drug_–_food_-_herba_dd

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DRUG – FOOD - HERBAL

INTERACTION

Prof..M.Aris Widodo

Program s2 biomedik DD



BANYAK OBAT OBAT BARU YANG DIKENALKAN., FDA MENYETUJUI

21 MOLEKUL OBAT BARU / TAHUN

SETIAP ORANG MENDAPAT 6 RESEP PERTAHUN

MANULA >65 TAHUN YANG JUMLAHNYA 12 % DARI POPULASI

MENGHABISKAN 30% PEMBELAJAAN OBAT

MANULA DI AMERIKA MENERIMA RATA 15 RESEP PERTAHUN

PASIEN YANG DIRAWAT DI RS MENERIMA 15 KALI PENGOBATAN/HARI

2/3 DOKTER YANG MELAKUKAN KUNJNGAN MENULIS SATU RESEP

64 % PENGGUNAAN ANTIBIOTIK DI RUMAH SAKIT TIDAK DIPERLUKAN

EFEK SAMPIMG OBAT MENINGKAT DENGAN BANYAKNYA OBAT

5% PENDERITA MRS OLEH KARENA EFEK SAMPING OBAT

EFEK AMPING OBAT SERING TERJADI PADA MANULA

BANYAK PENULISAN VITAMIN YANG SEBENARNYA TIDAK PERLU.



PREVALENSI INTERAKSI OBAT

MENINGKAT PADA PRAKTEK POLIFARMASI

DATA DARI MAY 1977:

JUMLAH MACAM OBAT YANG DIBERIKAN

0-5 6-10 11-15 16-20

JUMLAH PASIEN 4009 3861 1713 641

JUMLAH E.S. 142 397 478 347

RATE E.S. 4% 10% 28% 54%

POLIFARMASI BANYAK PADA MANULA



The “Prescribing Cascade”

•Common cause of polypharmacy inelderly

•Some common examples –NSAIA ->HTN->antihypertensive therapy

–Metoclopromide ->Parkinsonism ->Sinemet

–Dihydropyridine -> edema ->furosemide

–NSAIA ->H2 blocker ->delirium ->haldol

–HCTZ ->gout->NSAIA ->2nd antihypertensive

–Sudafed ->urinary retention ->alpha blocker

– Antipsychotic ->akithesia ->more meds



Prescription Drugs

•Elderly account for 1/3 of prescription drug use, while only

13% of the population

•Ambulatory elderly fill between 9-13prescriptions a year (new and refills)

