NSAIDs, ACETAMINOPHEN, & DRUGS USED IN GOUT

A. Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
IMMUNE RESPONSE
Immunologically competent cells are activated in response to foreign organisms or antigenic
substances
Liberated during inflammatory response
Many treatment strategies applied to the reduction of inflammation are targeted at the immune
process
Outcome
Beneficial
The invading organism to be phagocytosed or neutralized
Deleterious
Leads to chronic inflammation
No resolution of the underlying injurious process
INFLAMMATION
Common nonspecific manifestation of many diseases
2 forms
Acute
Chronic
Chronic
Release of important mediators that are not prominent in acute response
Rheumatoid arthritis
Conditions that results from the release of these mediators
Pain and destruction of bone and cartilage that can lead to severe disability
Leukocytes release lysosomal enzymes
Arachidonic acid is liberated
Prostaglandin (PG) is synthesized from the cyclooxygenase pathway
Cyclooxygenase pathway has 2 isoforms
COX 1-Tends to be homeostatic in function
- Expressed in non-inflammatory cells
COX 2-Induced during inflammation
- Expressed in activated lymphocytes, PMNs, other inflammatory cells
Lipoxygenase pathway
Yields leukotrienes
Chemotactic effect on eosinophils, neutrophils, and macrophages

Promote bronchoconstriction and alteration in vascular permeability

Kinins, neuropeptides and histamine are released together with complement components and
cytokines
Oxygen-derived free radicals
Hydrogen peroxide and hydroxyl radicals
Produced from neutrophils membranes
Interact with arachidonic acid to generate chemotactic factors that perpetuate inflammatory
process

THERAPEUTIC STRATEGIES
2 GOALS
1. Relief of pain
2. Slow or arrest the tissue-damaging process
ASPIRIN AND OTHER NSAIDs
NONSTEROIDAL ANTI-INFLAMMATORY DRUG (NSAIDs)
A. Chemistry and Pharmacokinetics
Weak organic acids except Nabumetone (a ketone prodrug metabolized to active acidic drug)
Well absorbed, food does not change bioavailability
Highly metabolized
Some by phase I followed by phase II mechanism
Some by direct glucoronidation (phase II alone)

B.

Renal excretion is the route for elimination

All undergo a degree of biliary excretion and reabsorption (enterohepatic circulation)
Mostly are highly protein-bound (98%) to albumin
Some are racemic mixtures (ibuprofen), single enantiomer (naproxen) and few have no chiral
center (diclofenac)
All can be found in the synovial fluid after repeated dosing
Drugs with shorter half-lives remain in the joints longer than their half-lives
Drugs with longer half-lives disappear at a rate proportionate to their half-lives
Pharmacodynamics
Anti-inflammatory activity is mediated chiefly through inhibition of biosynthesis of PGs
Additional mechanisms
Inhibition of chemotaxis
Down-regulation of interleukin-1 production
Decreased production of free radicals and superoxide
Interference with calcium-mediated intracellular events

Aspirin
Irreversibly acetylates and blocks platelet cyclooxygenase
Non-COX selective NSAIDs
Reversible inhibitors
Highly selective COX 2 inhibitors
Do not affect platelet function at their usual doses
Efficacy equals that of older NSAIDs
GI safety maybe improved
May increase edema and hypertension
Highly selective COX 2 inhibitors
Celecoxib, Etoricoxib
Available COX 2 drugs in the market
Rofecoxib and Valdecoxib
Withdrawn due to increase cardiovascular thrombotic events
Meloxicam
Related to piroxicam
Preferentially inhibits COX 2 over COX 1 at its lowest therapeutic dose of 7.5 mg
Fewer GI symptoms and complications
Inhibits synthesis of thromboxane A2 but no effect on platelet function
Aspirin, Indomethacin, Piroxicam and Sulindac
More effective in inhibiting COX 1
Ibuprofen and Meclofenamate
Inhibit 2 isoenzymes equally
Interfere with the homeostatic function of PGs
Reduce PG-mediated cytoprotection in the GI tract and autoregulation of renal function
Decrease the sensitivity of vessels to bradykinin and histamine
Affect lymphokine production
Reverse the vasodilation of inflammation
All gastric irritants
All drugs are nephrotoxic due in part to interference of autoregulation of renal blood flow
Hepatotoxicity can occur with any NSAID
No evidence show that they alter the course of an arthritic disorder
Appear to reduce the incidence of colon cancer when taken chronically (including aspirin)
50% reduction in relative risk after 5 years of intake
Mechanism for protective mechanism is unclear
ASPIRIN
Acetylsalicylic acid (ASA)
Prototype
Rarely used as an anti-inflammatory agent
Replaced by ibuprofen and naproxen
A. Pharmacokinetics
3 therapeutic dose ranges

