Terapi Gout dan

Rheumatoid Arthritis
(DMARDs)
Anggelia Puspasari

Bagian Farmakologi dan Terapi

Fakultas Kedokteran dan Ilmu Kesehatan
Universitas Jambi
Terapi Gout
 Gout Arthritis
• Joint inflammation that enhance by MSU in
sinovial.
• Related to hyperurecemia.
 Gouty arthritis - characteristics
• sudden onset • recurrent episodes
• middle aged males • influenced by diet
• severe pain • bony erosions on
• distal joints Xray
• intense inflammation • hyperuricemia
 Gout - cardinal manifestations

arthritis tophi

acute &
chronic HYPERURICEMIA

nephrolithiasis nephropathy
Tophi and arthritis
Hyperurecemia and Gout
Crystal-induced inflammation
 Hyperuricemia

hyperuricemia results when production exceeds

excretion
Urate production Pathway
Urate Excretion and
Reabsorbtion
Treating acute gouty arthritis

what strategies might be

effective?
 Drug therapy of gout
Inflamation
Control
Lowered serum
urate level
Decreased recurrent
attack
 Drugs used to treat gout

Acute Arthritis Drugs Urate Lowering Drugs

colchicine Xanthin oxidase
inhibitor
steroids

NSAID’s uricosuric

rest + analgesia + time

 Colchicine (MOA)
• Colchicine is an alkaloid obtained from
various colchicum spp.
• It has mitotic effect, greatest with rapid
turnover (eg. Neutrophile and GI
epithelium).
• Experimental data : decreased crystal
induced chemotactic factor and superoxide
anion activated by neutrophil, limit
neutrophil adhesion to endothelium.
 Colchicine (Pharmakokinetic)
• Absorption peroral rapid but variable.
• Peak [plasma] occur 0.5-2 h after dosing.
• 50% are protein bound.
• Vd large : kidney, liver and spleen.
• Significant enterohepatic circulation, oxidative
demethylation by CYP3A4 (DI : exe.cimetidine,
increased colchicine plasma coencentration)
• T ½ 9 h, still can detected in leucocyte and urine
in 9 d.
• 10-20% excreted in urine, feces primarily.
 Colchicine (Therapeutic uses)
• A minimum 3 d, but preferably 7-14 d.
• Effective 2/3 patient with gout acute attack if
given within 24 h.
• Pain, swelling and redness abate in 12 h and
completely gone within 48-72 h.
• New regimen FDA approve for acute attack1,2
mg (two tab), 0,6 mg one h later. Dose must
adjusted in patient exposed to inhibitor P-
glycoprotein or CYP3A4 within 14 d.
 Colchicine (adverse Effect)
• GI : nausea, vommiting, abdominal pain ,
diarrhoe, hemorrhagic gastropathy.
• Myelosuppresion, aplastic anemia.
Rabdomyolisis.
• Life treatening toxicity comcomitan therapy
with inhibitor P-glycoprotein or CYP3A4 .
Xanthine Oxidase
Inhibitor (allupurinol,
oxypurinol, Febuxostat)
 Allupurinol
• Inhibit xanthin oxidase and prevent synthesis
of urate from hypoxanthine and xanthine.
• Initially was synthesized as candidate
antineoplastic agent but lack of antineoplastic
activity.
• Allopurinol is analog of hypoxantine,
oxypurinol (metabolite) is analog xantine.
 Allupurinol (Pharmacokinetic)
• Rapidly absorption after oral ingestion, peak
[plasma] within 60-90 minutes.
• 20% excreted in feces, 70% excreted in urine.
• Metabolism by aldehide axidoreductase yield
oxypurinol
• T1/2 allupurinol 1-2 h, T1/2 oxypurinol 18-30
h.
 Allupurinol (Drug Interaction)
• Allupurinol increased T1/2 of probenecid,
probenesid increased clearance of oxypurinol.
• Allupurinol inhibit the enzym inactivation of
mercaptopurine and its derivate azatioprine by
xanthine oxidase.
• Interfere with hepatic inactivation of other drug,
include warfarine.
• Increased incidence of rash in patient receiving
ampicillin and allupurinol.
• Increase active metabolite of theophylline.
 Allupurinol (Therapeutic Uses)
• Available oral and intravenous.
• Oral th/ for primary and secondary gout, hyperuricemia
secondary to malignancies and calcium oxalate calculi.
• Avoid starting allupurinol during acute attack.
• Fluid intake should be sufficient, slightly alkali is preferred.
• Initial daily dose 100 mg, increased by 100 mg-increment
weekly__400-600 mg/daily, Hematology malignancies may
need up to 800/mg.
• Daily dose >300 mg/day should be divided.
• Must be reduced in GFR reduction.
 Allupurinol (Adverse Effect)
• Drowsiness, hypersensitivity, cutaneous
reaction, liver and renal disturbing.
• Oxypurinol has orphan drug status and is
available for compassionate use in the US for
patient intolerant of allupurinol.
 Febuxostat
• More potent and minimized risk than
allupurinol, form stable complex with oxidize
enzyme.
• Rapidly absorbed, highly protein bound and
Vd, excreted via hepar and renal.
• Available in 40-80 mg oral tablet.
• Monitoring liver function, nausea, joint pain
and rash.
• DI almost same with allopurinol.
 Rasburicase
• Recombinant urate oxidase (uric acid more
soluable and allantoin), shown to lower urate
level more effective than allupurinol.
• Used for pediatric patient for management
plasma urate level after chemoterapy.
 PEGLOTICASE
• Recombinant, pegylated uric acid spesific
enzym.
• Catalyzing oxidation of UA to allantoin
