Gout Medications

Gout Medications

http://evolve.elsevier.com/Edmunds/NP/

Class	Generic Name	Trade Name
NSAIDs	indomethacin	Indocin
	naproxen	Naprosyn
	sulindac	Clinoril
Colchicine	colchicine	Generic, Colcrys
Uricosuric agents	probenecid	Benemid
Interleukin-1 inhibitor	rilonacept	Arcalyst
Xanthine oxidase inhibitors	allopurinol	Zyloprim
	febuxostat	Uloric
Combination product		ColBenemid

Key drug. Drugs are listed in approximate order of use.

INDICATIONS

• Hyperuricemia

• Prophylaxis of gouty arthritis

• Acute gouty arthritis

Pharmacologic management of gout relies on the use of NSAIDs (see Chapter 36), colchicine, uricosuric agents (probenecid), and xanthine oxidase inhibitors (allopurinol and febuxostat) (Table 38-1).

TABLE 38-1

Pharmacologic Management of Different Phases of Gout

Preferred Class of Drugs	Goal of Therapy	Stage and Duration of Treatment
(1) Colchicine used as initial therapy (2) NSAIDs (3) Glucocorticoids (intraarticularly, orally, or parenterally as needed) (4) Intramuscular corticotropin	Reduce pain; reduce inflammation	Acute Stage usually requires treatment 1-2 wk
Colchicine NSAIDs	Prevention of further inflammatory episodes and pain	Post-Acute Stage: Drugs used to prevent rebound flare until serum urate <6 mg/dl, if urate-lowering therapy has been started
Uricosuric agents (probenecid) Uricostatic agents: xanthine oxidase inhibitors (e.g., allopurinol)	Prevent disease by reducing hyperuricemia to serum urate level <6 mg/dl	Chronic Stage: Usually requires lifelong treatment

Modified from Schlesinger N: Management of acute and chronic gouty arthritis: present state-of-the art, Drugs 64(21):2399-2416, 2004; Morgan L: Colchicine in acute gout, Aust Fam Physician 37(3):103, 2008.

Therapeutic Overview

Pathophysiology

Gout is a term that is used to describe a collection of disorders caused by the deposition of monosodium urate crystals in body tissue. The condition has become increasingly more common in the United States in the past 2 decades, in part because of the nation’s obesity crisis and a greater frequency of high blood pressure. Gout can be classified as primary or secondary. Primary gout, which affects males 10 times more often than females, is caused by an inborn error of purine metabolism that results in the overproduction or underexcretion of uric acid. Secondary gout is associated with hyperuricemia that results from other diseases or drugs that interfere with uric acid secretion. Secondary gout arises from a multitude of causes, including endocrine disorders, lead poisoning, high-dose salicylates (more than 3 g/day), myeloproliferative disorders, and chronic renal disease. Obese patients seem to have earlier onset of gout.

The basic pathology of gout generally is classified into one of two categories: overproduction or underexcretion of uric acid. A 24-hour urine collection is used to differentiate overproducers from underexcreters of uric acid.

Disease Process

Four phases generally are recognized in the development of gout. The first is asymptomatic hyperuricemia, which, as the name implies, is not associated with any clinical symptoms. Evidence suggests that the higher an individual’s serum uric acid level, the greater is the likelihood that acute gout will develop. Acute gouty arthritis, the next phase, typically presents as a sudden, exquisitely painful monoarthropathy. Although any synovial joint can be affected, the most common site for this painful manifestation is the metatarsophalangeal joint of the great toe. The third phase, the intercritical period, is the period between acute attacks. Most individuals who develop gout have a second episode of gout within 6 months to 2 years of the first attack. Untreated gout tends to result in more frequent, severe attacks of longer duration. However, some patients will never have a second attack. Finally, chronic tophaceous gout can occur. Tophi are sodium urate crystals that are deposited in the soft tissues and can occur in up to 50% of patients with gout. They tend to appear at any time from 2 or 3 years to 10 years after the onset of gout. The most common locations for tophi are synovium, prepatellar and olecranon bursae, the Achilles tendon, and the helix of the ear.

Hyperuricemia, defined as serum urate level >6 mg/dl in men and >7 mg/dl in women, is the strongest risk factor for development of gout. The higher the serum urate level, the greater is the incidence of acute gouty arthritis. Hyperuricemia alone, however, is not diagnostic. Studies involving acute gout attacks have found that uric acid levels have been low to normal in 12% to 43% of patients. Key risk factors for gout include hypertension, thiazide and loop diuretics, obesity, and alcoholism. These risk factors seem to be additive in terms of risk. Other risk factors for developing gout include age older than 60, family history, lead exposure (patients who consume “moonshine” whiskey have an even greater risk because moonshine tends to have a high lead content), and the use of other medications (e.g., low-dose aspirin [<2 g/day], cyclosporine, tacrolimus, ethambutol, pyrazinamide, nicotinic acid). Dietary intake of meat and seafood has been shown to significantly increase the risk that a gout attack will occur; consumption of dairy products is associated with the lowest risk of attacks. Excessive alcohol consumption—specifically beer and spirits, but not wine—is associated with increased risk of an attack. Conditions such as thyroid problems, kidney disease, anemia, hyperlipidemia, diabetes, vascular disease, trauma, surgery, and radiation treatment also may serve as triggers for gout.

