uric acid pathway pharmacotherapy in gout gout uric acid...
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อ.ภญ.ฐติมิา ดว้งเงนิ, MPharm, PharmD, BCPS, อภ.คณะเภสชัศาสตร ์ มหาวทิยาลยัสงขลานครนิทร์
20 มถินุายน 2557
Pharmacotherapy in Gout
การประชมุเชงิปฏบิตักิารงานเภสชักรรมคลนิกิ ครั >งที@ 18/2557“Pharmaceutical Care for Patients with Chronic Diseases”
เอกสารในหนังสอืหนา้ 245 – 273
Gout
Outline:
� Uric acid pathway
� Gout vs. hyperuricemia
� How to manage acute
gout attack?
� Chronic management
of gout
� Hyperuricemia - Who
should be treated?
Uric acid pathway
Purine synthesis
300-600 mg/d
PURINE
600 mg/d+ H+
Uric acid
GI tract 200 mg/d
• Mostly degraded by colonic bacteria
Urine 600 mg/d
Uric acid
1200 mg/d
Uric acid (pool)
1200 mg/d
• Glomerular filtration
• Proximal reabsorption and
secretionUrate transporters:
URAT1 (gene SLC22A12)
GLUT9 (gene SCL2A9)
URAT1 = urate/organic anion exchanger 1GLUT9 = glucose transporter 9
Gout & Hyperuricemia
� Hyperuricemia: uric acid level > 6.8 – 7.0 mg/Dl
� Chronic hyperuricemia � precipitation of MSU crystals
� + Predisposing factors e.g., trauma, surgery
Release of MSU crystals to joint space � inflammation
• Gout: presence of monosodium urate (MSU) crystals in joints, bones, and soft tissues
Hyperuricemia
Gout
∼ 10-30%
Asymptomatic hyperuricemia(progressive MSU deposition)
Acute gouty arthritis
Intercritical (interval) gout
Chronic recurrent gout
Tophaceous gout
http://health-fts.blogspot.com
Prevalence of Gout
� Male > Female
� Increase with age
Clin Rheumatol 2012;31:13-21
Clinical Presentation
http://health-fts.blogspot.com
• Arthritis, > 1 joint(s)
• Tophus or tophi
• Renal
• Urolithiasis
• Chronic interstitial
nephropathy (rare)
ชายไทย อาย ุ53ปี (สว่นสงู 162 ซม. นํ>าหนัก 82 กก.) อาชพีรับจา้ง มาหอ้งฉุกเฉนิในโรงพยาบาล
CC: ปวดนิ>วหวัแมเ่ทา้ดา้นซา้ย มาประมาณ 8 ชั@วโมง PTAHPI: เมื@อวานนี>ว ิ@งและปั@นจักรยานนานประมาณ 2 ชั@วโมง กอ่น
เดนิทางไปรว่มงานเลี>ยงฉลองแตง่งานที@ตา่งอําเภอ ดื@มเบยีร์ประมาณ 3 ขวด โดยมแีกงเครื@องในสตัวเ์ป็นกบัแกลม้
8 ชั@วโมง PTA (2.00 น.) ผูป้่วยเริ@มรูส้กึปวดนิ>วหวัแมเ่ทา้ดา้นซา้ย (pain 6/10) กนิ paracetamol 500 mg
เชา้วนันี>ตื@นขึ>นมา ยังคงมอีาการปวดอยู ่(pain 5/10) ไมม่ีปวดขอ้ที@ตําแหน่งอื@น และสงัเกตวา่นิ>วเทา้มลีกัษณะบวม แดง จงึมาโรงพยาบาล
PMH: Asthma (controlled) และ hypertension (วนิจิฉัยเมื@อ 1 เดอืนกอ่น BP 167/102 mmHg)
Med PTA: Salbutamol MDI 1-2 puff prnHCTZ 25 mg 1 x 1 pc
Allergy: NKDASH: ปฏเิสธการสบูบหุรี@
ดื@มสรุาและเบยีรบ์า้งในงานสงัคม ชอบกนิเนื>อสตัว ์ไมค่อ่ยรับประทานผักและผลไม ้
PE:
VS: BP 143/84 mmHg, PR 70/min, RR 20/min, Temp 36.5 CExt: No pitting edema, Left MTP joint is warm to touch
moderate swelling, tender and erythematous
Which one of the following is the best
way to diagnose the patient’s gout ?