Low range (< 300mg/day)

Effective in reducing platelet aggregation
Intermediate dose (300-2400 mg/day)
Have antipyretic and analgesic effects
High dose (2400-4000 mg/day)
Used for their anti-inflammatory effect
Readily absorbed
Hydrolyzed in blood and tissues to acetate and salicylic acid
Excretion is via the kidney
Alkalinization of urine affects rate of excretion

Nonacetylated Salicylates
A. Pharmacokinetics
Choline salicylate, sodium salicylate, salicyl salicylate
Reversible nonselective inhibitor of cyclooxygenase
Effective anti-inflammatory, less effective analgesics
Do not inhibit platelet aggregation
Administered in doses up to 3-4 g a day
Elimination is first order at low doses, with a half-life of 3-5 h
Elimination becomes zero order at high doses, half-life increases to 15 h or more
Bound to albumin
Preferred in patients with
Asthma
Bleeding tendencies
Renal dysfunction
Other Nonselective COX Inhibitors
A. Pharmacokinetics
Well absorbed after oral intake
Diclofenac
Phenylacetic acid derivative
Elevation of liver enzymes is common
GI ulceration less common
Diflusinal
Derived from salicylic acid
Clearance depends on renal and hepatic metabolism
Effective for cancer pain in bone metastases
Etodolac
Racemic acetic acid derivative
Does not undergo chiral inversion in the body
Given 3 to 4 times daily
Flurbiprofen
Propionic acid derivative
More complex mechanism of action
IV prep effective for perioperative analgesia in minor surgery
Ibuprofen
Phenylpropionic acid derivative
2400 g daily is equivalent to 4 g aspirin in anti-inflammatory effect
Oral prep in lower doses for analgesic effect
Effective in closing PDA in preterm infants
Same efficacy and safety as indomethacin
Oral and IV routes are equally effective
Decrease urine output less and causes less fluid retention than indomethacin
Concomitant administration with aspirin
Antagonizes platelet inhibition induced by aspirin
May decrease the total anti-inflammatory effect
Indomethacin

Indole derivative, potent with increased toxicity

Thrombocytopenia and aplastic anemia
Rare psychosis and hallucination
Used to accelerate closure of PDA
Ketoprofen
Propionic acid derivative
Inhibits both COX (nonselective) and lipoxygenase
Not superior to other NSAIDs in spite of dual effect

