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Interaksi Obat
Prof Lukman Hakim PhD Department of Pharmacology and Clinical Pharmacy Faculty of Pharmacy, Gadjah Mada University

Kuliah 2 kali yang menyenangkan begitu komentarku dalam hari. Abisnya jelasinnya enak sih. Apa mungkin karena bersifat review dari materi pak Waldi dan Bu Chairun kali ya sehingga lebih cepet nyantol. Mengapa kita perlu belajar interaksi obat? Ini penting karena sebenarnya outcome dari terapi adalah jumlah bersih dari interaksi antara pasien, lingkungan, obat dan penyakit.

Farmakokinetika

Farmakodinamika

Usia Sex Genetik/etnik INTERAKSI OBAT BB Lingkungan Status nutrisi Tingkat penyakit Sumber variabilitas pada respon obat

Edverse effect. toksisitas

Efek klinis

Interaksi Obat Multiple drug therapy dapat menimbulkan interaksi obat. Definis IO: Alterastion efek/potensi suatu obat (victim drug) oleh pemberian obat secara bersamaan dengan obat utama (perpertrator drug). Jika interaksi menghasilkan penghilangan efikasi atau menaikkan toksisitas, maka interaksi obat bermakna terapetik. Perpertrator drug: obat yang mempengaruhi. Victim drug: obat korban. Jadi, jangan terlalu takut. Walau secara teori (uji in vitro/in vivo) terjadi interaksi, tapi kalo secara klinis gak muncul ya gak masalah. Ada juga interaksi yang terjadi pada sekelompok orang tertentu, tapi gak terjadi pada populasi manusia yang lain. Jadi harus dipakai metode pengujian pada ranah klinik. Jadi kesimpulannya: 1. Interaksi obat tidak terjadi pada setiap orang, walau secara teoretis iya. 2. Kalaupun terjadi interaksi obat, belum tentu bermakana terapetik. 3. Interaksi obat adalah sesuatu yang unpredictable. 4. Interaksi obat juga bisa mengakibatkan kematian, jadi jangan disepelekan juga. Kata kunci dari Pak Lukman: Jangan terlalu dicemaskan, jangan juga diremehkan.

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Dalam praktek, si pasien bisa mendapat multiple medication dengan beberapa alasan: 1. Disengaja (intentional) Di sini dengan kombinasi obat justru memberikan benefit yang lebih besar, misal pada terapi penyakit infeksi (SMZ-TMP), kanker, hipertensi, diabetes. Misal ada obat A yang bisa memberi efek X pada kadar 500 mg. Kemudian jika dikombinasi dengan obat B maka dosisnya menjadi @ 250 mg sudah bisa menghasilkan efek X. Sehingga bisa menurunkan efek samping. Coontoh: kombinasi penisilin/sefalosporin dengan probenecid. Kedua obat ini dieksresi di tubulus renalis. Pada probenecid, dia selalu menang karena ikatan dengan protein lebih kuat. Sehingga obat yang satunya (penisilin/sefalosporin) gak jadi di ekskresi karena kalah ma probenecid dan akhirnya direabsorpsi lagi. Obat akan lebih lama tinggal di tubuh untuk melawan infeksi interaksi yang menguntungkan. Ada lagi, yaitu pada obat HIV. Saquinavir (diberikan sendirian) maka AUC-nya jelek. Tapi jika dikombinasi dengan ritonavir (inhibitor enzim) maka AUC-nya meningkat bisa mencapai 20 kali. Tantangan Anda sebagai farmasis adalah ketika menjadi formulator, yaitu memformulasikan obat-obat tsb dalam 1 sediaan.

Bisa juga pada pengobatan coexisting disease seperti: dibates dan hipertensi; HIV dan infeksi opurtunis. Infeksi opurtunis yaitu infeksi yang timbul akibat penurunan kekebalan tubuh. Infeksi ini dapat timbul karena mikroba (bakteri, jamur, virus) yang berasal dari luar tubuh, maupun yang sudah ada dalam tubuh manusia, namun dalam keadaan normal terkendali oleh kekebalan tubuh. Dalam pengobatan India (Ajur Veda), juga ada kombinasi loh.. Misal pada obat Piperacea dengan Zingiber. Kok bisa mereka tahu ya? Terus ada juga kunir-asem (kurkumin stabil pada suasana asam), atau beras-kencur (resin kencur bisa dinetralkan oleh amilum dari beras sehingga rasa getir berkutang). Ini namanya ilmu wisik dapet bisikan dari makhluk halus trus muncul feeling dari nenek moyang kita. 2. Tidak disengaja Dalam hal ini tidak diharapkan; bisa terjadi pemberian obat yang dari dokter yang berbeda; dan interaksi antara obat, OTC, herbal, dan nutrisi. Kasus OTC terjadi di RS CM. Seorang ibu yang mau dibedah. Ketika operasi berlangsung, sang dokter panik kok darahnya gak bisa berhenti. Akhirnya operasi ditunda dan luka ditutup kembali. Serlah diintrogasi, kata anaknya, sebelum dioperasi ibuya dikasih obat Cina (benzecuang) yang berkhasiat sebagai pengencer darah (antikoagulan). Makanya harus hati-hati, walo herbal

