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 JUMLAH PASIEN JUMLAH E.S. RATE E.S. 4009 142 4% 6-10 3861 397 10% 11-15 1713 478 28% 16-20 641 347 54%

POLIFARMASI BANYAK PADA MANULA

The Prescribing Cascade

Common cause of polypharmacy in elderly 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 9-13 prescriptions 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 nonadherence

Makanan minuman Vitamin and mineral supplements Herbal remedies Nutritional supplements Over-the-counter medications

INTERAKSI
Berbagai obat yangdigunakan unuk terapi dan Pencegahan penyakit

TIPE INTERAKSI OBAT

Drug-Drug Pharmacokinetic Drug-Drug Pharmacodynamic Drug-Food/Nutrient Drug-Disease .1 .2 .3 .4

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

Interaksi obat dengan obat, herbal atau makanan 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

Interaksi obat dengan obat, herbal atau makanan Diluar tubuh menyebaban perbahan sifat fisiko kimia obat sehingga terjadi efek Obat yang berkurang aupun efek toksik

INTERAKSI FARMAKODINAMI OBAT-HERBAL-MAKANAN

R1

R2

R1a EFFEK

INTERAKSI FARMAKOKINETIK
ABSORBSI
OBAT MEMPENGARUHI PROSES DISTRIBUSI METABOLISME EKSKRESI

KADAR OBAT DALAM DARAH TARGET MENINGKAT ATAU MENURUN

Pharmacokinetics

Pharmacodynamics

Dosage Regimen

Plasma Concen tration

Site of Action

Effects

K O N S E N T R S I O B A T P L A S M A

AREA UNDER CURVE = AUC

MINIMUM TOXIC CONCENTRATION

MINIMUM EFFECTIV CONCENTRATION

AUC

AUC

AREA UNDER CURVE PEMBERIAN DOSIS BERULANG

K O N S E N T R S I O B A T P L A S M A

KEGAGALAN TERAPI

REGIMEN B

MINIMUM TOXIC CONCENTRATION

TERAPI SUKSES

REGIMEN

MINIMUM EFFECTIV CONCENTRATION KEGAGALAN TERAPI

WAKTU PEMBERIAN OBAT

INTERAKSI FARMAKODINAMI OBAT DAN OBAT

INTERAKSI FARMAKOKNETIK OBAT DENGAN OBAT

Drug-Drug Interactions Affecting Absorption and Distribution

Outcome Object Drug(s) Precipitant Drug(s) Tetracycline, Ciprofloxacin Antacids, Iron abs. Pl con Warfarin Chloral hydrate

Generally absorption and distribution drug-druginteractions are not clinically important.

Drugs & Aging 1998;12:485-94

Hepatic Metabolism
Phase I (CYP 450) Oxidation hydroxylation dealkylation sulfoxidation Reduction Hydrolysis Phase II Conjugation glucuronidation sulfation glycine acetylation

Cytochrome P450 Phase I Isoenzymes, % Total and Substrate Examples

Substrate % Isoenzymes Olanzapine, Theophylline 17 CYP1A2 Phenytoin, Warfarin 26 CYP2C9/19 Codeine, Desipramine, Tramadol 2-4 CYP2D6 Chlorzoxazone, Ethanol 9-10 CYP2E1 Diazepam, Triazolam, Quinidine, 35-45 CYP3A4 Methadone, Carbamazepine

www.drug-interactions.com

Inhibitors of Hepatic Cytochrome P450

3A4 Erythromycin Azole
Nefazodone Clarithromycin Ritonavir Cimetidine

2D6 2C9/19 1A2 Fluoxetine Amiodarone Fluvoxamine Paroxetine Fluconazole Cimetidine antifungal Quinidine Fluvastatin Ciprofloxacin Ritonavir Fluoxetine Bupropion Isoniazid Cimetidine Sertraline Omeprazole Cimetidine
www.drug-interactions.com

Drugs That Interact with Theophylline

Inhibitors Cimetidine Propafenone Mexiletine Propranolol Erythromycin Ciprofloxacin Fluvoxamine

Inducers Barbiturates Phenytoin Smoking Rifampin Carbamazepine

Drugs Aging. 2003;20:71-84

JAPHA 2004;44:142-51

Drug-Drug Interactions With Warfarin

Anticoagulant Effect Mechanism PD PK PK PD PD PK Interacting Drug Aspirin Barbiturate Cimetidine Dipyridamole Fibrates Fluvoxamine PK Macrolides Phenytoin Quinolones Rifampin Sulfinpyrazone Thyroid hormones Ticlopidine

PK PK PK PK/PD PD PD

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

Clinically Significant Drug-Drug Interactions with AEDs

Outcome CBZ CBZ level CBZ level CBZ level CBZ level DPH level DPH level DPH level DPH level DPH level Interacting Drug Danazol Diltiazem Macrolides Propoxyphene Verapamil Amiodarone Cimetidine Fluoxetine INH Omeprazole Object Drug Carbamazepine level Carbamazepine Carbamazepine Carbamazepine Carbamazepine Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin

Neuropharmacology 2002;5:280-9

Inducers of Hepatic Cytochrome P450

3A4 Carbamazepine Phenytoin Phenobarbital Rifampin St. Johns wort 2D6 2C9/19 1A2 None Rifampin Smoking Phenobarbital Omeprazole Phenytoin Phenytoin

www.drug-interactions.com

Selected Phenytoin Induction Interactions

CYP Induced 3A4 Interacting Drug Phenytoin Phenytoin Phenytoin Phenytoin Object Drug Isoenzyme Methadone Quinidine Theophylline Warfarin

