NYERI, MEKANISME KERJA, DAN NSAID

Presentasi berjudul: "NYERI, MEKANISME KERJA, DAN NSAID"— Transcript presentasi:

1 NYERI, MEKANISME KERJA, DAN NSAID
Rustamaji Bagian Farmakologi dan Terapi Fakultas Kedokteran UGM 2015

2 Asesement nyeri AMA, 2010

3 Nyeri dan Analgesia Nyeri
“an unpleasant sensory and emotional experience with actual or potential tissue damage or described in terms of such damage” (International Association for the Study of Pain, 1979) Analgesia Kemampuan tubuh merespon impuls nyeri tanpa kehilangan kesadaran yang ditandai dengan berkurangnya rasa nyeri

4 Nyeri inflamasi Pelepasan substansi kimia dan enzim (mediator) yang mempengaruhi aktivitas dan sensitifitas neuron Prostaglandins, leukotrienes : Sensititasi reseptor Bradykinin and Pg : Stimulasi neuron secara langsung Histamine : Nyeri dan itching Akibatnya Kenaikan aktivitas nociceptor Hiperalgesia Edema neurogenik

5 Jalur nyeri Tipe neuron penghantar nyeri
- A : first pain, sharp (somatic pain) - C : second pain, dull (visceral pain)

6 Lintas spino-thalamic lateral
Jalur nyeri normal cortex thalamus Kerusakan jaringan histamine bradykinin etc. Lintas spino-thalamic lateral Ganglion dorsalis Serabut A or C

7 Jenis analgesia Narcotik Non narcotik morphine, codeine,
Mekanisme kerja di analgesik di CNS, namun mempunyai efek sedatif Non narcotik aspirin, ibuprofen, dll berkerja sebagai antiinfalamsi diperifer namun beberapa preparat mempunyai efek sentral

8 WHO Analgesic ‘Ladder’
Severe Moderate Mild Step 3 Strong opioids (e.g., morphine) with or without non-opioids Step 2 Weak opioids (e.g., codeine) with or without non-opioids Step 1 Non-opioids (e.g., NSAIDs, paracetamol)

9 Dosis NSAID

10 Dosis morfin

11 Dosis morfin iv

12 NSAID NonSteroidal Anti-Inflammatory Drugs

13 NSAID NSAIDs mencakup banyak preparat dan berasal dari turunan kimiawi yang berbeda-beda >70 NSAID diijinkan beredar dengan manfaat klinik sebagai antiinflamasi, analgesik, dan antipiretik Dunia: 70 juta orang/hari diresepi NSAID 230 juta orang/hari minum OTC golongan NSAIDs

14 Struktur kimiawi NSAID
O H3C O C O- Na+ C C OH H3C H H OH H3C C C H H Sodium salicylate (metabolite – dari pohon willow) Ibuprofen O C OH O C O C CH3 H3C N OH H O Asam asetilsalisilat (Aspirin) Acetominophen (kemampuan antiinflamasi rendah)

15 MEKANISME KERJA NSAID

16 Mekanisme kerja NSAID

17 Peran enzym Cyclo-oxygenase
Inhibitor COX nonselektif Inhibitor COX-2 selektif COX-1 COX-2 Otak dan ginjal Di picu kerusakan jaringan Mempengaruhi kondisi di seluruh tubuh Fisiologis Patologis GI: sitoprotektif Platelet aggregation Electrolyte homeostasis di ginjal Mempertahankan aliran darah ke ginjal Ginjal: electrolyte homeostasis Ginjal: blood flow maintenance Nyeri Demam Inflamasi Inhibisi COX-1 Menyebabkan: GI upset, ulseerasi, (Obat NSAID dengan buffered or enteric coatings tidak menurunkan risiko ESO ini)

18 Inhibitor Cox Aspirin (irreversible) Inhibitor COX-1 dan COX-2
Ibuprofen Acetaminophen Naproxen Inhibitor COX-2 selektif Celecoxib (Celebrex) - FDA warning Rofecoxib (Vioxx) - withdrawn Valdecoxib & Parecoxib - 2nd generation