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juga bisa berinteraksi dengan obat kimia. Contoh lain yaitu kurkumin yang salah satunya berkhasiat sebagai pengencer darah, jadi jangan diminum ketika menstruasi. Conditions that Place Patients at High Risk for Drug Interactions High risk associated with the severity of disease state being treated: Aplastic anemia Asthma Cardiac arrhythmia Critical care/intensive care patients Diabetes Epilepsy Hepatic disease Hypothyroid High risk associated with drug interaction potential of related therapy: Autoimmune disorders Cardiovascular disease Gastrointestinal disease Infection Psychiatric disorders Respiratory disorders Seizure disorders Interaksi obat dan adverse effect meningkat seiring jumlah obat yang dikonsumsi. Jumlah item obat yang digunakan bisa digunakan sebagai prediksi. 1. Efek samping terjadi pada 3-5% pasien yang menerima sedkit obat (< 4) 2. Efek sammping terjadi lebih pada 20 pasien yang menerima 10-20 obat. 3. Pasien di RS rata-rata menerima obat 5 macam 4. Pada penederita HIV rata-rata mendapat obat lebih dari 10 macam. HIV ujung-ujungnya adalah AIDS. Pasien, imunitasnya turun sehingga bisa menderita berbagai maca penyakit. Nah, tiap penyakit misal diobati 1-2 macam obat. Berarti kalo penyakitnya 5 bisa ada 1012an obat. Kalo pasien kena septum (penebalan jantung), sehingga sukar bernafas. Dikasihlah obat X dan Y. Terus hepar/livernya rusak juga. Eh, terus berimbas ginjalnya juga kena, lantaran kebanyakan minum obat, akhirnya pasien mati di sini, di sakit gainjalnya. Ini contoh ekstri, sih. Tapi emang rata-rata 14% pasien HIV menerima obat labih dari 10 item. 5. Pasien geriatri, pada tingkat biasa mendapat 2-5 obat. Jika sudah lebih dari 5 namanya polifarmasi, dan ini terjadi pada 20-40% pasien pada rentang umur ini. Wow, kasian ya.....

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Jumlah pengobatan Contribution of Drug Interactions to the Overall Burden of ADRs Drug interactions represent 35% of in-hospital ADRs. Drug interactions are an important contributor to number of ER visits and hospital admissions. The previous slides have reviewed information about the magnitude of adverse drug reactions and the burden they place on the healthcare system. How much do drug interactions contribute to the total number of preventable ADRs? Again, estimates of the numbers of patients injured due to drug interactions vary widely. However, some reasonable estimates come from the work of Dr. Lucien Leape and colleagues. {Leape} In a systems analysis of ADRs, they estimated that drug-drug interactions represent from 3-5% of all in-hospital medication errors. Drug interactions are also an important cause of patient visits to physicians and emergency departments.{Raschetti}

Daftar obat yang ditarik dari pasar sejak tahun 1990-an. Obat Fenfluaramine (antihistamin) Dexfenfuramine Terfenadine Mibefridil Astemizole Troglitozone Cisapride Alosetron Grepafloxacin Bromfenac Cerifastatin Nefazodone Disetujui Ditarik 1973 1996 1985 1997 1988 1997 1993 2000 1997 1997 ? ? 1997 1997 1998 1998 1999 2000 2000 2000 1999 1998 ? 2003 Rhabdomyolysis (kelumpuhan) Toksik hati Metabolic IO Metabolic IO Adverse effect Vulvular heart failure Vulvular heart failure Aritmia Low heart rate in elderly, IO Aritmia Gagal hati Aritmia Iskemik colitis (usus besar menyempit) aritmia Metabolic IO Metabolic IO Metabolic IO Metabolic IO Faktor risiko

