Following file comprises of information about interactions taking place between herbs-drug, herbs-herbs, it also highlights some of the cases of clinical laboratory test interactions taking place due to use of herbal medicines.

1. An Increasing Need To Monitor Herbal Medicines
PHYTOPHARMAVIGILANCE
Presented by:
ANUSHMA CHORSIYA
M.Pharm (Pharmacognosy and
Phytochemistry)
Delhi Pharmaceutical Sciences
and Research University

2. 1. Introduction
Pharmacovigilance etymological roots are: pharmakon (greek word
for drug) and vigilare (latin word for to keep watch).
Pharmacovigilance is the pharmacological science which deals with
detecting, understanding and preventing adverse drug reactions.
Herbal pharmacovigilance is the sub branch of Pharmacovigilance
which deals with monitoring, detecting and understanding various
adverse reactions taking place with herbal medicines.
Herbal pharmacovigilance deals with interactions taking place
between herbs and drug; herb and herb and also with interactions
taking place at clinical laboratory testing time.

3. What is Herbal Medicine ?
Herbal medicines are just plant - based medicines which may comprise of
either single moiety or whole plant or group of chemical moieties. These are
marketed as water based preparations (decoction, infusion, syrups, poultices,
lotions), alcohol based preparations (tinctures) and in many other forms like
powder, juices, creams, gargles and mouthwashes.
As per WHO March 2003 report , it was reported that about 40% of
population in China preferred traditional medicines of all health care delivered.
As per same report about 71% population in Chile, 40% in Colombia and
65% of India’s population in rural areas used Ayurveda and medicinal plants
for primary health care.
The World Health Organization estimates that 80% of the population of some
Asian and African countries uses herbal medicines for primary health care.

4. Herbal Market
The global herbal medicine market size was estimated to be of about USD 71.19
Billions in 2016 and is expected to grow.
While the extract segment generated revenue of about USD 27.1 Billions in 2016
and is expected to rise upto USD 44.6 Billions by 2024.
And as per Zion Market Research, report titled “HERBAL SUPPLEMENT
MARKET BY SOURCE , BY APPLICATION; BY FUNCTION: GLOBAL
INDUSTRY PERSPECTIVE, COMPREHENSIVE ANALYSIS AND FORCAST,
2017-2022” its estimated that , global herbal supplement market is expected to reach
approximately USD 86.74 billions by 2022, growing at a CAGR (Compound annual
growth rate) of around 6.8% between 2017 and 2022.
In 2016, Europe dominated the global herbal market and is expected to retain its
share uptill 2024 as per forcast.

5. Why is it Needed?
With increasing utilization of herbal medicines for self medication by
individuals cause of following reasons:
Mindset that herbal medicines have no adverse effects.
Cost effective as compared to conventional medicines.
Consumers preference for natural therapies.
Uncomfortableness of patient to discuss their medical problems.
Self medication of herbal medicines with prescribed medications as per
physicians, has lead to various adverse reactions ranging from mild to
severe that are being reported worldwide, has lead to monitor herbal
medicine usage.

6. 2. Reasons For Herbal Drug Interactions
Variety of adverse reactions have been reported and studied
related to herbal medicine medication. Upon studies
conducted it was reported that they are due to:
 Overusage of herbal medications leading to toxicity and ill
effects.
Interactions between herbs and conventional medications.
Usage of herbs for long term, interfered with clinical
laboratory tests leading to false indications and misleading
the physicians.

7. Facts about interactions
 Drug interactions cause of death for every 4th or 5th case.
At least 100 preoperative fatalities due to herb-drug/surgery
interactions.
>70-80 Herbs- increase risk of bleeding.
>30-40 Herbs possibly causes hepatic failure.
Ephedra reported cause of 54 deaths and 1600 adverse events.
Aleo vera injections – 4 deaths when injected in cancer patients.

8. 3. Categories of interactions
 Category 1: Hazardous
a. Aristolochic acid (Aristolochia sp.)
• 1993: 30 cases of kidney failure among Belgian women using powdered
Chinese herbs for weight control which was adulturated with Aristolochia sp.
• 2002: 237 of nephropathy in Asia and Europe was reported due to prolonged
effect of Chinese herbs for increased athletic performance which was
contaminated with Aristolochic acid.
Aristolochic acid is metabolically activated to carcinogen compound by
cytochrome P450.
b. Germander (Teucrium sp.)
• 1990’s: In France, 26 cases of hepatic toxicity after 9 weeks of use of
germander was reported which was used for weight and cholestrol reduction.

