OBAT ANALGESIK AINS/NSAIDs

OlehWiwik Kusumawati

CASEA 73 year old man who present to ambulatory care clinic for his regular follow up appointment complaining of increasing pain in his lower back, hips and right knee. Six month ago the patient was started on acetaminophen 500 mg tablets, two tablets four times daily, and has been talking more than prescribed over the last few weeks (he admits to taking three 500 mg tablets, four times daily). The patients is in clinic today complaining that increased dose has not been working and that he has been in moderate to severe pain for the last 3-4 weeks. He has been adherent to all drugs therapies.

The patient is a veteran who served in Korean conflict and worked in a factory for 35 years after his time in the military. His factory job often puts strain on his back and legs due to heavy lifting. Since retiring 15 years ago, the patient states that he has put on excess weight and developed many medical problems that are frustrating him

PENDAHULUANKASUS- KASUSNYERI ?OBAT ANALGESIK ?

PENDAHULUANNYERISOMATIK / SUPERFISIALVISCERALNYERI AKUTKRONISNYERIFISIK, TERMAL, KIMIA, ELEKTRIK

PENDAHULUANOBATANALGESIKANALGESIK NON NARKOTIK(OBAT AINS)ANALGESIK NARKOTIK(OPIAT)

OBAT ANALGESIK/EFEKNON NARKOTIK (OBAT AINS)NARKOTIK(OPIAT)AksiPerifer (menghambat PG)Sentral (mengaktivasi reseptor opiat)IndikasiNyeri ringan sedang (inflamasi)Nyeri beratSedasiTidak adaAda Dependensi & AdiksiTidak adaAda

OBAT AINS (NSAIDs)Analgesik Antiinflamasi NonsteroidNonsteroidal Anti-inflammatory DrugsEfek analgesikEfek antipiretikEfek antiinflamasi

Penggolongan SALISILAT (aspirin, asetosal, diflunisal, dll)PARAAMINOFENOL (asetaminofen/parasetamol)PIRAZOLON (dipiron/metampiron, aminopirin, fenilbutazon, dll)ASAM ORGANIK LAIN (ibuprofen, asam mefenamat, indometasin, diklofenak, dll)

The evolution of NSAID chemistry for the control of pain1853SalicylicAcidClass

Aspirin1970-PropionicAcidClass

Ibuprofenketoprofen1980-OxicamClass

PiroxicamMeloxicam

1990-AceticAcidClass

DiclofenacEtodolac

2000-CoxibClass

CelecoxibRofecoxibValdecoxibEtoricoxibParecoxibLumiracoxib

traditional, classic, non-COXIB NSAIDCOXIB

the most widely used class of drugsavailable as prescription & non-prescription (OTC)Common mechanism of action (COX inhibition)Different selectivity to COX-1 and COX-2Common clinical indicationsAnalgesic (CNS and peripheral effect) may involve non-PG related effects useful when pain is accompanied by inflammation Antipyretic (CNS effect) Anti-inflammatory (mainly by PG inhibition) have various side effects about 16,000 persons die every year due to NSAID used in US COX-inhibitors = NSAIDs

MEKANISME AKSI OBAT AINSTRAUMA/LUKAASAM ARAKIDONATKORTIKOSTEROIDFOSFOLIPIDPROSTAGLANDINOBAT AINSCOX 1 / 2SIKLOOKSIGENASE(COX)FOSFOLIPASE

Efek antipiretik PIROGEN ENDOGEN (INTERLEUKIN-1)PROSTAGLANDINOBAT AINSHIPOTALAMUSDEMAM

Efek antiinflamasiINFLAMASITumor, rubor, kalor, dolor, functiolaesaProstaglandinMeningkatkan permeabilitasVasodilatasi

painrednessheatswellinghoarsenessPROSTAGLANDINCOX-2COX-1COX inhibitor

GastricmucosalprotectionInflammationPainFeverCOX-1COX-2anti-inflammatoryExposed issues in marketing of COX-2 inhibitorsCOX-2 specific inhibitorcauses GI damagebleedingNon-specific COX-inhibitorCOX-2 specific inhibitorThe role of COX in inflammatory pain

SALISILATAspirin, Asetosal, Diflunisal, dll.Prototipe obat AINSEfek analgesik, antipiretik, antiinflamasiEfek antiinflamasi, urikosurik (dosis tinggi :2-4 gram)Efek antiagregasi trombosit (dosis rendah)Efek keratolitik, astringentREYE Sindrome

SALISILATAbsorbsi sempurna di lambungLama kerja 4 jam (4-6x/hari)Ekskresi meningkat dengan alkalinisasi urinIritasi saluran cerna (ulkus, perdarahan)Pseudoalergi (Bronkokonstriksi)