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Rofecoxib

1999

2004

Toksik jantung

Faktor-faktor obat yang mempengaruhi IO: 1. Dosis obat/konsentrasi 2. Jendela terapi yang sempit 3. BA yang rendah. Setelah di metabolisme bisa lebih rendah lagi. 4. Durasi pengobatan. Misal yang life-trathening/seumur hidup: sakit jantung, vaskuler, asma, DM. 5. Waktu dan urutan pemberian. PENTING !! Misal antasida dengan antibiotik golongan fluroquinolon (ciprofloxacin). Obat bisa diberikan dengan interval 1-2 jam jika urutannya benar. Lebih enak antibiotiknya dulu, 1-2 jam udah di metabolisme, aman, baru minum antasida. Kalo antasida dulu maka perlu waktu 4-6 jam. Karena antasida gak diabsrorpsi, kerja obat bersifat secara fisika kimia. Jika kurang dari 4 jam sudah diberi antibiotik maka antibiotik akan terikat pada logam Mg (dari antasida) sehingga gak diserap, kalo iya paling cuma dikit. Hingga akhrinya AUC rendah, akibatnya: 1) bisa membuka peluang resistensi mikro organisme; 2) pasien gak sembuh (under-dose dosis sub-terapetik). 6. Jumlah obat yang diresepkan 7. Rute pemberian 8. Fraksi metabolized. Zat aktif dalam bentuk apa? Parent compound, prodrug? Contoh: analapril asam enalapril; heroin morfin. 9. Prbolematika PK (nonlinear). Contoh obatnya fenitoin. Ketika diberi pada dosis terapi, ada inhibitor, terjadi problem farmakokinetika yang nonlinear, AUC meningkat tidak proporsional. Contoh lain methotrexat (obat kanker), lho lok pasien saya mati? 10. Kepatuhan

Drugs With Narrow Therapeutic Window Examples : 1. Aminoglycoside antibiotics : gentamicin, tobramycin. Bisa untuk bakteri gram negatif (Pseudomonas). ES: pada ginjal dan ketullian.

2. Anticoagulants : warfarin, heparins 3. Aspirin (salicylate derivatives) 4. Carbamazepine 5. Conjugated estrogens : OC pills 6. Cyclosporine 7. Digoxin 8. Esterified estrogens : OC pills 9. Hypoglycemic agents 10. Levothyroxine sodium

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11. Lithium 12. Phenytoin 13. Procainamide 14. Quinidine sulfate/gluconate 15. Theophylline (aminophylline) 16. Tricyclic antidepressants 17. Valproic acid

Interaksi pada tingkat in-vitro 1. Fenitoin mengendap pada dekstrosa (menyumbat infus) 2. Intravesikuler ampotericin mengendap pada bufer saline, tapi partikelnya halus, bisa mengakibatkan bladder wall necrosis. 3. Gentamisin berikatan kovalen dengan piperacillin, azlocillin, cefoxitin hilang dan mengendap di botol infus. efek antibiotik

INTERAKSI OBAT FARMAKOKINETIKA

Terjadi pada fase ADME 1. Absorpsi. Chelating, ubah gasrtric pH, makanan, metabolisme gut-wall, transport, pengosongan dan motilitas grastik, aliran darah. Parameter: BA (F po) 2. Distribusi protein binding, transporter Vd, t BA, Cl, t Cl, t

3. Metabolisme 4. Ekskresi

Mengganggu pada fase I dan II

Mengganggu pada sekresi tubular dan fungsi ginjal

Kalo sudah melibatkan faktor fisiologis (motiitas usus, inhibisi enzim, ganti reseptor, flora usus), gak bisa cukup 1-2 jam. Contoh: perokok berat (berapa batang sehari, sejak kapan?). Ketika dia stop merokok, butuh waktu 1 tahun untuk menormalkan fungsi metabolismenya. Jadi kalo ada yang berpengaruh pada enzim yang sama dengan perokok, ganti obat aja. Contoh lain, kalo ritonavir butuh waktu 1 minggu untuk membersihkannya. ABSORPSI Berubah pada: 1. Chelation/kompleksasi/adsorpsi. 2. pH gastrik 3. motilitas usus. Bisa mempercepat/memperlama aksi obat. Contoh: metoklopramid vs propentalin. Obat yang diabsorpsi di usus, maka BA-nya berpengaruh. 4. flora/gut metabolism 5. efek makanan

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Contoh: ketoconazole(optimal pada suasana asam) yang absorpsinya dipengaruhi oleh pH

Ketoconazole adalah fungisida yang ampuh lho. Pemberian pada suasana basa (dari sucralfat atau ranitidin) AUC-nya menurun secara tajam. Jika demikian, jamur bisa resistent.

