OBAT ANALGETIK,

ANTIPIRETIK & ANTI INFLAMASI

 NYERI
DEFINISI ASOSIASI
INTERNASIONAL

Pengalaman sensorik dan emosional yang

tidak menyenangkan berhubungan akibat
kerusakan jaringan, baik aktual maupun
potensial atau yang digambarkan dalam
bentuk kerusakan tersebut
 Klasifikasi nyeri
• Berdasarkan durasi (akut, kronis)
• Berdasarkan mekanisme patofisiologi (psikologis, nociceptif
(inflamasi), neuropati)
• Berdasarkan klinis (pasca bedah, keberadaan sel malignant,
neuropati, degeneratif)

14/03/21 3
14/03/21 4
14/03/21 5
14/03/21 6
 Wong-Baker FACES Pain
Rating Scale
Skala nyeri berdasarkan ekspresi wajah

Penilaian Skala nyeri dari kiri ke kanan:

•Wajah Pertama : Sangat senang karena ia tidak merasa sakit sama sekali.
•Wajah Kedua : Sakit hanya sedikit.
•wajah ketiga : Sedikit lebih sakit.
•Wajah Keempat : Jauh lebih sakit.
•Wajah Kelima : Jauh lebih sakit banget.
•Wajah Keenam : Sangat sakit luar biasa sampai-sampai menangis

14/03/21 7
Skala Nyeri 0-10 (Comparative Pain Scale) 0 = Tidak ada rasa sakit. Merasa normal.

• Skala nyeri 1-3 berarti Nyeri Ringan (masih bisa ditahan,

aktifitas tak terganggu)
• Skala nyeri 4-6 berarti Nyeri Sedang (menganggu aktifitas fisik)
• Skala nyeri 7-10 berarti Nyeri Berat (tidak dapat melakukan
aktifitas secara mandiri)

PENGGABUNGAN
 NYERI
• Rangsang : kimia, mekanik,
termal
• Ketika jaringan yang menerima
rangsang menjadi terluka,
terlepaskan mediator kimia seperti
prostaglandin dan leukotrien yang
membuat reseptor nyeri lebih
sensitif
• Rangsang diterima di ujung
syaraf, reseptor nyeri
menghasilkan impuls yang
diteruskan oleh sumsum tulang
belakang ke otak.
e n
ntteerrss
e
PPaaiinn ree… …
hheer
14/03/21 11
Keterangan:
IL : interleukin
TNF :Tumor necrosis
Factor
NGF : Nerve Growth
Factor
Substance P : Protein
CGRP : Calcitonin
Gene related peptide

14/03/21 13
 Phospholipid di membrane sel

Phospholipase

Arachidonic acid

Cyclooxygenase Lipoxygenases
(COX-1, COX-2)

Prostaglandins
PMNs

PGF2α PGE2 PGI2

Lymphokines
algesic pyrexia vasodilation
The events of the inflammtory response and mechanisms of anti-flammatory
 : ANALGESIK •
menghilangkan/mengurangi nyeri ringan sampai
sedang

: ANTIPIRETIK •
menurunkan demam

: ANTIINFLAMASI •
menanggulangi peradangan
 S tim u lu s

G a n g g u a n p d m e m b ra n s e l

P h o s p h o lip a s e in h ib ito rs P h o s p h o lip id s

C o rc o tic o s te ro id s
P h o s p o lip a s e

F a tty a c id s u b s titu tio n (d ie t) A r a c h id o n ic a c id

N S A ID . A S A
L ip o x y g e n a s e in h ib ito rs C y c lo -o x y g e n a s e
L ip o x y g e n a s e

L e u k o trie n e s
R e c e p to r le v e l a n ta g o n is ts

LTB 4 LTC4/ D 4 / E 4
P ro s ta g la n d in s T h ro m b o x a n e P ro s ta c y c lin

P h a g o c y te
a ttra c tio n ,
a c tiv a tio n
C o lc h ic in e
A lte r a tio n o f v a s c u la r
p e rm e a b ility , b ro n c h ia l L e u k o c y te
c o n s tric tio n , in c re a s e d m o d u la tio n
s e c re tio n

B ro n c h o s p a s m ,
In fla m a s i c o n g e s tio n , In fla m a s i
m u c u s p lu g g in g
OBAT NYERI
KLASIFIKASI NSAID
Efek pelepasan prostaglandin
 Penyempitan pembuluh darah meningkatkan
suhu tubuh.
 Efek langsung pada pusat pengatur suhu tubuh di
hipotalamus, yang menghasilkan demam.
 Peningkatan permeabilitas kapiler yang
menyebabkan rasa sakit dan pembengkakan pada
jaringan.
MOA penghambat inhibitor
1. Antiinflammatory effect
penghambatan enzim yang menghasilkan prostaglandin H
sintase (siklooksigenase, atau COX), yang mengubah
asam arakidonat menjadi prostaglandin, dan TXA2 dan
prostasiklin
2. Efek analgesic
 penghambatan perifer produksi prostaglandin