SALISILATAnalgesik & antipiretik (300-600 mg 3x sehari)Nyeri disertai inflamasi (penyakit inflamasi sendi/rheumatik), 3 6 gram/hariInflamasi sendi akut, 5 8 gram/hariPencegahan IMATopikal (metil salisilat)

PARASETAMOLDerivat paraaminofenolAsetaminofen Efek sentral dan perifer (lebih dominan perifer)Efek analgesik & antipiretik Efek antiinflamasi lemahEfek iritasi lambung minimalHepatotoksis, NABQI (dosis tinggi : 10-12 gram)

PARASETAMOLAbsorbsi pengosongan lambungEfek 15-30 menitKadar puncak 30-60 menitLama kerja 3-4 jamFrekuensi pemberian 4-6x/hariDosis 10 mg/kg BB/xDosis 500 -1000 mg/x

DIPIRON Derivat pirazolonMetamizole, Metampiron, Antalgin Efek analgesik & antipiretik Efek antiinflamasi lemahEfek diskrasia darah (agranulositosis, anemia aplastik, trombositopenia)Efek iritasi lambungEfek hipersensitif

DIPIRONEfek 30 menitKadar puncak 2 jamLama kerja 2-4 jamFrekuensi pemberian 4-6x/hariDosis 500 -1000 mg/xAnalgesik tanpa disertai inflamasiKombinasi dg obat lain, INJEKSI

ASAM MEFENAMATDerivat asam fenamatEfek analgesik kuatEfek antiinflamasi lebih lemah dibandingkan aspirin Diberikan bersama dengan makananKontra indikasi untuk ibu hamil dan anak kurang dari 14 tahunLama pemberian tidak lebih dari 7 hari

IBUPROFENDerivat asam propionatEfek analgesik sama dg aspirin Efek antiinflamasi lebih lemah dibandingkan aspirin (lebih dari 2400 mg/hari 600 mg 4x/hari)Metabolisme di liverWaktu paruh 2,5 jam, ikatan protein plasma 99 %

IBUPROFENEfek samping di lambung lebih jarangEfek samping : retensi cairan dan alergiPada penderita asma bronkial dapat menimbulkan bronkokonstriksi

DIKLOFENAKEfek analgesik, antipiretik dan antiinflamasiInhibitor sintesis prostaglandin yang potensialAbsorbsi per oral baikKadar puncak 1-2 jamUntuk penyakit inflamasi sendi kronisEfek samping : gangguan lambung

COX-2 inhibitorsthis drug was voluntary withdrawn by pharmaceutical company, following official request from FDA and EMEA, due to serious fatal adverse reactions

COX inhibitorAdministrationHalf-lifeSpecificCelecoxibOral8-11 hrValdecoxib*Oral8 hrParecoxibinj8 hrRofecoxib*Oral17 hrEtoricoxibOral24 hrLumiracoxibOral3-6 hrPreferentialDiclofenacOral, inj., supp., topical1.5 hrMeloxicamOral, inj., supp20 hrNimesulideOral3 hr

MELOXICAMDerivat oksikam, gol asam enolatEfek antiinflamasi, analgesik, antipiretikKadar puncak 4-5 jamIkatan protein plasma 99,4 %Kadar di cairan sinovial 40-50 %Metabolisme dengan SP-450, T 15-20 jam

MELOXICAMIndikasi : osteoartritisDosis 7,5 22,5 mg/hrMeloxicam 7,5 mg/hr selama 1 bulan resiko ES lebih rendah dibandingkan piroxicam 20 mg/hr atau diclofenac 100 mg/hr

NIMESULIDEIn vitro, menunjukkan selektivitas pada COX-2PO, mudah absorbsiKadar puncak 1-4 jamIkatan protein plasma 95 % T1/2 3 jamIndikasi anti inflamasi jangka pendekES, saluran cerna, kulit, sistem saraf 5-10 %

ROFECOXIBSelective COX-2 inhibitor yang potenSelektivitas lebih besar dari celecoxib, meloxicam, diclofenac dan indometasinDosis 12,5 mg/hr 25 mg/hr efektifitas setara dengan ibuprofen 2400 mg /hr, diclofenac 150 mg/hr, naproxen 1000 mg/hr dan celecoxib 200 mg/hrResiko ES gastrointestinal lebih ringan (ulkus, perdarahan)

KESIMPULANObat analgesik terdiri dari analgesik narkotik dan non narkotikAnalgesik non narkotik atau obat AINS (tradisionil dan selektif penghambat COX-2)Mekanisme kerja obat AINS, menghambat sintesis prostaglandinEfek samping obat AINS pada sistem GIT & Ginjal (tradisionil); pada sistem CV (COX-2 inhibitor)Penggunaan klinis yang rasional (kasus nyeri yang disertai inflamasi)