Adverse Drug Reactions &Drug InteractionsNoor Wijayahadi

Medication Error Deaths IncreasingPhillips DP. Annu Rev Public Health. 2002;23:135-50. Deaths from Medication Errors19831998

Adverse drug eventsAdverse drug events disebabkan oleh:Efek obat yang unwanted / unexpected Kesalahan pada prescribing / administrationMerupakan penyebab tersering iatrogenic injury pada penderita di RSPada umumnya preventableSering karena kesalahan prescribing / administration

Unwanted drug effectsAdverse drug reactions (ADRs)= ESOEfek merugikan / tidak menyenangkan dari suatu pengobatanPerlu pengurangan dosis atau dihentikanHati-hati pada pemberian di masa y.a.d.Side effectsminor unwanted reactions bisa ditolerirToxicityKerja obat pada dosis tinggi

Adverse drug reactionsAdverse drugs reactions (ADRs)Terjadi pada 10-20% pasien di RS5% penyebab kemasukan pasien ke RSPenyebab 1 / 1000 kematian di RS2 tipe ADRpredictable reactions (Type A)unpredictable reactions (Type B)

Type A (predictable)Sering terjadi dan dose-relatedRentan pada pasien dengan gangguan ginjal atau hati, anak2 dan manulaPenyebab:Aksi farmakologik berlebihanOverdosisPeningkatan sensitivitasRespons penghentian obat (withdrawal syndrome)Efek lain obat yang tidak merupakan efek farmakologik utama Obat tidak selektif / spesifik

1. Aksi farmakologik berlebihanMorfin, diazepin depresi nafasAntihipertensi hipotensiDigoksin bradikardiTeofilin palpitasiAntidiabetis hipoglikemiaWarfarin perdarahanMetoklopramid kejang / ekstra piramidalType A (predictable)

2. withdrawal syndromeDepresan SSP agitasi, takikardia, konvulsiSteroid krisis Addison akutKlonidin hipertensi berat + simpatisNarkotik gejala putus obatType A (predictable)

3. Efek lain yang tidak merupakan efek farmakologik utamaAntihistamin mengantukSteroid iritasi lambungAspirin perdarahanType A (predictable)

Type B (unpredictable)Jarang dan biasanya tidak dose-relatedReaksi alergiReaksi idiosinkrasiReaksi karena faktor genetikReaksi alergi (hypersensitivity)Tidak berhubungan dengan aksi farmakologi Timbul pada re-exposure, bahkan pada jumlah obat sedikitTermasuk di dalamnya: reaksi anaphylaxis

1. Reaksi alergi

Tipe 1. reaksi anafilaksisTipe 2. reaksi sitotoksis anemi hemolitikTipe 3. reaksi imun-kompleks serum sicknessTipe 4. reaksi dengan mediasi sel (reaksi tipe lambat)Type B (unpredictable)

Genetically determined effectsG6PD deficiencyacetylator polymorphism G6PD deficiencyacute haemolytic anaemia with sulphonamides and primaquineSlow acetylator statusrisk of systemic lupus with hydralazinerisk of peripheral neuropathy with isoniazid Idiosyncratic reactionsphocomelia with thalidomideType B (unpredictable)

StevensJohnson syndrome

allopurinollamotriginesulfonamidesdiclofenacethosuximideCiprofloxacinlevofloxacinibuprofencarbamazepinetetracyclineoseltamivirbarbituratesamoxicillinnevirapinephenytoinampicillinisotretinoinasam valproatazithromycinpirimetaminnistatinkokain

Strategi mengurangi resiko ESOSelaluAnamnesis riwayat pemakaian obat HanyaMenggunakan obat hanya bila ada indikasi jelasStopObat yang sudah tidak diperlukanCheckdose and response, terutama pada anak, manula, penderita gangguan ginjal, hepar ataupun jantung

Reporting ADRsObat Baru:Sudah teruji klinis pada 2000-3000 orangESO type A mungkin sudah terdeteksiESO type B belum diketahui Hati-hati pakai obat baru

