uric acid pathway pharmacotherapy in gout gout uric acid...

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


• 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



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 + …..


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


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




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)



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)



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



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


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


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


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


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

☺

uric acid pathway pharmacotherapy in gout gout uric acid...

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