Farmakoterapi

OBAT ANTI NYERI

M Fadhol Romdhoni
Laboratorium Farmakologi
Fakultas Kedokteran Univ. Muhammadiyah Purwokerto
DEFINISI NYERI

= Pengalaman sensorik dan emosional yang tidak

menyenangkan akibat kerusakan jaringan,

MEKANISME PROTEKSI TUBUH

(berfungsi melindungi & memberi tanda bahaya)
JENIS NYERI : SUMBER NYERI

NYERI • adanya kerusakan / inflamasi

NOSISEPTIF / jaringan  ujung saraf
INFLAMASI menerima rangsang nyeri

• berhub dg lesi sist syaraf

NYERI perifer / sentral
NEUROPATIK • mis. Neuropatik DM,
kompresi serabut saraf,
neuroma
NYERI
NOSISEPTIF-
NEUROPATIK
JENIS NYERI : LAMA NYERI

• terjadi segera setelah

NYERI AKUT trauma, operasi, atau lesi
saraf

NYERI KRONIK • terjadi kontinu (minimal 3

bulan)
 FISIOLOGI NYERI
STIMULUS

KERUSAKAN JARINGAN

MEDIATOR NYERI
(HISTAMIN, PG, BRADIKININ, LEOKOTRIEN, SEROTONIN DLL)

Transduksi
RESEPTOR NYERI (nociceptor)

Transmisi SARAF SENSORIS

Modulasi MEDULA SPINAL

Persepsi THALAMUS / KORTEKS PUSAT NYERI

JALUR TRANSMISI NYERI
(Golan et al., 2008)
JALUR TRANSMISI NYERI
 INFLAMASI / RADANG
Stimuli : panas, bhn kimia, mekanik
Tujuan tubuh menimbulkan reaksi radang :
Tanda radang 
1. Menetralkan dan menghancurkan bahan
berbahaya cardinal signs :
2. Mencegah penyebaran bahan berbahaya
3. Memperbaiki kondisi yang rusak  rubor

Proses yang terjadi :  calor

 kerusakan mikrovaskular  tumor,
 peningkt permeabilitas kapiler  dolor
 migrasi lekosit ke jar radang.
 functiolaesa
Mediator kimiawi yang dilepas secara lokal
histamin, 5 HT, bradikinin,PAF, substance P,
tromboksan, proton, radikal bebas, leukotrien,
prostaglandin
 DEMAM / PANAS

Suhu tubuh diatur oleh keseimbangan produksi dan hilangnya panas

oleh hipotalamus (normal termostat mengatur pd setpoint 37o C )

termoregulator
Demam : Ada gangguan keseimbangan pengaturan panas akibat
pelepasan zat pirogen (sitokin IL-1 , memicu peningkatan PG di
hipotalamus)
FEBRIS
 PENATALAKSANAAN NYERI

Tx Non-Farmakologis

Specific
COX2-inh
NSAID
Non specific
Non-Opioid /Konvension
Paracertamol, al
Tx Farmakologis/ Tramadol, dll
Ox antinyeri
Morfin,
Opioid
Pethidin, dll
 Terapi Nyeri : Non-farmakologik
Cognitive-Behavioral
• Relaxation
• Preparatory information
• Hypnosis

Physical Agents
• Application of superficial heat and cold
• Massage
• Exercise
• Immobilization
• Electroanalgesia (eg, TENS= transcutaneous electrical nerve
stimulation )
• Acupuncture

Carr DB, et al. AHCPR Pub. No. 92-0032. 1992.

TERAPI FARMAKOLOGIS

Bds target kerja obat :

1. Menghambat mediator nyeri

(transduksi):
 Analgetik non-opioid (NSAID, dll)
 Antiinflamasi steroid
2. Menghambat transmisi nyeri
 anestesi lokal
3. Blokade pusat nyeri di SSP (Persepsi)
 Analgesik opioid
 Paracetamol
 Anestesi umum
 ANALGETIK OPIOID

• “opioid” is a natural or Response Mu-1 Mu-2 Kappa

synthetic drug that binds

Analgesia
to opioid receptors
producing agonist effects
Respiratory
• RESEPTOR OPIOID : Mu Depression
(), Kappa () & Delta () Euphoria
• Resept delta : regulasi
Dysphoria
aktifitas resept Mu
• Sangat efektif Decrease GI
• Efek samping sering motility

Physical
Dependenc
e
 ANALGETIK OPIOID

Aktivasi Reseptor Opioid

menyebabkan :
- Me  konduktansi ion K
- Hiperpolarisasi
- Aksi potensial
terhambat
- Release
neurotransmitter
terhambat
Tx overdosis opioid
 Efek Farmakologis Analgetik Opioid

• Sedation and anxiolysis

– Drowsiness and lethargy
– Apathy
– Cognitive impairment
– Sense of tranquility
• Depression of respiration
– Main cause of death from opioid overdose
– Combination of opioids and alcohol is especially
dangerous
• Cough suppression
– Opioids suppress the “cough center” in the brain
• Pupillary constriction
– pupillary constriction in the presence of analgesics is
characteristic of opioid use
Efek Farmakologis Analgetik Opioid

• Nausea and vomiting

– Stimulation of receptors in an area of the medulla called
the chemoreceptor trigger zone causes nausea and
vomiting
– Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms (constipation)
– Opioids relieve diarrhea as a result of their direct actions
on the intestines
• Urine Retention
• Other effects
– Opioids can release histamines causing itching or more
severe allergic reactions including bronchoconstriction
– Opioids can affect white blood cell function and immune
function
 Analgesic Non Opioid Drugs
– Acetaminophen
– NSAID
• Non selective COX inhibitor
–Salicylic acid (aspirin)
–Asetic acid (indomethacine, ketorolac,
diclofenac)
–Propionic acid (ketoprofen)
–Anthranic acid (mefenamat)
–Enolic acid (piroxicam)
• Selective COX – 2 Inhibitor
–Rofecoxib
–Celecoxib
–Etedolac
 Analgesik Non-opioid