Reporting ADRs main method of post-marketing surveillance is by yellow card

Drug interactions

Drug interactionsEfek obat berubah karena adanya:Obat lain, makanan atau minumanOutcomeMerugikan, menguntungkan atau tidak bermakna secara klinisInterakasi PharmacokineticMempengaruhi absorbsi, distribusi, metabolisme or ekskresiInteraksi PharmacodynamicMempengaruhi efek obat pada pada tempat kerja (site of action)

WASPADA INTERAKSIObat dengan Index Terapi sempitwarfarin, digoxin, lithium, phenytoin, theophylline, gentamicin

Enzyme inhibitors dan inducerscimetidine, erythromycinrifampicin, phenytoin Obat yang rentan dalam farmakokinetikoral contraceptiveoral hypoglycaemics

Obat dengan efek farmakodinamik jelasbeta-blockersalcohol

Lokasi drug interactionsIntestinalFe menghambat absorbsi tetracycline & kuinolonSite of actionPropranolol mem-blok reseptor salbutamolLiverenzymes menjadi lebih aktif (induksi) oleh phenytoinenzymes menjadi kurang aktif (inhibisi) oleh cimetidinGinjalprobenecide mem-blok ekskresi pencillin (untung)thiazides mem-blok ekskresi lithium (berbahaya)

Drug InteractionsInteraksi farmasetikInteraksi farmakodinamikReceptor Interaksi farmakokinetikAbsorption, distribution, metabolism, elimination

1. Interaksi farmasetikObat suntik / infus jangan dicampurPerubahan warna, kekeruhan, presipitasiSiapkan obat on-time (tepat pada saat diperlukan)

2. Pharmacodynamic Drug InteractionsAdditive, synergistic, or antagonistic Efek Sinergis antibiotikOverlapping toxicities - ethanol & benzodiazepinesEfek Antagonis obat anticholinergic (oxybutinin atau amitriptyline dengan acetylcholinesterase inhibitors)

Pharmacodynamic Drug InteractionsAdditive 1 + 1 = 2Synergistic 1 + 1 > 2Antagonistic 1 + 1 < 2

Potensiasi 1 + 0 > 1

Pharmacodynamic InteractionsInteraksi lansung (direct)Antagonisme di tempat yang samaOpiat vs naloksonPestisida organofosfat vs atropinSinergisme di tempat yang samaMuscle relaxant vs aminoglikosidaBeta bloker vs Ca chanel blokerSinergisme di tempat bedaAlkohol vs depresanPenisilin vs aminoglikosidaInteraksi tak langsung (indirect)

3. Pharmacokinetic Drug InteractionsPerubahan absorbsi obatProtein binding effectsPerubahan eliminasi obatPerubahan metabolisme obat

Absorption InteractionsPerubahan motilitas GIPembentukan kelat (Chelation) Pengaruh adanya makanan

Perubahan AbsorbsiPengaruh adanya makanan Kebanyakan obat kecepatan absorbsinya menurun, tetapi tidak memanjangIndinavir absorbsi tinggi pada puasa, AUC and Cmax menurun sampai ~80% bila ada makanan tinggi kalori/lemak/protein Saquinavir, bioavailibilitas rendah (4%) pemberian bersama makanan berlemak meningkatkan AUC sampai ~ 570%

ChelationIrreversible binding of drugs in the GI tractTetracyclines, quinolone dengan ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)Penundaan pemberian dengan beda 2 jam menurunkan efek interaksiTetracycline diberikan 1 jam sebelum atau 2 jam sesudah makan dairy products (Ca+2)Perubahan Absorbsi

Perubahan motilitas GIIncreased motility - cisapride (R.I.P.), metoclopramideDecreased motility - narcoticsPerubahan pHPeningkatan pH lambung (antacids, omeprazole, cimetidine) menurunkan absorbsi obat yang memerlukan suasana asam agar terjadi absorbsi optimal: ketoconazole dan itraconazolePerubahan Absorbsi

