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Pericarditis is inflammation of the pericardium Pleurisy is a lungs inflammation
Disseminated intravascular coagulation is a condition in which small blood clots develop throughout the bloodstream, blocking small blood vessels Myopathy is a disease of the muscle in which the muscle fibers do not function properly
Nephrotic syndrome is a collection of symptoms due to kidney damage Aplastic anemia is a condition that occurs when your body stops producing enough new blood cells.
Renal Impairment. Renal impairment means that your kidneys are not functioning normally
Asymptomatic hyperuricemia is a term traditionally applied to settings in which the serum urate concentration is elevated but in which neither symptoms nor signs of monosodium urate (MSU) crystal deposition disease,
Pharmacology of gout
Pharmacology of gout
Muhammad Hamza Achakzai
University of balochistan
Treatment of gout
• There are two type of stages in gout
• 1)Acute gout
• 2)chronic gout
• Acute gout attacks can result from a number of conditions, including
excessive alcohol consumption, a diet rich in purines, and kidney disease.
NSAIDs, corticosteroids, or colchicine are effective alternatives for the
management of acute gouty arthritis. Indomethacin is considered the classic
NSAID of choice, although all NSAIDs are likely to be effective in
decreasing pain and inflammation. Intraarticular administration of
corticosteroids (when only one or two joints are affected) is also appropriate
in the acute setting.
• Urate-lowering therapy for chronic gout aims to reduce the frequency of attacks and
complications of gout. Treatment strategies include the use of xanthine oxidase inhibitors
to reduce the synthesis of uric acid or use of uricosuric drugs to increase its excretion and
uric acid metabolizer(Rasburicase)
• Xanthine oxidase inhibitors (allopurinol, febuxostat) are first-line urate-lowering agents.
• Uricosuric agents (probenecid) is used in patients which mainly act on the proximal
convilated tubules and inhibit the reuptake of uric acid
• 3rd group drugs mainly used in the metabolism of the uric acid
• Rasburicase pengloticase
• Colchicine is absorbed readily after oral administration
• reaches peak plasma levels within 2 hours
• a eliminated with a serum half-life of 9 hours.
• Metabolites are excreted in the intestinal tract and urine
• Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours
without altering the metabolism or excretion of urates and without other analgesic
• Colchicine produces its anti-inflammatory effects by binding to the intracellular
protein tubulin, thereby preventing its polymerization into microtubules and leading
to the inhibition of leukocyte migration and phagocytosis.
• It also inhibits the formation of leukotriene B4 and IL-1β. Several of colchicine’s
adverse effects are produced by its inhibition of tubulin polymerization and cell
• It prevents attacks of acute Mediterranean fever and may have a mild
beneficial effect in hepatic cirrhosis.
• Colchicine is also used to treat and prevent pericarditis, pleurisy, and
coronary artery disease, probably due to its anti-inflammatory effect.
Although it has been given intravenously, this route is no longer approved by
the FDA (2009).
Colchicine often causes diarrhea and may occasionally cause nausea, vomiting,
and abdominal pain. Hepatic necrosis, acute renal failure, disseminated
intravascular coagulation, and seizures have also been observed.
Colchicine may rarely cause hair loss and bone marrow depression, as well as
peripheral neuritis, myopathy, and, in some cases, death.
The more severe adverse events have been associated with the intravenous
administration of colchicine.
NSAIDS IN GOUT
• In addition to inhibiting prostaglandin synthase, NSAIDs inhibit
urate crystal phagocytosis.
• Aspirin is not used because it causes renal retention of uric acid at
low doses (≤ 2.6 g/d).
• Indomethacin is commonly used in the initial treatment of gout as
a replacement for colchicine.
• For acute gout, 50 mg is given three times daily; when a response
occurs, the dosage is reduced to 25 mg three times daily for 5–7
• All other NSAIDs except aspirin, salicylates, and tolmetin have been
successfully used to treat acute gouty episodes.
