Hyperuricemia patients with

These studies with wild-type and mutant cells defective in IMP dehydrogenase and the previous data with the adenylosuccinate synthetase-deficient cell line suggest that among the clinical population with dominantly inherited hyperuricemia, patients with partial deficiencies in these enzymes exist. It is hoped that these pharmacogenetic cell culture models for overproduction hyperuricemia will lead to the initiation of a search for hyperuricemia patients with either of these deficiencies. If such patients are found it may be possible to design chemotherapeutic regimens by which effectors (inhibitors) of purine synthesis might ameliorate the overproduction of purines by the de novo pathway. 

The risk of gout increases as the serum uric acid concentration increases, and approximately 30% of patients with levels greater than 10 mg/dL (greater than 595 pmol/L) develop symptoms of gout within 5 years. However, most patients with hyperuricemia are asymptomatic. Other risk factors for gout include obesity, ethanol use, and dyslipidemia. Gout is seen frequently in patients with type 2 diabetes mellitus and coronary artery disease, but a causal relationship has not been established. 

Uric acid excretion is reduced in patients with chronic kidney disease, putting them at risk for hyperuricemia. In patients with persistently acidic urine and hyperuricemia, uric acid nephrolithiasis can occur in up to 25% of patients in severe cases, uric acid stones can cause nephropathy and renal failure. Extreme hyperuricemia can occur because of rapid tumor cell destruction in patients undergoing chemotherapy for certain types of cancer (see Chap. 85). 

Although rarely performed, a 24-hour urine collection can be obtained to determine if the patient is an overproducer or an underexcretor of uric acid. Individuals who excrete more than 800 mg of uric acid in this collection are considered overproducers. Patients with hyperuricemia who excrete less than 600 mg/day are classified as underexcretors of uric acid. 

Pyrazinamide Adults Based on IBW 40-55 kg 1000 mg 56-75 kg 1500 mg 76-90 kg 2000 mg Children 15-30 mg/kg Hepatotoxicity, gastrointestinal symptoms (nausea, vomiting), non-gouty polyarthralgia, asymptomatic hyperuricemia, acute gouty arthritis, transient morbilliform rash, dermatitis Serum uric acid can serve as a surrogate marker for compliance FFTs in patients with underlying liver disease... 

Some patients with hyperuricemia may have nausea, vomiting, and lethargy. 

Tophi (urate deposits) are uncommon in gouty subjects and are a late complication of hyperuricemia. The most common sites of tophaceous deposits in patients with recurrent acute gouty arthritis are the base of the great toe, helix of the ear, olecranon bursae, Achilles tendon, knees, wrists, and hands. 

Potentially important laboratory abnormalities occurring with niacin therapy include elevated liver function tests, hyperuricemia, and hyperglycemia. Niacin-associated hepatitis is more common with sustained-release preparations, and their use should be restricted to patients intolerant of regular-release products. Niacin is contraindicated in patients with active liver disease, and it may exacerbate preexisting gout and diabetes. 

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In patients with Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation, Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. These patients also all have hyperuricemia because purines cannot be salvaged. 

Patients with Lesch-Nyhan syndrome have hyperuricemia, indicating an increased biosynthesis of purine nucleotides, and markedly decreased levels of hypoxanthine phbs-phoribosyl transferase (HPRT). The hyperuricemia can be explained on the basis of a decrease in which regulator of purine biosynthesis ... 

Becker M, Schumacher H, Wortmann R, MacDonald P, Eustace D, Palo W et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005 353(23) 2450-61. 

Allopurinol is an xanthine oxidase inhibitor. It reduces urate production and is used in primary and secondary urate overproduction. Therapy of hyperuricemia prevents recurring attacks of acute gouty arthritis. Allopurinol dosages are 300 mg/day for serum creatinine < 1.5 mg/dl and 100 mg/day for serum creatinine between 1.6-2.0 mg/dl. Reduction of tophi is slow with allopurinol, particularly in patients with giant tophi and renal insufficiency where drug dosage is limited. 

Uricosurics like probenecid, sulfinpyrasone and benzbromaron increase urate clearance and fractional excretion of filtered urate. They are used in underexcretors of urate. Uricosurics benefit patients with hyperuricemia, intact renal function and no history of nephrolithiasis. In tropical and subtropical climates where most of the Third World countries are situated, the prevalence of urolithiasis is >40%. The use of uricosurics is contraindicated in patients with a history of urolithiasis as the number and size of stones will be increased. Without an history of urolithiasis, uricosurics still should be applied with caution where the risk for dehydration is high. 

C. Pyrazinamide is known to cause hyperuricemia and precipitate gouty arthritis. Pyrazinamide-induced gouty arthritis does not respond to uricosuric therapy with probenecid but may respond to acetylsalicylic acid. Cycloserine (A) can cause headaches, confusion, tremors, and seizures, possibly secondary to low levels of magnesium in the cerebrospinal fluid cycloserine should be avoided in patients with epilepsy and mental depression. It is not associated with hyperuricemia. Thiacetazone (B) is an antibiotic that is rarely used in tuberculosis. The most common adverse reactions are general rashes and GI intolerance. Its use is not associated with hy-... 

In long-term treatment, the thiazides may produce hypokalemia, hyperglycemia hyperuricemia, and a 5% increase in plasma cholesterol indapamide has been shown not to increase plasma cholesterol or lipids at therapeuLic doses. Thiazides can cause hyponatremia in patients with large Water intake while on the drug hyponatremia may be associated with nausea, vomiting, and headaches. 

The thiazide diuretics are primarily used for most patients with mild or moderate hypertension. Used alone they can lower blood pressure by 10-15 mmHg. In more severe hypertension diuretics are used in combination with other agents. Adverse effects include hypokalemia (lowered serum potassium), impotence, impaired glucose tolerance, hyperlipidemia, and hyperuricemia (elevated uric acid in the blood). 

Adverse effects Thiazide diuretics induce hypokalemia and hyperuricemia in 70% of patients, and hyperglycemia in 10% of patients. Serum potassium levels should be monitored closely in patients who are predisposed to cardiac arrhythmias (particularly individuals with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides (see p. 160). Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia. 

Correct answer = D. Among black patients, diuretic and calcium channel blockers are more effective than ACE inhibitors or p-blockers. Diuretics are effective among the elderly. Thiazide diuretics cause hyperuricemia and can precipitate a gout attack in susceptible individuals. Thiazide diuretics increase LDL cholesterol and may increase the risk of atherosclerosis in patients with hyperlipidemia. Patients with evidence of elevated catecholamines are best treated with p-blockers. Thiazides cannot promote sodium excretion when renal function is severely impaired. The loop diuretics, such as furosemide, are used in patients with impaired renal function. 

Pharmacokinetics Intravenous injection of vincristine or vinblastine leads to rapid cytotoxic effects and cell destruction. This in turn can cause hyperuricemia due to the oxidation of purines to uric acid. The hyperuricemia is ameliorated by administration of the xanthine oxidase inhibitor, allopurinol (see p. 417). The agents are concentrated and metabolized in the liver and are excreted into bile and feces. Doses must be modified in patients with impaired hepatic function or biliary obstruction. 

Hyperuricemia. Many patients with glucose 6-phosphatase deficiency have high serum levels of urate. Hyperuricemia can be induced in normal people by the ingestion of alcohol or by strenuous exercise. Propose a common mechanism that accounts for these findings. 

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