gout meds

1. Gout
Pharmacotherapy

2. Gout- Risk Factors

3. What is Gout ?
• Gout is a disorder of purine metabolism, characterized by elevated serum uric
acid level.
• Higher level of serum uric acid may be due to overproduction or impaired
excretion of uric acid.
• It is characterized by interment attacks of acute arthritis produced by deposition
of sodium urate crystals in joints. ( Uric acid has low water solubility and gets
precipitated in the joints, kidney and subcutaneous tissues.)
• Secondary hyperuricemia may result due to excessive production (breakdown of
proteins and nucleic acids during cancer chemotherapy) or decreased excretion
(due to the use of thiazides, loop diuretics, ethambutol, clofibrate etc.) of uric
acid.

4. Cont.…
• Hyperuricemia refers to a serum uric acid level that is elevated more than two
standard deviations above the population mean.
• In most laboratories, the upper limit of normal is 7 mg/dL (uricase method).
• However, the level varies with the laboratory method used; the upper limit of
normal is about 1 mg/dL lower for women than for men.

5. Uric acid Production & Excretion
1. Uric acid, an end product of purine metabolism, is produced from both dietary and
endogenous sources.
2. Its formation results from the conversion of adenine and guanine moieties of nucleoproteins
and nucleotides.
3. Xanthine oxidase catalyzes the reaction that occurs as the final step in the degradation of
purines to uric acid.
4. The body ultimately excretes uric acid via the kidneys (300–600 mg/day; two-thirds of total
uric acid) and via the gastrointestinal (GI) tract (100–300 mg/day; one-third of the total uric
acid).
5. Uric acid has no known biological function.
6. The body has a total uric acid content of 1.0 to 1.2 g; the daily turnover rate is 600 to 800
mg.
7. At a pH of 4.0 to 5.0 (i.e., in urine), uric acid exists as a poorly soluble free acid; at
physiological pH, it exists primarily as monosodium urate salt.

6. Acute Gout
• This clinical presentation of gout is characterized by painful arthritic attacks of sudden
onset.
Pathogenesis
Monosodium urate crystals form in articular tissues; this process sets off an inflammatory
reaction.
• Trauma, exposure to cold, dietary overindulgence, or another triggering event may be
involved in the development of the acute attack.
Signs and symptoms
• The initial attack is abrupt, usually occurring at night or in the early morning as synovial
fluid is reabsorbed.
• This severe arthritic pain progressively worsens and generally involves only one or a few
joints.
• The affected joints typically become hot, swollen, and extremely tender. Seventeenth-
century

7. Cont.…
• The most common site of the initial attack is the first metatarsophalangeal
joint; an attack there is known as podagra. Other sites that may be affected
include the instep, ankle, heel, knee, wrist, elbow, and fingers.
• The first few untreated attacks typically last 3 to 14 days. The joint pain and
inflammation
• completely resolves, even when not treated and is a hallmark of the condition.
Later attacks may affect more joints and take several weeks to resolve.
• During recovery, as edema subsides, local desquamation and pruritus may occur.
• Systemic symptoms during an acute attack may include fever, chills, and
malaise.

8. Tophi- in Gout Patients

9. Diagnostic criteria
1. Definitive diagnosis of gouty arthritis can be made by demonstration of monosodium urate
crystals in the synovial fluid of affected joints. These needle-shaped crystals are termed
negatively birefringent when viewed through a polarized light microscope.
2. Serum analysis usually reveals an above-normal uric acid level: however, this finding is not
specific for acute gout. Other common serum findings include leukocytosis and a
moderately elevated erythrocyte sedimentation rate.
3. A dramatic therapeutic response to colchicine may be helpful in establishing the
diagnosis, but this is not absolute because other causes of acute arthritis may respond as
well.
4. When fluid cannot be aspirated from the affected joint, a diagnosis of gout is supported by:
• A prior history of acute monoarticular arthritis (especially of the big toe) followed by a
symptom-free period
• The presence of hyperuricemia
• Rapid resolution of symptoms after colchicine therapy
5. Other conditions that may mimic gout include pseudogout (calcium pyrophosphate dehydrate
crystal disease) or septic arthritis.

10. Clinical Features
Stage Features Pharmacologic
intervention
Asymptomatic
hyperuricemia
Plasma urate >6.0 mg/dL in women,
>7.0 mg/dL in men
None
Acute gout Acute arthritis
Typically first metatarsophalangeal joint
Excruciating pain
NSAIDs
Colchicine
Glucocorticoids
Intercritical phase Asymptomatic hyperuricemia 10% may
never have another acute attack
none
Chronic gout Hyperuricemia
Development of tophi
Recurrent attacks of acute gout
Allopurinol
Probenecid
Sulfinpyrazone
Note that the degree of hyperuricemia correlates with the likelihood of developing gout;
however, developing gout without hyperuricemia is possible. No pharmacologic intervention
is indicated for asymptomatic hyperuricemia, but the cause should be investigated.