• Probenecid are uricosuric drugs employed to decrease the body pool of urate
in patients with tophaceous gout or in those with increasingly frequent gouty
• In a patient who excretes large amounts of uric acid, the uricosuric agents
should not be used.
• Lesinurad (RDEA594) is a promising new uricosuric agent that is currently
in phase 3 trials.
• Uricosuric drugs—probenecid, sulfinpyrazone, fenofibrate, and losartan—inhibit
active transport sites for reabsorption and secretion in the proximal renal tubule so
that net reabsorption of uric acid in the proximal tubule is decreased..
• The secretion of other weak acids (eg, penicillin) is also reduced by uricosuric agents.
• In patients who respond favorably, tophaceous deposits of urate are reabsorbed,
with relief of arthritis and remineralization of bone.
• As acid level in urine are increase due to uric acid excretion the pH of the urine
should be maintan above 6.0 by administration of alkali
• Both of these organic acids cause equivalent GI irritation, but
sulfinpyrazone is more active in this regard.
• A rash may appear after the use of either compound.
• Nephrotic syndrome has occurred after the use of probenecid.
• Both sulfinpyrazone and probenecid may rarely cause aplastic anemia
• It is essential to maintain a large urine volume to minimize the possibility of
• Probenecid is usually started at a dosage of 0.5 g orally daily in divided doses,
progressing to 1 g daily after 1 week. Sulfinpyrazone is started at a dosage of
200 mg orally daily, progressing to 400–800 mg daily. It should be given in
divided doses with food to reduce adverse GI effects
• The preferred and standard-of-care therapy for gout during the period
between acute episodes is allopurinol, which reduces total uric acid body
burden by inhibiting xanthine oxidase
• Allopurinol is approximately 80% absorbed after oral administration and
has a terminalserum half-life of 1–2 hours.
• Like uric acid, allopurinol is metabolized by xanthine oxidase, but the
resulting compound, alloxanthine, retains the capacity to inhibit xanthine
oxidase and has a long enough duration of action so that allopurinol is given
only once a day
• Dietary purines are not an important source of uric acid.
• Quantitatively important amounts of purine are formed from amino acids, formate,
and carbon dioxide in the body.
• Those purine ribonucleotides not incorporated into nucleic acids and derived from
nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to
uric acid (Figure).
• Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a
decrease in the overall urate burden. The more soluble xanthine and hypoxanthine
• Allopurinol is often the first-line agent for the treatment of chronic gout in
the period between attacks and it tends to prolong the intercritical period.
• As with uricosuric agents, the therapy is begun with the expectation that it
will be continued for years if not for life.
• When initiating allopurinol, colchicine or NSAID should be used
untilsteady-state serum uric acid is normalized or decreased to less than 6
mg/dL and they should be continued for 6 months or longer.
• GI intolerance (including nausea, vomiting, and diarrhea)
• bone marrow suppression
• aplastic anemia may rarely occur.
• Hepatic toxicity and interstitial nephritis have been reported.
• When chemotherapeutic purines (eg, azathioprine) are given concomitantly
with allopurinol, their dosage must be reduced by about 75%.
• Allopurinol may also increase the effect of cyclophosphamide.
• Allopurinol inhibits the metabolism of probenecid and oral anticoagulants
and may increase hepatic iron concentration.
• Safety in children and during pregnancy has not been established.
• The initial dosage of allopurinol is 50–100 mg/d.
• It should be titrated upward untilserum uric acid is below 6 mg/dL; this level
is commonly achieved at 300–400 mg/d but is not restricted to this dose;
doses as high as 800 mg/d may be needed.
• As noted above, colchicine or an NSAID should be given during the first
months of allopurinol therapy to prevent the gouty arthritis episodes that
• Febuxostat is a non-purine xanthine oxidase inhibitor that was approved by
the FDA in 2009
• Febuxostat is more than 80% absorbed following oral administration.
• With maximum concentration achieved in approximately 1 hour and a half-
life of 4–18 hours, once-daily dosing is effective.