 NSAID mencegah aksi potensiasi prostaglandin sebagai

mediator endogen pada stimulasi saraf perifer (misalnya,
bradikinin).
3. Antipyretic effect
penghambatan produksi prostaglandin yang
menginduksi interleukin-1 (IL-1) dan interleukin-
6 (IL-6) sehingga me"reset" sistem
termoregulasi di hipotalamus, menyebabkan
vasodilatasi dan peningkatan kehilangan panas.
03/14/21
03/14/21
• Aspirin (acetylsalicylic acid)

• Nonacetylated salicylates:
• sodium salicylate
• magnesium salicylate
• choline salicylate
• sodium thiosalicylate
• sulfasalazine
• mesalamine
• salsalate
:ASPIRIN :Pharmacologic properties

– Salicylates adalah suatu asam

lemah dengan pKa 3.5.

– Senyawa ini diabsorbsi cepat di

lambung dan usus. pH rendah
lebih optimal absorbsinya
Metabolisme aspirin
– Salicylates mempunyai
t1/2 3—6 jam (jangka
pendek)

– Penggunaan jangka
panjang (pengobatan
arthritis) t1/2 meningkat
menjadi 15—30 jam,
karena enzymes glycine
and glucuronide
conjugation menjadi
jenuh
 Ekskresinya
– Bentuk utuhnya (unmetabolized salicylates)
diekskresi melalui ginjal.

– Jika pH urine naik di atas 8, clearance

meningkat sekitar empat kali lipat sebagai
akibat dari penurunan reabsorpsi dari salisilat
terionisasi dari tubulus.
Therapeutic uses :
• Salicylates diindikasikan/digunakan untuk :
– rheumatoid arthritis
– juvenile arthritis
– osteoarthritis
– other inflammatory disorders

• 5-Amino salicylates (mesalamine, sulfasalazine)

– Dapat digunakan untuk Crohn's disease.
– Salicylic acid is used topically to treat: fungal infections

• Aspirin
– has significantly greater antithrombotic activity than other
NSAIDs
Adverse effects :
1. Gastrointestinal 2. Hypersensitivity
effects (intolerance)
• nausea – rash
• vomiting – bronchospasm
• diarrhea or – rhinitis
constipation – Edema, or
• dyspepsia (impaired – an anaphylactic
digestion) reaction with shock,
• epigastric pain which may be life
• bleeding, and threatening.
ulceration (primarily Kejadian intoleransi : pada pasien
gastric). asthma, nasal polyps, recurrent
rhinitis, or urticaria
• Penggunaan aspirin atau salicylates untuk
menurunkan suhu pada pasien anakdapat
menyebabkan Reye's syndrome, yaitu suatu
sindroma yang dikarakteristik : vomiting, hepatic
disturbances, and encephalopathy that has a 35%
mortality rate.
 Acetaminophen is recommended as a substitute for
children with fever of unknown etiology.
3. contraindication

• May decrease the glomerular filtration rate, particularly

in patients with renal insufficiency.
• Occasionally produce mild hepatitis

• Prolong bleeding time.

• Salicylates are not recommended during pregnancy; they
may induce:
– postpartum hemorrhage
– premature closure of the fetal ductus arteriosus.
Drug interactions
 Aspirin : Keracunan dan penangannya

• Tanda keracunan pada orang dewasa : ganguan

pendengaran, vertigo

• Pada anak-anak, tanda keracunan : hiperventilasi dan

asidosis, dengan kelesuan yang menyertainya dan
hiperventilasi

• Penanganan :
1. Koreksi gangguan asam basa
2. Penggantian cairan elektrolit
3. Pembasaan urin dengan bicarbonate untuk
mereduksi reabsorbsi salicylate
4. Diuresis, hemodialisis
5. Pembersihan lambung/dimuntahkan
 NSAID

• NSAIDs diabsorbsi secara cepat setelah pemberian

oral

• NSAID terikat plasma proteins, terutama albumin.

• NSAIDs are
• metabolized in the liver
• excreted by the kidney
• t1/2 : 1 - 45 jam, sebagian besar : 10 -20 jam
Chemical Class Prototype Analgesia Antipyresis Antiinflammatory

Salicylates Aspirin +++ +++ +++

Para-aminophenols Acetaminophen +++ +++ Marginal

Indoles Indomethacin +++ ++++ ++++

Pyrrol acetic acids Tolmentin, +++ +++ +++
mefenamic acid
Propionic acids Ibuprofen, ++++ +++ ++++
naproxen
Enolic acids Phenylbutazone, +++ +++ ++++
piroxicam
Alkanones Nabumetone ++ ++ +++
Sulfonamide Celecoxib ++++ +++ ++++
 Propionic acid derivatives

(Ibuprofen, Fenoprofen, ketoprofen , naproxen)

– ibuprofen or ketoprofen tidak berinteraksi dengan

anticoagulants.

