2/29 Drugs for the Treatment of Gout

Question 1

What is generally the cause of gout?

Answer 1

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

Question 2

What drugs increase the risk of gout?

Answer 2

Certain drugs, particularly thiazide diuretics and immunosuppressant agents, especially cyclosporine, may impair urate excretion and thereby increase the risk of gout

Question 3

What are the classes of drugs used in treatment of acute gout?

Answer 3

NSAIDs

colchicine

glucocorticoids

Question 4

How are NSAIDs helpful in treating acute gout?

Answer 4

first-line drugs for acute gout; they inhibit urate crystal phagocytosis

Question 5

What NSAIDs are used to treat gout?

Answer 5

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

Question 6

How is colchicine used for treating gout?

Answer 6

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)

Question 7

How are glucocorticoids useful in treating gout?

Answer 7

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

Question 8

What are some ways to prevent gout/recurrent attacks?

Answer 8

lifestyle mods: diet modification, weight loss

Question 9

What are some pharmacological therapies for preventing recurrent attacks of gout?

Answer 9

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)

Question 10

How long is someone on urate-lowering therapy?

Answer 10

once started, Tx continues indefinitely

• pt is asymptomatic for vast majority of time

Question 11

What are some names and MOAs for urate lowering drugs?

Answer 11

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

Question 12

When are uricosuric agents indicated? XO inhibitors?

Answer 12

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

Question 13

What is pegloticase?

Answer 13

recombinant uricase available for treatment of severe chronic gout refractory to conventional antihyperuricemic therapy

Question 14

When are anti-inflamm agents used in treating gout?

Answer 14

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)

Question 15

What is the MOA for colchicine?

Answer 15

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

Question 16

How quickly does colchicine work?

Answer 16

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

Question 17

What are the clinical uses of colchicine?

Answer 17

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

Question 18

What are the ADRs of colchicine?

Answer 18

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

Question 19

What is the MOA for allopurinol?

Answer 19

purine analog that competitively and irreversible inhibits xanthine oxidase

Question 20

What are the clinical uses for allopurinol?

Answer 20

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

Question 21

What are the ADRs associated with allopurinol?

Answer 21

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

Question 22

What is the MOA for febuxostat?

Answer 22

non-purine xanthine oxidase inhibitor

Question 23

What is the clinical use of febuxostat?

Answer 23

treatment of chronic hyperuricemia in gout patients

Question 24

What are the ADRs of febuxostat? Contraindications?

Answer 24

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

Question 25

What is the MOA for pegloticase?

Answer 25

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

Question 26

What is the clinical use for pegloticase?

Answer 26

treatment of chronic gout refractory to conventional therapy

Question 27

What are the ADRs for pegloticase?

Answer 27

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

Question 28

What is the MOA for probenecid?

Question 29

What are the clinical uses of probenecid?

Answer 29

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

Question 30

What are the ADRs associated with probenecid? Contraindications?

Answer 30

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