Criteria for diagnosis of gout
� Rome criteria (1963)
� New York criteria (1966)
� American College of Rheumatology
preliminary criteria for gout (1977)
หนา้ 254-5
Rome Criteria
Urate crystal in synovial fluid
Meet at least 2 of the following:
� Painful, swollen joint with an abrupt onset, clearing
initially in 1-2 weeks
� Serum uric acid > 7 mg/dL (male) or > 6 mg/dL
(female)
� Tophi present
ACR preliminary criteria of diagnosis of acute gout
Meet at one of the following: � MSU crystals in synovial fluid during attack � Presence of proven tophous � At least 6 of the following criteria:
� More than 1 acute arthritis attack� Maximal inflammation developed within 1 day� Monoarthritis attack� Redness observed over joints� First MTP joint attack � Unilateral first metatarsophalangeal joint attack � Unilateral tarsal joint attack� Suspected tophous � Asymmetric swelling within a joint on a radiograph � Subcortical cysts without erosions on a radiograph� Hyperuricemia � Synovial fluid culture negative for organisms during attack
Arthritis Rheum 1977;20:895-900.
http://www.physio-pedia.com/Gout
metatarsophalangeal (MTP) joint
Tophous
http://health-fts.blogspot.com
http://health-fts.blogspot.com
Differential Diagnosis of Acute Gout
Diagnosis Synovial fluid finding
WBC /mm3
Gram stain/ culture
Synovial fluid crystal
Gout 2,000 –50,000
Negative MSU crystals(needle shaped, negative birefringence)
Pseudogout 2,000 –50,000
Negative CPPD crystals(rhomboid shaped, weak positive birefringence)
Septicarthritis
> 50,000 Positive No crystals
MSU = monosodium urate, CPPD = Ca pyrophosphate dihydrate
Am Fam Phys 2007;76:801-808.
ตารางที@ 3 หนา้ 256
Monosodium urate (MSU) crystal
Needle shaped, negative birefringent crystals
Clev Clin J Med 2008;78:s17-s21.
Pseudogout
Calcium pyrophosphate dihydrate (CPPD) crystal
Rhomboid shaped, weakly positive birefringent crystal
Clev Clin J Med 2008;78:s17-s21.
Which one of the following is the best way to diagnose the patient’s gout ?
A. Check joint for presence of monosodium
urate (MSU) crystals
B. Obtain synovial fluid gram stain and culture
C. Check serum uric acid concentration
D. Assess clinical symptoms
IL-1ββββ
Clin Rheumatol 2012;31:13-21
Which one of the following is the
best initial treatment regimen for
the patient’s attack ?
ACR 2012 Recommendations
Acute Gouty Arthritis
� Severity….based on self-reported pain (0-10 VAS)
Mild < 4Moderate 5 – 6 Severe > 7
� Extent… based on number of active joints
One or few small joints1 or 2 large joints (ankle, elbow, wrist, hip, shoulder)
Polyarticular (> 3 large joints or > 4 joints involving > 1 region)
Arthritis Care & Research 2012: 64:1431–1446.
แผนภมูทิี@ 1 หนา้ 258
Assess severity
Initial Therapy of Acute Gout Attack
* For acute gout if started w/in 36 hours of symptom onset
MonotherapyMild-moderate
NSAIDs/COX-2 inhibitor
Systemic corticosteroids
Colchicine*
Combination therapySevere
• NSAID + Colchicine• PO steroid + Colchicine• IA steroid + …..