Ketoconazole InteractionspH-dependent absorptionPiscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771

Protein Binding Displacement Interactions

Protein Binding InteractionsKompetisi ikatan pada lokasi protein or tissue binding Peningkatan kadar obat bebas (free/unbound) peningkatan efek farmakologik

Protein Binding interactions biasanya secara klinis tidak signifikan, karena tubuh mempunyai homeostasis yang besar

Drug Metabolism InteractionsMetabolisme obat bisa dihambat atau dirangsang oleh obat lain

Enzim sitokrom CYP 450 :CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others

Proportion of Drugs Metabolized by CYP450 Isozymes

Examples of CYP 450 Substrates, Inhibitors, & Inducers*Primary metabolic pathway

Substrates*InhibitorsInducersCYP3A4AlprazolamLovastatinQuetiapineClarithromycinRitonavirKetoconazoleRifampinCarbamazepineCYP2D6RisperidoneDesipramineDonepezilQuinidineFluoxetineParoxetineNone identifiedCYP1A2ClozapineTheophyllineCaffeineFluvoxamineCimetidineSmokingOmeprazoleCruciferous veg

CYP 450 InducersThe usual suspectsRifampinRifabutinCarbamazepinePhenobarbitalPhenytoin

CYP 450 InhibitorsThe usual suspectsCimetidineErythromycin , Chloramphenicol, INH KetoconazoleRitonavirFluoxetine, paroxetine (CYP2D6)Nefazodone (CYP3A4)Propranolol Fenilbutason alopurinol

Interaksi pada ekskresiPenisilin + probenesid kenaikan kadar pensMetrotreksat + salisilat toksisitas metDigoksin + kinidin toksisitas digoksinLitium + tiazid toksisitas litiumAminoglikosida + furosemid nefrotoksis

Most common single agent drug interactionsCimetidineDigoxinAntacidsWarfarinPropranololTheophylline

Drug WithdrawalsDrug Interactions & QT ProlongationRisk Benefit AnalysisLabeling changes - impact??

Drug Interaction LiabilityRisk vs. Benefit AnalysisMibefradil(Posicor)Terfenadine AstemizoleRitonavir(Norvir)Fluoxetine(Prozac)TherapeuticAreaAntihistaminesLiabilityDDI - QT prolongationAntihypertensive(Calcium Channel Blocker)CYP3A4 Inhibition - DDIsCompetitive in class?HIV Protease InhibitorCYP3A4, CYP2D6Inhibition - DDIsAntidepressantCYP2D6 Inhibition - DDIsAttempted R-fluoxetineDDI - QT prolongationCYP3A4 Inhibition - DDIsCompetitive in class?

Herb - Drug Interactions

Since not regulated by FDA, safety & efficacy not requiredLittle information available regarding drug interactionsExtrapolation of data to available products difficultIndependent lab tests many products (http://www.consumerlabs.com/)6/13 same preparations did not pass testingno detectable SAMe noted in one product8/17 valerian preparations did not pass testing4 - no detectable levels of valerenic acid4 - 1/2 the amount claimed on the labelHerb-Drug Interactions Limitations

St. Johns wort: CYP3A4 Induction EffectsIndinavirIndinavir + SJWPiscitelli SC et al. Lancet 2000;355:547-88 normal volunteersIndinavir AUC determined before and after 14 days SJW 300 mg TIDIndinavir AUC decreased by 57 19% in presence of SJW

Chart2

0.1990.12226318220.128750.1220816472

8.320753.12587111294.7368755.146547343

11.382254.805428535.790753.6510082658

8.25053.38037757824.8716252.8150785291

5.3533752.79662582092.1583751.7274302911

4.681253.85674617670.9958750.5679035224

2.8092.39540554280.4788750.268724733

Time

Indinavir Cp (g/ml)

