DRUGS USED IN

HYPERURICEMIA
Department of Pharmacology & Therapeutics
Faculty of Medicine Diponegoro University
2017
INTRODUCTION:
Hyperuricemia, and Why it is important

GOUT

- Incidence of AF
- Development of AF
HYPERTENSION
ATRIAL - Recurrence of paroxysmal
FIBRILLATION & permanent AF after
HYPERURICEMIA
catheter ablation
(SUA>7mg/dl (M)
/ >6mg/dl (F)

1. 20% mortality in first year

2. Substantial increase in the risk of
KIDNEY METABOLIC stroke, heart failure, and dementia
DISEASE SYNDROME

2
Uric acid metabolism

dietary intake purine bases cell breakdown

xanthine oxidase hypoxanthine

catalyzes
hypoxanthine to
xanthine & xanthine
xanthine to uric
acid
uric acid
Hyperuricemia

e t i o n
excr
c t i o n
produ

hyperuricemia results when production exceeds excretion

Hyperuricemia - mechanisms

excessive inadequate
production excretion

hyperuricemia
Hyperuricemia - mechanisms

overproducers underexcretors

hyperuricemia
 Principal of lowering total body pool of uric acid:

Xanthine
oxidase
block enhance Uricouric
agents
inhibitor production excretion

Recombinant net reduction in total body pool of

Urate oxidase
uric acid
Drugs That Block Production
of Uric Acid
 Allopurinol
• inhibitor of xanthine oxidase
• Isomer of hypoxanthine
• effectively blocks formation of uric acid
• The incidence of acute attack of gouty arthritis may increase
during the early months of allopurinol → co-administration of
colchicine, or NSAID, until steady-state serum uric acid is
normalized or decreased to less than 6 mg/dL for 6 months or
longer.
• pregnancy category C
Uric acid metabolism

dietary intake purine bases cell breakdown

oxypurinol
hypoxanthine

allopurinol
xanthine allopurinol
allopurinol
inhibits xanthine
oxidase
uric acid
Allopurinol

• Absorbed rapidly after oral ingestion, peak plasma level 60-90

mins
• Excreted in feces (20%) and urine (10-30%). The remainder is
metabolized to oxypurinol
• once daily dosing, start with 50-100 mg/day, to 800 mg/day
(once a day)
• lowers serum uric acid levels
• lowers urine uric acid levels
Allopurinol - usage indications
• management of hyperuricemia of gout
• management of hyperuricemia associated with chemotherapy
• prevention of recurrent calcium oxalate kidney stones

Common side effects:

• diarrhea, nausea, abnormal liver tests
• acute attacks of gout
• Rash → STOP ALLOPURINOL
Allopurinol - serious reactions
• fever, rash, SJS, toxic epidermal necrolysis
• hepatotoxicity, marrow suppression
• vasculitis
• drug interactions (ampicillin, thiazides, mercaptopurine, azathioprine)

• Note: due to its serious adverse reactions, Allopurinol is not

recommended for asymptomatic hyperuricemia
Febuxostat
• oral xanthine oxidase inhibitor
• chemically distinct from allopurinol
• 94% of patients reached urate < 6.0 mg/dl
• Metabolized in the liver, only 5% appear in the urine
• can be used in patients with renal disease (mild to moderate)
• Common adverse events: liver function abnormalities, nausea, joint
pain, rash, cardiovascular complications (infarct, stroke)
Febuxostat
• Starting dose 40 mg/day, max 80 mg/day.
• Increase in gout flares after initiation of therapy → treated with
NSAID or colchicine
• Drug interactions:
- Influences plasma levels of drugs that are metabolized by XO (e.g.
Theophylline, mercaptopurine, azathioprine).
Rasburicase
• Recombinant urate oxidase (uricase)
• Catalyzes the enzymatic oxidation of uric acid into alantoin
• Indicated for initial management in patients with leukemia,
lymphoma, and solid tumor malignancies who are receiving
anticancer therapy
• uricase speeds resolution of tophi
• Antibody against the drug
• Adverse reactions: hemolysis in glucose-6-phosphate dehydrogenase
(G6PD)-deficiency, methemoglobinemia, acute renal failure,
anaphylaxis, vomiting, diarrhea, fever, nausea, etc.
Pegloticase
• Recombinant urate oxidase (uricase)
• Similar to Rasburicase, but pegylated (attached to methoxy
polyethylene glycol (mPEG)) → prolong the circulating half-life and
diminish immunogenic response.
• IV infusion, administered 8 mg every 2 weeks.
• Not to be used in asymptomatic hyperuricemia.
• Adverse effects: anaphylaxis, nephrolithiasis, arthralgia, muscle
spasm, headache, anemia, nausea, hemolytic in patients with G6PD
deficiency.
Drugs That Enhance
Excretion of Uric Acid
Renal handling of uric acid