Arthritis Care & Research 2012: 64:1431–1446.
NSAIDs/COX-2 inhibitors
� All oral NSAIDs/COX-2 inhibitors are effective
� Low dose aspirin (75 – 150 mg/d) does not significantly
affect urate concentrations and should be continued if
required for cardiovascular prophylaxis
� No consensus on the topical NSAIDs and IM ketorolac
for the treatment of acute gout
ACR 2012 recommendation
Arthritis Care & Research 2012: 64:1431–1446.
ตารางที@ 5: ขนาดยา NSAIDs ตารางที@ 5 หนา้ 259
Colchicine
� Acute gout attack (within 36 hours of symptom onset)
� LD: 1.2 mg, then 0.6 mg 1 hour later
� MD (prophylaxis): 0.6 mg once or twice daily
– start 12 hours later, until gout attack resolved
� Avoid in patients with severe renal or hepatic impairment � bone marrow suppression or neuromyopathy
Colchicine dosing reduction: • CKD• CYP 3A4 and P-glycoprotein inhibitors
ACR 2012 recommendation
Arthritis Care & Research 2012: 64:1431–1446.
ตารางที@ 6 หนา้ 261
Corticosteroids
� Extent of joint involvement
� Oral prednisolone 0.5 mg/kg/day
� for 5 – 10 days and then stop OR
� for 2 – 3 days of full dose � taper for 7 – 10 days then stop
� 1-2 large joint(s): Intra-articular corticosteroids
� + oral corticosteroids/ NSAID/ colchicine
� Dose varies by the size of involved joint(s)
ACR 2012 recommendation
Arthritis Care & Research 2012: 64:1431–1446.
Which one of the following is the best initial treatment regimen for the patient’s attack ?
A. Prednisolone 10 mg PO daily
B. Triamcinolone 20 mg IA into affected joint
C. Colchicine 1.2 mg PO, followed by 0.6 mg
in 1 hour
D. Naproxen 500 mg PO BID
Inadequate response
Inadequate Response of an Initial Therapy
•< 20% improvement in pain score w/in 24 hours•< 50% improvement in pain score > 24 hours after initiating pharmacotherapy
Switch to another monotherapy
Combination therapy
Refractory to other agents+ IL-1 inhibitors (Ankinra 100 mg SC daily x 3 days)
Arthritis Care & Research 2012: 64:1431–1446.
แผนภมูทิี@ 1 หนา้ 258
Should Uric Lowering Therapy be Initiated?
� ACR 2012, recommend uric acid lowing therapy (ULT) for
gouty arthritis patients with one of the following:
� Tophus or tophi by clinical exam or imaging study
� Frequent acute gouty arthritis attacks (> 2 attacks/yr)
� CKD stage 2 or worse
� Past urolithiasis (uric acid stone)
Target of serum uric acid after treatment < 6 mg/dL < 5 mg/dL may be needed to improve S/Sx
Arthritis Care & Research 2012: 64:1431–1446.
แผนภมูทิี@ 2 หนา้ 262
6 เดอืนตอ่มา
ผูป้่วยมอีาการปวดขอ้ในลักษณะเดยีวกนันี> จงึไดม้าพบแพทยท์ี@โรงพยาบาลอกีครั >ง แพทยพ์จิารณาใหก้ารรักษาแบบเดยีวกนักบัครั >งกอ่น จากการตรวจทางหอ้งปฏบิตักิารครั >งนี> ไดผ้ลดงันี>
Na 138 K 4.1 Cl 99 HCO3- 24
BUN 28 Cr 1.5 Uric 7.5
ผูป้่วยเริ@มกนิยา colchicine อกีครั >งเมื@อคนืนี>
Which one of the following is the
most appropriate intervention for
this patient ?
