfarin.

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Warfarin decreased

anticoagulant

effect

not known potential

thrombotic

complications

Alcohol Increased

alcoholclearance

Ginseng increases

the activity ofalcohol

dehydrogenase

and aldehyde

dehydrogenase

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Main constituents: polisacharides, phenol,alkamides

Echinacea boosts the immune system and

helps fight colds and flu, aids wound healing

Used for prevention and treatment of upperrespiratory tract infection

Prepared from the roots and or other part of

the plants: E. purpurea, E. angustifolia, E.

pallida

Drug interaction: cause inflammation of the

liver if used with anabolic steroids,

methotrexate

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Remedy: Imboost

Drugs results mechanism Comments

Caffeine Reduction of

caffeine oral

clearance

Caffeine is a sustrate

of CYP1A2 which is

inhibited by

echinacea

This inteaction is

not clinically

relevant

Midazolam Increased (oralmidazolam) or

decreased

(systemic

midazolam)

clearance

Midazolam is asustrate of CYP3A4

Echinacea inhibits

intestinal CYP3A4,

whie it induces

hepatic CYP3A4

Therapeuticmanifestation is not

determined

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Main constituents: aliins

have several beneficial cardiovascular

effects: lowering blood pressure and serum lipid,

hypercholestrolemia, prevention

atherosclerosis and antithrombotic

activity.

Garlic oil has been reported to

interrupt thromboxane synthesis,thereby inhibiting platelet function.

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Warfarin over-

anticoagulation

additive effect

on coagulation

mechanism

Risk of bleeding.

Chlorpropamide A fall in glucose

level

Additive effect

Paracetamol Changes in

paracetamol

pharmacokinetics

variable

Not known

Ritonavir Severe GI toxicity Ritonavir inhibit

metabolism of

the active

ingredients of

garlic

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Roots and rhizome

Main compounds:Kavapyrones

Anxiolitics

Side effect :hepatotoxicDrugs results mechanism Comments

Alprazolam Semicomatose

state

Additive efect on

GABA receptors

Patient was

lethargic and

disoriented for

several hours

Levodopa Reduced

efficacy of

levodopa

Kava possesses

dopaminergic

antagonistic

properties

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=curcuma

Compounds: Curcuminoids (0.8 to 2%), including

curcumin, demethoxycurcumin

Indications and usage

Liver and gallbladder complaints

Loss of appetite

Precautions and adverse reactions

Stomach complaints: in the case of overdose. Stimulate the biliary tract, it should not be

administered if there is a bile duct blockage.

Colic can occur when the patient suffers from

gallstones. 37


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=turmeric

Compound: Curcuminoids (3-5%), including

curcumin, demethoxy curcumin,

bidemethoxy curcumin Indication/usage:

Dyspeptic complaints,

loss of appetite

Interaction: turmeric inhibit plateletaggregation, increase risk bleeding

Side effect:

stomach complaints can occur in the case of

overdose. 38


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jamu kunyit asam sebagai pelancar haid,

sebaiknya dihindari saat masa awalkehamilan, karena ekstrak kunyit memilikiefek stimulan pada kontraksi uterus dan

berefek abortivum

Asam untuk menstabilkan dan

mensuspensikan kunir, memberi rasa

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Main constituents: gingerols, zingerone

Used as an antinausea and antispasmodic agent

a potent inhibitor of thromboxane synthetase

and thus reduce platelet aggregation andprolongs bleeding time.

may lead to an increased risk of bleeding when

taken with warfarin.

Jahe

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The main constituents: triterpene acids

Effect: Anti-inflammatory (a reduction of acute

radiation reaction in rats),

antineoplastic (involve direct action on DNA

synthesis), ulcer-protective (reduced the formation of

stressinduced ulcers)

wound healing (an increase in peptidic

hydroxyproline content, tensile strength,collagen synthesis, angiogenesis and

epithelialization)

Precautions and Adverse Reactions

Allergic Contact Dermatitis 41


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Papain is a mixture of proteolytic enzymes

Papain has an antimicrobial, anthelmintic

and anti-ulcerative effect, edema-reducing

effect.

Usage: reduces edema, inflammation, herpes

zoster symptoms, diarrhea, and psoriasis

symptoms. contraindicated in pregnancy, because of

embryotoxic and teratogenic effect

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The pharmacological mechanisms by which

papain may affect coagulation are not

known.

Patients receiving warfarin should be advisedto avoid papain supplementation

Drugs results Comments

Warfarin Increased INR

INR used to determine the clotting tendency of blood

Normal INR = 0,8 1,2

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Compounds: caffeine, saponin, flavonoid,

prevent various cancers,

treat gastrointestinal disorders,

enhance cognition.

dried green tea leaves

contain substantial amounts of vitamin K,

brewed green tea :not considered a

significant source of the vitamin. large amounts of brewed green tea: potentially

antagonize the effects of warfarin.

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Side effects:

persons who have sensitive stomachs, chiefly due

to the chlorogenic acid and tannincontent. Hyperacidity, gastric irritation, reduction of

appetite, as well as obstipation or diarrhea,

could be the result of intense tea consumption.

These side effects can be generally avoidedby the addition of milk (reduction of the

chlorogenic acid and other tannins).

Drugs results mechanism Comments

warfarin decreased

anticoagulant

effect

green tea contain vit

K , antagonize

warfarin effect

potential

thrombotic

complications

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increase breast milk production during

nursing period

increased the expressions of prolactine and

oxytocin genes in lactating BALB/C mice andwas predicted to correlate with papaverine

content, which is only detected in mature S.

androgynus leaves

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Ibu-ibu hamil yang minum jamu cabe puyang

(RS Sardjiito): kesulitan persalinan

alkaloid piperin: berefek menghambatkontraksi otot, sehingga akan menyulitkan

persalinan

Diminum di awal kehamilan : memperkokoh

otot uterus, resiko keguguran kecilDiminum terus sampai akhir kehamilan, otot

uterus sulit kontraksi

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Daun: antiastma (melonggarkan pernafasan)

Dikeringkan, diserbuk untuk rokok, dihisap

Daun segar dilumatkan ditempelkan di pipiuntuk sakit gigi

Jika diseduh dan diiminum : keracunan

berupa midriasis

Bila disalahgunakan untuk mabuk sangat

berbahaya, bisa kematian

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Mengandung antrakinon untuk melancarkan

BAB

Mengandung skopoletin untuk menurunkan

tekanan darah

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Drew, A.K. and Myers S.P. 1997. Safety Issues

in Herbal Medicine: Implications for Health

Professions. The Medical Journal of

Australia. 166:538-541

2000. Physician Desk Reference for Herbal

Medicine

2011. Info POM, Vol. 12 No. 3. BPOM RI

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12 Safety of Herbal Medicine - Dr Rul