• Febuxostat is extensively metabolized in the liver. All of the drug and its
inactive metabolites appear in the urine, although less than 5% appears as
• Febuxostat is a potent and selective inhibitor of xanthine oxidase, thereby
reducing the formation of xanthine and uric acid without affecting other
enzymes in the purine or pyrimidine metabolic pathway.
• In clinical trials, Febuxostat at daily dosing of 80 mg or 120 mg was more
effective in lowering serum urate levels than allopurinol at a standard 300 mg
• Febuxostat is approved at doses of 40 or 80 mg for the treatment of chronic
hyperuricemia in gout patients.
• Although it appeared to be more effective then allopurinol as urate-lowering
therapy, the allopurinol dosing was limited to 300 mg/d, thus not reflecting
the actual dosing regimens used in clinical practice.
• As with allopurinol, prophylactic treatment with colchicine or NSAIDs
should be started at the beginning of therapy to avoid gout flares.
• The most frequent treatment-related adverse events are liver function
abnormalities, diarrhea, headache, and nausea.
• Febuxostat is well tolerated in patients with a history of allopurinol
• There does not appear to be an increased risk of cardiovascular events
• The recommended starting dose of febuxostat is 40 mg daily. Because there
was concern for cardiovascular events in the original phase 3 trials, the FDA
approved only 40 mg and 80 mg dosing.
• No dose adjustment is necessary for patients with renal impairment since it
is highly metabolized into an inactive metabolite by the liver.
• Pegloticase is the newest urate-lowering therapy to be approved for the
treatment chronic gout
Pharmacokinetics and Dosage:
• The recommended dose for pegloticase is 8 mg every 2 weeks administered
as an intravenous infusion.
• It is a rapidly acting drug, achieving a peak decline in uric acid level within
24–72 hours. The serum half-life ranges from 6 to 14 days.
• Urate oxidase enzyme, absent in humans and some higher primates, converts
uric acid to allantoin.
• This product is highly soluble and can be easily eliminated by the kidney.
• Pegloticase has been shown to maintain low urate levels for up to 21 days
after a single dose at doses of 4–12 mg, allowing for IV dosing every 2
• Pegloticase should not be used for asymptomatic hyperuricemia.
• Gout flare can occur during treatment with pegloticase, especially during the first 3–6 months of treatment, requiring prophylaxis with
NSAIDs or colchicine.
• Large numbers of patients show immune responses to pegloticase.
• The presence of antipegloticase antibodies is associated with shortened circulating half-life, loss of response leading to a rise in plasma urate
levels, and a higher rate of infusion reactions and anaphylaxis.
• Anaphylaxis occurs in more than 6–15% of patients receiving pegloticase. Monitoring of plasma uric acid level, with rising level as an
indicator of antibody production, allows for safer administration and monitoring of efficacy.
• In addition, other oral urate-lowering agents should be avoided in order not to mask the loss of pegloticase efficacy.
• Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea may occur.
• Other less frequent side effects noted include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea.
• There is some concern for hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency because of the formation of
hydrogen peroxide by uricase; therefore, pegloticase should be avoided in these patients.
• Corticosteroids are sometimes used in the treatment of severe symptomatic gout, by
intra-articular, systemic, or subcutaneous routes, depending on the degree of pain
• The most commonly used oral corticosteroid is prednisone. The recommended
oral dose is 30–50 mg/d for 1–2 days, tapered over 7– 10 days.
• Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40
mg (knee) of triamcinolone acetonide can be given if the patient is unable to take
• Drugs targeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept,
are used for the treatment of gout.
• Although the data are limited, these agents may provide a promising treatment
option for acute gout in patients with contraindications to, or who are refractory to,
traditional therapies like NSAIDs or colchicine.
• A recent study suggests that canakinumab, a fully human anti-IL-1β monoclonal
antibody, can provide rapid and sustained pain relief at a dose of 150 mg
• These medications are also being evaluated as therapies for prevention of gout
flares while initiating urate-lowering therapy