OBAT ANTINYERI, 2010 (Compatibility Mode)

Farmakologi
OBAT ANTI NYERI

Fathiyah Safithri
Laboratorium Farmakologi
Fakultas Kedokteran Universitas Muhammadiyah Malang
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DEFINISI NYERI
= Pengalaman sensorik dan emosional yang tidak
menyenangkan akibat kerusakan jaringan,

jaringan baik
aktual maupun potensial, atau yang digambarkan
dalam bentuk kerusakan tersebut
MEKANISME PROTEKSI TUBUH

(berfungsi melindungi & memberi tanda bahaya)
JENIS NYERI
Menurut Sumber Nyeri :
NYERI NOSISEPTIF / NYERI INFLAMASI
- adanya kerusakan / inflamasi jaringan ujung saraf menerima rangsang
nyeri
NYERI NEUROPATIK
- berhub dg lesi sist syaraf perifer / sentral
- mis. Neuropatik DM, kompresi serabut saraf, neuroma
NYERI NOSISEPTIF-NEUROPATIK
NEUROPATIK
Menurut lamanya,
AKUT
- terjadi segera setelah trauma, operasi, atau lesi saraf
KRONIK
- terjadi kontinu (minimal 3 bulan)
PROSES TIMBULNYA NYERI

STIMULUS
KERUSAKAN JARINGAN
MEDIATOR NYERI
(HISTAMIN, PG, BRADIKININ, LEOKOTRIEN, SEROTONIN DLL)
Transduksi
Transmisi
Modulasi
Persepsi
RESEPTOR NYERI (nociceptor)

SARAF SENSORIS
MEDULA SPINAL
THALAMUS / KORTEKS
KORTEKS PUSAT NYERI
TRANSDUKSI
JALUR TRANSmisi NYERI
FAST & SLOW PAIN PATHWAY
JALUR TRANSMISI NYERI
INFLAMASI / RADANG
Stimuli : panas, bhn kimia, mekanik
Tujuan tubuh menimbulkan reaksi radang :
1.
Menetralkan dan menghancurkan bahan

berbahaya
Tanda radang
cardinal signs :
2. Mencegah penyebaran bahan berbahaya
rubor
3. Memperbaiki kondisi yang rusak
calor
Proses yang terjadi :
tumor,
kerusakan mikrovaskular
peningkt permeabilitas kapiler
migrasi lekosit ke jar radang.
Mediator kimiawi yang dilepas secara lokal

histamin, 5 HT, bradikinin,PAF,
PAF, substance
P, tromboksan, proton, radikal bebas,
leukotrien, prostaglandin
dolor
functiolaesa
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
Terapi NYERI
A. TERAPI FARMAKOLOGI
1. Menghambat mediator nyeri
(transduksi):
analgesik non narkotik
NSAID
Antiinflamasi steroid
2.
Menghambat transmisi nyeri

anestesi lokal
3.
Blokade pusat nyeri di SSP (Persepsi)

Analgesik narkotik
Anestesi umum
B.
TERAPI NON FARMAKOLOGI
(Golan et al., 2008)
Terapi
Terapi
Terapi Nyeri Non-farmakologik

farmakologik
Cognitive-Behavioral
Relaxation
Preparatory information
Hypnosis
Physical Agents
Application of superficial heat and cold
Massage
Exercise
Immobilization
Electroanalgesia (eg, TENS= transcutaneous
t
electrical nerve
stimulation )
Acupuncture
Carr DB, et al. AHCPR Pub. No. 92-0032. 1992.
Pain Rating Scales
Mild
Moderate
Pain threshold
Pain tolerance
Severe
10
Choosing pain killer and its combinations

10 Pain Intensity Scale
Mild
Moderate
paracetamol
NSAID
or/+
NSAID
weak opioid
adjuvant
adjuvant
analgesic
analgesic
10
Severe
Strong opioid
NSAID
adjuvant
analgesic
Current view in selecting analgesic and antianti

inflammatory drugs
Efficacy (indication)
Safety (side effect)
Not only GI toxicity
Cardiovascular toxicity
Renal toxicity
Bleeding
Bone healing impairment etc
Suitability (contra-indication)
indication)
Availability
Pharmacokinetics and drug interaction
Daily cost
Evidence based medicine
ANALGESIK NON OPIOID
Analgesic Non Opioid Drugs

