Aznan Lelo

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
UNIBA
7 September 2011, UNIBA, Batam

Background
Polypharmacy is common among supplement
users
Many assume herbs and supplements are safe
Many pharmacological actions but dangerous
side effects and interactions exist
Be sure to ask your patients (non-judgmental)
Knowledge is our best weapon and protection

A Good Medication History:

AVOID Mistakes
Allergies?
Vitamins and herbs?
Old drugs and OTC? (as well as
current)
Interactions?
Dependence? Do you need a contract?
Mendel: Family Hx of benefits or
problems with any drugs?

Problems Associated with Use of

Herbal Medicines
Lack of QC & standardisation
Adulteration with other plants,
pharmaceutical drugs or heavy metals
Inappropriate use / misleading claims
Type A & B ADRs
Potential for drug interactions
Lack of knowledge re: interactions, ADRs

Common Adulterants and

Contaminants
steroids:

prednisolone, hydrocortisone,
triamcinolone, methyltestosterone

benzodiazepines:
chlordiazepoxide

heavy metals:
cadmium

diazepam, estazolam,

mercury, lead, arsenic, antimony,

analgesics and NSIADs:

acetaminophen,
aspirin, indomethacin, mefanamic acid

other drugs and chemicals:

hydrochlorothiazide, digitalis, caffeine, scopolamine,

atropine, strychnine, carbamazepine, phenytoin,
valproic acid, dipyrone, diacetyldiphenolisatin

Foraging and harvesting

Issues, problems, etc.
Misidentification
Potencies vary from batch to batch.
season to season.
Chemical composition varies
between cultivars, geography,
environmental conditions
Changing nomenclature
Botanical and medical

Herbals and Supplements:

Potential interactions with Rx Drugs
SAMe may increase homocysteine levels
St. Johns wort and Oral contraceptives
Ginkgo may increase anticoagulant effects
of ASA, warfarin, NSAIAs, ticlopidine, and
may interact with MAOIs
Bottom line: Try to know what your patient
is taking, and ask in a nonjudgmental way

Definitions and Terms

Side Effects: unintended, usually detrimental,
consequences
Adverse: untoward, unintended, possibly causing harm
AE: Adverse Event, Effect or Experience
ADE (AE associated with a Drug): an AE which
happens in a patient taking a drug
ADR (Adverse Drug Reaction): an ADE in which a
causal association is suspected between the drug and
the event
Unfortunately, these terms are frequently used
interchangeably

INCIDENCE of ADRs

ADRs are always under reported

ADRs are the 4th-6th largest cause for mortality in
the USA1
ADRs account for approximately 10% of hospital
admissions

1.
2.
3.

Norway 11.5%, France 13.0% UK 16.0%2

ADRs increase the length of hospital stay and

medical costs
15-20% of hospital budget may be spent dealing
with drug complications3
Lazarou et al.JAMA 1998, 279(15) 1000-5
Safety of Medicines. WHO/EDM/QSM/2002.2
White et al. Pharmacoeconomics,1999,15(5) 445-458

Drug Related Adverse Reactions

identify the suspected drug
identify factors that contributed to the
occurrence of the adverse reaction such as

multiple drug therapy,

drug-drug interactions
drug-herbal interactions
Drug food interactions
Excipients, colouring agents

Garlic
Efficacy: ? benefit for use in hyperlipidemia.
Possible other cardiovascular benefits.
Safety: good
Drug interactions: warfarin; possibly aspirin
and other antiplatelet adhesion drugs
(pharmacodynamic interaction); not with HIV
drugs (other 3A4 substrates?) but depends
on product (pharmacokinetic interaction)
(maybe raw garlic induces 3A4 but not
extracts??)

Garlic
Heat and acid inactivate allicin, enteric
coated products show best results
May increase effects of anticoagulants,
may inhibit thyroid preparations
Precautions and interactions: Inhibited
platelet aggregation (interaction with
anticoagulants), may reduce blood
sugar so use with caution with various
hypoglycemic agents

Echinacea
Efficacy: evidence for treatment not
prevention
Safety: good; rare allergy
Drug interactions:
dont give to patients taking immunosuppressive drugs
Antagonises immunosuppressants
Increased bleeding time

Pharmacokinetic:
may inhibit 1A2; may inhibit intestinal 3A4 but induce
hepatic so clinical significance unclear; effect on 2C9 is
considered minor

Ginkgo biloba
Efficacy: good for dementia and poor
peripheral circulatory problems
Safety: good; rare bleeding episodes
Drug interactions: no effect on 3A4,2C9 or
2D6 but may induce 2C19; may inhibit
platelet adhesion; possible (not
necessarily probable!) interaction with
blood thinners and warfarin so avoid or
close monitoring needed.