Ketorolac
Promoted for systemic use mainly as an analgesic
Used successfully to replace morphine in mild to moderate postsurgical pain
IV use restricted to 72 h
Oral prep is available
Risk of GI and renal damage with longer use
Nabumetone
Only nonacid NSAID
Prodrug converted to acetic acid, resembles naproxen
Very expensive
Half-life is more than 24 h, once daily
Less GI damage
Higher doses are often needed
Naproxen
Naphthlypropionic acid derivative
Only NSAID marketed as single enantiomer
Low incidence of GI bleeding but double that of ibuprofen
Oxaprozin
Propionic acid derivative
Very long half-life of 50-60 h
Uricosuric
Piroxicam
At high concentrations also inhibits PMN migration, decreases O2 radical production and
lymphocyte function
Long half-life permits once daily dosing
Sulindac
Sulfoxide prodrug
May inhibit development of colon, breast and prostate cancer
May elevate liver enzymes like diclofenac
Tolmetin
Short half-life of 1-2 h and not often used
Ineffective in the treatment of gout for unknown reason
Azapropazone, Carprofen, Meclofenamate, and
Tenoxicam
Rarely used
B. Mechanism of Action and Clinical Uses
Anti-inflammatory effects
Aspirin
Nonselective irreversible inhibitor of both COX isoenzymes
Inhibits platelet aggregation
Analgesic effects
Most effective in reducing mild to moderate pain thru its effect on inflammation
Antipyretic effects
Mediated by both COX inhibition in the CNS and inhibition of interleukin 1
Antiplatelet effects
Irreversible inhibition causes the antiplatelet effect to last for 8-10 days (life span of the platelet)
Other effects
Decreases the incidence of transient ischemic attacks (TIAs), unstable angina, coronary artery
thrombosis with MI and thrombosis after angioplasty

Other NSAIDs
Treatment of mild to moderate pain of inflammation
Arthritis
Gout
C. Toxicity
Therapeutic anti-inflammatory doses of aspirin
Gastric upset is most common
Chronic use
Gastric ulcerations, upper GI bleeding
Renal effects, including acute failure and interstitial nephritis
Small doses of aspirin
With aspirin sensitivity (especially associated with nasal polyps)
May experience asthma from the increased synthesis of leukotrienes
Higher doses of aspirin
Salicylism
Vomiting, tinnitus, vertigo, decreased hearing
Reversible by reducing the dose
Very high doses of aspirin
Respiratory alkalosis followed by metabolic acidosis (salicylate accumulation)
Respiratory depression, dehydration, hyperthermia, collapse, coma and death
Aspirin
Children with viral infections are at increased risk for Reyes syndrome
Hepatic fatty degeneration and encephalopathy
Maybe valuable in treating preeclampsia-eclampsia in pregnancy
Nonselective NSAIDs
Significant GI disturbances
Lower incidence than aspirin
Risk of renal damage with any NSAID
Phenylbutazone
Not used chronically
Causes aplastic anemia and agranulocytosis
COX-2-selective inhibitors
Reduced risk of GI effects
Gastric ulcers and GI bleeding
Do not have antiplatelet effect
Not cardioprotective
Not recommended in renal dysfunction
Active in the kidney
Celecoxib
Sulfonamide
May cause hypersensitivity
DISEASE MODIFYING, SLOW-ACTING ANTIRHEUMATIC DRUGS (DMARDS, SAARDS)
Disease-modifying drugs
Heterogenous groups of agents
Anti-inflammatory actions in several connective tissue diseases
Slowing or even reversal of joint damage
Effect never seen in NSAIDs
Slow-acting
6 weeks or 6 months for benefits to become apparent
Corticosteroids
Anti-inflammatory drugs with an intermediate rate of action
Slower than NSAIDs but faster than the other DMARDs
Too toxic for routine chronic use
Temporary control of severe exacerbations and long term use in patients with severe disease not
controlled by other agents
Methotrexate
1st choice to treat rheumatoid arthritis (RA)

MOA

Used in 60% of patients

Active in lower doses than those needed in cancer chemotherapy
Inhibition of aminoimidazolecarboxide ribonucleotide (AICAR) transformylase and thymidylate
synthetase with secondary effects on polymorphonuclear chemotaxis