11. Treatment goals
Treatment goals
1. To Relieve Pain and Inflammation
2. To Terminate the acuteAttack
3.To Restore Normal Function to theAffected joints
Therapy
1. General Therapeutic Principles
• a. The affected joint (or joints) should be immobilized.
• b. Anti-inflammatory drug therapy should begin immediately. For maximal therapeutic
effectiveness, these drugs should be kept on hand so that the patient may begin therapy as soon as a
subsequent attack begins.
• c. Urate-lowering drugs should not be given until the acute attack is controlled, as these drugs
may prolong the attack by causing a change in uric acid equilibrium. Urate-lowering agents can
begin within 1 to 2 weeks after the resolution of the attack.
2. Specific drugs
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Colchicine & Corticosteroids

12. Drug Classification
• NSAIDS: Indomethacin, naproxen, diclofenac, piroxicam, sulindac, etrocoxib
• Glucocortecosteroids: Prednisolone, methylprednisolone, triamcinolone

13. Treatment targets

14. Managing gout ……

15. Drug Targets At Site of Action

16. NSAIDS: Indomethacin, naproxen or piroxicam

17. Cont.…
• One of the strong anti-inflammatory drugs, e.g. indomethacin, naproxen or
piroxicam, is given in relatively high and quickly repeated doses.
• They are quite effective in terminating the attack, but may take 12–24 hours, i.e.
response is somewhat slower than with colchicine, but they are generally better
tolerated; majority of patients prefer them over colchicine.
• After the attack is over, they may be continued at lower doses for 3–4 weeks
while drugs to control hyperuricaemia take effect.

18. NSAIDS
• Indication:
• Treatment of inflammation & pain associated with acute attacks of gout
• Mechanism ofAction:
• Non-selective inhibitors of cyclooxygenase (COX) 1 & 2
• COX inhibition reduces the synthesis of prostaglandins that are involved in
mediating inflammatory responses & pain associated with gout.
• Side Effects:
• Increased bleeding (e.g. increase GI bleeding)
• Relative contraindications:
• Renal insufficiency (inhibiting prostaglandin synthesis can induce renal
failure)
• Peptic ulcer (increased risk for GI bleeding)
• CV disease (increased risk of stroke or MI)
• NSAID allergy
• Treatment with other anticoagulants (increased bleeding risk)

19. Acute gout: Colchicine
• It is an alkaloid from Colchicum autumnale which is neither analgesic nor anti-
inflammatory, but it specifically suppresses gouty inflammation.
• It does not inhibit the synthesis or promote the excretion of uric acid.
• Thus, it has no effect on blood uric acid levels
• Mechanism ofAction

20. MOA for Colchicine
• Sites of action of some anti-inflammatory drugs in a gouty joint. Synoviocytes damaged by uric acid crystals
release prostaglandins (PG), interleukins (ILs), and other mediators of inflammation. Polymorphonuclear
leukocytes (PMN), macrophages, and other inflammatory cells enter the joint and also release inflammatory
substances, including leukotrienes (eg, LTB4), that attract additional inflammatory cells. Colchicine acts on
microtubules in the inflammatory cells. NSAIDs act on cyclooxygenase-2 (COX II) in all of the cells of the
joint. MNP, mononuclear phagocytes.

21. Cont.…
• Indication:
• To reduce pain & inflammation associated with acute attacks of gout
• most effective when taken at the first sign of articular discomfort (at early
stages of neutrophil Chemotaxis & activation)
• colchicine treatment is typically reserved for patients with
contraindications, or who do not adequately respond to NSAIDs
• Can be combined with NSAIDs
NSAID
• Relative contraindications:
• Kidney or hepatic dysfunction (colchicine clearance is impaired)
• Side Effects:
• Diarrhea (common & dose-dependent), nausea & vomiting

22. Glucocorticoids (Corticosteroids)
• Drugs : Prednisolone, Methyl Prednisolone
• MOA:

23. Cont.…
• An alternative for patients with contraindications to both NSAIDs & colchicine
• Also indicated for patients for which NSAIDs and/or colchicine do not provide
acute sufficient pain relief
• Can be given by intra-articular injection, oral or parenteral administration, with
the route depending on the severity of symptoms and the number of joints
affected
• Relative contraindications:
• Diabetes (a common co-morbidity with gout)