Up to 90% of individuals with gout are underexcreters of uric acid. Normally, the kidneys turn over approximately 700 mg/dl of uric acid per day. Of that amount, about 10% is excreted. Normal serum uric acid in males ranges from 2 to 7 mg/dl; the normal range for females is 2 to 6 mg/dl. Any factor that interferes with the glomerular and renal tubular reabsorption of uric acid can result in elevated serum uric acid levels.

Overproduction of uric acid is much less common. It is often the result of another disease, frequently one associated with excessive rates of cell turnover. Hemolytic anemias, myeloproliferative and lymphoproliferative diseases, and psoriasis are examples of processes that may cause secondary gout resulting from overproduction of uric acid. Some inherited diseases and genetic abnormalities can cause primary gout through overexcretion of uric acid.

The most important differential diagnosis to be made in a patient with gout is the exclusion of a septic joint. Synovial fluid aspiration and examination help confirm the diagnosis. Fluid is sent for WBC and differential, crystal analysis, and Gram stain with culture. Examination of joint fluid with the use of a polarized microscope will reveal the presence of crystals. The presence of birefringent crystals in the synovial fluid does not exclude the possibility of infection because gout and infection can coexist in a joint.

Mechanism of Action

Use the following three mechanisms in the treatment of gout (Figure 38-1):

FIGURE 38-1 Suggested treatment algorithm for gout. (Modified from Gall EP: Hyperuricemia and gout. In Greene HL II et al, editors: Decision-making in medicine, ed 4, St Louis, 2007, Mosby.)

1. Increase the excretion of uric acid (uricosurics).

2. Decrease the synthesis of uric acid (allopurinol and febuxostat).

3. Decrease or stop the inflammatory response (NSAIDs, colchicine).

NSAIDs inhibit prostaglandin synthesis, thereby reducing the intensity of inflammation and pain in injured tissue. See Chapter 34 for a detailed discussion of prostaglandin inhibition.

The exact mechanism of action of colchicine is unknown. Colchicine affects leukocyte function to reduce lactic acid production. This results in decreased deposition of uric acid and reduction of the inflammatory response. Colchicine has no effect on uric acid metabolism and is not an analgesic.

Uricosuric agents (probenecid) are tubular blocking agents. They decrease serum uric acid levels by increasing urinary excretion of uric acid caused by inhibition of tubular reabsorption of urate. During this process, high concentrations of uric acid develop in the proximal renal tubules. This may predispose the patient to the development of urinary stones. For this reason, increased fluid intake is necessary and alkalinization of the urine is desirable when uricosuric therapy is initiated. Probenecid also inhibits the tubular secretion of most penicillins and cephalosporins. This increases the effectiveness of antibiotics.

Allopurinol and febuxostat inhibit xanthine oxidase, the enzyme that converts xanthine to uric acid. This reduces uric acid production by altering the breakdown of purines to produce xanthines rather than urates. Xanthines are much more soluble than uric acid and therefore have a much greater renal clearance. Different from uricosuric agents, allopurinol xanthine oxidase inhibitors do not promote uric acid secretion, so the level of uric acid in the renal tubules is not increased.

Treatment Principles

Standardized Guidelines

• American College of Rheumatology, Guidelines for the management of Gout. Available at http://www.rheumatology.org/practice/clinical/guidelines/gout.asp. Released in late 2012.

Evidence-Based Recommendations

• Treatment: colchicine, corticosteroids, and NSAIDs have unknown effectiveness.

• Prevention of recurrence: allopurinol, colchicine, sulfinpyrazone

No firm evidence-based guidelines have been put forth regarding when in the course of gout it is most appropriate to start urate-lowering therapy. This is essentially up to the patient and the clinician.

Cardinal Points of Treatment

• Gout treatment should be individualized and guided by principles of pharmacology.

• The ACR guidelines recommend xanthine oxidase inhibitors, either allopurinol or febuxostat, as first-line therapy to reduce uric acid levels.

• A uricosuric agent such as probenecid, fenofibrate or losartan can be added if the target serum urate level cannot be achieved with xanthine oxidase inhibitors alone.

• Treatment should be titrated to achieve a serum urate level of less than 6 mg/dl, but a reduction to 5 mg/dl might be needed to control signs and symptoms.

• Consider select pharmacogenetic screening of patients for the HLA-B∗5801 allele, which increases the risk of allopurinol hypersensitivity in high-risk populations, including Han Chinese.

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Tags: Pharmacology for the Primary Care Provider

Jul 22, 2016 | Posted by admin in PHARMACY | Comments Off

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