Ginkgo and coagulation and

pharmacodynamic interactions with
antiplatelet adhesion inhibitors
Coagulation in healthy adults (in absence of other
drugs)
Kohler et al. Blood Coagul Fibrinolysis. 2004;15:303-9.
(company study). No effect on coagulation parameters
in healthy adults after 7d of EGb761 120mg/d. n=50.

Ginkgo biloba
+ Diclofenac or + Tolbutamide Human Studies
Conclusions
No difference was observed in the metabolic
ratio between the two arms of the study
(tolbutamide alone and tolbutamide + Ginkgo)
No difference was seen between the clearances
of the two arms of the study (diclofenac alone
and diclofenac + Ginkgo)
Ginkgo extract does not appear to interact with
CYP2C9 substrates in humans

Ginkgo biloba
Precautions and interactions:
Ginkolide is a selective antagonist of platelet
aggregation. Case reports of subdural hematoma
and spontaneous bleeding with ASA use. Reports
of GI disturbances and CNS symptom
Ginkgo and caffeine may increase risk of subdural
hematomas
Ginkgo helped SSRI induced sexual dysfunction
91% in women, 76% in men (Cohen and Bartlik
1998)

Use with extreme caution with stimulants

Soy
Efficacy: increased soy ingestion may
decrease hot flashes and other
postmenopausal symptoms;
cardiovascular benefits as well.
Safety: good but use in breast cancer may
be risky
Drug interactions: not with with tamoxifen
but effect on CYP3A4 is unlikely

Ginseng
Efficacy: some evidence for applications in
geriatric patients (improved quality of life)
and in diabetes
Safety: good;
Drug interactions: no apparent induction of
CYP 3A4 but induction of 2C9 (warfarin) with
Am ginseng (Panax quinquifolius) but
maybe not Panax ginseng. May precipitate
hypoglycemia with insulin or oral
hypoglycermics.

Ginseng
Precautions and interactions: May increase BP.
Overuse can cause headaches, insomnia,
palpitations. Estrogen affects may cause vaginal
bleeding, fibrocystic breasts
Interacts with Lasix, decreases diuretic action
One study demonstrates enhanced alcohol
clearance in healthy men (Lee et al, 1987)
May induce mania when used concurrently with
antidepressants (Gonzalez-Seiji et al, 1995)
May potentiate MAO inhibitors (Shader et al, 1988)
May inhibit metabolism of barbituates
May potentiate stimulants (caffeine most studied)
May cause Haloperidol catalepsy

Saint Johns Wort

Contraindications: Severe depression with
akinetic mutism, suicidal tendencies, severe
agitation, hypersensitivity and pregnancy
(estrogen effects)
Precautions: photosensitivity
Interactions: May precipitate hypertensive crisis
with MAO inhibitors (Mueller & Shaefer,1996)
May induce serotonin syndrome with SSRIs
and with Triptans
Interferes with cyclosporine, may cause
transplant rejection
May cause hypertension with tyramine
containing foods
Safe with benzodiazapines

St. Johns Wort

Efficacy: good evidence for mild to
moderate depression
Safety: dont combine with other
medications unless under close
monitoring; possible photosensitivity
Drug interactions: a problem! Is a broad
spectrum P450 inducer and a pglycoprotein inducer.