Acetaminophen Tramadol

Mekanisme kerja hamb sintesa PG  sintetik weak -opioid

hipotalamus,  inhibisi re-uptake
norepinephrine dan
serotonin (5-HT3)

Efek samping Hepatotoksik Opioid-like effects

Sisson CB. In: Benzon HT, et al, eds. Essentials of Pain Medicine and Regional Anesthesia;
1999:59–62.
Acetaminophen
Memiliki efek Analgesic & antipyretic
Efek antiinflamasi?  hampir tidak ada / lemah
Efek samping  disebabkan o/ NABQI
- Hemolytic anemia
- Liver damage (large dose only)
(7-10%) Paracetamol (90-93%)

NABQI (N-asetyl benzoquinoneimine) conjugation

(sulfate or glucuronate)
gluthation 
conjugation
(sulfate or glucuronate)

excretion
10/02/2010 Ngatidjan, NSAIDsexcretion
- 23
 NSAID
(NON STEROIDAL ANTI INFLAMMATORY DRUG)

 Mekanisme kerja : Menghambat sintesa PG melalui

penghambatan enzim COX 1 dan atau COX 2
– NSAID konvensional menghambat COX-1 dan COX-2
– Inhibisi COX-1 gastrotoksik,  agregasi platelet
– Obat baru hanya menghambat COX-2 pada dosis terapi
 Antiinflammatory, analgesics and antipyretics
(few of them have also antithrombus and uricosuria activity)
• Some of them have long half life
(naproxen, salicylate, piroxicam, and phenylbutazone)
• May induce gastropathy
(dyspapsia, gastrotoxicity, gastric mucosal erosion,
subepithelial damage and hemorrhage, frank ulceration, gastric
mucosal necrosis)
 NSAID

1. Nonselective COX2-inhibitor
 antiinflamatory effects
 gastrointestinal, bronchial and renal side effects
 ibuprofen, ketoprofen, mefenamic acid, indomethacin

2. Selective COX2-inhibitor
 antiinflamatory effects
 minimal gastrointestinal, bronchial and renal side effects
 diflunisal, piroxicam, diclofenamate, diclofenac, meloxicam
 Efek terapi atau efek samping NSAID tergantung pada
penghambatan biosintesis prostaglandin. Inhibisi PG
synthetase menurunkan inflamasi dan selanjutnya
mengurangi nyeri.

 PROSTAGLANDIN (PG) =Merup autakoid, terdapat di

semua jaringan dg spektrum aktivitas yg bervariasi
 Fungsi :
– Inflamasi  sebagai mediator  COX 2
– Homeostatic COX 1, terdapat di lambung, usus, platelet,
mucosa bronkus dan ginjal
 Less GI side effects
More GI side effects
Diclofenac Celecoxib
Acetosal Indomethacin Ibuprofen
Ketorolac Piroxicam Ketoprofen
Meloxicam
Nimesulide
COXIB
Rofecoxib
Valdecoxib

non-
preferentially preferentially
COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic
(Finkel et al., 2009)
 Salicylate derivatives
(Acetosal, diflunisal, Na-salicylate)

• Acetosal  inhibits COX1 and COX2 (nonselective)

 antiiflamatory effect in large dose
 g.i. side effects : gastric ulcer

• Diflunisal, Na-salicylate
 more COX2 selective inhibitors
 side effects ?  less than those of acetosal
 Acetyl salicylic acid (ASA)

• Shows anti-thrombus activity  prevent

thromboembolism
a life threatening postoperative complication in patient who undergo
orthopedic procedure.

 small dose ASA  minimal side effects

 COX1
(cyclooxygenase-1)

ASA blocks

COX1-thrombocyte
• TX-A2 synthesis
(stimulate thrombocyte aggregation)
• COX1 can not be synthesized instantly
low dose acetosal
effectively inhibit COX1 thrombocyte
thrombocyte aggregation
COX1-endothel
- prostacyclin synthesis
inhibit thrombocyte aggregation
(antithrombotic properties)
- new COX-1 can be synthesized
low dose acetosal
ineffective in COX1 endothel inhibition
Antithrombotic
33 effect
 Side effects
1. Epigastric dyscomfort  pain
2. Gatric ulcer
3. Gastrointestinal bleeding
(melena)
4. Prolonged bleeding
5. Reye’s syndrome (in viral
infected infant)

(Finkel et al., 2009)

 Multimodal Analgesia

Morfin • Pengurangan dosis

tiap analgesik
• Meningkatkan
antinociception karena
Potensiasi efek sinergistik
• Mengurangi efek
samping tiap obat

NSAIDs,
acetaminophen,
blok saraf

Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048–1056.

ANALGETIK ADJUVANt
= Obat yang dikombinasikan pada obat analgetik utama (non
opioid / opioid) untuk me  efek analgetik,
menyeimbangkan efek & efek samping
- Sering dipakai untuk terapi nyeri neuropatik
Yang termasuk adjuvant :
 Kortikosteroid
 Neuroleptik
 Benzodiazepin
 Antidepressan (TCA : amitriptilin, doxepin, imipramin,
desipramin, nortryptilin )
 Antikonvulsan (karbamazepin, Phenitoin, Sodium
valproate, Gabapentin)
 Klonidin