CHAPTER 74

Drug therapy of gout

Our topic for the chapter is gout, a painful inflammatory disorder seen mainly in men. Symptoms result from deposition of uric acid crystals in joints. We begin by discussing the pathophysiology of gout, after which we discuss the drugs used for treatment.

Pathophysiology of gout

Gout is a recurrent inflammatory disorder characterized by hyperuricemia (high blood levels of uric acid) and episodes of severe joint pain, typically in the large toe. Hyperuricemia—defined as blood uric acid above 7 mg/dL in men, or 6 mg/dL in women—can occur through two mechanisms: (1) excessive production of uric acid and (2) impaired renal excretion of uric acid. Acute attacks are precipitated by crystallization of sodium urate (the sodium salt of uric acid) in the synovial space. Deposition of urate crystals promotes inflammation by triggering a complex series of events. A key feature of the inflammatory process is infiltration of leukocytes, which, once inside the synovial cavity, phagocytize urate crystals and then break down, causing release of destructive lysosomal enzymes. When hyperuricemia is chronic, large and gritty deposits, known as tophi, may form in the affected joint. Also, deposition of urate crystals in the kidney may cause renal damage. Fortunately, when gout is detected and treated early, the disease can be arrested and these chronic sequelae avoided.

Overview of drug therapy

In patients with gout, drugs are used in two ways. First, they are given short term to relieve symptoms of an acute gouty attack. Second, they are given long term to lower blood levels of uric acid.

In patients with infrequent flare-ups (less than three per year), treatment of symptoms may be all that is needed. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered first-line agents for relieving pain of an acute gouty attack. Glucocorticoids are an acceptable option. In the past, colchicine was considered a drug of choice for acute gout—even though it has a poor risk/benefit ratio. Today, colchicine is generally reserved for patients who are unresponsive to or intolerant of safer agents.

In patients with chronic gout, tophaceous gout, or frequent gouty attacks (three or more per year), drugs for hyperuricemia are indicated. Three types of drugs may be employed: agents that decrease uric acid production, agents that increase uric acid excretion, and agents that convert uric acid to allantoin. Agents that increase urate excretion are known as uricosuric drugs.

Drugs for acute gouty arthritis

Nonsteroidal anti-inflammatory drugs

For acute gouty arthritis, NSAIDs are considered agents of first choice. Compared with colchicine, NSAIDs are better tolerated and their effects are more predictable. Benefits derive from suppressing inflammation. Treatment should start as soon as possible after symptom onset. Most patients experience marked relief within 24 hours; swelling subsides over the next few days. Adverse effects of NSAIDs include GI ulceration, impaired renal function, fluid retention, and increased risk of cardiovascular events. However, since the duration of treatment is brief, the risk of these complications is low. Which NSAID should be used? There is no good evidence that any NSAID is superior to the others for treatment of gout. Commonly used drugs and dosages are as follows:

• Indomethacin [Indocin]—50 mg 4 times daily for 3 to 6 days

• Naproxen [Naprosyn]—500 mg 2 or 3 times daily for 3 to 6 days

• Diclofenac sodium [Voltaren]—50 mg 3 times daily for 3 to 6 days

NSAIDs are discussed at length in Chapter 71.

Glucocorticoids

Glucocorticoids (eg, prednisone), given PO or IM, are highly effective for relieving an acute gouty attack—although NSAIDs are generally preferred. Candidates for glucocorticoid therapy include patients who are hypersensitive to NSAIDs, patients who have medical conditions that contraindicate use of NSAIDs, and patients with severe gout that is unresponsive to NSAIDs. Because of their effects on carbohydrate metabolism, glucocorticoids should be avoided in patients prone to hyperglycemia. For oral therapy, prednisone can be used. The dosage is 20 to 40 mg on day 1, followed by progressively smaller doses over the next 8 days. For IM therapy, triamcinolone acetonide can be used. The dosage is 60 mg every 1 to 4 days as needed. Glucocorticoids are discussed at length in Chapter 72.

Colchicine

Colchicine [Colcrys] is an anti-inflammatory agent with effects specific for gout. The drug is not active against other inflammatory disorders. Colchicine is not an analgesic and does not relieve pain in conditions other than gout. The drug’s most common adverse effect is GI toxicity. In the past, colchicine was considered a first-line drug for gout. However, owing to the availability of safe and effective alternatives, its use has declined.

Therapeutic use

Colchicine has two applications in gout. First, it can be used short term to treat an acute gouty attack. Second, it can used long term to prevent attacks from recurring.

Acute gouty arthritis.

High-dose colchicine can produce dramatic relief of an acute gouty attack. Within hours, patients whose pain had made movement impossible are able to walk. Inflammation disappears completely within 2 to 3 days. Administration is oral only. Colchicine for IV use has been withdrawn.

Prophylaxis of gouty attacks.

When taken during asymptomatic periods, low-dose colchicine (0.6 mg once or twice daily) can decrease the frequency and intensity of acute flare-ups. Colchicine is also given for prophylaxis when urate-lowering therapy is initiated. Why? Because there is a tendency for gouty episodes to increase at this time.

Mechanism of action

We do not fully understand how colchicine relieves or prevents episodes of gout. We do know that colchicine does not decrease urate production or removal. How then might it work? At least in part, by inhibiting leukocyte infiltration: In the absence of leukocytes, there is no phagocytosis of uric acid and no subsequent release of lysosomal enzymes. How does colchicine inhibit leukocyte migration? It disrupts microtubules, the structures required for cellular motility. Because microtubules are also required for cell division, colchicine is toxic to any tissue that has a large percentage of proliferating cells. Disruption of cell division in the GI tract and bone marrow underlies major toxicities of the drug.

Pharmacokinetics

Colchicine is readily absorbed following oral dosing, both in the presence and absence of food. Large amounts re-enter the intestine via the bile and intestinal secretions, and then undergo reabsorption. Final elimination occurs primarily through two processes: metabolism by hepatic CYP3A4 (the 3A4 isozyme of cytochrome P450) and renal excretion of intact drug.

Adverse effects

Gastrointestinal effects.

The most characteristic side effects are nausea, vomiting, diarrhea, and abdominal pain. These responses, which occur during treatment of acute gouty attacks, result from injury to the rapidly proliferating cells of the GI epithelium. With the high doses used in the past, these GI effects developed in nearly all patients. However, with the lower doses used today, GI toxicity is less common, but still develops in 25% of patients. If GI symptoms occur, colchicine should be discontinued immediately, regardless of the status of joint pain.

Myelosuppression.

Injury to rapidly proliferating cells can suppress bone marrow function, and can thereby cause leukopenia, granulocytopenia, thrombocytopenia, and pancytopenia. Accordingly, colchicine should be used with caution in patients with hematologic disorders.

Myopathy.

Colchicine can cause rhabdomyolysis (muscle breakdown) during long-term low-dose therapy. Risk is increased in patients with renal and hepatic impairment, and in those taking statin drugs (eg, atorvastatin, simvastatin), which can cause rhabdomyolysis on their own. Patients should be monitored for sign of muscle injury (tenderness, pain, weakness).

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