– Fenoprofen dilaporkan menyebabkan sindrom

nephrotoksik.

– Penggunaan ibuprofen jangka panjang dapat

menyebabkan hypertension in women.
 Sulindac, tolmetin, Ketorolac

 Sulindac:
• Adalah suatu prodrug, yang dioksidasi menjadi suatu sulfone
• t1/2 16 jam karena mengalami enterohepatic cycling.
 Tolmetin:
• mempunyai efek paling kecil untuk agregasi platelet
• Paling besar kejadian anaphylaxis dibanding NSAIDs lain
• t1/21 jam.

 Ketorolac:
• Potensi untuk analgesic dan moderate antiinflammatory
• Dapat diberikan secara :
– intravenously or
– topically in an ophthalmic solution.
 Indomethacin

 Use: As anti-inflammatory

 Treatment of
• Ankylosing spondylitis
• Reiter syndrome
• Acute gouty arthritis.

– Indomethacin tidak direkomendasikan untuk

analgesic dan antipiretik, karena efek sampingnnya
yang beragam
 Piroxicam
– Piroxicam merupakan turunan oxicam asam enolic
– Piroxicam mempunyai t1/2 45 jam.
– Seperti aspirin and indomethacin, mempunyai ESO
bleeding and ulceration.
 Meclofenamate, mefenamic acid

– Mempunyai t1/2 2 jam.

– insiden gangguan gastrointestinal relatif tinggi
– Efek Analgesik, Antiinflamasi <<
– ESO: iritasi lambung, diare pada px tua,
hipersensitivitas, gangguan fungsi ginjal
 jangan > 7 hari
- Kontraindikasi : Hamil, usia < 14 tahun
 Nabumetone

• Pro-drug  metabolitnya aktif hambat enzim COX

• Tidak bersifat asam
• Tidak menghambat prostasiklin yang bersifat
sitoprotektif
• ESO relatif <
• Penggunaan klinis:
• Reumatoid Artritis
• Osteoartritis
 COX-2 Selective agents
Penghambatan COX-2 akan mengurangai respon
inflamasi dan nyeri tanpa menghambat aksi
cytoprotective dari prostaglandins

Contoh : Celecoxib [Celebrex], Rofecoxib [Vioxx],

Valdecoxib [Bextra]

Rofecoxib and valdecoxib sudah ditarik dari pasaran

karena menyebabkan heart attack and stroke
 MELOXICAM (MOVI - COX)
• Selektif menghambat COX-2
• Efek saluran cerna & ginjal (-)
• Penggunaan Klinis:
• Reumatoid Artritis
• Osteoartritis
 CELECOXIB (CELEBREX)
• Hambat PG terutama COX-2
• Antiinflamasi, analgesik & antipiretik
• Pengaruh agregasi platelet; edema (-)
• Penggunaan klinis:
Reumatoid Artritis, Osteoartritis
Hati–hati: asma, hipertensi, gangguan
jantung & ginjal, bumil, busu, < 18 tahun
 NIMESULIDE
• Golongan Sulfonanilide
• Antiinflamasi, analgesik & antipiretik
• Hambat PG terutama COX-2
• Iritasi lambung <
 PARA AMINO FENOL
• Fenasetin; Asetaminofen; Asetanilid

Parasetamol
• Digunakan pertama tahun 1893
• Menghambat sintesis PG di sentral
• Efek analgesik & antipiretik serupa Aspirin
• Antiinflamasi <<<
 Parasetamol vs Aspirin
• Tidak  antiinflamasi
• Tidak  anti gout
• Tidak  iritasi lambung
• Tidak  gangguan pernafasan
• Tidak  gangguan keseimbangan asam basa
• Tidak  efek metabolisme karbohidrat
• Hambatan sintesis PG  peroksid ↓
Overdose with acetaminophen:
accumulation of a minor metabolite, N-acetyl-p-benzoquinone,
which is responsible for hepatotoxicity.
 Efek Samping
• Jarang terjadi alergi
• Anemia hemolitik , Methemoglobinemia
• Nefropati
• Hepatotoksik
• Penanganan keracunan:
– Dimuntahkan (emesis) atau pembersihan lambung
– Pemberian N-acetyl cystine akan menetralkan
metabolitnya.

• Long-term use of acetaminophen has been

associated with:
– a 3-fold increase in kidney disease
– women taking more than 500 mg/day had a doubling
in the incidence of hypertension.
Terima kasih
14/03/21 76
Other antiinflammatory drugs are used in the more
advanced stages of some rheumatoid diseases.