19 Efek fisiologis

20 Penggunaan NSAID Anti-inflamasi
Mengatasi nyeri sedang (nhyeri kepala, strain otot) Rheumatoid and osteo-arthritis Antipiretik Profilaksis gangguan kardiovaskuler (myocardial infarction and stroke) Gout (aspirin meningkatkan sekresi asam urat) Profilkasis kanker colon-rectal (COX-2 inhibitor) Alzheimer’s

21 Peran Prostaglandin

22 Peran Prostaglandin Nyeri: Inflamasi: Protection of the gastric mucosa: Maintenance of renal blood flow: Fever: Platelets: PGI2 and PGE2 sensitize nerve endings to bradykinin, histamine, and substance P; lower the threshold of the C fiber nociceptors PGI2, PGD2 and PGE2 are vasodilators (edema, erythema) PGI2 PGE2 PGE2 near the hypothalamus; stimulated by cytokines such as IL-1B, IL-6, interferons alpha and beta, and TNF; alters body temperature set point PGI2 and PGD2 inhibit platelet aggregation TXA2 stimulates platelet aggregation

23 Pembagian NSAID

24 Kelas dalam NSAID Salisilat Asam propionat Asam asetat
Penghambat COX-2 selektif Parasetamol

25 Salisilat IC50(COX-2)/IC50(COX-1) Aspirin 166 Salsalate
NSAID IC50(COX-2)/IC50(COX-1) Aspirin 166 Salsalate ? Sodium salicylate Diflunisal Choline magnesium trisalicylate

26 Asam propionat NSAID IC50(COX-2)/IC50(COX-1) Ibuprofen** 15 Fenoprofen ? Ketoprofen Naproxen 0.6 Oxaprozin Flubiprofen Ibuprofen setara kemanfaatan kliniknya dengan aspirin namun lebih sedikit menimbulkan maslah gastrointestinal

27 Asam asetat IC50(COX-2)/IC50(COX-1) Diclofenac 0.7 Etodolac 0.1
NSAID IC50(COX-2)/IC50(COX-1) Diclofenac 0.7 Etodolac 0.1 Indomethacin 60 Sulindac 100 Tolmetin Ketorolac ?

28 Inhibitor COX-2 selektif
NSAID IC50(COX-2)/IC50(COX-1) celecoxib <0.001 rofecoxib valdecoxib

29 Parasetamol Analgesik antipiretik
Lemah menghambat COX-1 dan COX-2 (mungkin lebih ke penghambatan COX-2) Efek antiinfalamsi lemah Mungkin mengakifkan endogenous cannabinoid system Tidak menimbulkan masalah di gastrointestinal. Salah satu first drugs of choice pada manajemen nyeri kronik ringan sampai sedang Sering dikombinasikan dengan opiat untuk mengatasi nyeri sedang

30 Farmakologi

31 Farmakokinetik NSAID NSAID Hours to peak plasma level
Elimination half life (hours) Plasma protein binding (%) Disposition Aspirin – 0.25 L (75%), R (25%)* Diflunisal 2 - 3 8 - 12 99 L (>95%) Sodium salicylate 1 - 2 2 - 12 Acetaminophen 2 - 4 25 Ibuprofen 2 Fenoprofen Naproxen Diclofenac 1 Etodolac 6 - 7 Indomethacin 4 - 5 Sulindac 8 Tolmetin 1 - 5 Celecoxib 3 97 Rofecoxib 87 Valdecoxib 8 - 11 98

32 Dosis Aspirin Antitrombolitik : Dewasa: mg/hari akan memberikan kadar plasma ng/ml. T1/2 : 2-3 jam Analgesik/antipiretik: Dewasa: mg/4 jam dengn kadar plasma 60 µg/ml. T1/2 : 2-3 jam Antiinflamasi Dewasa:4-6 g /hari dengan kadar plasma µg/ml. T1/2: 12 jam. Dosis fatal : g menghasilkan kadar plasma > 450 µg/ml. T1/2 sekitar jam atau lebih.