9. • Jaundice disappears within 8 weeks discontinued use but returned promptly
after re-use started.
• The furano diterpenoids in germander causes reduction in glutathione
(reversed with cystine).
 Category 2: Potentially hazardous with prolonged internal use
a. Comfrey (Symphytum sp.)- contains pyrrolizidine alkaloids which are
hepatotoxins.
b. Chaparrel (Larrea sp.)- used as external anti-inflammatory agent for long
term but if used internally caused non-fatal kidney/liver damage.
c. Kava (Piper sp.)- Popular relaxant but in 2002, FDA issued a warning about
its association with liver toxicity. In 2003, Kava was banned in Germany.
d. Androstenedione- a non-herb supplement derived from animal adrenal glands
and gonads was used in conjunction with some heerbs as a testosterone
precursor to enhance muscle development but, now its banned. Its short term
use has little or no side effect but evidences of increased cancer rates with
long-term use.

10.  Category 3: Hazardous with acute excessive dosage
a. Pennrroyal oil (Hedeoma sp.) excessive use should be avoided
to treat colds as its hepatoxic/nephrotoxic compound.
b. Yohimbine (Rawolfia serpentina) marketed to treat impotence
for years. But have potential toxicity like hypertension,
anxiety, dizziness but rarely death.

11. 4. Adverse effects of Herbs
HERBAL DRUGS REPORTED ADVERSE EFFECTS
Hypericum perforatum (St.
John’s wort)
Gastrointerstinal disturbances, allergic reactions, fatigue,
dizziness, confusion, dry mouth, photosensitivity.
Ephedra sinica (Ephedra) Hypertension, insomnia, arrhythmia, nervousness,
tremor, headache, seizure, cerebrovascular events,
myocardial infraction, kidney stones.
Piper methysticum (kava) Sedation, oral and lingual dyskinesia, torticollis,
oculogyric crisis, exacerbation of Parkinson’s disease,
painful twisting movements of the trunk, rash.

12. HERBAL DRUGS REPORTED ADVERSE EFFECTS
Ferula assafoetide
(Asafoetida)
Causes methaemoglobinaemia
Caulophyllum thalictroides
(Blue cohosh)
Slows heart rate, decreases blood pressure,
oestrogen like hormonal activity, contains
salicylates
Eucalyptus oil Causes indigestion, muscular weakness, nausea,
vomiting, diarrhoea, kidney damage.
Teucrium chamaedrys
(Germander)
Cause liver damage
Cordalis spp. (Jin bu haun) Slows heart rate (bradycardia), causes
respiratory and CNS depression, toxic

13. HERBAL DRUGS REPORTED ADVERSE EFFECTS
Senecio vulgaris
(Groundsel)
Toxic, causes liver disease
Symphytum officinale
(Comfrey)
May cause liver disease
Triptergium wilfordii
(Thunder vine)
Powerful immunosuppressant effects
Ginkgo biloba Bleeding

14. HERBS ADVERSE EFFECT OVER :
Belladonna (Atropa belladonna), Dogbane
(Apocynum cannabinum), Foxglove
(Digitalis purpurea), Ginger (Zingiber
officinale), Ginseng (Panax spp.) and Lilly
of the valley (Convallaria majalis).
Cardiovascular system (heart rate, heart
rhythm, blood pressure)
Penny royal (Mentha pulegium), Mistletoe
(Phoradendron flavescens), Lobelia
(Lobelia inflata), Jin bu huan (Lycopodium
serratum), Germander (Teucrium
chamaedrys), Comfrey (Symphytum
officinale), Chaparral (Larrea tridentate)
May cause liver damage
Redstem wormwood (Artemisia scoparia),
Chinese goldthread (Coptis chinensis)
Displaces serum bilirubin from serum
albumin which may result in brain damage

15. 5. HERB-DRUG INTERACTIONS
The nature of herb-drug interaction is not due to chemical interaction
between herb and drug resulting in formation of something toxic, but its due
to alteration in drug metabolism and drug absorption, thus resulting in
alteration of drug bioavailability.
Two major pathways that explains interactions are:
1. Enzyme Inhibition: As majority of drugs oxidative biotransformation
takes place due to Cytochrome P450 oxidase enzyme and herbs
interferes with it.
2. Enzyme Induction: Herbs interferes in P- glycoprotein transporter
system.
 This ultimately results in synergistic or agonist interaction between drug
and herbs .

