2/29 Drugs for the Treatment of Gout Flashcards
What is generally the cause of gout?
Hyperuricemia, while a prerequisite, does not inevitably lead to gout; long-term treatment of asymptomatic individuals has not been proven effective
Hyperuricemia usually arises from underexcretion rather than overproduction of urate
Gout results from precipitation of urate crystals in the tissues and subsequent inflammatory response
What drugs increase the risk of gout?
Certain drugs, particularly thiazide diuretics and immunosuppressant agents, especially cyclosporine, may impair urate excretion and thereby increase the risk of gout
What are the classes of drugs used in treatment of acute gout?
NSAIDs
colchicine
glucocorticoids
How are NSAIDs helpful in treating acute gout?
first-line drugs for acute gout; they inhibit urate crystal phagocytosis
What NSAIDs are used to treat gout?
Naproxen, indomethacin, and sulindac are common NSAID choices due to potency and efficacy
Celecoxib used (off-label) - decreased incidence of GI adverse effects
All other NSAIDs (except aspirin, salicylates, and tolmetin) have been successfully used to treat gout
Oxaprozin lowers serum uric acid, but it should not be given to patients with uric acid stones as it increases uric acid excretion in the urine
Aspirin is not used because it can inhibit urate excretion at low doses; it is uricosuric at higher doses and can increase the risk of renal calculi; aspirin can also inhibit the actions of uricosuric agents
How is colchicine used for treating gout?
primary treatment for many years
use has declined due to toxicity
may be used in patients with contraindications to NSAIDs
(chronic kidney disease, active peptic ulcer disease, a history of NSAID-intolerance)
How are glucocorticoids useful in treating gout?
Glucocorticoids
(intraarticular, oral, or parenteral, depending on the number of joints involved)
sometimes used in the treatment of severe gout (particularly in patients with contraindications to both NSAIDs and colchicine)
rapid relief within hours of therapy
intra-articular injections are useful if only a few joints are involved and septic arthritis has been ruled out
What are some ways to prevent gout/recurrent attacks?
lifestyle mods: diet modification, weight loss
What are some pharmacological therapies for preventing recurrent attacks of gout?
anti-inflammatory prophylaxis
prevention of recurrences of acute gouty arthritis
antihyperuricemic (urate-lowering) therapy
prevention and reversal of the consequences of urate crystal deposition in joints (gouty arthropathy), urinary tract (nephrolithiasis), renal interstitium (rarely producing renal failure due to urate nephropathy), and tissues and parenchymal organs (tophi)
How long is someone on urate-lowering therapy?
once started, Tx continues indefinitely
- pt is asymptomatic for vast majority of time
What are some names and MOAs for urate lowering drugs?
Antihyperuricemic therapies reduce the serum urate concentration either by enhancing renal excretion of uric acid (uricosuric agents) or by decreasing urate synthesis (xanthine oxidase inhibitors)
Probenecid is the only potent uricosuric agent available in the U.S.
Available xanthine oxidase inhibitors include allopurinol and febuxostat
When are uricosuric agents indicated? XO inhibitors?
Uricosuric agents are indicated only in patients who have impaired renal excretion of uric acid (85% - 90% of cases)
xanthine oxidase inhibitors are likely to be effective in all cases warranting urate-lowering therapy
regardless of whether the cause is underexcretion or overproduction of urate
What is pegloticase?
recombinant uricase available for treatment of severe chronic gout refractory to conventional antihyperuricemic therapy
When are anti-inflamm agents used in treating gout?
Anti-inflammatory agents such as colchicine or indomethacin are used early in the course of uricosuric therapy
- mobilization of urate is associated with a temporary increase in the risk of acute gouty arthritis
(also the rationale for waiting at least 2 weeks after an acute flare has resolved before initiating urate-lowering therapy)
What is the MOA for colchicine?
binds to tubulin and prevents its polymerization into microtubules
leading to inhibition of leukocyte migration and phagocytosis
antimitotic effects
arresting cell division in G1 by interfering with microtubule and spindle formation
may alter neutrophil motility
renders cell membranes more rigid and decreases the secretion of chemotactic factors by activated neutrophils
How quickly does colchicine work?