33 Salisilisme (toksisitas Salisilat)
Dosis harian lebih dari 4 g Tinnitis, hearing loss frekuensi tinggi, headache, nausea, gangguan penglihatan. Stimulasi pusat pernafasanmenyebabkan hiperventilasi, yang mengakibatkan alkalosis respirasi.Akhirnya berakibat dehidrasia dan asidosis metabolik sebagai kompensasi Sodium bicarbonate diberikan unutak mencegah keasaman darah dan memacu pengeluaran salisilat melalui ginjal (sampai 30% lebih) Gejala bertahan 2-3 hari setelah henti obat

34 Penghambat COX2 dan penarikan
Nimesulide BPOM: efek hepatotoksisitas Rofecoxib (Vioxx) Merck Ditaraik oleh indusrinya Celecoxib (Celebrex) Pfizer FDA : tambahan peringatan atasa efek kardiovaskular Valdecoxib (Betxra) Pfizer FDA: karenaefek CV-risk and Stevens-Johnson syndrome

35 Toksisitas parasetamol
Hepatotoksisitas (gangguan hepar akut) Puasa merupakan faktor risiko toksisitas. Kadar glutathione di hepar rendah selama puasa Metabolit parasetamol dapat berinteraksi dengan protein hepatoseluler dan akan menyebabkan nekrosis Alkohol dan parasetamol memperberat kerusakan hati karena etanol menyebabkan kerusakan enzym di mikorosom hati sehinga meningkatakan produksi metabolit parasetamol antidotum N-acetylcysteine

36

37

38 Risiko terkena gangguan saluran cerna dan lama paparan NSAID
Insiden kumulatif gangguan GI % 2.5 2.0 Non-selective NSAIDs 1.5 1.0 The COX-2-selective NSAID rofecoxib carries a lower risk of gastrointestinal complications than non-selective NSAIDs The risk of peptic ulcer complications associated with the COX-2-selective NSAID rofecoxib has been investigated in a meta-analysis of eight randomized trials involving a total of 5435 patients with osteoarthritis.41 The risk of upper gastrointestinal bleeding or perforations and symptomatic peptic ulcers was reduced by 49% (p = 0.046) in patients receiving rofecoxib, compared with those receiving non-selective NSAIDs. Similar results have been obtained in trials with a second COX-2-selective NSAID, celecoxib. The incidence of gastrointestinal adverse events in patients with rheumatoid arthritis receiving treatment with celecoxib was significantly lower than in patients receiving other NSAIDs.42,43 0.5 Rofecoxib 1 2 3 4 5 6 7 8 bulan Lama pengobatan 9 10 11 12 Langman et al 1999 (meta-analysis)

39 Asam Lambung, NSAID, dan Kerusakan Dinding Lambung
FAKTOR PROTEKTIF FAKTOR AGRESIF Suasana asam NSAID H. pylori Lapisan mucus Asam lambung Pepsin Gradien ion Lapisan Bicarbonate Lingkungan optimal Prostaglandin Sel epitelial Gastric acid plays a central role in NSAID-associated gastroduodenal damage For the present, the majority of patients requiring NSAID therapy will continue to be treated with non-selective NSAIDs. All of these can cause damage to the gastroduodenal mucosa systemically after they are absorbed, by inhibiting the production of prostaglandins.45 This, in turn, reduces the synthesis and secretion of bicarbonate and mucus, and impairs mucosal blood flow. In addition, NSAIDs can cause direct topical physicochemical disruption of the mucosa. The net effect is that NSAIDs impair the mucosal barrier to gastric acid, which, together with pepsin, exacerbates the initial damage, potentially resulting in deeper erosions and peptic ulceration. Gastric acid can also enhance the direct absorption of some NSAIDs into the gastric mucosal cells, where they may interfere with cell metabolism, have a toxic effect on the mitochondria and cause cell disruption. Gastric acid thus plays a central role in the NSAID-associated gastroduodenal damage that can lead to 'Acid-NSAID Disease', with the concomitant potential for complications such as bleeding and perforation. Highly effective inhibition of gastric acid secretion with omeprazole has been shown to be an effective therapeutic approach to the management of 'acid-NSAID disease’.46-50 Pembuluh darah mukosa NSAID Produksi Bikarbonat Prostaglandin production Produksi mukus

