Month: October 2012

Management of Gout (Medications)

October 25, 2012 Adverse Drug Reactions, Drug Informatics, Pharmacotherapy No comments , , , ,

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying health problems. However, aspirin should not be used because it can alter uric acid levels and potentially prolong and intensify an acute attack.

Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used but used cautiously), and patients in the intensive care unit who are predisposed to gastritis. In patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

NSAIDs are prescribed at full dosage for 2-5 days to control the acute attack, and the dose is reduced to approximately one half to one fourth of that amount once the acute attack is controlled. Taper the dose down over approximately 2 weeks. But the consistent low-dose of NSAIDs used for 6-24 months may help to prevent the occurring of acute gout attack during the chronic lowering uric acid treatment.

Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.


Although colchicine was once the treatment of choice for acute gout, it is now a second-line approach because of its narrow therapeutic window and risk of toxicity.

Colchicine therapy must be initiated within 24 hours of onset of the acute attack to be effective. Dosing recommendation for colchicine in acute gout therapy have been modified in recent years because of an increased awareness of its toxicities. The most recent recommendations have been trending toward lowered daily and cumulative doses. The favored regimen is low-dose colchicine 1.8 mg total over 1 hour (1.2 mg PO initially then 0.6 mg q1hr, total not to exceed 1.8 mg over 1 hour-period).

Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min. Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

For prophylaxis the dose of colchicine is 0.6 mg bid or lower. In patients with renal insufficiency, this dose may need to be decreased to daily or overy-other-day administration. Even in prophylactic dose, colchicines can cause marrow toxicity and neuromyopathy in the setting of renal insufficiency. Long-term use of colchicine can lead to a muscle weakness associated with elevated levels of creatine kinase due to a drug-induced neuromyopathy, particularly in patients with renal insufficiency.


Corticosteroids can be given to patients with gout who cannot use NSAIDs or coclchicine, but adrenocorticotropic hormone (ACTH) would be preferred. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via ACTH.

ACTH 40 IU can be given to induce corticosteroid production by the patient’s own adrenal glands. Such a regimen dose not depend on the patient to properly taper prednisone. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.

Intra-articular, long-acting (depot) corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids.


Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid. It is the most effective urate-lowering agent. However, alcohol can interfere with effectiveness of allopurinol.

Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, and/or pruritic maculopapular rash. Less frequently, patients taking allopurinol can develop allopurinol hypersensitivity, which carries a mortality rate of 20-30%. Features of allopurinol hypersensitivity include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat allopurinol hypersensitivity.

Allopurinol hypersensitivity is more likely to occur in patients with renal insufficiency, patients who are taking a diuretic, and patients begun on 300 mg of allopurinol. Although allopurinol hypersensitivity is more common (although still rare) in patients with renal insufficiency, this effect dose not appear to be dose-related. Thus, a slow and careful titration of allopurinol dosing sufficient to achieve uric acid levels of less than 6 mg/dL is also recommended in these patients.

Allopurinol is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. The underlying mechanism is thought to be a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4%, the rate of organ failure and death is high. Treatment is with intravenous N-acetyl cysteine and steroids. Allopurinol should be discontinued in patients who develop a rash.

In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved.

While adjusting the dosage of allopurinol in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

Update from Medscape Reference at on Sep 6th 2013.


Pegloticase is a pegylated uric acid–specific enzyme that is a polyethylene glycol conjugate of recombinant uricase. It achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin, thereby lowering serum uric acid levels. Pegloticase is indicated for gout in adults refractory to conventional therapy (ie, when serum uric acid levels have not normalized and either signs and symptoms are inadequately controlled with xanthine oxidase inhibitors or uricosurics at maximum appropriate doses or xanthine oxidase inhibitors are contraindicated).

The dosage is 8 mg IV every 2 weeks. Complications include anaphylaxis, infusion reactions, flare of gout attacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia, muscle spasms, pyrexia, back pain, diarrhea, and rash.[134, 135] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a contraindication.[135]

The Management of Gout (Strategies)

October 16, 2012 Pharmacotherapy, Therapeutics No comments , ,

Gout is inflammation caused by monosodium urate monohydrate crystals, which is a common chronic disease. However gout can cause acute attack, which brings pain and inflammation. Also the uric acid crystals in the kidney will affect the renal function. If untreated, disorders gout causing can lead to joint destruction and renal damage.


Arthrocentesis of the affected joint is mandatory for all patients with new onset of acute monoarthritis and is very strongly recommended for those with recurrent attacks whose diagnosis has never been proven by microscopic visualization of crystals. Tophi also may be aspirated for crystal analysis under polarizing microscopy. When a patient presents with acute inflammatory monoarticular arthritis, aspiration of the involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of gout or pseudogout based on identification of crystals. Minute quantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.

A prior history of gout or pseudogout dose not rule out the possibility of acute septic arthritis. In fact, the later is more common in patients with a history of crystal-induced arthritis. Septic arthritis must be diagnosed and treated promptly, because irreversible damage can occur within 4-6 hours, and the joint can be completely destroyed within 24-48 hours. Note that some patients with infectious arthritis present with a hot swollen joint and an elevated serum uric acid level, but actually not gout. So differential diagnosis between acute gout attack and septic arthritis is important. Gout is diagnosed based on the discovery of urate crystals in the synovial fluid or soft tissues.

Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals. If crystals are seen, their shape and appearance under polarized light can aid in diagnosis.

In gout, crystals of monosodium urate (MSU) appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter, they are yellow when aligned parallel to the slow axis of the red compensator, but they turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence). Negatively birefringent urate crystals are seen on polarizing examination in 85% of specimens.

The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after negative analysis findings, the procedure can be repeated in another joint or with a subsequent flare. Crystals may be absent very early in a flare.