• OOA 24h, DOA 12.5 d, T ½ 14 d
• IM or IVFD, premedication with AH and
corticosteroid, 8 mg q2W
• Risk of anphylaxis higer with UA serum
>6mg/dl.
 Uricosuric Agent
(Probenesid, Sulfinpyrazone,
benzbromarone)
 Uricosuric Agent
• In human, urate is near complete filtered,
secreted and reabsorbed by the kidney.
• Reabsorption is mediated by an organic anion
transporter family member exe URAT-1,
GLUT-9 which can inhibited by uricosuric
drug (compete with this transporter)
 Probenecid (Pharmacokinetic)
• Competely absorbed after oral administration.
• Peak [plasma] reached in 2-4 h.
• T ½ 5-8 h.
• 85%-95% protein bound.
• Excreted by kidney (unchange form,
hydroxylated, glucoronide)
 Probenecid (Theraupetic used)
• Oral administration.
• Starting dose 250 mg bid, increased over 1-2
weeks 500-1000 mg bid.
• Increasing urine urate level.
• Needed liberal fluid intake to minimize risk of
renal stone.
• Probenecid should not be used in gouty patient
with nephrolithiasis.
 Probenecid (drug interaction and common
adverse affect)
• Ineffective in patient with renal insufficiency and
should avoid in those with CCl <50 ml/min.
• Inhibited MTX, clorfibrate, naproxen, ketoprofen
and indometachin excretion.
• Salicilate antagonize uricosuric effect of
probenesid.
• Caution in patient with peptic ulcer.
• Alkalinization of urine may prevent formation of
uric acid stone, hematuria, and costovertebral pain
associated with probenecid therapy.
 Benzbromarone
• Potent uricosuric agent.
• Hepatotoxicity has been reported in conjungtion with
this.
• It is metabolized to monobromine and dehalogenated
derivated have uricosuric effect.
• Uricosuric effect blunted by aspirin and sulfinpirazone.
• Available in europe as micronized powder, 40-80 mg
single daily dose.
• Combination allopurinol and benzobromarone more
effective than eithr drug alone, although lowering
plasma level oxypurinol.
Gout Therapy Guideline (ACR 2012)
Gout Therapy Guideline (ACR 2012)
Dietary intake (ACR 2012)
Terapi Rheumatoid
Arthritis (DMARDs)
 Introduction
• Rheumatoid arthritis is autoimune diseases caused
chronic sinovial inflammation and bone destruction.
• Pharmacology management with NSAID and
corticosteroid control inflammation and proven
analgesic but ineffective in preventing inhibiting the
underlying patogenic process.
• DMARDs retard or halt the underlying progression,
limiting joint damage but lacking antiinflamatory and
analgesic effect.
• DMARDs have shown slow teraupetic proven so
DMARDs actually combined with NSAID and/or
corticosteroid for pharmacology management RA.
 DMARDs
• Synthetic DMARDs consist of gold
compound, MTX, sulfasalazine,
hydroxychloroquin, leflunomide, azatioprine,
penicillamine, mynociline.
• Biologic DMARDs control cytokine
production and released (TNF blocker , IL-1
receptor antagonist)
 Metothrexat (MTX)
• Antifolate drug, inhibiting dyhidrofolate reductase,
blockade pyrimidine biosynthesis_blocking limfosit
proliferation. Activating NF-kB.
• Well PO absorbed at dose 7.5-25 mg weekly, oral
bioavailabilyity 60%, food delay absorbstion and lowering
peak [plasma], Vd 0,4-0,8 L/kg, protein binding 50%.
• Active metabolite polyglutamate, 7 hydroxy MTX
• Elimination via kidney in unchange form
• Terapy respone can be seen in 3-6 weeks.
• DI !!! NSAID, probenecid, penicillin G
• Side effect: mucosal ulceration and nausea (acute),
cytopenia, liver cirrhosis, acute pneumonia like syndrome
(chronic)
 Leflunamide
• Prodrug, completely metabolized to
teriflunamide.
• MOA: inhibiting lymphosite B prolif,
decreased cytokine, decreased UMP and
inhibit dihidroorotate dehidrogenase(arrest life
cycle cell, DNA-RNA synthetized decrease)
• Cholestiramin enhance elimination
• Elimination via biliar and renal.
 Sulfasalazine
• Prodrug, metabolized by colonic bacteria be 5
ASA(mesalamin) and sulfapiridin.
• Enhanced adenosine released and decreased
inflammation by bnding A2 adenosisn receptor
in inflammatory cell_reduced inflammatory
cytokine and TNF alfa.
 Aminoquinolines
( Hydroxychloroquin and chloroquin)
• Hydroxychloroquin less toxic and less potent
than chloquin.
• Teraupetic effect can be seen in 1-2 month for
RA.
• MOA: inhibiting chemotaxis PMN, inhibiting
cartilage condromucoprotease and cartilage
captehesin B)
• Side effect : corneal and renal toxicity.
 TNF blocker
• TNF alfa is proinflammatory cytokine that has
major role in the pathologic process in RA.
• Consist of recombinan soluable TNF receptor,
competitive with TNF receptor cell(etanercef) and
antibody of TNF alfa (infliximab, adalimumab)
• Neutralize effect of TNF so reduced pain,
morning stifness, tender and swollen joint.
• Teraupetic effect can be seen in 1-2 weeks
• Sinergy with MTX
 IL-1 receptor antagonist
• Anankira competitive binding IL-1
• Anankira available in SC injection
• Can be used as single therapy or combined
with other DMARDs ex TNF blocker.
• T ½ 4-6 y, available as SC injection one a
weeks.
Thax U