Long-Term Management of Gout
� Initiate ULT 1 – 2 weeks after the inflammation of the acute attack has resolved
� ULT may precipitate gout attack
� Use prophylaxis against acute attacks when initiating ULT:
� Colchicine 0.6 – 1.2 mg/d for up to 6 months OR
� NSAIDs/COX-2 inhibitors (for not more than 6 weeks)
� Consider losartan and fenofibrate for HTN and hyperlipidemia respectively, for their modest uricouric effects
Uric Lowering Therapy
Xanthine oxidase inhibitors • Allopurinol• Febuxostat (not available)
Uricosuric• Probenecid• Benzbromarone• Sulfinpyrazone
Recombinant urate-oxidase enzyme• Pegloticase (not available)
Allopurinol Allopurinol
� Xanthine oxidase inhibitor
� 1st line therapy for hyperuricemia
� Dose:
� starting dose < 100 mg/day for any patient
� 50 mg/day for CKD > 4
� gradually titrate every 2-5 weeks
� dose can be raised above 300 mg/day, even in
those with renal impairment
� Serious ADR: Allopurinol hypersensitivity syndrome
ตารางที@ 7 หนา้ 264
Allopurinol Hypersensitivity Syndrome
� Fever with rash is the most common clinical findings
� Severe cutaneous reaction may be found
� Mortality rate ∼ 20 – 25%
� HLA-B*5801 polymorphism� Han Chinese, Thai, Korean
http://www.cmaj.ca/content/182/5/476.full.pdf+html
J Dermatol 2011;38:246-254.
Reported HLA-B*5801 for allopurinol-induced cutaneous ADR
Race Reactions Selectivity
Han Chinese (Taiwan) SJS/TEN orDIHS/DRESS
51/51
Thai SJS/TEN 27/27
Caucasians SJS/TEN 15/27
Japanese SJS/TEN/DIHS 3/3
Japanese SJS/TEN 4/10
HLA-B*5801 Allele Frequencies
http://www.cmaj.ca/content/182/5/476/F5.large.jpg
HLA-B*5801 Testing
HLA-B*5801 testing
Positive Negative
Allopurinol-SJS/TEN 400 0Allopurinol tolerant 14,940 84,660
Predictive value 2.7% 100%
Pharmacogenomics. 2010;11:973-987.
� HLA-B*5801 is more evenly distributed among
difference ethnic group
� weaker association
� NOT routinely recommended as a screening tool
before starting allopurinol therapy
� Possible use to confirm the diagnosis
HLB*5801 – Apply to Clinical Practice
FebuxostatFebuxostat
� Dose: 40 – 80 mg/day� Gout flare prophylaxis is recommended when
initialing therapy� Can use in patient with HLA-B*5801 polymorphism� Thromboembolic events (MI, stroke) have been
reported !! � DI: azathioprine, mercaptopurine (↑ level)
Probenecid
� Initial dose:
� 250 mg BID x 1 week � 500 mg BID
� Absent of gout attack for > 6 months � may gradually decrease dose to maintain normal uric acid level (< 6 mg/dL)
� ? Subtherapeutic dose -- may inhibit renal urate secretion
Benzbromarone
� Inhibit proximal renal tubular urate reabsorption �↑ urinary urate excretion
� ↓ uric acid levels by 33–59% (dose-dependent)
� Usual dose: 50–200 mg PO daily
� Serious ADR: liver failure (require liver transplantation)
Sulfinpyrazone
� Dose � Initial: 100–200 mg BID for 1–3 wks � 200–400 mg BID � Absent of gout attack for > 6 months � may gradually
decrease dose to maintain normal uric acid level (< 6 mg/dL)
� CrCl < 10 mL/min � loss of uricouric effect
� Platelet aggregation inhibitor (unclear MOA)
� CI: phenylbutazone allergy
peptic ulcer disease (may aggravate)
serious blood disorders
Uricosuric agents – Class Effects (probenecid, benzbromarone, sulfinpyrazone)
� Urolithiasis (urate stone) ∼ 10%
Prevention:
� Adequate fluid intake (10 – 12 glasses /day)
� Maintain high urine pH
↑↑↑↑ urine pH … a diet high in citrus fruits, vegetables, or dairy products
↓↓↓↓ urine pH … a diet high in meat products or cranberries
� + Aspirin …. ↓ uricosuric effect
…. ↑ risk of bleeding (↓ aspirin excretion)
Pegloticase, IV � Pegylated recombinant form of urate-oxidase
enzyme (uricase)urate-oxidase
uric acid allantoin (water soluble metabolite)
� Approved for refractory gout � NOT for asymptomatic hyperuricemia � Prophylaxis gout flare (NSAID or colchicine) 1 week before
pegloticase and may continue for up to 6 months
� CI: G6PD deficiency � ? Risk of anaphylaxis and infusion-related reactions
� Premedicated with antihistamine + corticosteroid� Slow infusion in > 2 hours
http://health-fts.blogspot.com
Which one of the following is the most appropriate intervention for this patient ?