In crystal arthritis, the WBC count in the synovial fluid is usually 10,000-70,000/µL. However, it may be as low as 1000/µL or as high as 100,000/µL.

Even in the presence of crystals in the joint fluid, blood cultures are indicated if any sign of systemic toxicity is present. Septic arthritis can occur in patients with active crystalline arthropathy.

Gouty attacks are triggered by crystal formation in synovial fluid. They are not related to serum levels of uric acid. Thus, an elevated serum uric acid level does not prove the diagnosis of acute gout, although hyperuricemia is present in 95% of cases, and a normal level does not exclude the diagnosis. Renal uric acid excretion should be measured in high-risk patients, including those with renal calculi, strong family history of gout, and first attack before age 25 years.

Urinary Uric Acid

A 24-hour urinary uric acid evaluation is generally performed if uricosuric therapy is being considered. If patients excrete more than 800 mg of uric acid in 24 hours while eating a regular diet, they are overexcretors and thus overproducers of uric acid. These patients (approximately 10% of patients with gout) require allopurinol instead of probenecid to reduce uric acid levels.

Patients who excrete more than 1100 mg in 24 hours should undergo close renal function monitoring because of the risk of stones and urate nephropathy.

In patients in whom probenecid is contraindicated (eg, those with a history of renal stones or renal insufficiency), a 24-hour urine test of uric acid excretion does not need to be performed because the patient clearly will need allopurinol.

Serum Uric Acid

Measurement of serum uric acid is the most misused test in the diagnosis of gout. There is no direct relationship between serum uric acid levels and gout. As many as 10% of patients with symptoms due to gout may have normal serum uric acid levels at the time of their attack. An elevated serum uric acid level dose not indicate or predict gout. However, decreasing uric acid levels can trigger attacks of gout. And for the chronic treatment of gout serum uric acid levels is the goal.

Treatment Strategy of Gout

Gout is managed in 3 stages: 1.treating the acute attack; 2.providing prophylaxis to prevent acute flares; 3.lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals. (more…)

Pharmacotherapy Options in the Treatment of Obstructive Sleep Apnea

October 10, 2012 Pharmacotherapy, Respirology 4 comments , , ,

Sleep Apnea Multiparameter Record

Obstructive sleep apnea (OSA) is a form of sleep-disordered breathing that is characterized by frequent episodes of snoring and a cessation in breathing for greater than 10 seconds, resulting in disrupted sleep. OSA results from decreased motor tone of either the tongue or airway dilator muscles, causing complete or partial obstruction of the upper airway during sleep. Patients with OSA frequently suffer from daytime sleepiness and reduced quality of life, as well as cardiac, metabolic, and psychiatric disorders.  Obesity is the primary risk factor and contributes to the other disorders commonly diagnosed in this population.

Symptoms and Diagnosis

Untreated OSA is an independent risk factor for increased comorbidities, making it imperative to evaluate common signs and symptoms such as disruptive snoring, daytime sleepiness, obesity, and large neck circumference (>42 cm in men). Diagnostic criteria for OSA include either an apnea-hypopnea index (AHI) of greater than five events per hour plus symptoms of excessive daytime sleepiness or an AHI greater than 15 events per hour regardless of symptoms.

OSA is independently associated with disorders of the cardiovascular, endocrine, and central nervous systems. A study by Peppard et al examined the association between OSA and hypertension.[5] The investigators found OSA to be an independent risk factor for hypertension, and that treatment with continuous positive airway pressure (CPAP) improved blood pressure. A prospective study by Marin et al found that untreated OSA increased the odds by 2.87 for a fatal and 3.17 for a nonfatal cardiovascular event.[6] Studies have found a relationship between OSA and increased incidence of stroke (hazard ratio 2.86–3.56) and a prevalence of seizures in 10% to 45% in patients with OSA.[7,8] Central nervous system (CNS) disorders result from the fatigue and hypersomnolence associated with OSA.[1] Patients with OSA frequently develop insulin resistance that leads to a diagnosis of diabetes. Studies have confirmed that patients with moderate-to-severe OSA are likely to have an elevated fasting glucose level and 2-hour glucose tolerance.[9,10]

Treatment Options

Current treatment options for OSA include both non-pharmacologic and pharmacologic modalities (Table 1). CPAP is the treatment of choice, eliminating episodes of apnea and hypopnea by maintaining airway patency and creating a pneumatic splint.[11,12] Patient compliance with CPAP is estimated at 40% to 60% secondary to the cumbersome equipment required for therapy. Alternative therapies include weight loss, oral appliances, surgery, and drug treatment. Treatment goals include reducing risk factors for OSA, correcting underlying metabolic disorders, treating the consequences, and preventing episodes of apnea and hypopnea.

Tricyclic Antidepressants

It is thought that tricyclic antidepressants (TCAs) improve OSA by increasing rapid eye-movement (REM) sleep latency while decreasing the overall amount of time spent in REM sleep. This modification to sleep architecture possibly improves OSA since the condition worsens during REM sleep, especially in overweight patients.

Serotonin Agents

The selective serotonin reuptake inhibitors (SSRIs) are thought to increase upper airway muscle tone in addition to increasing the amount of serotonin in the brain, which can improve sleep apnea by stimulating the hypoglossal motoneurons.

Nicotine Products

In addition to respiratory stimulation, nicotine can possibly improve OSA by increasing the activity of muscles that dilate the upper airway.

Methylxanthine Derivatives

Although methylxanthine derivatives are also respiratory stimulants, these agents work by blocking adenosine receptors and stimulating ventilatory drive.

Inhaled Corticosteroids

Inhaled nasal corticosteroids can be used to improve airway patency. (more…)