•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•excretion
Uricosuric Agents
• Probenecid, Benzbromarone, Losartan
• blocks tubular reabsorption of uric acid (URAT-1 inhibitor)
• enhances urine uric acid excretion
• increases urine uric acid level
• decreases serum uric acid level
Uricosuric Agents
• moderately effective, less effective in elderly patients
• increases risk of nephrolithiasis
• contra-indications
• history of nephrolithiasis
• elevated urine uric acid level
• existing renal disease
• frequent, but mild, side effects
• some drugs reduce efficacy (e.g., aspirin)
Probenecid
• Highly lipid-soluble benzoic acid derivative
• MOA: URAT-1 inhibitor (inhibits reabsorption of uric acid)
• Drug interactions: aspirin antagonize the uricosuric effect of Probenecid.
Other intx: NSAIDs (naproxen, ketoprofen, indomethacin), penicillin-G
• Initial dose 250 mg twice daily, increased over 1-2 week to 500-1000 mg
• Liberal fluid intake
• The incidence of acute attack of gouty arthritis may increase during the
early months
• Mostly well-tolerated. AR includes: GI irritation, hypersensitivity reactions,
rash
Benzbromarone
• Potent uricosuric agent, URAT-1 inhibitor
• Registered with restriction in some countries due to its hepatotoxic
property
• Metabolized into monobromine and dehalogenated derivative, both
of which hava uricosuric action
• Excreted primarily in the bile
• The uricosuric action is blunted by aspirin or sulfinpyrazone
• Combination with Allopurinol enhance the effect of lowering serum
uric acid (SUA) level
Losartan
• Originally an angiotensin receptor blocker
• Inhibit uric acid transporter 1 (URAT1)
• Dose: 50mg/day
• Adverse effects: allergic reaction, breakdown of skeletal muscle,
nausea, vomiting, etc.
Lesinurad
• URAT1 inhibitor
• Used in combination with xanthine oxidase inhibitor
• Not for asymptomatic hyperuricemia
• Dose 200 mg once daily, taken in the morning
• Liberal fluids intake
• Adverse effects: headache, influenza, blood creatinine increased, and
gastroesophageal reflux disease
• Do not use in renal impairment, or in the presence of renal disease
Drugs Used in Gout
Colchicine
• Alkaloid from Colchicum autumnale
• Relieves pain and inflammation of gouty arthritis
• Inhibit leukocyte migration and phagocytosis, inhibits leukotriene B4
and IL-1B
• Adverse effects: diarrhea, nausea, vomiting, abdominal pain, hepatic
necrosis, acute renal failure, DIC, peripheral neuritis, myopathy,
death.
• Dose, prophylaxis: 0.6 mg (1-3x daily). Acute attack: 1.2 mg
NSAIDs
• Inhibit prostaglandin synthase, and urate crystal phagocytosis
• Aspirin is not used! → it causes renal retention of uric acid at low
dose
• Indomethacine : commonly used as a replacement for colchicine
Glucocorticoids
• Corticosteroids are sometimes used to treat severe symptomatic gout
• Intra articular, systemic, or subcutaneous route.
• Prednisone: 30-50 mg/day for 1-2 days, tapered over 7-10 days.
Interleukin 1 inhibitors
• Anakinra, canakinumab, rilonacept
• There is still a limited data on the use of these drugs
• For acute gout, in patients with contraindications to NSAIDs or
Colchicine
Thank you