farmakologi-interaksi-obat.pdf

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



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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


kombinasi obat antikanker

juga meningkatkan efektivitas

Centers for Education & Research on Therapeutics™ Blok Eergency/ Eergency/ TA 2015-2016 TA

kombinasi antibiotik antipseudomonas


kombinasi obat antikanker

juga meningkatkan efektivitas

kombinasi obat anti-HIV a

memperlambat memperlambat timbulnya resistensi virus terhadap obat

kombinasi obat antihepatitis


kombinasi obat untuk H. untuk H. pylori


kombinasi antibiotik betalaktam dengan penghambat penghambat betalaktamase


kombinasi sulfametoksazol dengan trimetoprim


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.


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:



Case 1: Torsades de Pointes (lethal arrhythmia)

antihistamine terfenadine


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.


EKG Normal


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.


Case 2: Rhabdomyolysis (lethal skeletal muscle damage)

Adapted from: Sinoway L, Li J. J Appl Physiol 2005;99:5 22.


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.


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


Fatal Rhabdomyolysis Death Dyspnea & CK 910 Fatigue Atorvastatin

Pravastatin 80mg

Pravastatin 40 mg

Fluconazole

Weeks


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


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.


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.


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.


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)


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


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




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


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


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



Spectrum of Consequences of Drug Metabolism  Inactive

products  Active metabolites – Similar to parent drug – More active than parent – New action unlike parent  Toxic

metabolites


Microsomal Enzymes  Cytochrome  Flavin

P450

mono-oxygenase (FMO3)


Phases of Drug Metabolism 

Phase I – Oxidation – Reduction – Hydrolysis



Phase II – Conjugation


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


Phase I - Drug Oxidation


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


Major Human CYP450 Isoforms  CYP1A2

 CYP2D6

 CYP2B6

 CYP2E1

 CYP2C8

 CYP3A4

 CYP2C9

 CYP3A5

 CYP2C19

 CYP3A6


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.


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


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


CYP3A Inhibitors 

Ketoconazole



Itraconazole



Fluconazole



Cimetidine



Clarithromycin



Erythromycin



Troleandomycin



Grapefruit juice

NOT Azithromycin


CYP3A Inducers 

Carbamazepine



Rifampin



Rifabutin



Ritonavir



St. John’s Wort


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.


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


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


Cytochrome P450 1A2 

Induced by smoking tobacco



Catalyzes primary metabolism of:



Theophylline

Imipramine

Propranolol

Clozapine

Inhibited by: Many fluoroquinolone antibiotics Fluvoxamine

Cimetidine


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


P - Glycoprotein Tissue Distribution

Marchietti S, et al. Clinical relevance of drug-drug and herb -drug interactions mediated by the


Digoxin and PGP  Digoxin

is a PGP substrate

 Increased

digoxin plasma conc. when combined with: Quinidine

Verapamil

Talinolol

Clarithromycin

Erythromycin

Itraconazole

Ritonavir


Drug-Disease Interactions 

Liver disease



Renal disease



Cardiac disease ( hepatic blood flow)



Acute myocardial infarction?



Acute viral infection?



Hypothyroidism or hyperthyroidism?


Grapefruit Juice and Felodipine

Hours after Dose

Dresser GK, et al. Clin Pharmacol Ther 2000;68(1):28 –34.

Hours after Dose



Drug-Herbal Interactions St. John’s Wort with: – Indinavir – Cyclosporine – Digoxin – Tacrolimus – Possibly many others



After St. John’s Wort

farmakologi-interaksi-obat.pdf

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