Centers for Education & Research on Therapeutics™
Blok Emergency/ TA TA 2015-2016
Interaksi obat Dr. Risdawati Djohan, M.Kes.,Apt
Centers for Education &
Blok Emergency/ TA 2014-2015 TA Research on Therapeutics™
a
Centers for Education &
Blok Emergency/ TA 2014-2015 TA Research on Therapeutics™
a
Centers for Education &
Blok Emergency/ TA 2015-2016 TA Research on Therapeutics™
Interaksi yang menguntungkan: penisilin dengan probenesid, probenesid probenesid menghambat sekresi penisilin di tubuli ginjal kadar penisilin dalam plasma
efektivitasnya dalam terapi gonore
a
kombinasi obat antihipertensi
meningkatkan efektivitas dan mengurangi efek samping
kombinasi obat antiasma
meningkatkan efektivitas
kombinasi obat antidiabetik
meningkatkan efektivitas;
kombinasi antibiotik antipseudomonas
meningkatkan efektivitas
kombinasi obat antikanker
juga meningkatkan efektivitas
Centers for Education & Research on Therapeutics™ Blok Eergency/ Eergency/ TA 2015-2016 TA
kombinasi antibiotik antipseudomonas
meningkatkan efektivitas
kombinasi obat antikanker
juga meningkatkan efektivitas
kombinasi obat anti-HIV a
memperlambat memperlambat timbulnya resistensi virus terhadap obat
kombinasi obat antihepatitis
meningkatkan efektivitas
kombinasi obat untuk H. untuk H. pylori
meningkatkan efektivitas
kombinasi antibiotik betalaktam dengan penghambat penghambat betalaktamase
meningkatkan efektivitas
kombinasi sulfametoksazol dengan trimetoprim
meningkatkan efektivitas
Centers for Education & Research Therapeutics™ Blok Emeron Emergency/ gency/ TA 2015-2016 TA
Faktor yang memudahkan terjadinya interaksi obat: polifarmasi Survei (1977) – insidens – insidens efek samping pada pasien dirawat di rumah sakit karena polifarmasi : 3,5% pada pemberian 0-5 macam obat 54% pada pemberian 16-20 macam macam obat
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
Interaksi obat penting secara klinik, jika
meningkatkan toksisitas dan/atau mengurangi efektivitas Terutama jika menyangkut obat dengan batas keamanan yang sempit (indeks terapi yang rendah atau slope log DEC yang curam) misalnya: glikosida jantung antikoagulan obat-obat sitostatik.
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
Batas Keamanan
Dosis terapi median atau dosis efektif median (=ED50): Dosis yang menimbulkan efek terapi pada 50% individu disebut Dosis letal median (=LD50): dosis yang menimbulkan kematian pada 50% individu, atau menimbulkan keracunan pada 50% individu (dosis toksik 50% = TD50) Dalam studi farmakodinamik di laboratorium, indeks terapi suatu obat dinyatakan dalam rasio berikut:
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
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Case 1: Torsades de Pointes (lethal arrhythmia)
antihistamine terfenadine
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Ventricular Arrhythmia (Torsades de Pointes) with Terfenadine Use
39-year-old female Rx with terfenadine 60 mg bid and cefaclor 250 mg tid 10 d Self-medicated with ketoconazole 200 mg bid for vaginal candidiasis
2-day Hx of intermittent syncope
Palpitations, syncope, torsades de pointes (QTc 655 msec)
Monahan BP et al. JAMA 1990;264(21):2788 –2790.
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EKG Normal
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Symptomatic Medroxyprogesterone Ketoconazole
Cefaclor
H
Terfenadine
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Day of Administration Monahan BP et al. JAMA 1990;264(21):2788 2790.
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Case 2: Rhabdomyolysis (lethal skeletal muscle damage)
Adapted from: Sinoway L, Li J. J Appl Physiol 2005;99:5 22.
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Rhabdomyolysis: Atorvastatin & Fluconazole
76-year-old male with Hx of chronic atrial fibrillation and aortic stenosis
Initial prescription medications: – Bisoprolol – Digoxin – Warfarin – Doxicycline – Fucidic acid
– Prednisolone – Esomeprazole – Pravastatin – Fluconazole
Kahri J et al. Rhabdomyolysis in a patient receiving atorvastatin and fluconazole. Eur J Clin Pharmacol 2005;60:905 907.
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Rhabdomyolysis in Association with Atorvastatin and Fluconazole Use
Pravastatin dosage increased from 40mg to 80mg/day
Pravastatin changed to Atorvastatin 40mg
After 7 days – Extreme fatigue
After 3 weeks – Hospitalized for dyspnea – Creatinine 1.36 – CK 910 I.U.