•One survey: Average of 5.7

prescription medicines per patient•Average nursing home patient on 7

medicines



Non-prescription Drugs

•Surveys indicate that elders take average of

2-4 nonprescription drugs daily

•Laxatives used in about 1/3-1/2 of elders -

many who are not constipated•Non-steroidal anti-inflammatory medicines,

sedating antihistamines, sedatives, and H2

blockers are all available without a

prescription, and all may cause major side

effects



Adverse Drug Reactions

•About 15% of hospitalizations in the

elderly are related to adverse drug

reactions

•The more medications a person is

on, the higher the risk of drug-drug

interactions or adverse drug

reactions

•The more medications a person is

on, the higher the risk of non-

adherence



Makanan minuman

Vitamin and mineral

supplementsHerbal remedies

Nutritional supplements

Over-the-counter medications

INTERAKSI

Berbagai obat yangdigunakan unuk terapi dan

Pencegahan penyakit



TIPE INTERAKSI OBAT

.1Drug-Drug Pharmacokinetic

.2Drug-Drug Pharmacodynamic

.3Drug-Food/Nutrient

.4Drug-Disease



Interaksi obat

interaksi farmakodinami

interaksi farmakoinetik

interaksi diluar tubuh



Interaksi obat dengan obat, herbal atau makanan

Secara farmakodnami terjadi perubahan efek oleh karena bahan yang

Ber interaksi bekerj a pada reseptor yang sama atauyang berbeada

Akibatnya terjadi efek obat yang meningkat atau menurun


Secara farmako kinetik terjadi perubahan efek oleh karena bahan yang

Ber interaksi menurunkan atau meningkatkan kadar obat melalui proses

absorbsi, distribusi Metabolisme dan ekskresi sehingga terjadi efek obat

Yang meningkat atau menurun


Diluar tubuh menyebaban perbahan sifat fisiko kimia obat sehingga

terjadi efek Obat yang berkurang aupun efek toksik



R1

R1a

R2

EFFEK

OBAT-HERBAL-MAKANAN

INTERAKSI FARMAKODINAMI



INTERAKSI FARMAKOKINETIK

OBAT MEMPENGARUHI PROSES

ABSORBSI

DISTRIBUSI

METABOLISME

EKSKRESI

KADAR OBAT DALAMDARAH TARGET

MENINGKAT ATAU

MENURUN



Pharmacokinetics Pharmacodynamics

Dosage

Regimen EffectsPlasmaConcen

tration

Site of

Action



K

O

N

S

E N

T

R

S

I

O

B

A

T

PL

A

S

M

A

MINIMUM TOXIC CONCENTRATION

MINIMUM EFFECTIV CONCENTRATION

AUC AUC

AREA UNDER CURVE = AUC

AREA UNDER CURVE PEMBERIAN DOSIS BERULANG



TERAPI SUKSES REGIMEN A

KEGAGALAN TERAPI REGIMEN B

KEGAGALAN TERAPI

WAKTU PEMBERIAN OBAT

K

O

N

S

E N

T

R

S

I

O

B

A

T

PL

A

S

M

A

MINIMUM TOXIC CONCENTRATION

MINIMUM EFFECTIV CONCENTRATION



INTERAKSI FARMAKODINAMI

OBAT DAN OBAT

INTERAKSI FARMAKOKNETIK

OBAT DENGAN OBAT



Drug-Drug Interactions Affecting

Absorption and Distribution

Precipitant Drug(s)Object Drug(s)Outcome

Antacids, IronTetracycline, Ciprofloxacin

abs.

Chloral hydrateWarfarin

Pl con

•Generally absorption and distribution drug-drug-

interactions are not clinically important.

Drugs & Aging 1998;12:485-94



Hepatic Metabolism

)450Phase I (CYP

•Oxidation

hydroxylation

dealkylationsulfoxidation

•Reduction

•Hydrolysis

Phase II

•Conjugation

glucuronidation

sulfation glycine

acetylation



Cytochrome P450 Phase I Isoenzymes,

% Total and Substrate Examples

Isoenzymes%Substrate

CYP1A217Olanzapine, Theophylline

CYP2C9/1926Phenytoin, Warfarin

CYP2D62-4Codeine, Desipramine, Tramadol

CYP2E19-10Chlorzoxazone, Ethanol

CYP3A435-45Diazepam, Triazolam, Quinidine,

Methadone, Carbamazepine

www.drug-interactions.com



Inhibitors of Hepatic Cytochrome P450

2 A1 19/9C2 6D24 A3

Fluvoxamine AmiodaroneFluoxetineErythromycin

CimetidineFluconazoleParoxetine Azole

antifungalCiprofloxacinFluvastatinQuinidineNefazodone

FluoxetineRitonavir Clarithromycin

IsoniazidBupropionRitonavir

SertralineCimetidineCimetidine

Omeprazole Cimetidine




Drugs That Interact with Theophylline

Inhibitors

•Cimetidine

•Propafenone

•Mexiletine

•Propranolol

•Erythromycin

•Ciprofloxacin

•Fluvoxamine

Drugs Aging. 2003;20:71-84

Inducers

•Barbiturates

•Phenytoin

•Smoking

•Rifampin

•Carbamazepine

JAPHA 2004;44:142-51



Drug-Drug Interactions With WarfarinInteracting DrugMechanism Anticoagulant Effect