24. Combine-Therapy
• Colchicine + NSAID
• Colchicine + oral glucocorticoid
• NSAID + intraarticular glucocorticoid
• Colchicine + intraarticular glucocorticoid
• Oral glucocorticoid + intraarticular glucocorticoid

25. Intercritical Gout
• INTERCRITICAL GOUT is the symptom-free period after the first attack.
• This phase may be interrupted by the recurrence of acute attacks.
• A. Onset of subsequent attacks varies. In most untreated patients, the second attack
occurs within 2 years of the first, but in some it may be delayed for 5 to 10 years.
• A small percentage of patients never experience a second attack. If hyperuricemia is
insufficiently treated, subsequent attacks may become progressively longer and more
severe and may involve more than one joint.
• B. Treatment goals
• 1. To reduce the frequency and severity of recurrent attacks
• 2. To minimize urate deposition in body tissues, thereby preventing progression to
chronic tophaceous gout

26. Xanthine oxidase inhibitors
Allopurinol, Febuxostat
Mechanism ofAction
• Allopurinol by inhibiting xanthine oxidase enzyme reduces plasma urate levels.
• Its active metabolite aloxanthine is non-competitive inhibitor of xanthine oxidase
enzyme.
• It reduces urate crystals in the kidney joints, and soft tissue.
• There is an increase in the levels of xanthine and hypoxanthine in plasma which are
effectively excreted in urine.

27. Cont.…
• Indications
• Allopurinol is considered by many to be the drug of choice for lowering uric
acid levels because of its effectiveness in both under excretors and
overproducers, but it is specifically the preferred urate-reducing agent for
patients in the following
• categories:
• (i) Patients who are clearly overproducers (over excretors) of uric acid
• (ii) Patients with recurrent tophaceous deposits or uric acid stones
• (iii) Patients with renal impairment (but dose needs to be decreased)
• Adverse effects
• Hypersensitivity: Skin rashes, itching, erythema, headache, fever, and rarely Stevens-
Johnson syndrome.
• GIT: Nausea, vomiting, diarrhoea, and occasionally hepatotoxicity may also occur.
• Contraindications: in children, pregnancy, lactation, patients with liver and kidney
diseases.

28. Cont.…
• Drug interactions
• Allopurinol + 6 mercaptopurine
• Because allopurinol inhibits purine degradation, caution should be used when a
patient is taking other purine analogues.
• For example, azathioprine and its active form 6 mercaptopurine are anticancer
and immunosuppressive drugs that contain a purine backbone, and 6-
mercaptopurine is metabolized by xanthine oxidase.
• Inhibition of xanthine oxidase by allopurinol can result in toxic levels of
coadministered mercaptopurine or azathioprine because of decreased degradation
of the latter drugs.
• Therefore, the dose of mercaptopurine or azathioprine should be reduced by
approximately 75% when allopurinol is coadministered.

29. Cont.…

30. Febuxostat
• MOA
• Febuxostat is a non-purine selective inhibitor of xanthine oxidase, the enzyme
that catalyses the conversion of hypoxanthine to xanthine to uric acid, thereby
decreasing serum concentration of uric acid.
• Pharmacokinetics:
Absorption: Rapidly and well absorbed from the gastrointestinal tract. 1-1.5
hours.
Distribution: Plasma protein binding: Approx 99%, mainly to albumin.
Metabolism: Extensively metabolised via conjugation by uridine diphosphate
glucuronosyltransferase (UGT) enzyme system.
Excretion: Via urine (approx 49%, mainly as metabolites and 3% as unchanged
drug) and faeces (approx 45%, mainly as metabolites and 12% as unchanged
drug).

31. Indications
• Oral
Hyperuricaemia with gout
Adult: For chronic cases: Initially, 40 mg once daily. If serum uric acid >6
mg/dL after 2 weeks, increase dose to 80 mg once daily; may be further
increased to 120 mg once daily if necessary.
Oral
Cancer therapy-induced hyperuricaemia
Adult: In patients with intermediate to high risk of tumour lysis syndrome: 120
mg once daily. Start 2 days before the beginning of cytotoxic therapy and
continue for 7-9 days based on chemotherapy duration.
• Current evidence indicates it has similar efficacy as allopurinol (Becker et al,
2010), but has a greater incidence of all-cause mortality and cardiovascular
mortality compared to allopurinol

