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What is gout?
Gout is a familial metabolic disease associated with high blood levels of uric acid (hyperuricemia). The disease is characterized by attacks of arthritis and urinary calculi, which are caused by deposits of sodium urate crystals in joints, cartilage and the kidneys.
What are the common clinical signs and symptoms of gout?
During the initial attacks, the usual presentation is sudden pain in a single joint, most often the metatarsophalangeal joint of a great toe.
Whom does gout usually affect?
Men. Onset is usually in the 40's.
What is uric acid?
Uric acid is the end product o purine metabolism and is excreted mainly via the kidney.
What is the definition of hyperuricemia?
Hyperuricemia is usually defined as a serum concentration of uric acid greater than 7mg/dL. It is important to note that hyperuricemia is not always associated with gout; however, gout is always preceded by hyperuricemia.
What are the causes of hyperuricemia?
* Idiopathic enzyme defects in purine metabolism- 90% of cases (this is known as primary gout)
* Disease states associated with rapid production and destruction of cells- myeloproliferative disorders and malignancies, especially those treated with chemotherapy or radiation (this is known as secondary gout)
* Weakly acidic drugs such as clofibrate, thiazides and salicylates can cause decreased renal excretion of uric acid
* Other causes include excessive alcohol intake, kidney disease, high purine diets, starvation, and obesity.
How is gout treated?
It depends on whether the patient is suffering from an acute attack or a chronic case. The general treatment strategy is as follows:
- Reduce inflammation (via NSAIDs)
- Facilitate the excretion of uric acid (via uricosuric agents)
- Decrease the production of purines (via allopurinol)
Acute gout: What pharmacologic agents are available for treating an acute attack of gout?
Aspirin is an NSAID- can it be used in the treatment of gout?
No! Aspirin, because it is a salicylate, inhibits uric acid secretion into the renal tubules and therefore is contraindicated in the treatment of gout. It also antagonizes the effects of probenecid and sulfinpyrazone.
Indomethacin (Indocin): What is its therapeutic use?
It is the drug of choice to treat acute attacks of gout.
What is this drug's mechanism of action?
It reversibly inhibits cyclooxygenase. Consequently, the production of prostaglandins and thromboxane, which are responsible for inflammation, is reduced.
State indomethacin's adverse effects.
- Headache, vertigo
- Abdominal distress
- Renal toxicity
- Hypersensitivity reactions
Phenylbutazone (Azolid): What is the classification of this drug?
Phenylbutazone, like indomethacin, is an NSAID.
What is the mechanism of action?
Same as that of indomethacin.
What is phenylbutazone's therapeutic use?
Phenylbutazone was used more often in the past for treating acute cases of gout. However, because it has a high incidence of side effects, it is not used frequently today.
State the adverse effects of this drug.
- Skin rash
- Aplastic anemia and agranulocytosis
Colchicine: What is the mechanism of action?
Colchicine reduces the inflammatory response by binding to microtubular protein, thus inhibiting neutrophil migration and phagocytic activity. (Neutrophils are largely responsible for the inflammation and pain associated with gout). Colchicine also decreases leukotriene B4 formation.
Does colchicine affect the production or excretion of uric acid?
What is this drug's route of administration?
Oral or IV
State colchicine's therapeutic use.
Colchicine is used to treat both acute and chronic gout. A dramatic response to colchicine makes the diagnosis of gout likely.
What are the adverse effects of colchicine?
* Most common effects- GI distress (vomiting, diarrhea, abdominal pain)
* Acute poisoning after large doses can lead to nephrotoxicity, bloody diarrhea, and shock
* With chronic use- possible agranulocytosis, alopecia, and aplastic anemia
* Myopathy has been reported (rare)
What are the relative contraindications to colchicine use?
Colchicine is contraindicated in patients who have GI disease, hepatitis or renal disease.
Chronic Gout: What pharmacologic options are available for a chronic case of gout?
- Uricosuric agents: probenecid and sulfinpyrazone
Uricosuric Agents: What are they?
Weak organic acids that interfere with the renal processing of uric acid.
Give two examples.
1. Probenecid (Benemid)
2. Sulfinpyrazone (Anturane)
What is the mechanism of action of these drugs?
The actions of uricosuric agents are dependent upon their serum concentrations:
* At low concentrations they reduce the renal excretion of uric acid by inhibiting uric acid secretion into the renal tubules.
* At therapeutic concentrations they increase uric acid excretion by inhibiting uric acid reabsorption in the proximal tubule.
It is important to remember that low doses of uricosuric agents and salicylates such as aspirin actually increase serum uric acid concentration.
What is the route of administration for these drugs?
What is their therapeutic use?
Treatment of chronic gout (to avoid attacks) and severe hyperuricemia. These drugs are not indicated in the treatment of acute attacks of gout.
What are the adverse effects of probenecid and sulfinpyrazone?
* They can precipitate an acute attack of gouty arthritis in the early stages of treatment.
* Gastrointestinal distress
* Allergic dermatitis
Allopurinol (Lopurin): What is it?
Allopurinol is an isomer of hypoxanthine.
What is xanthine oxidase?
Xanthine oxidase is the enzyme that catalyzes the terminal steps of uric acid synthesis. It converts hypoxanthine to xanthine and xanthine to uric acid.
How does allopurinol work?
Allopurinol and its metabolite alloxanthine competitively inhibit the enzyme xanthine oxidase.
What are the therapeutic uses of allopurinol?
- Treatment of chronic gout
- Treatment of the hyperuricemia associated with Lesch-Nyhan syndrome, hematologic disorders (polycythemia vera, myeloid metaplasia) or antineoplastic therapy prevention of renal calculi.
State the route of administration for allopurinol.
Can you combine allopurinol with other antigout drugs?
Yes. Because urate-lowering drugs can initially precipitate an acute gout attack, colchicine is often given concurrently with allopurinol or the uricosuric agents.
What are this drug's adverse effects?
Allopurinol is usually well tolerated but can cause hypersensitivity reactions (allergic dermatitis, fever) and gastrointestinal distress (diarrhea, abdominal pain). Attacks of acute gout may occur during initial months of therapy.
Are allopurinol, probenecid, and sulfinpyrazone indicated in the treatment of acute attacks?
No. These drugs are usually begun once the acute attack in under control. Remember to use indomethacin and colchicine for acute attacks.
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