OBAT AINS (ANALGESIK ANTIPIRETIK)

Oleh

Wiwik Kusumawati

TUJUAN

1. Menyebutkan tentang penggolongan obat AINS

2. Menjelaskan tentang mekanisme kerja (farmakodinamik) obat AINS (analgesik, antipiretik, antiinflamasi)

3. Menjelaskan farmakokinetik obat AINS (analgesik antipiretik)

4. Menjelaskan aspek EBM obat AINS (analgesik antipiretik)

5. Menentukan penggunaan klinis obat AINS (analgesik antipiretik)

OBAT AINS (NSAIDs)

Analgesik Antiinflamasi Nonsteroid

Nonsteroidal Anti-inflammatory Drugs

Efek analgesik

Efek antipiretik

Efek 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

pain

1853

SalicylicAcidClass

Aspirin

1970-

PropionicAcidClass

Ibuprofenketoprofen

1980-

OxicamClass

PiroxicamMeloxicam

1990-

AceticAcidClass

DiclofenacEtodolac

2000-

CoxibClass

CelecoxibRofecoxibValdecoxibEtoricoxibParecoxib

Lumiracoxib

traditional, classic, non-COXIB NSAIDtraditional, classic, non-COXIB NSAID COXIBCOXIB

painpain

redness heat

swelling hoarseness

PROSTAGLANDIN

COX-2COX-1

COX inhibitor

ProstaglandinesPGE2, PGI2, TXA2

ProstaglandinesPGE2, PGI2, TXA2

Gastricmucosal

protection

InflammationPainFever

COX-1 COX-2

anti-inflammatory

Exposed issues in marketing of COX-2 inhibitors

COOH

Arachidonic acid

COX-2 specific inhibitor

causes GI damagebleeding

Non-specific COX-inhibitor COX-2 specific inhibitor

The role of COX in inflammatory pain

MEKANISME AKSI OBAT AINS

TRAUMA/LUKA

ASAM ARAKIDONAT

KORTIKOSTEROID

FOSFOLIPID

PROSTAGLANDIN

OBAT AINSCOX 1 / 2

SIKLOOKSIGENASE

1, 2, 3?

FOSFOLIPASE

Efek antipiretik

PIROGEN ENDOGEN

(INTERLEUKIN-1) PROSTAGLANDIN

OBAT AINS

HIPOTALAMUS

DEMAMPIROGEN EKSOGEN

(infeksi Virus, bakteri, dll)

SALISILAT

Aspirin, Asetosal, Diflunisal, dll.

Prototipe obat AINS

Efek analgesik, antipiretik, antiinflamasi

Efek antiinflamasi, urikosurik (dosis tinggi :2-4 gram)

Efek antiagregasi trombosit (dosis rendah)

Efek keratolitik, astringent

REYE Sindrome

SALISILAT

Absorbsi sempurna di lambung

Lama kerja 4 jam (4-6x/hari)

Ekskresi meningkat dengan alkalinisasi urin

Iritasi saluran cerna (ulkus, perdarahan)

Pseudoalergi (Bronkokonstriksi)

SALISILAT

Analgesik & antipiretik (300-600 mg 3x sehari)

Nyeri disertai inflamasi (penyakit inflamasi sendi/rheumatik), 3 – 6 gram/hari

Inflamasi sendi akut, 5 – 8 gram/hari

Pencegahan IMA

Topikal (metil salisilat)

PARASETAMOL

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

PARASETAMOL

Absorbsi – pengosongan lambung

Efek 15-30 menit

Kadar puncak 30-60 menit

Lama kerja 3-4 jam

Frekuensi pemberian 4-6x/hari

Dosis 10 mg/kg BB/x

Dosis 500 -1000 mg/x

DIPIRON

Derivat pirazolon

Metamizole, Metampiron, Antalgin

Efek analgesik & antipiretik

Efek antiinflamasi lemah

Efek diskrasia darah (agranulositosis, anemia aplastik, trombositopenia)

Efek iritasi lambung

Efek hipersensitif

DIPIRON

Efek 30 menit

Kadar puncak 2 jam

Lama kerja 2-4 jam

Frekuensi pemberian 4-6x/hari

Dosis 500 -1000 mg/x

Analgesik tanpa disertai inflamasi

Kombinasi dg obat lain, INJEKSI

IBUPROFEN

Derivat 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 %

IBUPROFEN

Efek samping di lambung lebih jarang

Efek samping : retensi cairan dan alergi

Pada penderita asma bronkial dapat menimbulkan bronkokonstriksi

IBUPROFENIbuprofen for the treatment of feverThe most frequently used are ibuprofen and paracetamol. The effectiveness of ibuprofen in fever reduction, and the effectiveness compared to paracetamol and aspirin, has been investigated in a large number of clinical trials.