3A4 1A2 2C9

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

Effect on Levels Interacting Drug Amiodarone Clarithromycin Propafenone Quinidine Verapamil

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

Drug-Drug PD Interactions
Interacting Drug (s) K+ & K+ sparing diuretics Verapamil Diuretics SSRI, Dextromethorphan, Pseudoephedrine, Anorexiants MAOI Thioridazine Object Drug ACE-I Beta blockers Digoxin MAOI Meperidine Hydroxyine

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
Outcome Interacting Drug Object Drug

BP NSAIDs Antihypertensives risk of PUD NSAIDs Corticosteroids diuretic effect NSAIDs Diuretics Indomethacin Triamterene K+ anticoagulant NSAIDs Warfarin effect

CNS Polypharmacy and Falls in Elderly Persons

5 4

Adjusted odds ratio

3 2.37 2 1.54 1 0 0 1 >2 CNS - active medications (n) 1

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

Drug-Food/Nutrient Interactions

Drug

Effect

Phenytoin
Isoniazid Phenytoin

Folate
Vit B6 Absorption with NG feedings

Levodopa
Captopril

High protein meals effect blood-brain transport Altered taste sensation

Clinically Significant Drug St. John Wort Interactions

Outcome serotonergic syndrome levels, transplant digoxin levels breakthrough bleeding indinavir levels withdrawal sxs levels theophylline levels INR
CPT 2004;75:1-12

Object Drug Antidepressants Cyclosporine rejection Digoxin Estrogen Indinavir Methadone Tacrolimus Theophylline Warfarin

Other Clinically Significant Herb- Drug Interactions

seizure threshold seizure threshold digoxin activity saquinavir levels risk of bleeding risk of bleeding risk of bleeding risk of bleeding

Outcome

Interacting Drug
Wormwood Gingko biloba Hawthorne Garlic Feverfew Garlic Ginger Ginkgo Ginseng
Lancet 2000;355:134-8.

Object Drug
Anticonvulsants Anticonvulsants Digoxin Saquinavir Warfarin Warfarin Warfarin Warfarin Warfarin anticoagulant

Clinically Important Drug-Disease Interactions Determined by Expert Panel Consensus Disease Drug
BPH, constipation, dementia CHF (systolic dysfunction) HTN, insomnia PUD DM Depression COPD,dementia, falls COPD, DM, syncope CHF (systolic Postural hypotension, seizures Seizures DM, PUD Insomnia Heart block Anticholinergics Antiarrhythmics (Type 1A) Amphetamines Aspirin Atypical antipsychotics Barbiturates Benzodiazepines Beta-blockers CCB 1st generation dysfunction) Chlorpromazine Clozapine Corticosteroids Decongestants Digoxin

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

Clinically Important Drug-Disease Interactions Determined by Expert Panel Consensus

Disease
Parkinsons disease Chronic renal failure CRF, CHF, HTN PUD BPH, constipation, dementia Falls BPH Falls Insomnia Postural hypotension, Seizures Arrhythmias, BPH,
dementia, falls, heart block postural hypotension Falls

Drug
Metoclopramide Nitrofurantoin Non-aspirin NSAIDs Non-aspirin, non-COX II NSAIDs Opioid analgesics Sedative/hypnotics Skeletal muscle relaxants SSRIs Theophylline Thioridazine seizures Thorazine Tricyclic antidepressants constipation

Typical antipsychotics

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 217% of all Rx's and up to 6-42% of elderly patients. Incidence of potentially clinically significant drug interactions is low in the elderly (usually must involve narrow therapeutic range drug and inhibitor/inducer of drug metabolism or renal excretion) There is evidence suggesting that adverse health outcomes associated with drug-drug interactions is infrequent. Drug-disease interactions occur in 6.2-40% of elderly patients 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 in homeostatic mechanisms and diminished functional reserve.

Drug Interactions Are Avoidable

Previous adverse Contraindicated Drug reactions drugs interactions Avoidable
Probably avoidable Uncertain Total

Totals

7
------7

57
---3 60
Gosney et al. Lancet 1984;2:564

67
37 29 133

131
37 32 200

Strategies to Prevent/Manage Drug Interactions

1. Encourage patients to report all prescription, overthe- counter and complementary and alternative drugs 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 sources 4. 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 withdrawing a drug that can inhibit or induce hepatic metabolism. 9. Regularly review the need for chronic medicationsreduce 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 dimana Obat bekerja Misalnya di enzim, di reseptor dikanalion dan tempat lain Yang secara tidak langsung meningkatkan ligand atau nerotrasmiter

Reseptor adrenergik cholinergik Enszim acetylcholine esterase Na-K ATP ase COx1 dan COX2 Kanalion Ca dan |Na

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 Warfarin (Coumadin) 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 also produce 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, but extremely difficult to predict)

Pharmacokinetics and the Liver

Acetylation and conjugation do not change appreciably with age Oxidative metabolism through cytochrome 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 drug induced confusion NSAIA (and COX-2s) 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 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

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 biloba), particularly a standardized extract known as EGb 761, appears to produce improvements 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 methysticum) 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 (Hypericum perforatum) is well known for its antidepressant effects, and an analysis of 27 studies involving more than 2,000 people confirmed that the herb is an effective treatment for mild to moderate depression. Valerian (Valeriana officinalis) 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 purpurea 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 it may 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