FARMAKOTERAPI

OSTEOARTHRITIS
 PENDAHULUAN

-Degenerative joint disease

-Prevalensi meningkat seiring dg usia, meningkat
2-10x dr usia 30-65 th
 Risk Factors for Osteoarthritis

Age older than 50

Crystals in joint fluid or cartilage
High bone mineral density
History of immobilization
Injury to the joint
Joint hypermobility or instability
Obesity (weight-bearing joints)
Peripheral neuropathy
Prolonged occupational or sports stress
Etiology
Calcium deposition
Congenital or developmental
Endocrine
Genetic defects :interleukin-1 family,interleukin-4
receptor
Infectious
Metabolic
 Neuropathic
Post-traumatic
Rheumatologic diseases (other than primary
osteoarthritis)
Obesity
Occupation :carpenters, agricultural workers
Sport : boxing, baseball pitching, cycling, football
 Patofisiologi
1. Primary (idiopathic) OA
- the most common type, has no identifiable cause
a. Localized OA, involving one or two sites
b. Generalized OA, affecting three or more sites.
C. Erosive OA : erosion and marked proliferation in the
proximal and distal interphalangeal joints of the hands.
2. Secondary
- known cause e.g rheumatoid
- another inflammatory arthritis, trauma, metabolic
or endocrine disorders
ANATOMI
Tulang Rawan Normal
- Tulang rawan memiliki sifat viscoelastik yg memberikan
lubrikasi :
- - gerakan,
- shock absorbency during rapid movements
- load support.
- Lapisan tlg rawan sempit tebalnya 2 3 mm walaupun
demikian tlg rawan artikular yg sehat bantalan sendinya
tahan thd jutaan beban dan bukan beban tiap tahun.
-
Tulang rawan tdd :
* a complex, hydrophilic, extracellular matrix (ECM)
* mengandung air sebesar 75% - 85% , chondrocytes 2-
5% ( sel dlm tlg rawan), protein kolagen, protein lain
jumlah sedikit, proteoglycans, molekul hyaluronic acid
rantai panjang

- Bila tulang rawan cedera chondrocytes bereaksi dgn

mengganti daerah yg rusak dan meningkatkan sintesis
kandungan matiks utk perbaiki dan restorasi tlng rawan
- chondrocytes diberi nutrisi oleh cairan sendi pergerakan
sendi (+) nutrisi masuk melalui tlng rawan

- Pada saat imobilisasi , nutrisi ke sendi tdk ada oleh

karena itu aktivitas fisik scr normal bermanfaat utk
kesehatan sendi
Osteoarthritic Cartilage
- Kontributor utama perkembangan OA :
* Pengaruh mekanik,faktor genetik,inflamasi ,chondrocyte
yg berfungsi menyimpang loss of articular cartilage.

- OA diawali dgn kerusakan tlng rawan , melalui trauma

atau cedera lain, beban sendi yg berlebihan krn obesitas
dll., instabilitas atau cedera sendi yg menyebabkan beban
abnormal

-Aktivitas chondrocyte meningkat dlm usaha menghilangkan

dan memperbaiki kerusakan
- Destruksi aggrecans oleh enzim proteolytic (ADAMTS-5)
berperan pd kerusakan tlng rawan, jg keterlibatan reseptor
kolagen (DDR-2,) yg lokasinya di permukaan sel chondro-
cyte

-Kerusakan tulang sendi memicu destruksi aggrecans

mengeluarkan DDR-2 ke kolagen meningkatkan aktivitas
MMP-13 yg menghancurkan kolagen stimulasi DDR-2
lebih banyak kolagen dan tlng rawan hancur.
 - OSTEOARTHRITIS
-
tulang subchondral mengeluarkan vasoactive peptides
dan MMPs
neovaskularisasi dan peningkatan permeabilitas tlng
rawan sebelahnya dan berkontribusi hilangnya tlng
rawan
substantial loss of cartilage menyebabkan ruang sendi
menyempit dan berkembang nyeri, sendi alami deformasi

tlg rawan sisa melunak dan tjd fibrillasi ( celah vertikal

tlng rawan ), terdapat pemisahan , hilangnya tlng rawan
dan paparan underlying bone
Saat tlng rawan hancur dan tulang subchondral
sebelahnya mengalami perubahan patologis