Dx: Renal Failure and DEATH Kahri J et al. Eur J Clin Pharmacol 2005;60:905 –907
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Fatal Rhabdomyolysis Death Dyspnea & CK 910 Fatigue Atorvastatin
Pravastatin 80mg
Pravastatin 40 mg
Fluconazole
Weeks
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
Insidens interaksi obat sulit diperkirakan, k/ 1. Dokumentasi masih sangat kurang
2. Seringkali lolos dari pengamatan dokter (k/ pemahaman mekanisme dan kemungkinan terjadinya interaksi obat kurang baik) interaksi obat berupa peningkatan toksisitas reaksi
idiosinkrasi
interaksi obat berupa penurunan efektivitas diduga akibat
bertambahnya keparahan penyakit terlalu
banyak obat yang saling berinteraksi sehingga sulit untuk
diingat
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
3. kejadian atau keparahan interaksi dipengaruhi oleh variasi individual : pasien lanjut usia penyakit parah kapasitas metabolisme polimorfisme genetik Penyakit tertentu: gagal ginjal a/ penyakit hati yang kronik penyakit jantung kongestif faktor-faktor lain dosis besar obat ditelan bersama-sama penggunaan obat bebas/suplemen/ herbal, merokok, dll.
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
Istilah
Hiperreaktif efek dihasilkan pada dosis rendah sekali
Hiporeaktif
efek dihasilkan pada dosis dosis tinggi
sekali
Hipersensitif
efek yang berhubungan dengan alergi
obat.
Supersensitif keadaan hiperreaktif akibat denervasi atau
akibat pemberian kronik suatu bloker reseptor yang merupakan denervasi farmakologik.
Toleransi keadaan hiporeaktif akibat pajanan obat
bersangkutan sebelumnya.
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
Istilah
Takifilaksis atau toleransi akut toleransi yang terjadi dengan cepat setelah pemberian hanya beberapa dosis obat
Jika toleransi timbul akibat pembentukan Resisten antibodi terhadap obat, misalnya terhadap insulin.
Idiosinkrasi istilah yang digunakan untuk efek obat yang aneh (bizzare), ringan maupun berat, tidak tergantung dari besarnya dosis, dan sangat jarang terjadi. – digunakan secara simpang siur istilah ini berubah menjadi reaksi alergi obat atau akibat perbedaan genetik.
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
Mekanisme interaksi obat 1. Interaksi farmaseutik atau inkompatibilitas (datap terjadi sebelumdan sesudah pemakaian obat)
2. interaksi farmakokinetik – GI tract – Plasma – Liver – Kidney
3. Interaksi farmakodinamik – dpt terjadi di organ target – dpt terjadi sistemik ( misal tekanan darah)
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
INKOMPATIBILITAS Terjadi di luar tubuh antara obat yang tidak dapat dicampur (inkompatibel) interaksi
langsung secara fisik a/kimiawi inaktivasi obat pembentukan endapan perubahan warna dan lain-lain perubahan yang tidak terlihat
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
INKOMPATIBILITAS (lanjutan) Interaksi farmaseutik yang penting (bagi seorang dokter):
interaksi antar obat suntik
interaksi antara obat suntik dengan cairan infus i-a antara obat dg obat a/ obat dg vehicle Gentamisin + karbenisilin inaktivasi gentamisin penisilin G + vitamin C inaktivasi penisilin G amfoterisin B dlm lrt garam fisiologis a/lrt Ringer amfoterisin B mengendap fenitoin dalam larutan dekstrosa 5% fenitoin mengendap
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
INTERAKSI FARMAKOKINETIK
Salah satu obat mempengaruhi – Absorpsi – Distribusi – Metabolisme atau – Ekskresi dari obat kedua, kadar
plasma obat kedua
Akibatnya: toksisitas
atau
atau efektivitas obat
– Interaksi farmakokinetik tidak dapat diekstrapolasikan ke obat
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Interaction in the GI Tract
Sucralfate, some milk products, antacids, and oral iron preparations
Block absorption of quinolones, tetracycline, and azithromycin
Omeprazole, lansoprazole, H2-antagonists
Reduce absorption of ketoconazole, delavirdine
Didanosine (given as a buffered tablet)
Reduces ketoconazole absorption
Cholestyramine
Binds raloxifene, thyroid hormone, and digoxin
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Interactions in the Plasma
To date, most protein “bumping” interactions described are transient and lack clinical relevance
The transient increase in free drug is cleared more effectively
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Spectrum of Consequences of Drug Metabolism Inactive
products Active metabolites – Similar to parent drug – More active than parent – New action unlike parent Toxic
metabolites
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Microsomal Enzymes Cytochrome Flavin
P450
mono-oxygenase (FMO3)
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Phases of Drug Metabolism
Phase I – Oxidation – Reduction – Hydrolysis
Phase II – Conjugation
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Interactions Due to Drug Metabolism Nearly
always due to interaction with Phase I enzymes, rather than Phase II
Commonly due to cytochrome P450 enzymes which have highly variable activity and, in some cases, are genetically absent or over-expressed
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Phase I - Drug Oxidation
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Cytochrome P450 Nomenclature, e.g., for CYP2D6
CYP = cytochrome P450
2 = genetic family
D = genetic sub-family
6 = specific gene
NOTE: This nomenclature is genetically based; it does not imply chemical specificity
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Major Human CYP450 Isoforms CYP1A2
CYP2D6
CYP2B6
CYP2E1
CYP2C8
CYP3A4
CYP2C9
CYP3A5
CYP2C19
CYP3A6
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CYP450 Activity in the Liver Relative Importance of P450s in Drug Metabolism CYP2E1
Relative Quantities of P450s in Liver
CYP1A2
CYP2C
?