32. Drugs Increasing Excretion of Uric acid
Probenicide, sulfinpyrazone, benzbromarone
• Uricosuric drugs are organic acids that inhibit the reabsorption of uric acid by
inhibiting anionic transport sites of the renal proximal tubule; inhibiting renal
reabsorption enhances uric acid clearance.
• Probenecid
• For patients who can't tolerate allopurinol, or require additional urate
lowering; can be combined with a xanthine oxidase inhibitor
• Typically administered concomitantly with colchicine to reduce the
likelihood of gouty flare-up
• Can lower mean serum uric acid by 30-40%
• Not effective in the setting of renal dysfunction
• It can promote kidney-stone formation in patients with high urinary
uric acid levels, and is contraindicated in patients with a history of kidney
stones (nephrolithiasis)

33. URICOSURICS/ Increasing uric acid excretion
• Uricosuric drugs are organic
acids that inhibit the reabsorption
of uric acid by inhibiting anionic
transport sites of the renal
proximal tubule; inhibiting renal
reabsorption enhances uric acid
clearance.
• MOA:
• Probenecid, sulfinpyrazone and
benzbromarone.
• They acts as competitive inhibitors
of reabsorption of uric acid in
proximal tubules.
Mechanism of Action of Probenecid. Probenecid inhibits both the Organic Anion Transporters (OAT) in
the basolateral membrane of cells in the proximal tubule. This results in reduced clearance and increased
plasma levels of drugs normally secreted by this mechanism (e.g. penicillin). In addition, probenecid also
inhibits Urate Transporters (URAT) in the apical membrane of the proximal tubule, which decreases uric
acid reabsorption, resulting in an increased urinary excretion of uric acid, which is beneficial in patients
with gout.

34. MOA
• Uric acid is freely filtered by the glomerulus, secreted & normally 90% is
reabsorbed by anionic active transport sites in the proximal tubule.
• Uricosuric drugs are organic acids that inhibit anionic transport sites of
the renal tubule
• Probenecid (& sulfinpyrazone) inhibit the active transport sites that cause
net reabsorption of uric acid in the proximal tubule of the kidney.
• Uric acid is the only important endogenous compound whose excretion is
significantly increased by probenecid
• As the excretion of uric acid increases, the body's pool of urate decreases,
although the plasma concentration may not be greatly reduced
• Tophaceous deposits of urate can be reabsorbed, with relief of arthritis and re-
mineralization of bone.

35. Cont.…
• Indications:
• Chronic treatment of gout - for patients suffering from frequent, recurrent
acute attacks of gout for patients who can't tolerate allopurinol, or require
additional urate lowering can lower mean serum uric acid by 30-40%
• Therapy should not be started until 2-3 weeks after an acute attack
• Typically administered concomitantly with colchicine
• Not effective in the setting of renal dysfunction
• Contraindications:
• Patients with chronic kidney disease (creatinine clearance <80 mL/min) in
whom uricosuric drugs have reduced efficacy due to renal impairment
• Pharmacokinetics:
• completely reabsorbed by renal tubules & metabolized very slowly

36. Cont.…
• Side Effects:
• GI irritation, allergic dermatitis (rash)
• kidney stone formation (associated with the increase in uric acid excretion; therefore the
urine volume should be maintained at a high level, and at least in early treatment, urine pH
should be kept above 6.0 by administering alkali)
• Nephrotic syndrome has occurred
• Aplastic anemia (rare)
• Major drug interactions:
• Probenecid interferes with the renal secretion of penicillin, other beta-lactam
antibiotics, and methotrexate, thereby decreasing their renal clearance, increasing
their half-life, and elevating their plasma concentrations (if dosage adjustments are not
made).
• Aspirin - antagonizes the uricosuric action of probenecid.
• Aspirin (>325 mg) reduces the tubular secretion of uric acid from the blood into the
tubules, resulting in elevated serum uric acid, and reduced uric acid in the renal tubule
& urine.
• This indirectly interferes with the effect of probenecid to block uric acid reabsorption (less
uric acid can be reabsorbed if there is less uric acid secreted into the urine upstream of
probenecid's site of action on the URAT transporter).

37. General Considerations for Uricosuric Drugs
• Plenty of fluids and urinary alkalinizers should be given concurrently to prevent precipitation of uric
acid crystals in the kidney tubules.
• These drugs are ineffective in the presence of renal damage.
• Probenecid is also used along with penicillins to decrease their renal excretion.
• Uricosuric drugs should not be used if
• Creatinine clearance is <50ml/min.
• History of nephrolithiasis (uric acid or calcium stones)
• Evidence of overproduction of uric acid (> 800 mg of uric acid in a 24-hour urine collection)
• Oral
Hyperuricaemia with gout
Adult: 250 mg bid for 1 wk, followed by 500 mg bid thereafter.
• Adjunct to antibacterial therapy
Adult: 500 mg 4 times daily. Treatment of uncomplicated gonorrhoea: 1 g as a single dose together
w/ an oral antibacterial, or 30 min before an injected antibacterial.