AspirinPD

BarbituratePK

CimetidinePK

DipyridamolePD

FibratesPD

FluvoxaminePK

MacrolidesPKPhenytoinPK

QuinolonesPK

RifampinPK

SulfinpyrazonePK/PD

Thyroid hormonesPD TiclopidinePD

N Engl J Med. 2003; 14;349:675-83; JAPHA 2004;44:142-51



Clinically Significant

Drug-Drug Interactions with AEDs

Object DrugInteracting DrugOutcome

CarbamazepineDanazol CBZ

level

CarbamazepineDiltiazem CBZ level

CarbamazepineMacrolides

CBZ levelCarbamazepinePropoxyphene CBZ level

CarbamazepineVerapamil CBZ level

Phenytoin Amiodarone DPH level

PhenytoinCimetidine DPH level

PhenytoinFluoxetine DPH level

PhenytoinINH DPH level

PhenytoinOmeprazole DPH level

Neuropharmacology 2002;5:280-9



Inducers of Hepatic Cytochrome P450

2 A1 19/9C2 6D24 A3

SmokingRifampinNoneCarbamazepine

OmeprazolePhenobarbitalPhenytoin

PhenytoinPhenytoinPhenobarbital

Rifampin

St. John’s wort




Selected Phenytoin

Induction Interactions

Object DrugInteracting DrugCYP

IsoenzymeInduced

MethadonePhenytoin3A4

QuinidinePhenytoin3A4

TheophyllinePhenytoin1A2

WarfarinPhenytoin2C9

Neuropharmacology 2002;5:280-9.



Selected Drugs Secreted

by Renal Tubules

Basic (cationic) Agents

• Amiodarone

•Cimetidine

•Digoxin•Procainamide

•Quinidine

•Ranitidine

•Trimethoprim

•Verapamil

Acidic (Anionic) Agents

•Cephalosporins

•Indomethacin

•Methotrexate•Penicillins

•Probenecid

•Salicylates

•Thiazides



Drug-Drug Interactions With Digoxin

Interacting DrugEffect on Levels

Amiodarone

Clarithromycin

Propafenone

Quinidine

Verapamil

Drug Saf. 2000;23:509-32; JAPHA 2004;44:142-51



Drug-Drug PD Interactions

Object DrugInteracting Drug (s)

ACE-IK+ & K+ sparing diuretics

Beta blockersVerapamil

DigoxinDiureticsMAOISSRI, Dextromethorphan,

Pseudoephedrine, Anorexiants

MeperidineMAOI

HydroxyineThioridazine



Drug- TCA PD Interactions

•Concurrent use with any other drugs with

antimuscarinic properties

•Concurrent MAOI

•Type I antiarrhythmics

•Clonidine

•Guanadrel

•Guanethidine



Drug-NSAID PD Interactions

Object DrugInteracting DrugOutcome

AntihypertensivesNSAIDs BP

CorticosteroidsNSAIDs risk of PUD

DiureticsNSAIDs diuretic effect

TriamtereneIndomethacin

K+

WarfarinNSAIDs

anticoagulanteffect



CNS Polypharmacy and Falls in

Elderly Persons

1

1.54

2.37

0

1

2

3

4

5

A

d j u s t e d o d d s r a t i o

0 1 >2

CNS - active medications (n)