A. Continue colchicine
B. Start allopurinol and NSAIDs
C. Start allopurinol and continue colchicine
D. Discontinue colchicine and start allopurinol
E. Start allopurinol and prednisolone
Start allopurinol 1-2 weeks later (after acute arthritis resolve)
Causes of hyperuricemia
Comorbidity�Hypertension�Obesity �Metabolic syndrome�Type 2 diabetes�Chronic kidney disease
Hereditary
Drug-induced
Diet (high purine)-induced
Drug-induced Decreased Renal Urate Clearance
� Diuretics (Thiazides and Loops)
� Cyclosporin, Tacrolimus
� Low dose aspirin (< 325 mg/day)
� Ethambutol
� Pyrazinamide
� Ethanol (esp. beer and spirit, but not wine)
� Levodopa
� Methoxyflurane
� Laxative abuse (alkalosis)
� Salt restriction
ตารางที@ 8 หนา้ 267
Diet & Lifestyle for Gout Patients
� งดอาหารที@ purine สงู เชน่ � เครื@องในสตัว ์เนื>อเป็ด/ไก ่กุง้ หอย ปลา (เชน่ ปลาดกุ ปลา
อนิทรยี ์ปลาซารด์นีกระป๋อง) กะปิ นํ>าซปุตา่งๆ � ผัก เชน่ เห็ด กระถนิ ชะอม ขี>เหล็ก หน่อไม ้เห็ด
หน่อไมฝ้รั@ง ดอกกะหลํ@า� ถั@วดํา ถั@วแดง ถั@วเขยีว ถั@วเหลอืง � เบยีร ์ขนมปังผสมยสีต ์
� หลกีเลี@ยงเครื@องดื@ม alcohol � Alcohol � lactic acid � ↓ การขบั uric
Low purine diet
ตารางที@ 4 หนา้ 257
Gout: Summary
� Acute onset of severe joint pain. � Swelling, effusion, warmth, erythema, and/or
tenderness of the involved joint(s).� Arthrocentesis with synovial fluid analysis shows
strongly MSU crystal.� NSAIDs, colchicine, or corticosteroids are used to treat
acute disease. � Allopurinol, uricosuric agents are used as uric acid-
lowering drugs when long-term prevention of crystal deposition is indicated.
� Complications include joint destruction, kidney disease, and urolithiasis.
� Acute onset of severe joint pain. � Swelling, effusion, warmth, erythema, and/or
tenderness of the involved joint(s).� Arthrocentesis with synovial fluid analysis shows
strongly MSU crystal.� NSAIDs, colchicine, or corticosteroids are used to treat
acute disease. � Allopurinol, uricosuric agents are used as uric acid-
lowering drugs when long-term prevention of crystal deposition is indicated.
� Complications include joint destruction, kidney disease, and urolithiasis.
Thank you
☺
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