Transcript herabal-drugx

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The aim of this presentation is to highlight the
clinicalinteractions between herbal product and
prescribeddrugs
►Mechanism of Drug- Herb interactions
►Literature review
►Systematic review
►Strategies to minimize Drug-Herb interaction
Introduction
• Surveys show that two-thirds of womenuse herbs
for perimenopausal symptoms, 45% of parentsgive
their children herbal treatments and 45%
ofpregnant women try herbal remedies.
• 16% of prescription drug users consume herbal
sup-plements
• The altered drug response of herb-drug interactions
depends on factors related to:
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Drug
Herbs
Dose
Administration route
Pharmacokinetic
Pharmacodynamic
• Species
• Dose
• Administration route
Patient
• Genetic
Polymorphism
• Age
• Pathological
conditions
Cytochrome P450
• Many herbs (e.g. St John’s wort, kava and garlic,.
coumarins and caffeine) have been identified as substrates,
inhibitors and/or inducers of CYP enzymes.
CYP
ST John’s wort
(2 w)
Green tea
• Ginkgo
• Garlic
• Genseng
CYP
P-glycoprotein
• Like CYP, P-glycoprotein could cause inhibition,
activation, or induction by herbs. Curcumin,
ginsenosides, piperine, sylimarin and catechins may
affect P-glycoprotein-mediated drug transport. St John’s
wort induces the intestinal expression of P-glycoprotein
both in isolated cells and in healthy volunteers.
Pharmacodynamic
• A few pharmacodynamic interactions have also been
described. Pharmacodynamicinteractions may be
synergetic(e.g. interaction between the anticoagulant
warfarinwith antiplatelet herbs), or antagonistic (e.g.
kava possesses dopaminergic antagonistic
propertiesand hence might reduce the
pharmacological activity ofthe anti-parkinson drug
levodopa) .
• The World Health Organization (WHO) defines
herbal supplements as "Finished, labelled,
medicinal products that contain active
ingredients from aerial or underground parts of
plants, or other plant material, or combinations
of, whether crude state or as other preparations “.
WHO Programm on Traditional Medicines:
Guidelines for the assessment of herbal medicines.
Geneva: World Health Orginization, 1991.
• 32 drugs interacting with herbal medicines in humans.
• E.g. anticoagulants (warfarin, aspirin and phenprocoumon)
 sedatives and antidepressants (midazolam, alprazolam&amitriptyline)
 oral contraceptives
 anti-HIV agents (indinavir, ritonavir and saquinavir)
 cardiovascular drug (digoxin)
 immunosuppressants (cyclosporine and tacrolimus)
 anticancer drugs (imatinib and irinotecan).
Evidence for herb-drug interactions
►Case reports
 Unreported? 70% “don’t ask-don’t tell”
►Lab studies
 Define mechanisms
► Recent interest in CYP450 induction
►Human studies
 Trials using probe drugs
 May be done on healthy population
 Genetic polymorphisms
De Smet, Br J Clin Pharm 2006; 63:258-67
Current Pharmaceutical Design, 2006,Vol. 12, No.
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Current Pharmaceutical Design, 2006,Vol. 12, No.
35
Current Pharmaceutical Design, 2006,Vol. 12, No.
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Current Pharmaceutical Design, 2006,Vol. 12, No.
35
• The majority of reports concern drugs with a
narrowtherapeutic index such as warfarin and
digoxin.
• Increasedanticoagulant effects could be expected
when warfarinis combined with coumarincontaining herbs (e.g.boldo, fenugreek, papaya ,
mango) or with antiplatelet herbs(e.g. danshen,
garlic, ginkgo).
• Vitamin K containing herbs
(e.g. green tea) can antagonized the
anticoagulant effect of warfarin.
• Six weeks after starting cranberry juice a 70-year-old man
under warfarin was admitted to hospital with an INR >50.
He died of a gastrointestinal and pericardial haemorrhage.
(Cranberry juice contains antioxidants, including flavonoids,
which are know to inhibit CYP enzymes)
Grant P. Warfarin and cranberry juice: an
interaction.J. Heart. Valve Dis. (2004) 13 25–26.
Interactions with
cardiac inotropic
drugs
In a single-blind, placebo-controlled study
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Digoxin
Induced
PGP
St
John’s
wort
• Reduce
Digoxin
Digoxin
Reduce
digoxin
Gum
Guag
clinical trials
Interactions with
antihypertensive drugs
• Surprisingly, an elderly patient was found to
have anincrease in blood pressure after
taking ginkgo (a peripheral vasodilator)
while receiving a thiazide diuretic.
• There is no rationalpharmacological
mechanism to explain this
unusualinteraction.
Interaction with oral
hypoglycemic drugs
• Clinical studies have shown that gumguar reduced
the absorption of metformin andglibenclamide. By
contrast, anothertrial showed that gum guar
enhanced the insulinogenicand blood glucose
lowering effect of glibenclamide.
• A fall in glucose levels has been reported in a 40year-old diabetic woman taking chlorpropamide and
garlic.
This event is likelybecause of an additive
effect on glucose level .
Capasso F., Gaginella T.S., Grandolini G., Izzo A.A. Phytotherapy.
