Treatment of gout

2. Gout?
 Precipitation of urate crystals (MSU) in the tissues
& the subsequent inflammatory response
 Acute gout (painful distal monoarthritis, joint
destruction, subcutaneous deposits ‘tophi’, renal
calculi & damage)
 Most common form of inflammatory arthritis in the
elderly.

3.  Uric acid, the end product of purine metabolism, is
relatively insoluble compared to its hypoxanthine
& xanthine precursors (normal value ~5mg/dL)
 Hyperuricemia arises from underexcretion rather
than overproduction (~10% of cases) of urate.
 Mutations of one of the renal urate transporters,
URAT-1, are associated with hypouricemia

4. Diagnosis?
 Features
 Pain, swelling, redness & stiffness of the joint
 Presence of tophi, MSU crystals in the aspirated joint
fluid
 Other types of gout viz Ca2P2O7. 2H2O, oxalate,
hydroxyapatite etc (pseudogout)

5.  The aims of treatment are to:
 Decrease the symptoms of an acute attack
 Decrease the risk of recurrent attacks
 Lower serum urate levels
○ Urate lowering drugs (synthesis inhibitors & uricosuric
agents)
○ Low purine diet
○ Conversion of urate to allantoin

6.  The substances available for these purposes are:
 Drugs that relieve inflammation & pain (NSAIDs,
colchicine, glucocorticoids)
 Drugs that act by inhibition of urate formation
(allopurinol, febuxostat) or to augment urate excretion
(probenecid)

10.  Acute gout
 Painful arthritic attack of sudden onset
 Usually at night / in the early morning
 Involves 1/more joints
 Most common site is 1st metatarsophalangeal joint
(podagra)
 Other sites may be affects (ankle, knee etc)
 Systemic Sx (fever, chills etc)

11.  Chronic gout
 Subcutaneous tophi (pinna, eyelids, nose etc)
 Urate crystals in kidney (urate nephropathy due to
hyperuricosuria)
 Joint cartilage damage due to tophi followed by
deformity
 Joint pain & stiffness in between the attacks

12. Classification of Drugs Used in Gout
 Acute gout
 Inhibits neutrophil migration into joints (Colchicine)
 Antiinflammatory & analgesics (NSAIDs, Prednisolone)
 Chronic gout
 Urate synthesis inhibitors (Allopurinol, Febuxostat)
 Increase urate excretion (Probenecid, Benzbromarone,
Sufinpyrazone)
 Convert uric acid to allantoin (Rasburicase,Pegloticase)

13.  Colchicine
 One of the oldest (for acute gout)
 Considered 2nd line therapy (narrow therapeutic window
& high rate of S/E, particularly at higher doses)
 Antimitotic effects: arresting cell division by interfering
with microtubule & spindle formation (greatest on cells
with rapid turnover e.g., neutrophils, GI epithelium)
 Lowers body temperature, increases the sensitivity to
central depressants, depresses the resp center,
enhances the response to sympathomimetic agents,
constricts blood vessels, & induces HTN by central
vasomotor stimulation

15.  PKs
 Absorption of oral colchicine is rapid but variable & PPB
is 50%.
 The formation of colchicine-tubulin complexes in many
tissues contributes to its large volume of distribution.
 Significant enterohepatic circulation.
 May undergo demethylation by CYP3A4.
 Other CYP3A4 substrates, viz cimetidine, have been
associated with an increase in colchicine plasma t1/2 &
the emergence of colchicine toxicity.

16.  Acute Gout
 Colchicine dramatically relieves acute attacks of gout.
 Pain, swelling, & redness abate within 12 hours and are
completely gone within 48-72 hours.
 1mg stat, followed by 0.25mg 1-3 hourly till response
occurs / diarrhea? (usually within 12 hrs)
 The dose must be adjusted in pts exposed to inhibitors
of P-glycoprotein or CYP3A4 within the previous 14
days

17.  Prophylaxis
 Particularly in the early stages, the typical dose is 0.5
mg taken orally 3 or 4 days/wk for pts who have <1
attack per year
 0.5 mg daily for pts who have >1 attack per year
 0.5mg bid / tid for pts who have severe attacks
 The dose must be decreased for pts with impaired renal
function
 In the early stages of allopurinol or probenecid therapy
to prevent acute attack

18.  Familial Mediterranean Fever
 Daily colchicine is useful for the prevention of attacks of
familial Mediterranean fever and prevention of
amyloidosis, which may complicate this disease