Acetaminophen
NSAID
Non selective COX inhibitor
Salicylic
Salicylic acid (aspirin)
Asetic
Asetic acid (indomethacine, ketorolac,
diclofenac)
Propionic
Propionic acid (ketoprofen)
Anthranic
Anthranic acid (mefenamat)
Enolic
Enolic acid (piroxicam)
Selective COX 2 Inhibitor
Rofecoxib
Celecoxib
Etedolac
Analgesik Non-opioid
opioid
Acetaminophen
Tramadol
Mekanisme kerja hamb sintesa PG

hipotalamus,
sintetik weak -opioid

inhibisi re-uptake
norepinephrine dan
serotonin (5-HT3)
Efek samping
Opioid-like effects
Hepatotoksik
Sisson CB. In: Benzon HT, et al, eds. Essentials of Pain Medicine and Regional Anesthesia;
Anesthesia
1999:5962.
Acetaminophen
A c e to m in o p h e n M e
ta b o lis m
eta
A c - g lu cu ro n id e
Ac
A c - su lfate
C yto ch ro m e P - 4 5 0
R ea ctive ele ctro p h ilic

c o m p o u n d (A c *)
G ood
GSH
G S -A c *
A c * - p ro tein
A c - m erc a p tu rate
B ad
H e p atic c ell d eath
NSAID
(NON STEROIDAL ANTI INFLAMMATORY DRUG)
phospholipids
arachidonic acid
COX-2
COX
COX-1
1
cyclic
endoperoxides
PGI2
stimulates platelet
aggregation,
vasoconstriction
hyperalgesia
PGD2
inhibits platelet
aggregation,
vasodilator
5-HPETE
TXA2
inhibits platelet
aggregation,
vasodilator,
PGE2
vasodilator,
hyperalgesia
LOX
PGF2
PGF2alfa
LTA4
LTB4
chemotaxis
LTC4
bronchoconstriction
myometrial contr.
LTD4
hyperalgesia
LTE4
brochoconstriction
increase
vascular
permeability
zilueton
zafirlukast
montelukast
10/02/2010
Ngatidjan, NSAIDs - GOUT
32
(Nijkamp et al., 20
NSAID
Effects :
Analgesics
Antiiflammation (most)
Antipyretics (most)
Uricosuria (some)
NSAID
Mekanisme kerja :
Menghambat sintesa PG melalui penghambatan enzim
COX 1 dan atau COX 2
NSAID konvensional menghambat COX-1
COX dan COX-2
Inhibisi COX-1 gastrotoksik, agregasi platelet
Obat baru hanya menghambat COX-2
COX pada dosis terapi
Efek : secara umum = analgetik, antiinflamasi, antipiretik

Dosis antipiretik >>> dosis analgetik, antiinflamasi
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
ASA
COX1
(cyclooxygenase
(cyclooxygenase-1)
blocks
ASA
COX1-thrombocyte
COX1-endothel
TX-A2 synthesis
(stimulate thrombocyte aggregation)
COX1 can not be synthesized instantly
- prostacyclin synthesis
inhibit thrombocyte aggregation
(antithrombotic properties)
- new COX-1 can be synthesized
low dose acetosal

effectively inhibit COX1 thrombocyte
low dose acetosal

ineffective in COX1 endothel inhibition
thrombocyte aggregation
10/02/2010
Ngatidjan, NSAIDs - GOUT
Antithrombotic effect
37
Summary of analgesic, anti-inflammatory

inflammatory and
antipyretic activity of NSAIDs (ED50 in mg/kg)
ketorolac
indomethacin
diclofenac
ketorolac
indomethacin
diclofenac
naproxen
ibuprofen
piroxicam
naproxen
ibuprofen
piroxicam
120
60
100
50
80
40
ketorolac
indomethacin
diclofenac
naproxen
ibuprofen
piroxicam
60
30
40
20
5
4
3
2
20
10
1
0
0
analgesic
antipyretic
anti-inflammatory
NSAID
Analgesic
Anti-inflammatory
Antipyretic
ketorolac
0.7
0.9
indomethacin
2.1
diclofenac
0.4
naproxen
13
56
0.5
ibuprofen
45
10
piroxicam
100
1.7
tenoxicam
100
1.7
aspirin
228
162
18
Less GI side effects

More GI side effects
Acetosal
Ketorolac
Indomethacin Ibuprofen
Piroxicam Ketoprofen
Diclofenac
Meloxicam
Nimesulide
Celecoxib
Rofecoxib
Valdecoxib
COXIB
preferentially
nonnon
COX-1
COX-2
COX-1
COX-2
selective
selective selective
selective
selective
COX
inhibitor inhibitor
inhibitor
inhibitor inhibitor
preferentially
anti-inflammatory
anti
analgesic
(Rang et al., 2003)
(Finkel et al., 2009)