40 Kerusakan dinding saluran cerna dan keasaman saluran cerna
Total area hemoragi di mukosa % 5 Intraduodenal saline Intraduodenal indomethacin 40 mg/kg 4 3 2 NSAID-associated gastroduodenal damage is pH-dependent The central role that gastric acid plays in NSAID-associated gastroduodenal injury has been highlighted in animal studies which demonstrate that such NSAID-associated damage is highly pH-dependent.51 Intraduodenal indomethacin, 40 mg/kg, caused marked macroscopic gastric mucosal damage in pylorus-ligated rats when the luminal pH was 2.0 or 4.0, but damage fell to control levels when the luminal pH was raised to 5.5 or 7.0. Through selective inhibition of the gastric acid pump, omeprazole, 20 mg once daily, achieves highly effective control of intragastric pH, maintaining the intragastric pH above 4.0 for the majority of the 24-hour period.52 This explains the predictably high efficacy of omeprazole, 20 mg once daily, in managing 'acid-NSAID disease’, which has been documented in extensive clinical trials.46,48 1 2.0 4.0 5.5 7.0 pH lumen gaster Elliott et al 1996

41 Pompa asam dan sekresi asam
HCI HCl Cl- H+ Protein kinases K+ Protein kinases Acid pump Ca2+ Ca2+ Cl- Ca2+ Release of Ca2+ from intracellular stores K+ Release of Ca2+ from intracellular stores Omeprazole inhibits the acid pump of the gastric parietal cell, the final step in gastric acid secretion Omeprazole achieves highly effective 24-hour control of gastric acid secretion by targeted inhibition of the gastric acid pump, which is the final step in the secretion of gastric acid. The acid pump is a unique enzyme, an H+, K+-ATPase, located in the parietal cells within the oxyntic glands of the stomach. When stimulated, the acid pump uses energy, derived from the hydrolysis of ATP, to transport hydrogen ions (H+) out of the parietal cell, in exchange for potassium ions (K+) re-entering the cell. The hydrogen ions mix with chloride ions to form gastric (hydrochloric) acid, which is then secreted into the stomach. In contrast to omeprazole, H2-receptor antagonists, such as ranitidine, partially inhibit gastric acid secretion by blocking the H2-receptor on the gastric parietal cell. Together with acetylcholine and gastrin receptors, the histamine receptor is one of three types of different receptors on the basolateral membrane of the gastric parietal cell which modulate gastric acid secretion. Inhibition of gastric acid secretion with H2-receptor antagonists can be overcome by stimulation of the other receptors, which explains the inadequate efficacy of the H2-receptor antagonists in controlling meal-stimulated acid secretion.53,54 Consequently, H2-receptor antagonism does not provide as effective and predictable control of intragastric pH as specific inhibition of the acid pump with omeprazole.52 With receptor-mediated inhibition of gastric acid secretion, there is also the potential for tolerance to develop, and this has been repeatedly reported with the H2-receptor antagonists.55-59 Protein kinases cAMP ACh (M3) Gastrin Acetylcholine Histamine

42 Faktor risiko NSAID di saluran cerna
Terkait pasien Usia > 60 tahun Riwayat ganguan saluran cerna Terkait obat Poatensi toksisitas obat Dosis tinggi Penggunaan bersama antikoagulan Faktor lain Durasi pengobatan Wanita Penyakit kardiovaskuler H. Pylori Merokok Alkohol dispepsia

43 Penggunaan morfin dan pethidine di Indonesia

44 Estimasi kebutuhan morfin dan pethidine