38. Sulfinpyrazone
• Pharmacokinetics
• 4-6 hr, or up to 10 hr. Readily absorbed from the GI tract.
• Time to peak plasma concentration: 1-2 hr. Plasma protein binding:Approx 98%.
• Undergoes partial hepatic metabolism by reduction to the sulfide and oxidation to
the sulfone and to hydroxy-compounds. Via urine (as unchanged drug and
metabolites); via faeces (approx. 5% of the drug).
• Plasma half-life:Approx 2-4 hr.
• ADR: Nausea, vomiting, diarrhoea, abdominal pain, GI bleeding, rashes, aplastic
anaemia, agranulocytosis, leucopenia, thrombocytopenia, raised liver enzymes,
jaundice, hepatitis, renal impairment, salt and water retention, acute renal failure.

39. Cont.…
• Indications
• Hyperuricaemia with gout
• Adult: Initially, 100-200 mg bid, increase gradually over 2-3 wk to 600 mg daily.
Maintenance dose (after plasma-urate concentration is controlled): 200 mg daily
in divided doses. Max: 800 mg daily.
• Renal impairment: Mild to moderate: Reduce dose. Severe: Contraindicated.
Hepatic impairment: Severe:Avoid.

40. Benzbromarone
• Description: Benzbromarone reduces plasma concentrations of uric acid by
blocking renal tubular reabsorption and possibly by increasing intestinal
elimination of uric acid.
• Pharmacokinetics:
Absorption: Partially absorbed from the GI tract.
Distribution: Extensively bound to plasma proteins.
Metabolism: Metabolised in the liver.
Excretion: Mainly excreted in the faeces, a small amount appears in the urine.
• ADR : GI effects; acute attack of gout, uric acid renal calculi, renal colic. May
cause liver damage.
• Dose
• Oral
Hyperuricaemia with gout
Adult: 50-200 mg daily. PO 50-200 mg/day.

41. Uricolytics / Drugs Increasing Metabolism
• Examples: Rasburicase, Pegloticase
• Urate oxidase (uricase) metabolizes insoluble uric acid to soluble allantoin in the
birds. This enzyme is absent in humans.
Urate oxidase

42. Rasburicase
• Rasburicase is a recombinant urate-oxidase enzyme produced by a genetically
modified Saccharomyces cerevisiae strain.
• The cDNA coding for rasburicase was cloned from a strain of Aspergillus flavus.
• MOA: Rasburicase catalyzes enzymatic oxidation of uric acid into an inactive and
soluble metabolite (allantoin).
• Indications: For treatment of hyperuricemia, reduces elevated plasma uric acid
levels (from chemotherapy)
• Drugs used to treat lympohoid leukemia, non-Hodgkin's lymphoma and acute
myelogenous leukemia often lead to the accumulation of toxic plasma levels of
purine metabolites (i.e. uric acid). The injection of rasburicase reduces levels of uric
acid and mitigates the toxic effects of chemotherapy induced tumor lysis.

43. Pegloticase
• Pegloticase (Krystexxa) was also approved in 2009 and is a form of uricase (urate
oxidase), which catalyzes the oxidation of uric acid to allantoin, which is water
soluble and easily excreted.
• It is indicated for the relatively small number of gout patients (50,000 Americans)
who cannot be treated with other urate lowering drugs (refractory patients).
• It needs to be given by IV infusion every 2 to 4 weeks.
• Patients need to be closely monitored for anaphylaxis and infusion reactions.
Pretreatment with antihistamines and corticosteroids is needed.
• A large percentage of patients develop pegloticase antibodies, which results in
decreased effectiveness.
• Prophylaxis with colchicine or Nonsteroidal agents is also appropriate.
• It is much more expensive than other urate lowering drug therapies.

44. Other Drugs that increase Uric acid excretion
• Losartan (Cozaar), an angiotensin II receptor blocker (ARB), might be a
useful antihypertensive agent in the patient who has both hyperuricemia and
hypertension because this agent can lower serum uric acid levels by inhibiting
the uptake of uric acid by the urate anion exchange transporter in the proximal
tubule. This effect is minimal or not seen in otherARBs.
• Fenofibrate (TriCor) is a fibric acid agent used to treat elevated cholesterol
and triglyceride levels. It has been shown to decrease serum uric levels by
increasing renal uric acid clearance and would be a useful agent in the patient
with both hyperlipidemia and hyperuricemia.
• Vitamin C may lower the serum uric acid level. One study noted a 0.5 mg/dL
decrease when 500 mg was given daily.

45. The End………………………..