In the GI Tract Sejumlah interaksi terjadi di saluran GI dan menurunkan masukan obat ke sirkulasi sistemik. Secara khusus dicatat yaitu: 1. Obat yang mengadung aluminium, contoh sucralfat (Carafate) dan antasida menurunkan absorpsi dari antibiotik yang mahal dan ampuh seperti ciptofloxacin (Cipro) dan azithromycin (Zithromax). Kerugian: finansial dan tubuh (resisten dan sub-terapi). Makanya, ganti obat maagnya degan famotidin atau nisatidin. 2. Wanita yang mengkonsumsi suplemen besi (ex: ferro fumarat), hati-hati jika dia mendapat resep obat golongan quinolon, tetrasiklin atau azithromycin. 3. Obat seperti ketoconazole (Nizoral) dan delavirdine (Rescriptor) membutuhkan suasana asam supaya dalam bentuk tak bermuatan dan akhirnya lebih mudah diabsopsi. Kelarutannya bisa turun secara drastis ketika pasien mengkonsumsi omeprazole (Prilosec), lansoprazole (Prevacid), atau H2-antagonists karena meningkatkan pH lambung. Sucralfat, beberapa produk susu, antasida, dan sediaan oral dari besi (+ Hb darah) Omeprazol, lansoprazol, H2-antagonis (obat basa) Didanosin (diberikan sebagai tablet yang dibufer) Kolestiramin Blok absoooorpsi quinolon, tetrsiklin, dan azithromycin Menurunkan absopsi ketoconazol, delavirdin

Menurunkan absorpsi ketoconazol

Mengikat raloksifen, hormon tiroid, dan digoksin

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Floroquinolone (Ciprofloxacin) dan didanosin (dengan buffernya Al3+/Mg2+ antacide) menurunkan AUC ciprofloxacin hingga 80%.

Solusinya: 1. Pemberian ciprofloxacin minimal 2 jam sebelum atau 6 jam setelah antasida. 2. Menggunakan enteric coated didanosine.

FOODS HIGH IN TYRAMINE Kolestiramin pada dasarnya merupakan ion-exchanger, sedangkan kebanyakan obat merupakan ion, sehingga bisa terjadi interaksi. Jadi semua obat bisa gak efektif donk, padahal kan kolestiramin gak hanya terdapat pada obat tok, di makanan pun banyak. Tapi tenang, kadang gak nimbulin makna klinis. Atau minum setelah 1-2 jam. Lagian juga pada 1 orang bisa interaksi, tapi belum tentu pada orang lain walau sama-sama normal. Tentu adanya namanya variabilitas biologis, apalagi kalo ada yang hari atau ginjalnya rusak. Makanan yang banyak mengandung tiramin: 1. Ale, Avocados (terutama jika mateng bgt) 2. Pisang (ortuku kalo nelen obat pake pisang tuh, njuk piye dab???) 3. Bean pods, lima beans, butter bean (kacang-kacangan) 4. Canned Figs, Caviar (ikan kaleng) 5. Cheese (terutama yang udah aged) 6. Chicken livers (jeroan, senengannya bu Sulih pas di Australia) 7. Chocolate, Coffee, Cola beverages 8. Fermented meats (salami, pepperoni, summer sausage) 9. Herring (pickled or dry) 10. Raspberries 11. Soy sauce, Sour cream, Tofu 12. Wines (especially red) sarden pizza

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13. Yeast preparations, Yogurt

Obat yang berefek pada absorpsi Mekanisme aksi Kolestiramin Binding agent Objek obat Acetaminophen, diclofenac, digoxin, glipizide, furosemide, iron,lorazepam, methotrexate, metronidazole, piroxicam Carbamazapine, diclofenac, furosemide, tetracycline, thiazides Fenilbutazon Hasil Menurunkan absorpsi

Colestipol

Binding agent

Menurunkan absorpsi Menurunkan absorpsi

Desipramine

Menurunkan motilitas GI

METABOLISME (di Liver dan GI tract) Kebanyakan interaksi obat lebih terjadi di fase 1 dibanding fase II, terutama pada enzim sitokrom P-450.

Cytochrome P450 Isoforms This slide lists the major cytochrome P450 isozymes that are responsible for metabolism of drugs in humans. We will cover these enzymes in some detail. Because many drugs are metabolized principally by these enzymes, important interactions between drugs can be predicted by using a list of drugs that are inhibitors or inducers of that enzyme. This simplifies the search for interacting drugs and provides a framework for prediction of interactions. Next we will review how these enzymes are named. CYP1A2 CYP3A CYP2C9 CYP2C19 CYP2D6

Terfenadin dan Astemizol Berinteraksi dengan: - Antifungal imidazol (eg. ketokonazol, flukonazol) - Inhibitor CP-450 (eg ketokonazol, flukonazol, simetidin) menyebabkan aritmia jantung. Terfenadin dan Astemizol telah dilarang di US market (1998/99) karena kasus interaksi obat. Astemizole vs Erythromycin