ANALGETIK OPIOID
opioid is a natural or
synthetic drug that binds
to opioid receptors
producing agonist effects
RESEPTOR OPIOID : Mu
(), Kappa () & Delta ()
Resept delta : regulasi
aktifitas resept Mu
Sangat efektif
Efek samping sering
Response
Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependenc
e
Mu-1
Mu-2
Kappa
Aktivasi Reseptor Opioid

menyebabkan :
- Me konduktansi ion K
- Hiperpolarisasi
- Aksi potensial
terhambat
- Release
neurotransmitter
terhambat
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
Analgetik Opioid
Indicated for musculoskeletal pain :
-
Severe injury
Oncogenic pain
Pain that is not alleviated by NSAIDs or other analgesics
Contraindicated for :
-
Patients with respiratory problems
Chronis usage of the drugs may cause :

-
Tolerance decrease of the effect
Addiction need to a compulsive use
Dependency (physically or psychologically)

psychologically
Multimodal Analgesia
Morfin
Potensiasi
Pengurangan dosis
tiap analgesik
Meningkatkan
antinociception karena
efek sinergistik
Mengurangi efek
samping tiap obat
NSAIDs,
acetaminophen,
blok saraf
Kehlet H, Dahl JB. Anesth Analg.. 1993;77:10481056.

1993;77:1048
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
OBAT ANESTESI LOKAL
OBAT LOKAL ANESTESI

Obat Lokal Anestesi ---> obat yg menyebabkan blokade konduksi impuls di sepanjang
jalur saraf pusat maupun perifer secara reversibel setelah anestesi regional
Dibedakan 2 golongan :
1. Amida (Bupivacaine, Nupercaine, Etidocaine, Lidocaine,
Mepivacaine, Prilocaine, Ropivacaine)
2. Ester (Chloroprocaine, Cocaine, Procaine, Tetracaine)
Mekanisme kerja obat anestesi lokal
Obat lokal anestesi mencegah proses depolarisasi membran saraf dengan

memblok aliran ion Na hambatan transmisi impuls saraf (blokade konduksi)
Kualitas hambatan terjadi setelah pemberian sangat tergantung pada :
karakteristik obat yaitu potensi (ditentukan oleh kelarutan dalam lemak); onset (ditentukan
oleh pKa) dan durasi (ditentukan oleh ikatan protein), volume konsentrasi yang dipakai
penambahan vasokonstrikor (epinephrin) : memperlambat penyerapan dan
memperpanjang efek durasi anestesi 60%.
lokasi penyuntikan
kecepatan penyuntikan
posisi dan kondisi pasien
Cara Penyuntikan
Infiltrasi anestesi :
Penyuntikan
Penyuntikan lokal anestesi ke lokasi yg akan
dianestesi.
Blok anestesi:
Menyuntikkan
Menyuntikkan lokal anestesi di sekitar saraf utama
yg jaraknya jauh dari lokasi yg akan dianestesi.
Kriteria ideal obat anestesi lokal

1. Onset cepat
2. Durasi panjang
3. Dapat dititrasi
4. Toksisitas rendah
5. Tempat kerja terlokalisir
6. Khusus menghambat nyeri,
tidak berefek pada fungsi motorik
7. Dosis relatif kecil
8. Efek samping minimal
9. Reversibel
OBAT ANESTESI LOKAL

OBAT
Prokain
Lidokain
Mepivacaine
Prilokain
Bupivakain
Ropivakain (Naropin)
(Levobupivakain) Chirokain
DURASI
MAX
2-4%
1-2%
1-2%
1-2%
0,5%
2,5
2,5-7,5%
1 jam
1-2 jam
1-2 jam
1-2 jam
5-7 jam
6-8 jam
1000 mg
500 mg
500 mg
500mg
200 mg
LIDOKAIN
Mekanisme Kerja :
cegah transmisi impuls saraf atau blokade konduksi mel
hambat lintasan ion sodium melalui kanal Na di membran
saraf
Farmakokinetik :
Absorbsi & distribusi dipengaruhi tempat injeksi, dosis,
epinephrine dan sifat farmakologi.
Faktor terkait : usia, status kardiovaskuler dan fungsi hepar.
Eliminasi metabolisme hepar
ANESTESI UMUM
GENERAL ANAESTHETICS
THE FIRST GENERAL
ANAESTHETICS
Nitrous oxide, 1880,
Laughing gas
Ether, 1846, explosive
Chloroform, 1847,
Toxic to the liver
THEORIES OF ANAESTHETIC
ACTION
LIPID THEORY Anaesthetics
dissolve in lipid part of cell
membranes and depress
membrane activity
PROTEIN THEORY Anaesthetics
bind to hydrophobic protein site
in membranes and depress
activity
Depression of transmitter release
rather than nerve conduction.
Not via receptors
We dont really know how they
FOUR STAGES OF ANAESTHESIA

