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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.
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”.
Sumber variabilitas pada
respon obat
Usia
Sex
Genetik/etnik
INTERAKSI OBAT
BB
Lingkungan
Status nutrisi
Tingkat penyakit
Farmakodinamika
Farmakokinetika
Efek klinis Edverse
effect.
toksisitas
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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 10-
12an 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 3–5% 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 Disetujui Ditarik Adverse effect Faktor risiko
Fenfluaramine
(antihistamin)
1973 1997 Vulvular heart failure
Dexfenfuramine 1996 1997 Vulvular heart failure
Terfenadine 1985 1998 Aritmia Metabolic IO
Mibefridil 1997 1998 Low heart rate in elderly, IO Metabolic IO
Astemizole 1988 1999 Aritmia Metabolic IO
Troglitozone 1997 2000 Gagal hati
Cisapride 1993 2000 Aritmia Metabolic IO
Alosetron 2000 2000 Iskemik colitis (usus besar
menyempit)
Grepafloxacin 1997 1999 aritmia
Bromfenac 1997 1998
Cerifastatin ? ? Rhabdomyolysis (kelumpuhan) Metabolic IO
Nefazodone ? 2003 Toksik hati Metabolic IO
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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 � efek antibiotik
hilang dan mengendap di botol infus.
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 ½
3. Metabolisme � Mengganggu pada fase I dan II � BA, Cl, t ½
4. Ekskresi � Mengganggu pada sekresi tubular dan fungsi ginjal �Cl, t ½
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)
Blok absoooorpsi quinolon, tetrsiklin, dan
azithromycin
Omeprazol, lansoprazol, H2-antagonis (obat
basa)
Menurunkan absopsi ketoconazol, delavirdin
Didanosin (diberikan sebagai tablet yang
dibufer)
Menurunkan absorpsi ketoconazol
Kolestiramin 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) � pizza
9. Herring (pickled or dry) � sarden
10. Raspberries
11. Soy sauce, Sour cream, Tofu
12. Wines (especially red)
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13. Yeast preparations, Yogurt
Obat yang berefek pada absorpsi
Mekanisme aksi Objek obat Hasil
Kolestiramin
Colestipol
Desipramine
Binding agent
Binding agent
Menurunkan motilitas
GI
Acetaminophen, diclofenac,
digoxin, glipizide, furosemide,
iron,lorazepam, methotrexate,
metronidazole, piroxicam
Carbamazapine, diclofenac,
furosemide, tetracycline,
thiazides
Fenilbutazon
Menurunkan
absorpsi
Menurunkan
absorpsi
Menurunkan
absorpsi
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. John’s wort
Various herb’s 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, 1–2% non-Caucasians
Hyperactive in up to 30% of East Africans
Catalyzes primary metabolism of:
• Codeine, Dextro-methorphan
• Many β-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 codeine’s 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 β-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 co-
prescribed 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 inter-
patient 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 20–30% of Asians, 3–5% 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.
I n t e r a k s i O b a t P a k L u k m a n | 14
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.
I n t e r a k s i O b a t P a k L u k m a n | 15
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. 17β-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) AUC (ug.min/mL)
S R S R
Control 77.5 79.5 19.3 22.2
GFJ 163.6 163.0 29.9 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 :
I n t e r a k s i O b a t P a k L u k m a n | 16
- decreases talinolol AUC, Cmax, and Fel (p < 0.001) � decreases bioavailability of talinolol.
- does not affect CLr, T1/2 elimination, Tmax.
Constituents in grapefruit juice preferentially inhibit an intestinal uptake process rather than P-
glycoprotein.
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:
– Persons aged > 35 years old are at greater risk
– Smoking > 15 cigs/day places women at greater risk
Management:
– Avoid combination.
– Women on OC are adviced not to smoke, or use another contraception method
Daya analgetik parasetamol sebelum dan setelah pemberian brokoli 7-kali pada mencit jantan
BALB/C
I n t e r a k s i O b a t P a k L u k m a n | 17
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 John’s Wort
2. Ginkgo biloba
3. Kava
I n t e r a k s i O b a t P a k L u k m a n | 18
It has been suspected that herbal remedies could interact with other herbals or even prescription
drugs. Ingestion of St. John’s 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 (P-
GP), 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. John’s Wort.{Piscitelli} After
administration of St. John’s 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.
John’s 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
I n t e r a k s i O b a t P a k L u k m a n | 19
1. Digoxin, Fenoxfenadine, Irinotecan : memodulasi P-glycoprotein � kadar obat ↓
2. Cyclosporin, OC pills, Ritonavir, Venlafaxine : induksi CYP3A4 & modulasi Pgp � kadar
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
I n t e r a k s i O b a t P a k L u k m a n | 20
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)