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Preliminary reports indicate that erythromycin and astemizole can cause QT interval prolongation and cardiac arrhythmia due to astemizole. Risk factors : Not specific Related drugs: Troleandomycin, clarithromycin and terfenadine may also inhibit astemizole metabolism Management: 1. Avoid combination 2. Use loratadine or cetirizine instead of astemizole 3. Certirizine, fexofenadine, loratadine = non-sedating antihistamines Astemizole vs Fluvoxamine Fluvoxamine appears to inhibit astemizole metabolic enzyme and increases Cp of astemizole leading to cardiac arrhythmia Risk factors : Not specific Related drugs : Terfenadine, fluvoxamine and astemizole are metabolized by CYP3A4 Management: 1. Avoid combination 2. Use loratadine or cetirizine instead of astemizole Astemizole vs Ketoconazole Ketoconazole can increase Cp astemizole leading to QT interval prolongation and cardiac arrhythmia due to astemizole Faktor risiko: tidak spesifik Related drugs : Miconazole, itraconazole, and fluconazole may also inhibit astemizole metabolism. Terfenadine concentrations are increased with the antifungal agents. Management : Avoid combination Use loratadine or cetirizine instead of astemizole

CYP3A Inducers Carbamazepine Rifampin Rifabutin St. Johns wort

Various herbs extracts vs CYP 2D6 and 3A4 activities Ginkgo biloba extract (120 mg, 2x a day, PO; 14 days). Siberian Ginseng extract (485 mg, 2x a day, 14 days) Saw Palmetto extract (320 mg/day, 14 days) The valerian supplement contained a total valerenic acid content of 5.51 mg/tablet (every night, 14 days)

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Garlic extract (3 x 600 mg twice daily) for 14 days A decaffeinated green tea (GT; Camellia sinensis) extract (4 capsules/day, 14 days). Each GT capsule contained 211 +/- 25 mg of green tea catechins and <1 mg of caffeine

Against 30 mg dextromethorphan (CYP 2D6 activity) and 2 mg alprazolam (CYP 3A4 activity) did not affect elimination of the two drugs in 11 human volunteers Cytochrome P450 2D6 Absent in 7% of Caucasians, 12% non-Caucasians Hyperactive in up to 30% of East Africans Catalyzes primary metabolism of: Codeine, Dextro-methorphan Many -blockers Many tricyclic antidepressants

Inhibited by: Fluoxetine, Haloperidol, Paroxetine, Quinidine CYP2D6 metabolizes many of the cardiovascular and neurologic drugs in use toaday. Study of CYP2D6 has led to understanding the failure of codeine to relieve pain in some patients. Codeine is actually a pro-drug that is converted to morphine. Codeine itself is much less active as an analgesic, but causes nausea and other adverse effects. The absence of cytochrome P450 2D6 in 7% of Caucasians means that these individuals cannot metabolize codeine to the active metabolite, morphine, and therefore will get little, if any, pain relief from codeine.{Caraco} However, they will experience codeines adverse effects, particularly if the dose is increased in the futile attempt to obtain pain relief. Thirty percent of Ethiopians studied had multiple copies of the 2D6 gene (up to 13) and increased eynzyme activity resulting in ultrarapid metabolism. {Akilillu} Ultra-rapid metabolism results in lower blood levels following a standard dose of any drug metabolized by this enzyme. Therefore these patients may have an inadequate response to standard dosages of -blockers, narcotic analgesics, or antidepressants and may require higher dosages for clinical effectiveness. Several commonly used medications inhibit CYP2D6. These include quinidine{Branch} as well as haloperidol and some other antipsychotics. {Shin 1999}, {Shin 2001} The well-described pharmacokinetic interaction between Selective Serotonin Reputake Inhibitor (SSRI) antidepressants and tricyclic antidepressants appears to be due to the fact that fluoxetine and paroxetine are both potent inhibitors of CYP2D6 {Bergstrom}, {Leucht} and render patients metabolically equivalent to people who do not have the enzyme. This increases the plasma levels of tricyclic antidepressants and increases the potential for side effects. In contrast, patients coprescribed fluoxetine or paroxetine with codeine may experience no analgesic benefit, since codeine requires CYP2D6 for metabolism to morphine.

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Cytochrome P450 2C9 Absent in 1% Caucasians and African-Americans Primary metabolism of: Most NSAIDs (including COX-2), S-warfarin (the active form), Phenytoin Inhibited by: Fluconazole