A quick reference to herbal medicine, SpringerVerlag, Berlin, Heidelberg,
2003.
INTERACTIONS WITH ANTIINFLAMMATORY DRUGS
• Many paper showed that Liquorices increased the plasma
prednisolone concentrations in six healthy men.
• Glycyrrhizin, which is astrong inhibitor of 11 betahydroxysteroiddehydrogenase ,influences prednisolone
pharmacokinetics by inhibiting its metabolism.
Chen M.F., Shimada F., Kato H., Yano S., Kanaoka M. Effect of
oral administration of glycyrrhizin on the pharmacokinetics of
prednisolone. Endocrinol. Jpn. (1991) 38 167–174.
STRATEGY FOR ELIMINATING TOXICITY
ARISING FROM DRUG-HERB INTERACTIONS
1. PredictingDrug-Herb Interactions
• It is necessary to assess the clinical risks by predicting
qualitatively and quantitatively drug-herb interactions.
STRATEGY FOR ELIMINATING TOXICITY
ARISING FROM DRUG-HERB INTERACTIONS
2. Identification of Drugs that Interact with Herb
• The identification of drugs causing drug-herb interactions and the mechanisms
involved are important in term of rational use of therapeutic drugs.
• The application of high throughput approaches to the study of drug-herb, herbCYP and herb- PgP interactions is becoming possible. If potential toxic drugherb interactions have been observed, the combined use of related drugs and
herbs should be generally avoided. In some cases where the avoidance is
difficult, proper dose adjustment or alternative drugs may be needed.
STRATEGY FOR ELIMINATING TOXICITY
ARISING FROM DRUG-HERB INTERACTIONS
3. Therapeutic Drug Monitorin
Due to frequent pharmacokinetic drug-herb interactions, monitoring
of plasma concentrations of drugs with narrow therapeutic indices
are always important in patients also taking herbs.
STRATEGY FOR ELIMINATING TOXICITY
ARISING FROM DRUG-HERB INTERACTIONS
4. Design of Hard Drugs to Eliminate Toxicity Arising from
Drug-Herb Combinations
• It appears that the chemical properties of a drug critical for
herbal interaction include
(i) being a CYP substrate,
(ii) being a PgP substrate,
(iii) Induction/ inhibition of CYP
• Hard drugs :not metabolized by CYPs and/or not
transported by PgP.
• Example:
bisphosphonates (e.g. etidronate and alendronate,)
and certain ACE inhibitors (e.g. enalaprilat and
lisinopril).
Conclusion
• Although some drug– herb interactions may be
clinically insignificant (e.g. interaction between
gum guar andpenicillin V), others may have
serious consequences (e.g.interaction between
St John’s wort and cyclosporine).
• Withdrawal of a chronically administered herbal
product that acts as an inducer in a patient
stabilized on effective drug therapy can result
in untoward pharmacological
or toxic effects
limitation
• Reported drug-herb interactions are ANECDOTAL (single reports).
• Herbal medicines are mixtures of more than one active ingredient.
makes it difficult to draw useful comparisons between clinical
studies or case reports.
• The likelihood of herb±drug interactions could be higher than
drug±druginteractions.
• fewer than 40% of patients disclose their herbal supplement
usage to their physician and many physicians
are unaware of the potential for–
drug herb interactions .
Take Home
Message
Checking for herb-drug interactions
►Natural Standard (www.naturalstandard.com).
Subscriptions for PDA/desktop available.
 Partial database at MedlinePlus.gov
►Natural Medicines Comprehensive Database
(www.naturaldatabase.com). Subscription
service.
Induction
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Induction is a term used to describe a physiologica adaptive response to continued xenobiotic exposure.
It is characterized by enhanced gene transcription and/ortranslation, stabilized messenger ribonucleic
acid, or inhibited protein turnover. The end result can be increased amounts of proteins that determine
drug disposition such as metabolic enzymes or transporters. The dose of the inducer determines its
cellular concentration and hence the extent of induction. The resulting clinical effects usually start within
a few days of repeated administration. After withdrawal of the inducer, reversal is generally complete
within 1 week.
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Case reports of reduced exposure and reduced degree and/or duration of drug response have often
served as mportant stimuli for formal study of herbal–drug interactions [10]. A common in vivo method
uses a drug probe that is a relatively safe substance inactivated or eliminated primarily by a single
metabolic process (e.g. midazolam and cytochrome P450(CYP)3A4) or transport process (e.g.
fexofenadine and P-glycoprotein). increasingly popular is the use of probe ‘cocktails’ that determine the
activities of multiple eliminating pathways on a single occasion. The probes are administered before and
then after a suitable treatment period with a particular herbal product to examine their effects on
clearance of the probe.
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The molecular mechanisms that govern the inductive response are well established and in vitro tools
are available to predict whether herbal products or their chemical constituents might cause a clinically
important drug interaction. The most prominent mechanisms for induction are ligand-dependent
transcriptional activation of nuclear receptors, such as the pregnane X (PXR), constitutive androstane
(CAR) or aryl hydrocarbon receptors (AhR). Convenient cell-based screening assays for activation of
nuclear receptors are routinely used. Further investigations in the cultured primary human hepatocyte
model are performed to confirm induction of gene expression.