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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.html8/12/2019 12 Safety of Herbal Medicine - Dr Rul
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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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Drugs results Mechanism Comments
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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Drugs results Mechanism Comments
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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Drugs results Mechanism Comments
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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