Drug-Herb Interaction - PowerPoint Presentation

Slide1

Drug-Herb Interaction

Presented by:

Dr.Rania

MagadmiSlide2

The aim of this presentation is to highlight the clinicalinteractions between herbal product and prescribeddrugs

. Slide3

Mechanism of Drug- Herb interactions

Literature review

Systematic review

Strategies to minimize Drug-Herb interaction

Outlines:Slide4

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

Outlines:Slide5

The altered drug response of herb-drug interactions depends on factors related to:

Mechanism of Interaction:Slide6

Pharmacokineti

c

PharmacodynamicSlide7

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. Cytochrome P450

CYP

CYPSlide8

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. Slide9

Pharmacodynamic

A few

pharmacodynamic

interactions have also been described. Pharmacodynamic

interactions 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) .Slide10

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 “.

Literature Review

:

WHO

Programm

on Traditional Medicines:

Guidelines for the assessment of herbal medicines.

Geneva: World Health

Orginization

, 1991.Slide11

32 drugs interacting with herbal medicines in humans.

E.g. anticoagulants (

warfarin

, aspirin and phenprocoumon)

sedatives and antidepressants (midazolam, alprazolam&amitriptyline) oral contraceptivesanti-HIV agents (indinavir, ritonavir and saquinavir)

cardiovascular drug (

digoxin

)

immunosuppressants

(cyclosporine and

tacrolimus

)

anticancer drugs (

imatinib

and

irinotecan

).

Literature Review:Slide12

Evidence for herb-drug interactions

Case reports

Unreported

? 70% “don’t ask-don’t tell”

Lab studiesDefine mechanismsRecent 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; 63:258-67Slide13

Drugs that have been reported to interact

w

herbs

Current Pharmaceutical Design, 2006,Vol. 12, No. 35 Slide14

Drugs that have been reported to interact

w

herbs

Current Pharmaceutical Design, 2006,Vol. 12, No. 35 Slide15

Drugs that have been reported to interact

w

herbs

Current Pharmaceutical Design, 2006,Vol. 12, No. 35 Slide16

Drugs that have been reported to interact

w

herbs

Current Pharmaceutical Design, 2006,Vol. 12, No. 35 Slide17

The majority of reports concern drugs with a narrowtherapeutic index such as

warfarin

and

digoxin

.Increasedanticoagulant effects could be expected when warfarinis combined with coumarin-containing 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

.

Interactions with CVS

Pharmacotherapy:Slide18

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.Slide19

Interactions with cardiac

inotropic

drugs

In a single-blind, placebo-controlled study .

clinical trialsSlide20

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.Slide21

Interaction with oral hypoglycemic drugs

Clinical studies have shown that gumguar reduced the absorption of

metformin

and

glibenclamide. 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 40-year-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.Slide22

INTERACTIONS WITH ANTI-INFLAMMATORY DRUGS

Many paper showed that Liquorices increased the plasma

prednisolone

concentrations in six healthy men.

Glycyrrhizin, which is astrong inhibitor of 11 beta-hydroxysteroiddehydrogenase ,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.Slide23

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. Slide24

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, herb-CYP and herb- PgP interactions is becoming possible. If potential toxic drug-herb 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.Slide25

STRATEGY FOR ELIMINATING TOXICITY

ARISING FROM DRUG-HERB INTERACTIONS

3.

Therapeutic Drug

MonitorinDue to frequent pharmacokinetic drug-herb interactions, monitoring of plasma concentrations of drugs with narrow therapeutic indices are always important in patients also taking herbs. Slide26

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 CYPSlide27

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).Slide28

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 Slide29

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±drug

interactions.

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 . Slide30

Take Home MessageSlide31

Checking for herb-drug interactions

Natural Standard (

www.naturalstandard.com

). Subscriptions for PDA/desktop available.

Partial database at MedlinePlus.govNatural Medicines Comprehensive Database (www.naturaldatabase.com). Subscription service.Slide32
Slide33

Induction

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.

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.

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.