19.  Adverse Effects
 NVD & abdominal pain are the most common & the
earliest signs of impending colchicine toxicity (Should
be discontinued as soon as these symptoms occur)
 Acute intoxication causes hemorrhagic gastropathy
 Other serious side effects include myelosuppression,
leukopenia, granulocytopenia, thrombocytopenia,
aplastic anemia, & rhabdomyolysis
 Life-threatening toxicities are associated with
concomitant administration of P-glycoprotein / CYP3A4
inhibitors

20.  Colchicine vs NSAIDs
 Colchicine is more toxic than NSAIDs
 Prefer NSAIDs over colchicine (whenever possible)
 Use colchicine when diagnosis is in doubt (as it
specifically relieves gout & not other arthritides)

21. NSAIDs in Acute Gout
 Non-salicylate anti-inflammatory drugs are preferred
(indomethacin, naproxen, piroxicam, diclofenac)
 Better tolerated than colchicine (esp indomethacin)
 Inhibit chemotaxis of PMNs & phagocytosis of urate
crystals into the inflammed joints.
 ASA & salicylates have biphasic effect (<2gm/d vs
>5gm/d) & block the uricosuric effect of probenecid

22.  High dose ASA can promote nephrolithiasis
(due to uricosuric effect)
 Used early in the course of uricosuric therapy
(mobilization of urate is associated with a
temporary increase in the risk of acute gouty
arthritis)

24. Corticosteroids in Acute Gout
 Reserved for refractory cases (not responding to /
not tolerating NSAIDs/colchicine)
 Avoid systemic steroids (toxicity)
 Prednisolone 40-60mg/d x 3-5 days followed by
dose tapering over 2-3 wks
 Intra-articular injection of soluble steroid
(hydrocortisone) is usually preferred

25.  Response to steroids is dramatic
 Intr-articular inj is indicated when large joints are
involved (knee)

26. Drugs Used for Chronic Gout
 Allopurinol (suitable for overproducers)
 Inhibits xanthine oxidase & prevents the synthesis of
urate from hypoxanthine and xanthine
 Even though underexcretion rather than overproduction
is the underlying defect in most gout pts, allopurinol
remains effective therapy
 Mobilization of tissue stores of uric acid can precipitate
acute attack (NSAIDs/colchicine)

29.  Allopurinol facilitates the dissolution of tophi &
prevents the development / progression of chronic
gouty arthritis.
 The formation of uric acid stones disappears
(prevents the development of nephropathy)
 Rapid oral absorption, t ½ is ~ 2hrs (active
metabolite oxypurinol / alloxanthine t ½ =24 hrs),
no PPB.
 Excreted unchanged

30.  Therapeutic Uses of Allopurinol
 Primary hyperuricaemia (gout)
 When uricosuric drugs can’t be used
 Secondary hyperuricaemia (anticancer therapy induced)
○ Drug-induced hyperuricaemia (thiazides, ethambutol,
pyrazinamide, levodopa etc)
 Adjuvant with SSG for Kalazar (Leishmaniasis)

31.  ADRs:
 Occasionally induces drowsiness
 Hypersensitivity reactions (may manifest after months /
years of therapy)
 Pruritic, erythematous, or maculopapular eruption, but
occasionally the lesion is urticarial or purpuric
 Rarely, TEN / Stevens-Johnson syndrome occurs (can
be fatal)
 Transient leukopenia or leukocytosis & eosinophilia are
rare
 Hepatomegaly & elevated levels of transaminases in
plasma and progressive renal insufficiency may occur

33.  Drug Interactions
 Allopurinol increases the t1/2 of probenecid & enhances
its uricosuric effect
 Probenecid increases the clearance of oxypurinol,
thereby increasing its dose requirement
 Decreased metabolism of 6-MP & its derivative
Azathioprine (dose reduction of 6-MP to 1/4th or 1/3rd)
 Monitoring of prothrombin activity is recommended in
pts receiving warfarin & allopurinol

34.  More hypersensitivity reactions with thiazides & when given
to pts with renal insufficiency
 Bone marrow suppression is increased when allopurinol is
administered with cytotoxic agents (cyclophosphamide)
 Allopurinol with theophylline leads to increased accumulation
of an active metabolite of theophylline, 1-methylxanthine
 Increased incidence of rash in pts receiving concurrent
allopurinol & ampicillin