Pharmacokinetics
70% absorbed after oral administration
Metabolized to less active hydroxylated metabolite
Half-life 6-9 h, may stay as long as 24 h
Concentration is increased in the presence of hydroxychloroquine
Principally excreted in the urine, 30% in the bile
15-25 mg weekly-30-35 mg weekly
Decreases the appearance of new lesions
Adverse effects
Nausea and mucosal ulcers are most common
Progressive dose related hepatotoxicity (enzyme elevation), cirrhosis is rare
Rare hypersensitivity reaction lung reaction with acute shortness of breath
Incidence of GI and liver function abnormalities can be reduced with the use of leucovorin 24 h
after each weekly dose or by the use of daily folic acid
CI in pregnancy
Chlorambucil
MOA and pharmacokinetics
Through its metabolite, phenylacetic acid mustard, cross-links DNA preventing cell replication
70% bioavailability
Completely metabolized with excretion completed in 24 h
Adverse effects
Dose related bone marrow suppression is most common
Infertility with azoospermia and amenorrhea
Risk on neoplasia is increased, tenfold for leukemia after 3 years of use
Cyclophosphamide
MOA
Major active metabolite phosphoramide mustard, cross-links DNA to prevent cell replication
Active against RA when given orally at 2mg/kg/d
Adverse effects
Dose related infertility in both men and women
Bone marrow suppression
Alopecia
Hemorrhagic cystitis, rarely bladder CA
Cyclosporine
MOA
Inhibits IL-1 and IL-2 receptor production and secondarily inhibits macrophage-T cell interaction
and T cell responsiveness
Pharmacokinetics
Absorption is incomplete and erratic
Grapefruit juice increases its bioavailability by 62%
Metabolized by CYP3A and subjected to a lot of drug interactions (DI)
Retards formation of new bony erosions
Adverse effects
Nephrotoxic
Toxicity is increased by DI with diltiazem, potassium-sparing diuretics
Hypertension, hyperkalemia, hepatotoxicity, gingival hyperplasia, hirsutism
Azathioprine
MOA
Major metabolite 6-thioguanine suppresses inosinic acid synthesis, B and T cell function,
immunoglobulin production and IL-2 secretion
Pharmacokinetics
Rapid metabolizers clear the drug 4 times more rapidly than slow metabolizers
Adverse effects

Bone marrow suppression

GI disturbances
Increase in infection risk
Lymphomas may increase
Fever, rash, hepatotoxicity signal allergic reaction

Mycophenolate mofetil
No well controlled data regarding its efficacy in RA
Chloroquine and hydroxychloroquine
MOA
Used mainly in malaria and in rheumatic disease
Mechanism in RA is unclear
Suppression of T lymphocyte responses to mitogen
Decreased leukocyte chemotaxis
Stabilization of lysosomal enzymes
Inhibition of RNA and DNA synthesis
Trapping of free radicals
Pharmacokinetics
Rapidly absorbed, 50% protein-bound
Extensively tissue bound particularly in melanin-containing tissue like the eyes
Deaminated in the liver
Half-life of up to 45 days
Indications
Approved for RA but are not very efficacious
No evidence show that they improve bony damage
Usually takes 3-6 months to obtain results
Adverse effects
Ocular toxicity may occur at doses greater than 250 mg/d chloroquine and 6.4 mg/kg/d for
hydroxychloroquine
Ophthalmic monitoring every 6-12 months
Dyspepsia, nausea, vomiting, abdominal pain, rashes and nightmares
Safe in pregnancy
Gold
Used in the 1960s, but because of their toxicity, they are infrequently used today
Intramuscular formulations (contains 50% gold)
Aurothiomalate
Aurothioglucose
Oral formulation (contains 29% gold)
Auranofin
MOA
Main MOA
Alters the morphology and functional capabilities of human macrophages resulting to monocyte
chemotactic factor-1, IL-8
IL-1beta and vascular endothelial growth factor are inhibited
IM gold compounds
Alter lysosomal enzyme activity, reduce histamine release, inactivate complement 1 and suppress
phagocytic activity of PMN
Oral gold compounds
Inhibit release of prostaglandin E2 and leukotriene B4
Pharmacokinetics
High bioavailability after IM administration
Concentrates in the synovial membranes, liver, kidney, spleen, lymph nodes, and bone marrow
One month after IM injection, 75-80% of the drug is eliminated from the serum
Total body half-life is approximately 1 year
Oral gold compound is 25% bioavailable
Excreted 66% in the urine and 33% via the feces
No correlation between serum gold concentration and either efficacy and toxicity
Effective for active rheumatoid arthritis
Slows radiologic progression of the disease