CYP1A2 CYP2C
CYP3A CYP2D6 CYP2E1 CYP3A
CYP2D6
Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.
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Polymorphic Distribution Multiple groups of traits in which each constitutes >1% of the population s t c e j b u S f o r e b m u N
91%
9% PM
EM Increasing Metabolic Capacity
URM
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Cytochrome P450 3A
Responsible for metabolism of: – Most calcium channel blockers – Most benzodiazepines – Most HIV protease inhibitors – Most HMG-CoA-reductase inhibitors – Most non-sedating antihistamines – Cyclosporine
Present in GI tract and liver
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CYP3A Inhibitors
Ketoconazole
Itraconazole
Fluconazole
Cimetidine
Clarithromycin
Erythromycin
Troleandomycin
Grapefruit juice
NOT Azithromycin
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CYP3A Inducers
Carbamazepine
Rifampin
Rifabutin
Ritonavir
St. John’s Wort
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Cytochrome P450 2D6 Absent
in 7-9% of Caucasians, 1 – 2% of non-Caucasians
Over-expressed Catalyzes
in up to 30% of East Africans
primary metabolism of:
Codeine Many -blockers Many tricyclic antidepressants Inhibited
by:
Fluoxetine Paroxetine
Haloperidol Quinidine
Aklillu E et al. J Pharmacol Exp Ther 1996;278(1):441 446.
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Cytochrome P450 2C9
Absent in 1% of Caucasians and African-Americans
Primary metabolism of: • Most NSAIDs (including COX-2) • S-warfarin (the active isomer) • Phenytoin
Inhibited by fluconazole
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Cytochrome P450 2C19
Absent in 20 – 30% of Asians, 3 – 5% of Caucasians
Primary metabolism of:
Diazepam
Phenytoin
Omeprazole
Clopidogrel
Inhibited by: Omeprazole Ketoconazole
Isoniazid
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Cytochrome P450 1A2
Induced by smoking tobacco
Catalyzes primary metabolism of:
Theophylline
Imipramine
Propranolol
Clozapine
Inhibited by: Many fluoroquinolone antibiotics Fluvoxamine
Cimetidine
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Drug Transporters
P-Glycoprotein and others
Pump drugs out of cells, which alters distribution
Found in the following tissues: – Gut – Gonads – Kidneys – Biliary system – Brain (blood-brain barrier) – Placenta
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P - Glycoprotein Tissue Distribution
Marchietti S, et al. Clinical relevance of drug-drug and herb -drug interactions mediated by the
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Digoxin and PGP Digoxin
is a PGP substrate
Increased
digoxin plasma conc. when combined with: Quinidine
Verapamil
Talinolol
Clarithromycin
Erythromycin
Itraconazole
Ritonavir
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Drug-Disease Interactions
Liver disease
Renal disease
Cardiac disease ( hepatic blood flow)
Acute myocardial infarction?
Acute viral infection?
Hypothyroidism or hyperthyroidism?
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Grapefruit Juice and Felodipine
Hours after Dose
Dresser GK, et al. Clin Pharmacol Ther 2000;68(1):28 –34.
Hours after Dose
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Drug-Herbal Interactions St. John’s Wort with: – Indinavir – Cyclosporine – Digoxin – Tacrolimus – Possibly many others
Centers for Education & Research on Therapeutics™ Blok Emergency/ TA 2015-2016
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After St. John’s Wort