Summary of SJW Interactions

(adapted from Henderson et al. Br J Clin Pharmacol 2002;54:349-346)
Drug
CYP
Effect Management
HIV protease inhibitors
Induce 3A4
Stop and measure

viral load
(nelfinavir,ritonavor,saquinavir)
HIV non-nucleoside RTI
Induce 3A4
Stop and measure

(efavirenz,nevirapine)
viral load
warfarin
Induce 2C9
Stop and adjust warfarin

dose
cyclosporin
Induce PStop and adjust

glycoprotein
cyclosporine dose
oral contraceptives
Induce 3A4
Stop and use alternate

birth control
anticonvulsants
Induce 3A4
Stop and adjust

anticonvulsant dose
digoxin
Induce PStop and adjust digoxin

glycoprotein
dose
theophylline
Induce 1A2
Stop and adjust

theophylline dose
Triptans
Increase
Stop

(sumatriptan)
serotonin
SSRI
Increase
Stop

(fluoxetine,sertraline, etc)
serotonin

St. Johns Wort

With SSRIs, triptans - symptoms
characteristic of serotonin syndrome
Theophylline (CYP1A2), cyclosporin
(CYP3A4) and warfarin (CYP2C9) reports of a reduction in the serum concs
With COC - reports of breakthrough
bleeding - reduced efficacy?
Advice published by the IMB and CSM

Saw Palmetto
Uses: For male genitourinary problems (BPH),
prostate cancer, antisepsis
Likely safe in usual doses for up to one year
Likely effective for BPH symptoms
Possibly effective for adjunctive therapy for
prostate cancer
Precautions and interactions: Due to antitestosterone action do not use in pregnancy or
children, can cause stomach upset, no
psychotropic interactions

Testosterone Synthesis
Cholesterol

Pregnenolone
DHEA
Androstenedione
Testosterone

Evening Primrose
Uses: Lower cholesterol, treat atopic
dermatitis, arthritis, PMS, mastalgia
High in gamma-linolenic acid (GLA) and linolenic
acid, prostaglandin precursors, essential fatty acids
Safe in usual doses, increases delivery
complications
Precautions and interactions: May aggravate
temporal lobe epilepsy, interacts with some antiseizure medications, case reports of seizures in
schizophrenics on phenothiazines

Valerian
Valeriana officinalis root extract used to
promote sleep
Increases levels of GABA in CNS
Possibly safe in short term (14 days),
possibly unsafe for long term use
(withdrawal)
Possibly effective for subjective sleep
quality
May potentiate CNS depressants
especially benzodiazapines

Feverfew
Uses: Migraine headaches (vasoconstrictive),
used for menstrual problems and fever
Possibly safe in usual doses
Possibly effective in preventing and decreasing
severity of migraines
Precautions and interactions: Leaves can cause
mouth ulcerations, may cause menstrual or
lactation problems, occasional GI side effects,
may increase effects of anticoagulants, reported
hypertensive crisis with triptans

Ephedra Problems
Synergistic effect with caffeine, decongestants,
and stimulants
Pro-arrhythmic effects with cardiac glycosides
and halothane
MAO inhibitors potentiate stimulation effects
Can increase agitation associated with SSRIs
Overdose syndrome can be fatal
May be detected in urine screening as a banded
substance

Kava Kava
Uses: Nervous tension (anxiety), stress and
agitation, insomnia
Likely effective: Head to Head comparison to
benzodiazapines showed equal efficacy for anxiety
(Woelk, 1993)

Kava pyrones have central muscle-relaxing,

anticonvulsive, hypnotic/sedative effects by
interaction with ion channels and GABA sites
liver failures even with short term use

Kava Kava Interactions

Synergy with Alcohol. EtOH potentiates
Kava toxicity
Reports of coma with Kava and Xanax
Potentiates all CNS depressants
Antagonizes dopamine, do not use in
Parkinsons patients
Interaction with cimetidine causes
confusion and disorientation

Interaksi obat-temulawak
Anti-platelet : dapat menyebabkan resiko
perdarahan
Warfarin :
peningkatan efek antikoagulan
sehingga terjadi perdarahan
Camptohecin : penghambatan kerja
camptothecin dalam menginduksi apoptosis sel
kanker payudara
Ibuprofen :
peningkatan resiko perdarahan

 Meclorethamin :

Bromelain :
Ginkgo biloba:
Bawang putih :

Penghambatan kerja
meclorethamin dalam
menginduksi apoptosis sel
kanker payudara
peningkatan efek antiagregasi
peningkatan efek ginkgo
biloba menyebabkan
resiko perdarahan
Terjadi penurunan gula
darah

Seem to have low

pharmacokinetic drug interaction
potential

Ginger
Valerian
Milk thistle
Saw palmetto
Black cohosh
CoQ10
glucosamine

What can we do?