Relieves the pain and inflammation of gouty arthritis in 12-24 hours without altering the metabolism or excretion of urates and without other analgesic effects
What are the clinical uses of colchicine?
second-line therapy for acute gout
narrow therapeutic window
high rate of side effects, particularly at higher doses
Most effective if treatment is initiated within 12-24 hours of symptom onset; diminished likelihood of benefit for acute attacks that have been ongoing for more than 72-96 hours
Used at low doses between attacks for prolonged anti-inflammatory prophylaxis
What are the ADRs of colchicine?
Often causes diarrhea
- may occasionally cause nausea, vomiting, and abdominal pain
Hepatic necrosis, acute renal failure, disseminated intravascular coagulation, and seizures can occur
contraindicated in patients with advanced renal or hepatic impairment
More severe adverse effects are associated with IV administration (no longer FDA-approved)
Acute overdose is characterized by burning throat pain, bloody diarrhea, shock, hematuria, and oliguria; fatal ascending CNS depression has been reported
Treatment with colchicine should not be repeated within 14 days to avoid cumulative toxicity
What is the MOA for allopurinol?
purine analog that competitively and irreversible inhibits xanthine oxidase
What are the clinical uses for allopurinol?
Preferred and standard-of-care therapy for gout during the period between acute episodes
Also used as an antiprotozoal and for management of chemotherapy-associated hyperuricemia
What are the ADRs associated with allopurinol?
Can precipitate acute gouty arthritis
- NSAID or colchicine should be used for prophylaxis during the first few months of therapy
GI intolerance including nausea, vomiting, and diarrhea; allergic rash occurs in 3% of patients
Dosage reduction of chemotherapeutic purines (6-mercaptopurine, azathioprine) is required
Inhibits metabolism of probenecid
What is the MOA for febuxostat?
non-purine xanthine oxidase inhibitor
What is the clinical use of febuxostat?
treatment of chronic hyperuricemia in gout patients
What are the ADRs of febuxostat? Contraindications?
Can precipitate acute gouty arthritis
NSAID or colchicine should be used for prophylaxis during the first few months of therapy
Generally well tolerated, even in patients with a history of allopurinol intolerance
Most frequent side effects are liver function abnormalities, diarrhea, headache, and nausea
Concurrent use with azathioprine or 6-mercaptopurine is contraindicated
What is the MOA for pegloticase?
recombinant mammalian uricase covalently attached to methoxy polyethylene glycol to prolong circulating half-life and reduce immunogenicity
uricase converts uric acid to allantoin and is absent in humans due to mutational inactivation
IV dosing every 2 weeks reduces urate levels
What is the clinical use for pegloticase?
treatment of chronic gout refractory to conventional therapy
What are the ADRs for pegloticase?
Can precipitate acute gouty arthritis
NSAID or colchicine should be used for prophylaxis while initiating therapy
Infusion reactions are common and anaphylaxis has been reported
Most patients exhibit an immune response
antibody formation is associated with reduced half-life, decreased response, and higher incidence of infusion reactions
rising plasma uric acid levels indicate antibody production and allows for monitoring of safety and efficacy
Contraindicated in G6PD deficiency due to concern for hemolytic anemia
What is the MOA for probenecid?
What are the clinical uses of probenecid?
Treatment of hyperuricemia associated with gout when use of allopurinol or febuxostat is contraindicated, or when tophi are present
Originally developed to prolong penicillin blood levels
What are the ADRs associated with probenecid? Contraindications?
Increased uric acid secretion increases the likelihood of renal stone formation
- Large urine volume must be maintained to minimize this complication
- contraindicated in patients with uric acid stones
Generally well tolerated; mild GI irritation and rash are common
Aspirin and other salicylates may diminish the effect of probenecid