1.Analgesia
2. Delirium
loss of consciousness,
delirious excitement
reflex activity
3. Surgical anaesthesia
deep unconsciousness,
respiratory depression
muscle relaxation
4. Medullary paralysis
respiratory & cardiovascular, depression, death
ADVERSE EFFECTS
Respiratory & cardiac depression
Sensitisation of heart to catecholamines
Malignant hyperthermia
Aspiration of gastric contents use endotracheal tube
Hepatotoxicity
Renal toxicity
ADJUNCTS TO ANAESTHESIA
(Preanaesthetic medications)
Benzodiazepines/ Barbiturates
Reduce anxiety & produce sedation
Opioids
Analgesia,
Depression of cough
Anticholinergic drugs
Decrease risk of bradycardia
Neuromuscular blocking agents
Paralysis
ANESTESI INHALASI
Enflurane ( Ethrane ).
Halothan ( Fluothane )
Isoflurane (Forane ).
Desflurane.
Sevoflurane.
OBAT ANTI GOUT
(Golan et al., 2008)(Golan et al., 2008)

(Finkel et al., 2009)
Drugs used in Gout and

Hyperuricemia
Allopurinol : prevents or treats hyperuricemia
Uric acid is formed by purine metabolism and an
enzyme xanthine oxidase. Allopurinol prevents
formation by inhibiting xanthine oxidase.
Colchicine : used to treat or prevent acute attacks of
gout. Drug of choice for acute attacks. Decreases
inflammation by affecting leukocytes.
Probenecid : increases urinary excretion of uric acid.
Not effective in acute attacks.
Sulfinpyrazone : uricosuric similar to Probenecid. Not
for acute attacks.
Guidelines for Treating Gout
in accute attack
analgesic NSAIDs
uricosuric agent
colchicin
glucocorticoids (if necessary)
Maintenance drugs are Allopurinol, Probenecid, and

Sulfinpyrazone
Colchicine needed for several weeks to prevent acute attacks
while serum levels are being lowered
Need high fluid intake, alkaline urine to prevent renal calculi
Migraine
Migraine:: a neurological disease characterized by attacks
of headache, photophobia, phonophobia, and nausea.
3 times more common in women than men
Up to 28 million people in the US are affected
The 4 phases of a migraine

Prodrome
Occurs hours to days before
migraine without headache
Aura
Neurological phenomena such as
disturbance of vision just before
headache
Pain phase
Headache on one side of head
with nausea, photophobia and
other classic migraine symptoms
Postdrome
Exhaustion, irritability, depression
Causes of Migraine
Increased excitability of CNS
Meningeal blood vessel dilation
Activation of perivascular sensory trigeminal
nerves
Pain impulses
Vasoactive neuropeptides contain:
substance P
calcitonin gene-related
related peptide (CGRP)
neurokinin A
combination of increased pain sensitivity,
tissue and vessel swelling, and inflammation
Evidence for neural

causes :
Evidence for vascular

cause:
1. During the aura phase,
there is a decrease in
cerebral blood flow
(indicating that ischaemia
maybe causing the aura)
2. During a throbbing
headache, there is
cerebral vascular dilation
(the stretch of the vessels
triggers nerve endings
around the vessels)
3. Headache can be triggered
by vasodilators (e.g.. GTN)
and reversed by
vasoconstrictions
1. Pain sensitive trigeminal

nerves innervate cerebral
vessels
2. Trigeminal nerves release
a peptide CGRP (calcium
gene related peptide)
3. CGRP is elevated during a
migraine
4. Sumatriptan inhibits the
release of CGRP (also acts
as a 5HT1D agonist)
Pathophysiology:Triggers
Triggers
Emotional
Physical
Chemical
Locus Cerulus
Sympathetic System
Dorsal Raphe
Release of NE
Release of 5-HT
Vasoconstriction
stimluation of 5-HT 2B or 5Ht 7
stimulates chemo center
Vasoconstriction
Nausea & vomiting
Acute Treatment: Drug Therapy
Analgesics/combination analgesics
NSAIDs
Opioids
Neuroleptics/antiemetics
Migraine specific
Triptans
Ergotamines
Prophylaxis Therapy
Anticonvulsants: topiramate, valproate,
Keppra, gabapentin
Tricyclics
Amitriptylene, nortriptylene, trazodone
Beta Blockers
Timolol, propranolol, nadolol
Calcium channel blocker verapamil