tlng rawan alami erosi sempurna , tulang subchondral

menjadi padat, halus dan berkilau

tulang jadi rapuh, lebih kaku dgn penurunan kemampuan

menahan beban dan berkembang sklerosis dan fraktur
kecil. terbentuk tulang baru ( osteophytes) ,jg tampak
jarak batas sendi dari tlg rawan yg alami destruksi
Perkembangan OA
Damage to articular cartilage
( trauma, excess joint loading from obesity,instability or
injury of the joint)

metabolic activity of chondrocytes

synthesis of matrix constituentswith swelling of

cartilage ( hypertrophic phase )
(sbg respon thd kerusakan, stimulated by the peptide annexin,
parathyroid hormone-related protein)

loss of cartilage
 turnover
(increased collagen synthesis and destruction)

Destruction outpacing formation/loss of cartilage)

(matrix metalloproteinases (MMPs)
Chondrocytes contribute to:
- Hilangnya dan sekresi MMPs sbg respon thd mediator
inflamasi pd OA (IL-1 dan TNF- )

- Undergo apoptosis induction of NO syntethase and

production of toxic metabolites fewer chondrocytes to
synthesize matrix components hyporesponsive to the
anabolic stimulus transforming growth factor-

progressive cycle of cartilage destruction and loss of

chondrocytes
 CLINICAL PRESENTATION
General
Mild symptoms for months to years
Typical age :usually >50 years.

Symptoms
Pain in the affected joints (hands, knees,hips )
Pain is most commonly associated with motion,pain in
late disease can occur with rest
Joint stiffness in the morning < 20-30 that resolves with
motion; recurs with rest

Signs
Joint stiffness with or without joint enlargement.
Crepitus a crackling or grating sound heard with joint
movement that is caused by irregularity of joint surfaces
 Limited range of motion that may be accompanied by
joint instability.
Late-stage disease is associated with joint deformity
(figure 95-3 )

Laboratory Tests
No specific laboratory tests useful in the diagnosis.

Other Radiologic TestsPlain Radiographic Films

Joint space narrowing, appearance of osteophytes in
moderate disease (gambar 95-4)
Abnormal alignment of joints and joint effusion in late
disease.
 DIAGNOSIS
Hip OA
Pain in the hip, ESR <20 mm/h, femoral or
acetabular (two of the three)
Osteophytes on radiography, or joint space
narrowing on radiography.

Knee OA
Pain at the knee,osteophytes on radiography
Age > 50 years,
Morning stiffness 30 , crepitus on motion,bony
enlargement, bony tenderness, or palpable
warmth
Characteristics of osteoarthritis in the diarthrodial joint.
 TERAPI

DESIRED OUTCOME
- to educate the patient, caregivers, and relatives
- to relieve pain and stiffness
- to maintain or improve joint mobility
- to limit functional impairment
- to maintain or improve quality of life
 GENERAL APPROACH TO TREATMENT
The primary objective to alleviate pain
Acetaminophen up to 4 g/day (initially)
If this is ineffective NSAIDs or COX-2
selective inhibitor (celecoxib)
Application of capsaicin or methylsalicylate
topical creams adjuncts for pain control
Glucosamine and chondroitin in combination
moderate to severe arthritis
- Joint aspiration followed by glucocorticoid or
hyaluronate concomitantly with oral
analgesics or after their lack of efficacy
- Opioid analgesics final medication if other
therapies are unsuccessful
- Symptoms are intractable or there is significant
loss of function joint replacement
ALGORITME
OA
Terapi
a. Non farmakologi
- Exercise utk hindarkan stress pd sendi sambil
perkuat otot periartikuler
- Hindari muatan berlebihan pd sendi lutut dan
pinggul dg gunakan alat bantu (tongkat, sepatu
ortopaedi), turunkan BB, edukasi perlindungan
sendi
- Akupunktur tdk direkomendasikan
Physical and Occupational Therapy
Physical therapywith heat or cold treatments
and an exercise program to maintain and
restore joint range of motion and to reduce pain
and muscle spasms
Warm baths or warm water soaks (rendam air
hangat) decrease pain and stiffness
Surgery
OA with functional disability and/or severe pain
unresponsive to conservative therapytotal joint
replacement (arthroplasty) of the knee ,total hip
replacement
b. Farmakologi
- Parasetamol utk nyeri ringan (pilihan pertama) ,
sedangkan NSAID lbh efektif utk nyeri sedang ad
berat
* ESO : hepatotoxicity, renal toxicity (long-term
use)
- Topikal NSAID, capsaicin krim sekuat NSAID
lokal.
- Injeksi kortiko intra-artikuler sgt efektif tx nyeri &
inflamasi isolated joint
 Hand OA
- The patients should be treated with either topical or oral
NSAIDs, topical capsaicin, or tramadol
-The patients not be treated with opioid analgesics or
intraarticular therapies