Weiner D, et al. Gerontol 1998;44:217-21



Drug-Food/Nutrient Interactions

Drug Effect

Phenytoin ↓ Folate

Isoniazid ↓ Vit B6

Phenytoin ↓ Absorption with NG

feedings

Levodopa High protein meals effect

blood-brain transport

Captopril Altered taste sensation



Clinically Significant

Drug –St. John Wort Interactions

Object DrugOutcome

Antidepressantsserotonergic syndrome

Cyclosporine levels, transplant

rejectionDigoxin digoxin levels

Estrogenbreakthrough bleeding

Indinavir indinavir levels

Methadonewithdrawal sx’s

Tacrolimus levels

Theophylline theophylline levels

Warfarin INR CPT 2004;75:1-12



Other Clinically Significant Herb- Drug

Interactions

Object DrugInteracting DrugOutcome AnticonvulsantsWormwood seizure threshold

AnticonvulsantsGingko biloba seizure threshold

DigoxinHawthorne digoxin activity

Saquinavir Garlic saquinavir levels

WarfarinFeverfew risk of bleedingWarfarinGarlic risk of bleeding

WarfarinGinger risk of bleeding

WarfarinGinkgo risk of bleeding

WarfarinGinseng

anticoagulant Lancet 2000;355:134-8.

Clinically Important Drug Disease



Clinically Important Drug-Disease

Interactions Determined by Expert Panel

Consensus DrugDisease – AnticholinergicsBPH, constipation, dementia

– Antiarrhythmics (Type 1A)CHF (systolic dysfunction)

– AmphetaminesHTN, insomnia

– AspirinPUD

– Atypical antipsychoticsDM

–BarbituratesDepression –BenzodiazepinesCOPD,dementia, falls

–Beta-blockersCOPD, DM, syncope

–CCB 1st generationCHF (systolicdysfunction)

–ChlorpromazinePostural hypotension, seizures

–ClozapineSeizures –CorticosteroidsDM, PUD

–DecongestantsInsomnia

–DigoxinHeart block

Lindblad C, Hanlon J et al. (abstract) J Am Geriatr Soc 2004;52:S135



Clinically Important Drug-Disease

Interactions Determined by Expert Panel

Consensus DrugDisease –MetoclopramideParkinson’s disease

–NitrofurantoinChronic renal failure

–Non-aspirin NSAIDsCRF, CHF, HTN

–Non-aspirin, non-COX II NSAIDsPUD

–Opioid analgesicsBPH, constipation, dementia –Sedative/hypnoticsFalls

–Skeletal muscle relaxantsBPH

–SSRIsFalls

–TheophyllineInsomnia

–ThioridazinePostural hypotension,

seizures –ThorazineSeizures

–Tricyclic antidepressants Arrhythmias, BPH,constipation

dementia, falls, heart block

postural hypotension

–Typical antipsychoticsFalls



Learning Objectives

At the conclusion of this talk the participant should be able

to:

•List the 4 major types of drug interactions that can occur

in the elderly

•Discuss the epidemiology of the different types of drug

interactions in the elderly

•Implement strategies to prevent/manage drug

interactions in the elderly



Epidemiology of Drug-Drug or

Drug-Disease Interactions

•Incidence of potential drug-drug interactions ranges from 2-17% of all Rx's and up to 6-42% of elderly patients.

•Incidence of potentially clinically significant drug interactionsis low in the elderly (usually must involve narrow therapeuticrange drug and inhibitor/inducer of drug metabolism or renal

excretion) •There is evidence suggesting that adverse health outcomesassociated with drug-drug interactions is infrequent.

•Drug-disease interactions occur in 6.2-40% of elderlypatients

•Drug disease interactions may result in higher risk of adverse outcomes (e.g., decline in functional status and

increased health services use) due to alterations inhomeostatic mechanisms and diminished functional

reserve.



Drug Interactions Are Avoidable

Gosney et al. Lancet 1984;2:564

Previous

adverse

reactions

Contraindicated

drugs

Drug

interactions

Totals

Avoidable 7 57 67 131

Probably

avoidable

---- ---- 37 37

Uncertain ---- 3 29 32

Total 7 60 133 200



Strategies to Prevent/Manage

Drug Interactions

1. Encourage patients to report all prescription, over-

the- counter and complementary and alternativedrugs at every health care encounter.