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CYP2C9 has a polymorphic distribution in the population and is missing in 1% of Caucasians. It is the major enzyme responsible for metabolism of many of the non-steroidal anti-inflammatory drugs (NSAIDs), including the second generation cyclooxygenase-2 (COX-2) specific inhibitors. A number of other important medications have their metabolism primarily catalyzed by CYP2C9. An important drug metabolized by this enzyme is warfarin (Coumadin ), and almost all interpatient variability in warfarin levels and anticoagulant effects can be explained on the basis of CYP2C9 activity (not the differences in protein binding as originally thought). Most of the traditional NSAIDs and the COX-2 specific drugs are metabolized by CYP2C9. The azole antifungal agent fluconazole(Diflucan) is a potent inhibitor of CYP2C9. Fluconazole, at conventional doses, abolishes CYP2C9 activity. An interaction between fluconazole and warfarin results in at least a 2-fold increase in warfarin blood level, a reduction in warfarin clearance, and increased anticoagulation.{Black} Clinical studies have identified a significant interaction between fluconazole and celecoxib (Celebrex), leading to a 2-fold increase in celecoxib plasma concentrations.{Celebrex} A clinical pharmacokinetic study showed an increase in phenytoin area under the plasma concentration curve (AUC) following fluconazole administration,{Touchette et al 1992} and symptomatic phenytoin toxicity has been reported with concomitant administration of fluconazole and phenytoin.{Cadle et al 1994} Cytochrome P450 2C19 Absent in 2030% of Asians, 35% Caucasians Primary metabolism of: Diazepam, Phenytoin, Omeprazole Inhibited by: Omeprazole, Isoniazid, Ketoconazole Cytochrome P450 2C19 is notable because of its genetic absence in such a high percentage of Asians (approximately 20-30%). This enzyme metabolizes many anticonvulsants, diazepam (Valium ), omeprazole (Prilosec ) and several of the tricyclic antidepressants. Asians have reduced clearance of diazepam compared to Caucasians, {Ghoneim} and, in fact, a survey of Asian and Western physicians showed the use of lower doses of diazepam in Asians.{Rosenblat} Asian patients may have a lower omperazole dosage requirement for effective treatment of Helicobacter Pylori. According to the omeprazole package insert, Asians have about a 4-fold increase in the AUC of omeprazole compared to Caucasians, and the labeling recommends that one should consider dosage adjustment.{Prilosec PDR} In addition, the poor metabolizer genotype for CYP2C19 resulted in a higher cure rate for H. Pylori than the rapid metabolizer genotype in an Asian population treated with omeprazole as part of dual therapy.{Furuta 1998} Similar results have been shown more recently with proton pump inhibitors in a triple therapy regimen.{Furuta 2001) Ketoconazole{Atiba} and omeprazole{Ko} are inhibitors of CYP2C19, and have the potential for clinically significant interactions with substrates of CYP2C19 such as diazepam{Ishizaki} or phenytoin.{Prichard} Isoniazid, used to treat tuberculosis, is an inhibitor of CYP2C19 {Desta}and should be prescribed cautiously to patients taking phenytoin and other drugs metabolized by CYP2C19. Cytochrome P450 1A2 Induced by smoking tobacco Catalyzes primary metabolism of: Theophylline, Imipramine, Propranolol, Clozapine Inhibited by: Many fluoroquinolone antibiotics, Fluvoxamine, Cimetidine Cytochrome P450 1A2 is an important drug metabolizing enzyme in the liver that metabolizes many commonly used drugs including theophylline, imipramine, propranolol, and clozapine.

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CYP1A2 is significantly induced in a clinically relevant manner by tobacco smoking. The clearance of theophylline, imipramine, propranolol and clozapine are all increased by smoking. Thus, people who smoke may require higher doses of some medications that are substrates of CYP1A2. In contrast, a smoker would require a decrease in theophylline dosage if, for example, smoking were discontinued and the enzyme no longer induced. This topic has been recently reviewed by Zevin and Benowitz.{Zevin} Drug-Food Interactions 1. Tetracyclines and milk products 2. Warfarin and vitamin K-containing foods 3. Grapefruit juice 4. Fam Brassicaceae (Cruciferous) Several drugs are known to interact with foods,{Williams} some of which are listed here. One of the early observations was the reduced absorption of tetracycline when taken with milk products. The chelation of tetracycline by calcium prevents it from being absorbed from the intestines. Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage requirement for warfarin by a pharmacodynamic antagonism of its effect. Patients should be counseled to maintain a consistent diet during warfarin therapy. Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism of many drugs. This was first described for felodipine (Plendil) {Bailey 1991} but has now been observed with several drugs.{Kane} This interaction can lead to reduced clearance and higher blood levels when the dugs are taken simultaneously with grapefruit juice. With regular consumption, grapefruit juice also reduces the expression of CYP3A in the GI tract.{Lown} Makanan dan produk yang kaya akan Vitamin K 1. Alfalfa tablets 2. Broccoli 3. Brussels sprouts 4. Cabbage 5. Cauliflower (raw) 6. Green leafy vegetables (spinach, collard greens) 7. Green tea 8. Liver 9. Soybean 10. Vegetable oils (canola, soybean) 11. Watercress Vitamin K berefek sebagai antikoagulan. Ini bagus sekali kalo kita lagi normal karena mencegah penjedalan darah. GFJ banyak mengadung resveratrol dan naringenin.