Sheet1

Pre SJW

TimeRDSGGSJSSDDODRBHMeanSD

00.0860.3360.0580.380.2380.2250.2050.0640.1990.1222631822

0.55.2178.0777.88611.1994.9695.43913.13611.0048.320753.1258711129

17.65912.92515.49912.57412.5885.38618.61713.33911.382254.80542853

25.3127.7168.0588.91510.0995.50415.1648.1828.25053.3803775782

33.5355.3966.2495.8557.3153.58510.3344.8895.3533752.7966258209

42.1564.774.0023.6415.0050.5936.9512.1774.681253.8567461767

50.9981.0651.6482.5923.7690.9263.3721.092.8092.3954055428

reported as ug/ml

Post SJW

TimeRDSGGSJSSDDODRBHMeanSD

00.1510.1450.070.4060.0520.0960.1070.0030.128750.1220816472

0.55.3942.6280.27713.8554.2140.3490.27310.9054.7368755.146547343

16.87210.4822.4999.627.9925.9192.5780.3645.790753.6510082658

22.4334.0353.5124.785.6313.99611.413.1764.8716252.8150785291

30.7992.1810.9922.1962.2711.5586.1791.0912.1583751.7274302911

40.3980.9120.5931.1431.6330.7532.0080.5270.9958750.5679035224

50.2120.5410.3440.6680.7680.4540.80.0440.4788750.268724733

Sheet1

00.122263182200.1220816472

03.125871112905.146547343

04.8054285303.6510082658

03.380377578202.8150785291

02.796625820901.7274302911

03.856746176700.5679035224

02.395405542800.268724733

Time

Indinavir Cp (g/ml)

Sheet2

Sheet3

Garlic - Saquinavir InteractionN = 10 healthy subjectsSaquinavir 1200 mg TID x 3d - AUCGarlic caplets BID x ~3 weeksRepeat saquinavir AUCDiscontinue garlic x 10 daysRepeat saquinavir AUC

SaqSaqSaq +GarlicPiscitelli S et al. Clin Infect Dis 2002;34:234-238

Grapefruit Juice InteractionsFlavinoids in grapefruit juice can inhibit gastrointestinal CYP3A4 and first pass metabolismCan increase concentrations of various CYP3A4 substrates - esp. those with low FSaquinavir AUC increases 50 - 200%BenzodiazepinesCalcium channel blockersWide variability - amount of GF juice, timing of intake and drug dosing, interpatient variability in CYP3A4 gut activity

Beneficial Drug InteractionsSaquinavir & ritonavirSaquinavir poorly absorbed, TID dosing, high pill burdenCombination with ritonavir results in 20-fold increase in CssAllows for BID dosing and decreased dose from 1800 mg TID to 400 mg BIDCyclosporin and ketoconazoleClozapine and fluvoxamine??

Drug Interaction Resourceswww.drugdigest.org/DD/Interaction/ChooseDrugswww.medscape.com/druginfo/druginterchecker http://health.discovery.com/webapps/drugchecker.dohttp://medicine.iupui.edu/flockhartwww.druginteractioncenter.orgwww.mims.co.id

10 Years, 16 Unsafe Brand Drugs1996: Trancopal1997: Fen-Fen1998: Duract1998: Posicor1999: Raxar1999: RotaShield1999: Hismanal1999: Trovan2000: Rezulin2000: Propulsid2000: Lotronex*2001: Baycol2004: Vioxx2005: Tysabri2005: Bextra2005: Palladone* Reintroduced with new safety programTwo generic drugs withdrawn for safety in 20+ yearsSource: FDA Medwatch

4 Systems For Safer PrescribingDrug Utilization ReviewEmerging Information ManagementRx Distribution NetworkElectronic Prescribing

Plus many morePharmacogenomics / Personalized MedicationsMedicare Part DPatient Safety Organizations

Mendapat resep tertulis lebih berbahaya daripada menjadi2nd hand smoke.Paul Wallace, MD, January 12, 2005 speaking at SOS Rx