Results of the clinical trials consistently show that a single dose of ibuprofen is more effective than paracetamol at reducing temperature over an 8 hour period. The onset of effect of ibuprofen starts within 30 minutes of dosing. Ibuprofen has been shown to be more effective than paracetamol in reducing high fevers, particularly above 39°C (102°F).

Symptoms of FeverInfections can disrupt the body temperature balance, and lead to temperatures higher than 37.4°C (a fever). Fevers can lead to increased loss of fluid from the body causing dehydration, discomfort for a child, and in a small proportion of children, febrile convulsions.A fever over 38°C or 100°F should be treated. The key to treating a fever is to reset the body's thermostat to bring the temperature back down to around 37°C or 98.5°F. Giving a child plenty to drink, to compensate for the fluid lost through sweating is important to avoid dehydration.

IBUPROFENIbuprofen and gastrointestinal bleeding

Serious gastrointestinal side effects associated with ibuprofen are dose-related: most occur with the high doses prescribed by doctors for the long term treatment of chronic disorders such as arthritis. This problem is extremely rare at the low doses recommended for short-term treatment with over-the-counter ibuprofen products and the risk is therefore negligible. In fact, the available evidence shows that the incidence of gastrointestinal side effects with over-the-counter doses of ibuprofen (up to 1200 mg/day) is comparable with that associated with paracetamol (acetaminophen). comparisons with other NSAIDs have consistently demonstrated that ibuprofen has the lowest risk of gastrointestinal side effects of any drug in its class.

Levels of Evidence

Level I - Evidence obtained from a systematic review of all relevant randomized controlled trials.

Level II - Evidence obtained from at least one properly designed randomized controlled trial.

Level III.1 - Evidence obtained from well designed controlled trials without randomization.

Level III.2 - Evidence obtained from well designed cohort or case control analytic studies preferably from more than one centre or research group.

Level III.3 - Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments.

Level IV - Opinion of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Effect of Interventions on Fever

1. Paracetamol  vs. Sponging

2. Paracetamol + Sponging vs. Sponging

3. Paracetamol + Sponging vs. Paracetamol

Effect of Interventions on Fever

Paracetamol  vs. Sponging Paracetamol alone was found to be more effective in reducing the child's temperature when compared to sponging alone The mean reduction in temperature in the paracetamol group at one hour ranged from 0.8°C to 1.1°C. On the final measurement in these studies (1-4 hours) the mean reduction in temperature ranged from 0.9°C to 1.85°CIn the sponge only groups the mean reduction at both one hour and on final measurement ranged from 0.55°C to 0.75°C

Effect of Interventions on Fever

Paracetamol + Sponging vs. Sponging

The combination of paracetamol and sponging was found to be more effective than sponging alone.

A significant decrease in the mean reduction in temperature on final measurement between the group treated with paracetamol and sponging (range from 1.7°C to 1.3°C) when compared with the group who received sponging alone (range 0.55°C to 1.2°C).

Effect of Interventions on Fever

Paracetamol + Sponging vs. Paracetamol

The combination of paracetamol plus sponging was more effective in lowering temperature than paracetamol alone

The mean reduction in temperature in groups receiving medication plus sponging ranged from 1.3°C to 1.7°C.

In those groups receiving only paracetamol, the mean reductions on final measurement ranged from 0.9°C to 1.3°C

EBMIntoksikasi Parasetamol

48 % kasus intoksikasi dirujuk ke RS di UK disebabkan oleh overdosis parasetamol

100-200 kematian/tahun

Hepatotoksis - NABQI

Prinsip manajemen : monitoring kadar obat dalam plasma

Tx N-asetilsistein (metabolisme, oksidasi dan konjugasi)

Kasus 1

Seorang anak umur 5 tahun karena kecapaian main mendadak sorenya demam tinggi. Oleh ibunya anak tersebut segera dibawa berobat ke dokter praktek karena takut panyakitnya akan menjadi berat.

Kasus 2

Seorang laki-laki usia 60 tahun mengeluh nyeri pada lutut dan pinggang sudah beberapa hari. Sakit seperti ini sudah 1 tahun dan kumat-kumatan. Nyeri dirasakan lebih berat pada waktu bangun tidur pagi. Karena setelah minum obat yang dijual bebas tidak ada perubahan maka dia segera berobat ke rumah sakit.