 Intramuscular gold is given as test dose of 5-25 mg then as 50 mg weekly for 20 weeks
Adverse effects
Pruritic skin rashes in 15-20% with eosinophilia
Stomatitis and metallic taste in the mouth is common
Thrombocytopenia, leucopenia and pancytopenia in 1-10%
Aplastic anemia is rare but fatal
30-40% discontinue therapy in a year
Penicillamine
Metabolite of penicillin
D isomer is used to treat RA
Rarely used today because of toxicity
Sulfasalazine
MOA
Metabolized to sulfapyridine and 5-aminosalicylic acid
Sulfapyridine is the active moiety in treating RA
Pharmacokinetics
10-20% is absorbed after oral administration
Fraction undergoes enterohepatic recirculation when intestinal flora liberates its metabolites
Half-life of 6-17 h
Initially used for inflammatory bowel disease
Effective for active rheumatoid arthritis
Slows radiologic progression of the disease
Adverse effects
Nausea, vomiting, headache and rash are common
Hemolytic anemia and methemoglobinemia is rare
Pulmonary toxicity
Reversible infertility in males
Not teratogenic
TNF--Blocking Agents
Cytokines
Central role in immune response and RA
TNF- appears to be the heart of the inflammatory process
Affects cellular function via activation of TNF receptors
Administered soluble TNF receptors by combining with soluble TNF- can inhibit effects of
endogenous cytokines
3 drugs interfering with TNF- are approved for treatment of RA
1. Adalimumab
Fully human IgG1 anti-TNF monoclonal antibody
Down regulates macrophage and T cell function
Given subcutaneously, half-life of 10-20 days
Effective as monotherapy and in combination with methotrexate and other DMARDS
Clearance is decreased by 40% in the presence of methotrexate
Risk of macrophage-dependent infection (TB and other opportunistic infections) is increased
No increased incidence of solid malignancies
2. Infliximab
Chimeric ( 25% mouse, 75% human)
Same MOA as adalimumab
Given IV, relationship between serum concentration and effect
Half-life of 9-12 days
Concurrent therapy with methotrexate
Reduces the prevalence of antichimeric antibodies
Decreases the rate of formation of new erosions more than methotrexate alone
Upper respiratory tract infection, nausea, headache, sinusitis rash and cough are common
Risk of macrophage-dependent infection (TB and other opportunistic infections) is increased
No increased incidence of solid malignancies
3. Etanercept
Recombinant fusion protein comprising 2TNF receptors linked to immunoglobulin
Acts as a decoy decreasing the cellular actions of TNF-

 Given subcutaneously, absorbed slowly with peak concentration after 72 h, half-life of 4.5 days
Incidence of activation of latent TB is numerically but not statistically lower
No increased incidence of solid malignancies
Abatacept
Costimulation modulator that inhibits activation of T cells
Given as IV infusion in patients who have had an inadequate response to DMARDS or TNF
antagonists
Increased upper respiratory tract infection
Not used in combination with TNF antagonist
Rituximab
Chimeric monoclonal antibody targeting B cells
Used for RA refractory to antiTNF agents
Given as IV infusion, can be combined with methotrexate
Leflunomide
Prodrug that is rapidly metabolized to a compound that inhibits dihydroorotate dehydrogenase
Enzyme required by activated lymphocytes for the synthesis of pyrimidines that are needed for
RNA
synthesis
Results in cell cycle arrest
Cholestyramine increases clearance of the drug by 50%
As effective as methotrexate in RA
Combined with methotrexate

Adverse effects
Diarrhea occur in 25%
Elevation of liver enzymes
Mild alopecia, weight gain and increase BP
ALL disease-modifying agents can cause severe or fatal toxicities
Careful monitoring of patients who take these drugs is mandatory