16. EVIDENCE BASED INTERACTIONS
A. Hypericum perforatum (St. John’s-wort)
DRUGS/ENZYME EFFECTS
Phenprocoumon, Digoxin,
Cyclosporin/Tacrolimus, Indinavir,
Irinotecan, Amitriptyline
Reduced therapeutic effect
Oral contraceptives Suspected unwanted pregnancy/ breakthrough
bleeding
Substracts for P-glycoprotein Increased expression of P-gp
Cytochrome P450
a. Substracts for isoform 1A2, 2D6,
2E1, 3A4
b. Substracts for isoform 1A, 3A, 2E1
c. Substracts for isoform 1A2, 2C9,
2C9, 3A4
No effect/CYP enzyme induction
a. In open-label human study
b. In animal study
c. In-vitro studies in animal or human tissues.

17. B. Pinax spp. (Ginseng)
DRUGS/ ENZYMES EFFECTS
Warfarin
a. Controlled clinical trial in healthy
subjects
b. Case reports or series
c. Animal studies
d. In-vitro studies in animal or human
tissue
a. No effect
b. Decreased INR
c. No effect
d. Anticoagulant effect
Digoxin Increased AUC of Digoxin
Opoids Decreased activity
Mytomycin C Synergistic effect
Phenelzine Increased CNS side effects and manic
effects.

18. C. Piper mesthysticum (Kava Kava)
D. Zingiber officinale (Ginger)
DRUGS/ENZYMES EFFECTS
Alprazolam, cimetidine,
barbiturates and benzodiazepines
Additive effects with CNS
depressants
Cytochrome P450 Inhibition
L-Dopa Decreased efficacy
DRUGS/ENZYMES EFFECTS
Anticoagulants Increased bleeding
Insulin, Chlorpropamide, Glipizide,
Tolbutamide
Decreased hypoglycemic
Verapamil, Felodipine, Amlodipine Synergistic effect can cause risk
of developing arrhythmias

19. E. Piper nigrum (Black pepper)
F. Cinnamomum verum (Cinnamon)
DRUGS/ENZYMES EFFECTS
Lovastatin, Ketoconazole, Itraconazole Hepatic metabolism decreased
Antacids Action decreased
Phenytoin, Carbamazepine, Tranquilizers,
Propranolol (in healthy volunteers)
Increased AUC
Rifampin, Theophylline (Pulmonary
Tuberculosis patients)
Increased AUC
DRUGS/ENZYMES EFFECTS
Glimepiride, Glyburide, Insulin,
Pioglitazone, Rosiglitazone,
Chlorpropamide, Glipizide, Tolbutamide
and other diabetic medications
Synergistic effect , causes blood sugar to
go too low

20. G. Syzygium aromaticum (Clove)
Fluoroquinolones Effectiveness decreased
Anti hypertensive drugs Increased AUC
Tetracycline Phototoxicity risk increased
DRUGS/ENZYMES EFFECTS
Anticoagulants (Heparin, Warfarin) Increased bleeding
NSAIDs like Aspirin, Diclofenac,
Ibuprofen, Naproxen and others
Increased bleeding
Anti-epileptic drugs like phenytoin Decreased effect in children
Damage liver

21. 6. Herb-Herb Interactions
“Can herbs interact with each other?” is a big question which is their in
everyone’s mind and everybody has answer to off this question.
Yes, herbs interacts with each other but its not always in a positive way
sometimes herb-herb ineraction causes toxicity and harmful effects.
There major mechanism of action involves:
a. Synergistic effect of both herbs.
b. Effect of one drug increased by other.
c. One herb can cancel effect of another.
d. One herb can increase effect of another.
e. Effect of both the herb can be decreased.
f. One herb can increase side effect of other.

22. HERB 1 HERB 2 EFFECT
Swaetzia
madagascariensis Desv.
(Ceasalpiniaceae)
Securidaca longipedunculata
Erythrophelum guineense
Gardenia ternifolia (Rubiaceae)
Opilica celtidifolia (Opiliaceae)
Nauclea latifolia
Serious/dangerous
consequences (profuse
diarrhea and vomiting,
increased toxicity or even
lead to death)
Securidaca
longipedunculata
Fresen. (Polygalaceae)
Sclerocarya birroea
Cassia italica
Serious/dangerous
consequences (profuse
diarrhea and vomiting,
increased toxicity or even
lead to death)
Erythrophelum
guineense
(Ceasalpiniaceae)
Any plant Serious/dangerous
consequences (profuse
diarrhea and vomiting,
increased toxicity or even
lead to death)

23. HERB 1 HERB 2 EFFECTS
Cassia italica
Securidaca
longipedunculata
Combretum micranthum
Afrormosia laxiflora
(Fabaceae)
Mild consequences
(benign diarrhea,
dizziness, headaches,
fever)
Lannea velutina A.Rich.
(Anacardiaceae)
Tamarindus indica
Cassia nigricans Vahl.
(Ceasalpiniaceae)
Securinega virosa
Ficus hetrofila
(Moraceae)
Bridelia farruginea
Benth. (Euphorbiaceae)
Effect of one canceled by
other