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OBAT YANG BERINTERAKSI DENGAN GRAPE FRUIT JUICE (GFJ) 1. Benzodiazepines : midazolam, triazolam 2. Cyclosporine 3. Dyhydropyridine Calcium-channel blockers : amlodipine, felodipine, nifedipine, nisoldipine, nitrendipine 4. Theopylline 5. Verapamil 6. 17-estradiol Efek GFJ pada profil PK dan PD felodipin.

This figure demonstrates the effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.{Dresser} The top graph shows felodipine plasma concentrations at specific time points, up to 24 hours, following administration of a single dose of felodipine with 250 cc of grapefruit juice or water. The bottom graph shows systolic and diastolic blood pressure from the same time points. Compared to water, there is an increase in felodipine plasma concentrations, as well as a decrease in systolic and diastolic blood pressure. This demonstrates a potentially clinically significant effect of the grapefruit juice-felodipine interaction. Efek GFj pada talinolol Cmax (ng/mL) S Control GFJ 77.5 163.6 R 79.5 163.0 AUC (ug.min/mL) S 19.3 29.9 R 22.2 30.1

GFJ administered together with a racemic 10 mg/kg (po) in rats GFJ did not change T1/2 elimination of talinolol Grape fruit juice reduces talinolol bioavailability Pharmacokinetics of talinolol (50 mg, PO) was determined with water, with 1 glass of GFJ (300 mL), and after repeated GFJ (900 mL/d, 6 days) in 24 healthy white volunteers A glass or repeated administration of GFJ :

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- decreases talinolol AUC, Cmax, and Fel (p < 0.001) - does not affect CLr, T1/2 elimination, Tmax.

decreases bioavailability of talinolol.

Constituents in grapefruit juice preferentially inhibit an intestinal uptake process rather than Pglycoprotein. GFJ vs oral digoksin Digoksin merupakan substrat dari P-glycoprotein, tidak dimetabolisme olah CYP 3A4. Pada penelitian 7 subjek menerima single dose digoksin 1mg dengan air atau GFJ (3x/hari, 5 hari) sebelum pemberian digoksin untuk memaksimalkan efek P-glycoprotein. GFJ menurunkan konstanta kecepatan absorpsi digoksin and meningkatkan absorpsi lag time (p<0.05). GFJ tidak mengubah Cmax, AUC, T1/2 elim, atau CLr digoksin. Penghambatan pada P-gp intestinal P-glycoprotein tidak menunjukkan peran yang penting pada interaksi obat yang melibatkan GFJ. Bromocriptine vs Isometheptene A patient on bromocriptine developed hypertension and ventricular tachycardia after taking isometheptene (a sympathomimetic) Risk factors : Not specific (can be to any person) Related drugs : Phenylpropanolamine (another sympathomimetic) also interacts with bromocriptine Management : Avoid combination (with other sympathomimetics), although a causal relationship has not been established conclusively. Chlorpropamide vs Ethanol Excessive ethanol intake may lead to hypoglycemia. An antabuse-like reaction may occur in patients taking sulfonylureas. Risk factors : Not specific (can be to anyone/any case) Related drugs : Insulin and other oral hypoglycemic agents, including tolbutamide, cause hypoglycemia. Taking phenformin may develop lactic acidosis when consuming ethanol

Management : Avoid combination. Cigarette smoking vs Oral contraceptive Risk of OC-induced adverse cardiovascular events is increased by smoking Risk factors: Management: Avoid combination. Women on OC are adviced not to smoke, or use another contraception method Persons aged > 35 years old are at greater risk Smoking > 15 cigs/day places women at greater risk

Daya analgetik parasetamol sebelum dan setelah pemberian brokoli 7-kali pada mencit jantan BALB/C

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1. Parasetamol mempunyai daya analgetik 54, 74 % 2. Brokoli menaikkan % daya analgetik parasetamol

Daya analgetik salisilat sebelum dan setelah pemberian brokoli 7-kali mencit jantan BALB/C

1. Salisilat mempunyai daya analgetik 56,84% 2. Brokoli menaikkan % daya analgetik salisilat Onset dan durasi fenobarbital sebelum dan setelah pemberian jus brokoli 7-kali pada mencit jantan

1. Brokoli memperlama onset fenobarbital tetapi tidak signifikan (P > 0,05) 2. Brokoli mempercepat durasi fenobarbital (P <0,05)

Drug-Herbal Interactions 1. St Johns Wort 2. Ginkgo biloba 3. Kava

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It has been suspected that herbal remedies could interact with other herbals or even prescription drugs. Ingestion of St. Johns wort has resulted in several clinically significant interactions with drugs that are metabolized by CYP1A2 or CYP3A, including indinavir (Crixivan) {Piscitelli} and cyclosporin (Sandimmune and Neoral). {Breidenbach} {Ruschitzka}. An interaction with digoxin (Lanoxin) has also been reported that may be mediated by interference with P-glycoprotein (PGP), a transport system that pumps drugs across membranes. {Johne} These interactions, are most likely due to induction of the cytochrome P450 isozyme or the drug transporter, and have caused decreased plasma concentrations of prescription drugs. In the case of cyclosporin, subtherapeutic levels resulted in transplant organ rejection. It is likely that many drug-herbal interactions exist but have not yet been detected. It is therefore important that healthcare providers obtain a complete drug history that includes herbal remedies and other natural products and dietary supplements and that they be alert to potential interactions.