OTHER ANALGESICS
Acetaminophen
A. Classification and prototype
Only over-the-counter non-anti-inflammatory analgesic commonly available in the United States
Phenacetin
Toxic prodrug
Metabolized to acetaminophen (responsible for analgesic effect)
Still available in some other countries
B. Mechanism of action
Active metabolite of phenacetin
Weak COX-1 and COX-2 inhibitor in peripheral tissues
Accounts for its lack of anti-inflammatory effect
May inhibit a third enzyme, COX-3, in the CNS
C. Effects
Analgesic and antipyretic agent lacking anti-inflammatory or antiplatelet effects
D. Pharmacokinetics and clinical use
Effective for the same indications as intermediate-dose aspirin
Partially metabolized by the liver to inactive sulfate and glucoronide
N-acetyl-p-benzoquinone
Minor but highly active metabolite
Toxic to both liver and kidney in high doses
Aspirin substitute
Children with viral infections
Aspirin intolerance
Well absorbed orally
Half-life is 2-3h
Unaffected by renal function
Lacks anti-inflammatory effects
Does not affect uric acid levels

Can be used with probenecid

Lacks platelet-inhibiting properties
Useful for mild to moderate pain
Toxicity
Negligible toxicity
Dangerous hepatotoxin when taken in overdose or by patients with liver impairment
People who regularly consume 3 or more alcoholic drinks per day are at increased risk for
acetaminophen-induced hepatotoxicity
Requires oxidation to cytotoxic intermediates by phase I cytochrome P450 enzymes
Occurs if substrates for phase II conjugation reactions (acetate and glucuronide) are lacking.
Acetylcysteine
Sulfhydryl donor, may be lifesaving after an overdose

E.

DRUGS USED IN GOUT

Gout
Associated with increased serum concentrations of uric acid
Acute attacks involve joint inflammation initiated by precipitation of uric acid crystals
A. Classification and prototype
Treatment strategies
Reducing inflammation during acute attacks
Colchicines, NSAIDs, or glucocorticoids
Accelerating renal excretion of uric acid with uricosuric drugs
Probenecid or sulfinpyrazone
Reducing the conversion of purines to uric acid by xanthine oxidase
Allopurinol
B. Anti-inflammatory drugs used for gout
Indomethacin
1. Mechanism
Effective in inhibiting the inflammation of acute gouty arthritis
Reduction of prostaglandin formation and the inhibition of crystal phagocytosis by macrophages
Indomethacin and glucocorticoids
2. Effects
Reduce the synthesis of mediators of inflammation by inflammatory cells in the gouty joint
3. Pharmacokinetics and clinical use
Preferred for the treatment of acute gouty arthritis
Oral prep for indomethacin
Glucocorticoids
Oral (prednisone)
IV (triamcinolone acetonide)
4. Toxicity
Indomethacin
Renal damage or bone marrow depression
Short courses of glucocorticoids
Can cause behavioral changes and impaired glucose control
Colchicine
1. Mechanism
Selective inhibitor of microtubule assembly
Reduces leukocyte migration and phagocytosis
May also reduce production of leukotriene B4 and decrease free radical formation
2. Effects
Reacts with tubulin and interferes with microtubule assembly
Mitotic poison
3. Pharmacokinetics and clinical use
More specific but replaced by NSAIDs in the treatment of acute gout because of diarrhea
Lower doses
Prophylaxis of recurrent episodes of gout
Management of Mediterranean fever
Disease of unknown cause

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Fever, hepatitis, peritonitis, pleuritis, arthritis, and occasionally amyloidosis

Absorbed readily after oral administration
Parenteral preparation is not recommended
As little as 8 mg in 24 h maybe fatal