24. 7. Effect of Herbal Medicines on
Clinical Laboratory Testing
Knowledge about interferences between herbal medicines and
clinical laboratory testing is also an important aspect as intake of
herbs may change results of lab testing thus showing false indications
which further misleads the physicians.
Abnormal laboratory test results due to use of herbal drugs can be
classified into 3 categories:
a. Abnormal test results due to direct interference of a component of
the herbal medicine with the assay.
b. Unexpected concentration of a therapeutic drug due to drug-herb
interactions.
c. Abnormal test results due to toxic effects of the herbal product.

25. A. Abnormal test results due to direct interference of a
component of the herbal medicine with the assay
Herbal medicines interferes with assay of conventional drugs used for
therapeutic monitoring.
For instance, when assay of digoxin was performed using FPIA (Fluorescence
Polarization Immunoassay) in individuals taking herbal medicines like ginseng,
oleander, ashwagandha, siberian ginseng and Chinese medicine (Chan Su, Lu-
hen-Wan or Dan Shen), then the result shown by the test showed decreased
concentration of digoxin in sample thus misleading the physician.
This happened as all the above listed herbs have steroidal moieties in their
chemical constituents and digoxin also have steroid moiety, but herbal moieties
have greater affinity towards antibodies thus binding with majority of them and
resulting in demonstration of lower percent of antibodies binded with digoxin and
misleading the assay.

26. B. Unexpected concentration of a therapeutic drug due to
drug-herb interactions
This condition arises due to physiological effects which either effects
toxicity or enzyme induction due to use of herbal products.
a. For example, unexpected low level of therapeutic drugs due to interaction
with St. John wort as, hyperform induced CYP3A4 and CYP2BC which
activates steroid and xenobiotics receptors while, hypericin induces p-
glycoprotein drug transporter and reduces the efficacy of drugs not
metabolised by hepatic pathway.
b. Self medication with St. John’s Wort may lead to failure of treatment due
to significant decrement in plasma-drug concentration and increament in drug
metabolism.

27.  Unexpected presence of a drug in a patient who never used that drug, this
condition arises due to adulteration of herbal medicines with western
medicines. Some of such incidences are described below:
a. NSAIDs and benzodiazepines found in Chinese medicines sold outside
Asia.
b. In a clinical lab study, a boy was diagnosed with aplastic anemia, on
further analysis it was noted that the herbal medicine he was taking was
adultered with phenylbutazone, but was not listed as a ingredient in the
package.
c. Presence of phenytoin in a proprietary Chinese medicine marketed for
controlling epilepsy.

28. C. Abnormal test results due to toxic effects of the herbal
products
 Kelp (a sea weed) tablets are rich in vitamins and minerals but contains a
substantial amount of iodine . A women taking 6 kelp tablets a day for a year,
exhibited hyperthyroidism, with no history about thyroid disease. After
discontinuing it, her hyperthyroidism resolved and thyroid function test results
returned to normal.
Drug induced hepatitis due to Mistletoe.
Drug-induced hepatotoxicity in patients taking germander been reported in Europe.
Liquorice induced pseudoaldosteronism and hyopkalemia, since liquorice contains
glycyrrizic acid, which inhibit enzyme 11-ß-hydroxysteroid dehydrogenase which
converts cortisol to cortisone leading to increament in concentration of cortisol,
further resulting in decreament in renin activity and aldosterone concentration in
serum.

29. 8. Conclusion
With increasing demand of herbal medicine globally, its need of the hour to
educate individuals about effects occurring with the use of herbal medicines,
though in many of the studies they have proved to be beneficial for the
treatment and prophylaxis of certain diseases, one should not ignore its adverse
effects.
Individuals should change their mindset that herbal medicines are free from
adverse effects and should consult physicians before starting herbal therapy and
should update him/her about history also if one in already on herbal therapy.
There are cases reported about interaction of herbal medicines with
conventional drugs, whose adverse reactions ranges from mild to fatal which
may further cause death also.

30.  Herbs not only interacts with conventional drugs but also among themselves
leading to toxicity or decrement of therapeutic index of one herb by other.
 Apart from herb-drug and herb-herb interactions reported, one can’t ignore
its interference with clinical laboratory tests, misleading physicians.
 Thus from all detailed information present, one could conclude that
vigilance plays a vital role in monitoring all these interactions and
highlighting it among population to increase their knowledge about herbal
medicines interactions and adverse effects.

31. Thank you….