Mean plasma concentration time course of indinavir This slide shows the mean plasma concentration time course of indinavir in eight healthy volunteers with indinavir alone or after taking indinavir with St. Johns Wort.{Piscitelli} After administration of St. Johns wort, a 57% reduction was observed in the indinavir area under the plasma concentration-time curve (AUC), indicative of reduced exposure to indinavir. This study prompted a public health advisory released by the FDA on February 10,2000 (www.fda.gov/cder/drug/advisory/stjwort.htm) about the risk of drug interactions between St. Johns wort and other medications. The potential for loss of therapeutic efficacy due to this interaction suggests the importance of taking a complete medication history. Pengaruh SJ Wort terhadap

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1. Digoxin, Fenoxfenadine, Irinotecan : memodulasi P-glycoprotein

kadar obat kadar

2. Cyclosporin, OC pills, Ritonavir, Venlafaxine : induksi CYP3A4 & modulasi Pgp obat

3. Alprazolam, Amitriptyline, Imatinib, Indinavir, Midazolam, Omeprazol, Simvastatin, Tacrolimus, Verapamil : induksi CYP3A4. 4. Warfarin : induksi CYP2C9 Ginkgo biloba (40-60 mg; 2x sehari; 2-3 bulan) Efek: antioksidan, menghambat agregasi platelet (ginkgolide = inhibitor PAF), menyembuhkan Alzheimer Efek samping: Perdarahan okular & intraserebral Interaksi Obat: aspirin, parasetamol, ergotamin, kafein, warfarin, tiklopidin, klopidogrel, dipiridamol, garlic, diuretik (gol. Tiazid) Kava (Piper methysticum) Zat aktif : kavapiron Efek : penenang, sedatif ES : disorientasi, gangguan kendali otot Penggunaan kronis : gangguan kimia darah, hipertensi paru, nafas pendek, mata merah, berat badan turun Interaksi obat : CNS depressants, L-dopa, nembutal, barbiturat, Xanax Drug-Drug Interactions: A Stepwise Approach 1. Take a medication history 2. Remember high risk patients - Any patient taking 2 medications - Anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc 3. Check pocket reference 4. Consult pharmacists/drug info specialists 5. Check up-to-date website www.epocrates.com*

In closing, it is impossible to remember all of the drug interactions that can occur. It is therefore important to develop a stepwise approach to preventing adverse reactions due to drug interactions. First, taking a good medication history is essential. The AVOID Mistakes mnemonic presented on the next slide can help healthcare practitioners to develop good habits when performing this task. Second, it is essential that physicians develop an understanding of which patients are at risk for drug interactions. Of course any patient taking two medications is at some risk. Studies show that the rate of adverse drug reactions increases exponentially in patients taking 4 or more medications.{Jacubeit} Importantly, some categories of drugs are especially at high risk for

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interactions. These categories include anticonvulsants, antibiotics, and certain cardiac drugs such as digoxin, warfarin, and amiodarone. Third, any time a patient is taking multiple drugs, we recommend that the first step be to check a readily available pocket reference, recognizing that the interaction may not be listed and a more complete search may be required. Fourth, consult other members of the healthcare team. Depending upon the practice setting, this may be a hospital pharmacist, a specially trained office staff nurse, or the nearby pharmacist in community practice. Fifth, use one of the computerized databases available. Up- to-date databases are maintained by gsm.com and epocrates.com, and others. The latter can be placed on a hand-held computer (e.g. Palm Pilot) and can be configured to automatically update each time you synchronize with the desktop computer. The Medical Letter Drug Interaction Program is inexpensive and updated quarterly. Please check the following web sites for more learning tools 1. www.arizonacert.org (drug interactions) 2. www.drug-interactions.com (P450-mediated drug interactions) 3. www.torsades.org (drug-induced arrhythmia) 4. www.penncert.org (antibiotics) 5. www.dcri.duke.edu/research/fields/certs.html (cardiovascular therapeutics) 6. www.sph.unc.edu/healthoutcomes/certs/index.htm (therapeutics in pediatrics) 7. www.uab.edu (therapeutics of musculoskeletal disorders)