4. Toxicity
Troublesome diarrhea
Can severely damage the liver and kidney
Dosage must be carefully limited and monitored
Overdose is often fatal
C. Uricosuric agents
1. Mechanism
Probenecid, sulfinpyrazone
Organic weak acids
Compete with uric acid for reabsorption by the weak acid transport mechanism in the proximal
tubules of the kidney
May also compete with uric acid for secretion by the tubule at low doses
2. Pharmacodynamics
Aspirin in doses of less than 2.6 g daily should not be used for analgesia in patients with gout
Causes retention of uric acid by inhibiting the secretory transporter
3. Effects
Act primarily in the kidney
Inhibit the secretion of a large number of other weak acids (e.g., penicillin, methotrexate) in addition
to inhibiting the reabsorption of the uric acid
4. Pharmacokinetics and clinical use
Chronic gout is treated orally with a uricosuric agent or allopurinol
Are of no value in acute gouty arthritis
Best withheld for 1-2 weeks after an acute episode
5.

Toxicity
May precipitate an attack of acute gouty arthritis during the early phase of their action
Avoided by simultaneously administering colchicines or indomethacin
May share allergenicity with sulfonamide drugs
Diuretics, antimicrobials, oral hypoglycemic drugs
With the ensuing increase in uric acid excretion
Predisposition to formation of renal stones
Urine volume should be maintained at high level
Urine pH maintained at 6.0 early in the treatment by administration of an alkali
Allopurinol

D.
Purines
Formed from amino acids, formate and carbon dioxide in the body that are not incorporated into
nucleic acids
Converted to xanthine or hypoxanthine
Oxidized to uric acid
1. Mechanism
Preferred and standard-of-care therapy for gout in the intercritical period (between acute episodes)
Reduces total uric acid body burden by inhibiting xanthine oxidase
2. Effects
Inhibition of xanthine oxidase
Increases the concentration of the more soluble hypoxanthine and xanthine
Decreases the concentration of the less soluble uric acid
Less likelihood of precipitation of uric acid crystals in joints and tissues
3. Pharmacokinetics and clinical use
Metabolized by xanthine oxidase to alloxanthine but retains its capacity to inhibit the enzyme
Given oral once daily for chronic gout
Adjunct to cancer chemotherapy
Slows the formation of uric acid from purines released by the death of large numbers of neoplastic
cells
4. Toxicity and drug interactions
Withheld 1-2 weeks after an acute episode of gouty arthritis

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E.

Can precipitate acute attacks of gout during the early phase of treatment
GI upset, rash, and rarely, peripheral neuritis, vasculitis, or bone marrow dysfunction, including
aplastic anemia
Inhibits the metabolism of mercaptopurine and azathioprine
Drugs that depend on xanthine oxidase for elimination
Febuxostat
First nonpurine inhibitor of xanthine oxidase
80% absorbed after oral administration
All drugs and metabolites appear in the urine
No dosage adjustment required for patients with renal impairment
Potent and selective inhibitor that reduces the formation of xanthine and uric acid
No other enzymes involved in purine and pyrimidines metabolism is inhibited
More effective at 80 or 120 mg than the standard 300 mg dose of allopurinol
Prophylactic treatment with colchicine or NSAIDs should start at the beginning of treatment to avoid
gout flares
Toxicity includes liver function abnormalities, diarrhea, headache and nausea
Well tolerated in patients with history of allopurinol intolerance

F. Pegloticase
Newest urate-lowering therapy approved for the treatment of refractory chronic gout
Recombinant mammalian uricase
Rapidly acting IV drug
Achieves peak decline of uric acid within 24-72h

Half-life 6.4-13.8 days

Urate oxidase converts uric acid to allantoin that can be easily excreted in the kidneys
Absent in humans and some higher primates
Able to maintain low urate levels for up to 21 days at doses 4-12 mg

IV dosing every 2 weeks

Adverse effects
o Infusion reaction and gout flare (most common)
o Nephrolithiasis
Anemia
o Athralgia
Muscle spasm
o Headache
Peripheral edema
o Nausea
Diarrhea
o URTI
UTI
Hemolytic anemia
o
o

Patients with G6PD

Formation of hydrogen peroxide by uricase

Antibody formation
o
o
o

Shortening of circulating half-life

Loss of response
Monitor uric acid levels

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