dialog with NDs and other prescribers

recommend the best products
ask patients about herbals they may be taking
herbals should not usually be recommended for
acute or serious illnesses
avoid herbal use with drugs with narrow
therapeutic window, esp. warfarin, cyclosporin,
digoxin, HIV protease inhibitors, theophylline,
carbamazepine
stay informed

Steps for Detecting and Advising on

Herbal/Drug Interactions
Is the patient taking any herbal supplements?
Does the herbal have efficacy for the intended
use?
Is the product reliable? (i.e.,what are they
REALLY taking?)
Is the Rx drug one with a narrow therapeutic
margin?

Evaluation of Herbal/Drug Interactions

Speculative or Theoretical
e.g. St. Johns Wort and tyramine containing foods
due to MAOI effects or evening primrose oil and risk
for bleeds with warfarin

In vitro effects
e.g. ginkgo and microsomal studies showing inhibition
of CYP2C9

In vivo - animal studies

e.g. kava and alcohol

In vivo - human case reports

e.g. ginkgo and warfarin bleeds

In vivo - healthy human volunteer studies

e.g. indinivir and St. Johns Wort

In vivo - clinical studies in patients

Herbal Medicines
................. Not all that is
natural is
harmless

Herb Drug Interactions

Dong Quai: taken for menopausal symptom control. Do not
mix Dong Quai with warfarin (anticoagulants), St John's Wort
and some antibiotics such as sulfonamides, quinolones.
Echinacea: mostly taken as an immune boost to prevent cold
and flu. Do not mix Echinacea with some heart medications,
antifungal medications, HIV medications and anti-anxiety
medications.
Ephedra: A powerful decongestant. Contains ephedrine, which
can open up bronchial passages. It's controversial because it's
a powerful stimulant that can raise blood pressure, cause
insomnia and high blood pressure. Do not mix with heart
medications or if you are being treated for high blood pressure,
glaucoma or thyroid problems.
Feverfew: taken to reduce the severity of migraines. Do not
take with other migraine medications, as, it may raise heart
rate and blood pressure. Feverfew has the potential to react
with warfarin anti-coagulants, increasing the thinning of blood.

Herb Drug Interactions

Ginkgo: increases blood flow and circulation throughout the body, can
also help improve memory. May interact with anti-coagulant medications
such as Aspirin, Coumadin, heparin and warfarin, causing the blood to
thin too much, and provoking a serious bleeding disorder. A recent report
in the New England Journal of Medicine describes a case of a man who'd
been taking Aspirin to prevent a heart attack and had spontaneous
bleeding into the eye from the iris within a week of taking a daily dose of
ginkgo.
Garlic: is thought to help lower cholesterol and prevent the formation of
blood clots that could lead to heart attacks. Garlic capsules may increase
blood thinning if you are already on anti-coagulants. Do not take with
diabetes medication because it may cause a decrease in blood sugars.
Ginseng: used to help reduce stress, boost energy and improve stamina,
and may also help lower cholesterol. Can cause nervousness and
excitation, and overuse can lead to headaches, insomnia and heart
palpitations. Can increase blood pressure. Should not be used if you are
taking prescriptions for high blood pressure or Coumadin.
Hawthorn: claimed to be effective in helping reduce angina attacks by
lowering blood pressure and cholesterol levels. Should not be taken
digoxin, a heart medication. The mix may lower heart rate too much.

Herb Drug Interactions

Kava: is used to treat anxiety. It's also used to relieve
insomnia and nervousness. Do not take Kava if you have a
history of liver problems. Also do not mix with
antidepressants, sedatives, and do not mix Kava with
alcohol.
Licorice: used to treat coughs, colds and peptic ulcers.
High doses can lead to increased blood pressure, water
retention and potassium loss. Do not use with diuretics or
digoxin because it could lead to further loss of potassium,
essential for heart function.
St. John's wort: a natural anti-depressant for mild to
moderate depression. Do not take with other antidepressants, HIV medications, oral contraceptives, some
heart/blood thinning medications and Tamoxifen (a cancer
drug).
Valerian: a mild sedative with hypnotic effects, used to
promote sleep, Should not be taken with alcohol or Valium.