• Gold compounds:
– Aurothioglucose
– Gold sodium thiomalate
– Auranofin

– may retard the destruction of bone and joints by an

unknown mechanism.

– These agents have long latency.

– Aurothioglucose and gold sodium thiomalate are
administered intramuscularly.
– Auranofin is administered orally and is 95% bound to
plasma proteins.
 Side effects: Gold compounds
 Serious:
• gastrointestinal disturbances, dermatitis, and mucous
membrane lesions.

 Less common effects:

• aplastic anemia
• proteinuria

 Occasional:
• nephrotic syndrome.
 Penicillamine

– Penicillamine is a chelating drug (will chelate gold)

that is a metabolite of penicillin.

– Penicillamine has immunosuppressant activity, but

its mechanism of action is unknown.

– This agent has long latency.

– The incidence of severe adverse effects is high; these

effects are similar to those of the gold compounds.
• Methotrexate
– Methotrexate is an antineoplastic drug used for
rheumatoid arthritis that does not respond well to
NSAIDs or glucocorticoids.
– Methotrexate commonly produces hepatotoxicity.

• Chloroquine and hydrochloroquine

– Chloroquine and hydrochloroquine are antimalarial drugs.
– These agents have immunosuppressant activity, but their
mechanism of action is unknown.
– Used to treat joint pain associated with lupus and arthritis

• Adrenocorticosteroids
Nonopioid analgesics and antipyretics

– Aspirin, NSAIDs, and acetaminophen

(Paracetamol):

– are useful for the treatment of mild-to-moderate pain

associated with integumental structures, including
pain of muscles and joints, postpartum pain, and
headache.

– These agents have:

• antipyretic activity
• have antiinflammatory activity at higher doses
except for acetaminophen
 Drugs Used for Gout
• Gout
– Gout is a familial disease characterized by:
• recurrent hyperuricemia
• arthritis
• severe pain
– it is caused by deposits of uric acid (the end-
product of purine metabolism) in joints, cartilage, and
the kidney.
– Acute gout is treated with:
• Nonsalicylate NSAIDs, particularly indomethacin &
colchicine.

– Chronic gout is treated with:

1.uricosuric agents: They increase the elimination of
uric acid:
– probenecid
– sulfinpyrazone
2.inhibits uric acid production:
– allopurinol
• Colchicine
– Colchicine is an alkaloid
– It is used for relief of inflammation and pain in acute
gouty arthritis.
– Reduction of inflammation and relief from pain occur
12—24 hours after oral administration.
– The mechanism of action in acute gout is unclear.
– Colchicine:
• prevents polymerization of tubulin into
microtubules and inhibits leukocyte migration and
phagocytosis.
• inhibits cell mitosis.
– The adverse effects after oral administration, which
occur in 80% of patients at a dose near that
necessary to relieve gout, include nausea, vomiting,
abdominal pain, and particularly diarrhea.

– IV administration reduces the risk of gastrointestinal

disturbances and provides faster relief (6—12 h) but
increases the risk of sloughing skin and subcutaneous
tissue.

– Higher doses may (rarely) result in liver damage and

blood dyscrasias.
• NSAIDs: acute gout
– indomethacin
– naproxen
– sulindac

– NSAIDs are preferred to the more disease-specific

colchicine because of the diarrhea associated with the
use of colchicine.
• Probenecid and sulfinpyrazone

• are organic acids

• reduce urate levels by acting at the anionic transport site
in the renal tubule to prevent reabsorption of uric acid.

• These agents are used for chronic gout, often in

combination with colchicine.

• Probenecid and sulfinpyrazone undergo rapid oral

absorption.
• These agents inhibit the excretion of other drugs that are actively
secreted by renal tubules, including penicillin, NSAIDs,
cephalosporins, and methotrexate.

• Increased urinary concentration of uric acid may result in the

formation of urate stones (urolithiasis).

• This risk is decreased with:

1. the ingestion of large volumes of fluid or
2. alkalinization of urine with potassium citrate.

• Common adverse effects include gastrointestinal disturbances

and dermatitis; rarely, these agents cause blood dyscrasias
• Allopurinol
• Allopurinol inhibits the synthesis of uric acid by inhibiting
xanthine oxidase, an enzyme that converts hypoxanthine to
xanthine and xanthine to uric acid.

• Allopurinol is metabolized by xanthine oxidase to alloxanthine,

which also inhibits xanthine oxidase. Allopurinol also inhibits de
novo purine synthesis.

• Allopurinol commonly produces gastrointestinal disturbances

and dermatitis. This agent more rarely causes hypersensitivity,
including fever, hepatic dysfunction, and blood dyscrasias.

• Allopurinol should be used with caution in patients with liver

disease or bone marrow depression.