2. Support the implementation of electronic prescribing and/or the use by patients of one pharmacy with

updated drug interaction software.

3. Work with pharmacists and be familiar with drug

interaction information sources4. Consider whether drug therapy is necessary

5. When adding a new drug to regimen, screen for potential drug-drug interactions.



Strategies to Prevent/Manage

Drug Interactions

6. When adding a new drug to regimen in a patient,

screen

for potential drug-disease interaction.

7. If drug interaction can not be avoided, adjust doses

and

or/dosage intervals for affected medication and monitor

the patient closely.

8. Carefully monitor other drug therapy when withdrawinga drug that can inhibit or induce hepatic metabolism.

9. Regularly review the need for chronic medications-

reduce polypharmacy



Interaksi farmakokinetik

makanan merubah proses absorbsi distribusi metabolisme

dan ekskresi obat sehingga kadar obat dalan plasma dan pada target

Sel menurun atau meningkat sampai ada efek toksik.

Interaksi farmakodinamik

makanan atau komponen makanan berinteraksi ditempat dimanaObat bekerja Misalnya di enzim, di reseptor dikanalion dan tempat lain

Yang secara tidak langsung meningkatkan ligand atau nerotrasmiter

Reseptor adrenergik cholinergikEnszim acetylcholine esterase

Na-K ATP ase

COx1 dan COX2

Kanalion Ca dan |Na



Warfarin (Coumadin)

The amount of Vitamin K in your body affects how

this drug works. It is best to eat the same amount

of Vitamin K every day. Vitamin K is present in

meats and green leafy vegetables (broccoli,

cabbage, collard greens, kale, lettuce & spinach).

Alfalfa sprouts, watercress, soy products, liver,

beef, pork contain significant amounts of Vitamin

K. Do not make large changes in the amount of these foods you eat every day while taking this

medicine.

Limit amount of alcohol to 1-2 drinks per day.

Vitamin E, Fever Few, Gingko Biloba, Don Quai,

ginger, garlic, Vitamin C and green tea may alsoproduce an enhanced anticoagulant effect with

Warfarin.



Warfarin* Common Name: Coumadin*

Cautions: Keep a steady level of vitamin K in your diet. Vitamin K foods

include green leafy vegetables (such as broccoli, cabbage, collard greens,

kale, lettuce, spinach), soybean oil, meats, dairy products, egg yolks and liver.

Do not change your diet or vitamin intake significantly without asking your

physician.Do not drink alcohol. Limit caffeine-containing foods and beverages

(chocolate, coffee, tea, colas) to one serving per day. Do not take oral,

vitamin-fortified diet beverages (such as Ensure or Boost) unless you are

already using them. Do not participate in weight reduction diets while on this

medication.

Avoid products with ginseng (such as Ginsana).Continue these precautions until your doctor or pharmacist says otherwise.



Grapefruit juice can actually inhibit the body's absorption of

certain drugs including:

Vinblastine (for combating cancer)

Cyclosporine (for supressing organ rejection following

transplant)

Losartan (for controlling high blood pressure)

Digoxin (for treating congestive heart failure)

Fexofenadine (for alleviating allergy symptoms)



Pharmacokinetics

•Absorption: Not highly impacted

by aging

•Variable changes in first pass

metabolism due to variable

decline in hepatic blood flow

(elders may have less first pass

effect than younger people, butextremely difficult to predict)



Pharmacokinetics and the

Liver •Acetylation and conjugation do not

change appreciably with age

•Oxidative metabolism throughcytochrome P450 system does

decrease with aging, resulting in a

decresed clearance of drugs

•Hepatic blood flow extremely

variable



Pharmacodynamics:

What the Drug does to the Body

•Some effects are increased –Alcohol causes increase is

drowsiness and lateral sway in older people than younger people at same

serum levels

–Fentanyl, diazepam, morphine,

theophylline

•Some effects are decreased –Diminished HR response to

isoproterenol and beta -blockers



Drug-Drug Interactions

•Common cause of ADEs in elderly•Almost countless – good role for

pharmacist and computer or on-line

programs•Some common examples

–Statins and erythromycin and other antibiotics

–TCAs and clonidine or type 1Anti-arrythmics

–Warfarin and multiple drugs

– ACE inhibitors increase hypoglycemic effect of sulfonylureas



Drug-disease Interactions

•Patient with PD have increased risk of druginduced confusion

•NSAIA (and COX-2’s) s can exacerbate

CHF•Urinary retention in BPH patients on

decongestants or anticholinergics

•Constipation worsened by calcium,

ahticholinergics, calcium channel blockers•Neuroleptics and quinolones lower seizure

thresholds



Drug-Food Interactions

•Interactions between drugs and food

–warfarin and Vitamin K containing foods

(remember green tea, as well)

–Phenytoin & vitamin D metabolism –Methotrexate and folate metabolism

•Drug impact on appetite

–Digoxin may cause anorexia

– ACE inhibitors may alter taste

Herbals and



Herbals and

Supplements:Potential

interactions with Rx Drugs•SAMe may increase homocysteine levels

•St. John’s 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



High Risk Situations

•Patient seeing multiple providers

•Patient on multiple drugs

•Patient lives alone and/or has

cognitive impairment

•Discharge from hospital or any

change in venue



Ginkgo (Ginkgo bi loba ), particularly a standardized

extract known as EGb 761, appears to produceimprovements in awareness, judgment, and social function

in people with Alzheimer's disease and dementia. In a

year-long study of 309 people with Alzheimer's disease,

those taking EGb 761 consistently improved while those

on placebo worsened.

Kava kava (Piper methyst icum ) has become popular as

a treatment for anxiety, but recent reports have traced liver

damage to enough people who have used kava that the

U.S. FDA has issued a warning regarding its use and other countries, such as Germany and Canada, have taken kava

off of the market



St. John's wort (Hyper icum perforatum ) is well known

for its antidepressant effects, and an analysis of 27 studiesinvolving more than 2,000 people confirmed that the herb

is an effective treatment for mild to moderate depression.

Valerian (Valeriana o ff icinal is ) has had a long tradition as

a sleep-inducing agent, with the added benefit of producing no hangover feeling the next day.

Echinacea preparations (from Echinacea pu rpu rea and

other Echinacea species) may bolster immunity. In a

study of 160 volunteers with flu-like symptoms, echinacea

extract reduced both the frequency and severity of cold

symptoms.



Is there anything I should watch out for?

Used correctly, many herbs are considered safer than

conventional medications, but because they are

unregulated, herbal products are often mislabeled and may

contain undeclared additives and adulterants.

Some herbs are associated with allergic reactions or

interact with conventional drugs.

Self-prescribing herbal products will increase your risk, so it

is important to consult your doctor and an herbalist before

taking herbal medicines..



Some examples of adverse reactions from certain popular

herbs are described below

St. John's wort causes sensitivity to the sun's ultraviolet

rays, and may cause an allergic reaction, stomach upset,fatigue, and restlessness. Studies show that St. John's wort

also interferes with the effectiveness of many drugs,

including warfarin (a blood thinner), protease inhibitors for

HIV, possibly birth control pills, and many other medications. In addition, St. John's wort must not be taken

with anti-depressant medication.

The Food and Drug Administration (FDA) has issued a

public health advisory concerning many of these

interactions.

Kava kava and echinacea have both been linked to liver

toxicity. Again, kava has been taken off the market in

several countries because of the liver toxicity.



Valerian may cause oversedation, and in some people itmay even have the unexpected effect of overstimulating

instead of sedating.

Feverfew (Tanacetum parthenium) may cause agitation.

Bleeding time may be altered with the use of garlic,ginkgo, feverfew, ginger (Zingiber officinale) and ginseng

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