Knee OA
- It can can use acetaminophen, oral or topical NSAIDs,
tramadol, or intraarticular corticosteroid injections
- It recommends not to use nutritional supplements (e.g.,
chondroitin sulfate, glucosamine) or topical capsaicin.
-If does not response to full-dose acetaminophen use of
oral or topical NSAIDs or intraarticular corticosteroid
injections
-Health care providers should not use oral NSAIDs in
patients with contraindications
to these agents
-For persons age 75 years use of topical rather than oral
NSAIDs, conditionally recommends the use of tramadol,
duloxetine, or intraarticular hyaluronan injections
- If the patient has a history of a symptomatic or
complicated upper GI ulcer cyclooxygenase 2 (COX-2)
inhibitor or a nonselective NSAID in combination with a
proton-pump inhibitor
 Pharmacologic modalities for hand OA
- It should be treated with either topical or oral NSAIDs,
topical capsaicin, or tramadol
- Its not be treated with opioid analgesics or intraarticular
therapies
Parasetamol
- The ACR, ELAR,OARSI parasetamol is first-line drug
therapy for pain management in OA
- Efficacy aspirin, naproxen, ibuprofen, and other
NSAIDs
- Terapi awal utk nyeri ringan ( hand and knee )
- Dikombinasi dgn acetylcystein ( fixed dose) pd pasien dgn
liver disease
- Di klinik jarang digunakan , outcome klinik < bila
dibandingkan dgn NSAID
- Waspadai hepatotoksisitas (dosis > 4 g/hari ), renal toxicity
( long term usage)
 Terapi topikal
- Capsaicin,diclofenac gel, piroxicam gel
- Diberikan terapi tunggal atau kombinasi dgn terapi oral
( tdk boleh bersamaan )
- Utk OA hands, elbows, and wrists, and the lower
extremities (ankles, feet, and knees )
-to be considered when first-line agents fail, are contra-
indicated, or are poorly tolerated
- FDA approvel : diclofenac gel
-Topical rubefacients methylsalicylate, trolamine salicy-
late, other salicylates short-term efficacy in the treatment
of acute pain OA
NSAID dan COX-2 inhibitor
- bila tx dosis maks parasetamol(4g/hari) tdk berrespon dan
dg effusi sendi.
- kombinasi pamol + NSAID efektif
- Px dg inflamasi sendi : pilihannya NSAID
- Efek serius : GI bleeding, disfungsi renal, peTD , retensi
cairan, eksaserbasi HF.
- COX-2 inhibitor seefektif NSAID non selektif, dg ESO
retensi Na dan penurunan GFR.
 Rofecoxib withdrawn in 2004 because of increased
cardiovascular events (aritmia) analysis of the
Adenomatous Polyp Prevention on Vioxx (APPROVe)
trial
Celecoxib is less often used now and carries a black box
warning for cardiovascular and GI risks
The newer COX-2 inh: Etoricoxib 30 mg, Lumiracoxib
100 mg/day ~ celecoxib
* are not FDA approved , but are marketed in several
other countries ( Indonesia dll )
- ESO : retensi Na dan penurunan GFR
What to monitor ...
- Efektivitas : respon nyeri dan inflamasi
- ESO :
* Kidney diseases
- Acute renal insufficiency, tubulointerstitial
nephropathy, hyperkalemia, renal papillary necrosis
- Monitor nilai Cr, BUN 3 to 7 days of drug initiation
-Monitor kadar K, tek darah , edema perifer, BB, nilai
ALT,AST, keluhan lambung, warna faeses, complete blood
count ( 2-4 mgg setelah terapi )
Tramadol
- Add-on therapy for patients taking concomitant NSAIDs or
COX-2selective inhibitors
- Pada pasien yg KI dg COX inhibitor (nyeri sedang ad berat)
- It can be used with acetaminophen
- Dosage : 50-100 mg every 4-6 jam ( MD 400 mg/hari)
- Monitor : - efektivitas terapi : nyeri