35.  Febuxostat
 A novel non-purine inhibitor of xanthine oxidase
 Rapidly absorbed orally
 Magnesium hydroxide & aluminum hydroxide delay
absorption
 High PPB & has a volume of distribution of 50 L
 Extensively metabolized by oxidation (CYPs 1A2, 2C8,
& 2C9) and non-CYP enzymes conjugation via UGTs

36.  More potent & selective inhibitor of XO
 80-120mg/d OD
 Used for chronic gout or secondary hyperuricaemia
 Very suitable for pts intolerant to allopurinol
 ADRs:
 Liver dysfunction, diarrhea, headache

37.  Uricosuric Agents
 In humans, urate is filtered, secreted, and reabsorbed
by the kidneys
 Reabsorption predominates, such that the net the
amount excreted usually is ~10% of that filtered
 Reabsorption is mediated by an organic anion
transporter family member, URAT-1, which can be
inhibited
 Uricosurics viz probenecid, sulfinpyrazone,
benzbromarone, & losartan compete with urate for the
transporter (inhibiting its reabsorption)

38.  Determination of 24 hr urine uric acid excretion is
essential to identify the most appropriate urate-
lowering drug & to check for significant preexisting
renal insufficiency
 “Underexcretors” of uric acid (<800 mg in 24 hr)
 Renal insufficiency / a history of nephrolithiasis, or
those who might benefit from the cardioprotective
effect of low-dose aspirin therapy should not take
uricosuric agents.

39.  Candidates for probenecid therapy must have:
 Underexcretion (<800 mg in 24 hours on a regular diet
or <600 mg in 24 hours on a purine-restricted diet)
 Creatinine clearance >60 ml/min
 No history of nephrolithiasis

40.  Probenecid
 Inhibits the reabsorption of uric acid by organic anion
(acid) transporters (URAT-1)
 Tubular secretion of a number of drugs is also inhibited
viz methotrexate, penicillis, cephalosporins etc
 Decreases the biliary secretion of rifampin, leading to
higher plasma levels
 Salicylates block the uricosuric action of probenecid

42.  PKs
 Absorbed completely after oral administration
 PPB is 85%-95%
 Secreted actively by the proximal tubule

43.  Uses:
 Gout
 250 mg bid, increasing over 1-2 wks to 500-1000 mg bid
 Liberal fluid intake should be maintained (to minimize
the risk of renal stones)
 Should not be used in gouty pts with nephrolithiasis or
with overproduction of uric acid
 Concomitant colchicine / NSAIDs are indicated early in
the course of therapy to avoid precipitating an attack of
gout

44.  Combination with Penicillin
 Probenecid was developed for the purpose of delaying
the excretion of penicillin
 Usually for gonorrhea (both for NPPNG & PPNG)

45.  ADRs:
 Generally well tolerated
 Mild GI irritation at higher doses
 Use with caution in pts with peptic ulcer
 Ineffective in pts with renal insufficiency & should be
avoided in those with creatinine clearance of <50 ml/min
 Hypersensitivity reactions (mild)

46.  Benzbromarone
 Potent uricosuric agent that is used in Europe
 Hepatotoxicity has been reported
 Yields active metabolites & excreted primarily in the bile
 Allopurinol + Benzbromarone combination is more
effective than either drug alone
 Effective in pts with renal insufficiency
 Prescribed to pts who are either allergic / refractory to
other drugs

47.  Sulfinpyrazone:
 Pyrazolone derivative related to phenylbutazone
 Uricosuric action is additive with probenecid
 Inhibits platelet aggregation
 Well absorbed orally with 98% PPB
 Inhibits the metabolism of sufonylureas & warfarin
 Causes gastric irritation (CI in PUD pts)

48.  Rasburicase
 Recombinant urate oxidase (converts uric acid into the
soluble & inactive metabolite allantoin)
 Lower urate levels more effectively than allopurinol
 Given in initial management of hyperuricaemia in
pediatric pts with leukemia, lymphoma
 Therapeutic efficacy may be reduced by the production
of Ab against the drug (immunogenic)

49.  ADRs:
 Hemolysis in G6PD-deficient pts
 Methemoglobinemia
 Acute renal failure
 Anaphylaxis
 Vomiting, fever, nausea, headache, abdominal pain,
constipation, diarrhea & mucositis

50.  Treatment Algorithm for Acute Gout