ACE inhibitors
SSRIs
Atypicals
Severity Migraine
severity
last
TTT
mild Migraine
<2 hours
analgesics (Aspirin,
Acetaminophen , NSAIDS ) ,
Antiemetic
<4 hours
refractory to above
give Antiemetic , analgesics ,
Triptan agents .
4-6 hours
refractory to above
give Other Antiemetic ,
Serotonin Agonist
(Dihydroergotamine , Triptans)
6 to 72 hours
refractory to above
Emergency ttt
Headache
Moderate Migraine
Headache
Severe Migraine
Headache
Severe Refractory
Migraine Headache
status migrainosus
over 72 hours
Mild migraine
Simple analgesics
NSAIDs
Isometheptene (Midrin, etc.)
Metoclopramide (Reglan) may be added to reduce nausea
and enhance drug absorption
Moderately severe migraine
NSAIDs
Isometheptene
Ergotamine, oral or intranasal
Sumpatriptan (Imitrex), oral or intranasal
Zolmitriptan (Zomig), oral
Naratriptan (Amerge), oral
Rizatriptan (Maxalt), oral
DHE, intranasal
With oral agents, metoclopramide may be added to reduce
Severe migraine
Ergotamine plus an antiemetic, both administered by
suppository
Sumatriptan, subcutaneous injection, intranasal or
oral
Zolmitriptan, oral
Naratriptan, oral
Rizatriptan, oral
DHE, intramuscular or intranasal
Extremely severe migraine
Ketorolac (Toradol), 60 mg intramuscularly
DHE, intravenous, plus metoclopramide
Dopamine antagonist
Opioids

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Farmakologi

OBAT ANTI NYERI

menyenangkan akibat kerusakan jaringan,

MEKANISME PROTEKSI TUBUH

PROSES TIMBULNYA NYERI

RESEPTOR NYERI (nociceptor)

JALUR TRANSmisi NYERI

FAST & SLOW PAIN PATHWAY

JALUR TRANSMISI NYERI

Menetralkan dan menghancurkan bahan

2. Mencegah penyebaran bahan berbahaya

3. Memperbaiki kondisi yang rusak

Proses yang terjadi :

peningkt permeabilitas kapiler

migrasi lekosit ke jar radang.

Mediator kimiawi yang dilepas secara lokal

Suhu tubuh diatur oleh keseimbangan produksi dan hilangnya panas

Menghambat transmisi nyeri

Blokade pusat nyeri di SSP (Persepsi)

TERAPI NON FARMAKOLOGI

(Golan et al., 2008)

Terapi Nyeri Non-farmakologik

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

Pain Rating Scales

Choosing pain killer and its combinations

Current view in selecting analgesic and antianti

ANALGESIK NON OPIOID

Analgesic Non Opioid Drugs

Mekanisme kerja hamb sintesa PG

sintetik weak -opioid

R ea ctive ele ctro p h ilic

H e p atic c ell d eath

Ngatidjan, NSAIDs - GOUT

Efek : secara umum = analgetik, antiinflamasi, antipiretik

- new COX-1 can be synthesized

low dose acetosal

low dose acetosal

Ngatidjan, NSAIDs - GOUT

Summary of analgesic, anti-inflammatory

Less GI side effects

(Rang et al., 2003)

(Finkel et al., 2009)

Aktivasi Reseptor Opioid

Efek Farmakologis Analgetik Opioid

Efek Farmakologis Analgetik Opioid

Pain that is not alleviated by NSAIDs or other analgesics

Patients with respiratory problems

Chronis usage of the drugs may cause :

Tolerance decrease of the effect

Addiction need to a compulsive use

Dependency (physically or psychologically)

Kehlet H, Dahl JB. Anesth Analg.. 1993;77:10481056.

= Obat yang dikombinasikan pada obat analgetik utama (non

OBAT ANESTESI LOKAL

OBAT LOKAL ANESTESI

Mekanisme kerja obat anestesi lokal

Obat lokal anestesi mencegah proses depolarisasi membran saraf dengan

Kriteria ideal obat anestesi lokal

OBAT ANESTESI LOKAL

FOUR STAGES OF ANAESTHESIA

OBAT ANTI GOUT

(Golan et al., 2008)(Golan et al., 2008)

(Finkel et al., 2009)