- ESO : mual, konstipasi, mengantuk, kecemasan,
depresi pernapasan ( over dosage)
 DULOXETINE
- Golongan selective serotonin and norepinephrine reuptake
inhibitor
- osteoarthritic pain of the knee
- Juga utk major depressive disorder, generalized anxiety
disorder,fibromyalgia, and diabetic peripheral neuropathic
pain
- Monitor : - nyeri sendi ( efektivitas )
- mual, mulut kering, somnolence ( ESO)
Kortikosteroid
- Kortiko sistemik tdk direkomendasikan ok inflamasi bkn
komponen primer patofis OA.
- Injeksi intraartikuler (triamcinolone hexacetonide 40 mg)
efektif utk aspirasi efusi sendi yg nyeri dan bengkak
- Frekuensi : 3-5x / thn :
* Potential systemic effects of steroids
* The need for more frequent injections indicates little
response to the therapy)
- Triamsinolon acetonide inj ( kenacort i.a )
- methylprednisolone acetate & triamcinolone hexacetonide
similar efficacy
- Efektif selama 4-8 mgg
Viscosupplement
- Pengganti as hyaluronat di sendi yg rusak pd OA
- Na hyaluronat, hylan ( alami di cairan sendi)
buat lingk viscous, bantalan sendi, jaga fgs
normal sendi
- sbg lubrikan & shock absorber pd sendi, shg
lindungi tlg rawan dr kerusakan
- dipakai bila analgesik gagal utk OA lutut ( di-
berikan once weekly dg 3-5 x injeksi seri) relief
nyeri bertahan ad 6 bln
 Hyaluronate Injections
Containing hyaluronic acid (HA; sodium hyalu-ronate)
- Available for intraarticular injection for treatment of knee
OA decrease pain
- HA is an important constituent of synovial fluid and
endogenous HA have anti inflammatory effects.
- Its used to first to 2nd of OA
- HA products are injected once weekly for either 3 or 5
weeks
- Lbh efektif drpd intra artikuler kortikosteroid ( Cochrane
review )
- Nice guideline tdk menawarkan ( do not offer )
Glukosamin dan chondroitin
- Glukosamin endogen (monosakarida amin)
*disintesis dr glucosa, bagian integral pd bio-
sintesis proteoglikans & glikosaminoglikan
(substrat hyaluronic acid), yg bentuk blok tlg rawan
- Chondroitin sulfat, subtrat utk pembentukan
matrik sendi & memblok enzym yg bertangung jwb
kerusakan tlg rawan
- kombinasi gluko dan chondro : moderate to severe
OA
- Dari bbrp trial ( meta analisis ) tdk terbukti efektif
 Analgesik opioid
- Digunakan Low-dose opioid analgesic bila terapi nyeri
gagal dgn aetaminophen, NSAIDs, intraarticular
injections, or topical therapy
- For patients with underlying diseases ( renal failure,
cardiovascular disease) opioid analgesics can effectively
relieve pain
- Waktu pemberian by the clock
- Pemberian btk Sustained-release (SR) ( MST),
hydromorphone and fentanyl transdermal patch
- ESO : nausea, somnolence, constipation,dizziness
* elderly patients more susceptible to
adverse effects
1. Pasien a.n Tn. Br, usia 56 thn, BB 70 kg, masuk
rumah sakit dgn keluhan nyeri dan bengkak bagian
tempurung kaki. Keluhan sudah 3 hari. Hasil foto
rontgen pd genu menunjukkan osteoarthritis. Pasien
mendapat terapi parasetamol 4 x 1000 mg selama 3
hari. Setelah 3 hari keluhan nyeri masih tetap. Apa
yang anda monitor dan sarankan

2. Pasien a.n Ny. Sr, usia 63 thn, BB 60 kg, masuk

rumah sakit dgn keluhan berak darah warna hitam
serta nyeri pd pergelangan kaki. Riwayat penyakit
osteoartritis dan mengkonsumsi obat piroksikam 2 x
10 mg, neurobion tab 1x1, glukosamin 2x1. Di
bangsal, pasien mendapat terapi injeksi ketoprofen,
asam traneksamat injeksi. Apa yang anda analisis
dan sarankan