Reabsorption of uric acid

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindicated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the creatinine clearance is 50 mL/minute or less. Its uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. 

Probenecid and sulfinpyrazone increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. They should only be... 

Pharmacokinetics Allopurinol is approximately 90% absorbed from the Gl tract. Effective xanthine oxidase inhibition is maintained over 24 hours with single daily doses. Allopurinol is cleared essentially by glomerular filtration oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid. 

When probenecid (ColBENEMID) is given in sufficient amounts, it will block the active reabsorption of uric acid in the proximal tubules following its glomerular filtration, thereby increasing the amount of urate eliminated. In contrast, low dosages of probenecid appear to compete preferentially with plasma uric acid for the proximal tubule anionic transport system and thereby block its access to this active secretory system. The uricosuric action of probenecid, however, is accounted for by the drug s ability to inhibit the active reabsorption of filtered urate. 

A) By inhibiting proximal tubular reabsorption of uric acid... 

A. Probenecid blocks active reabsorption of uric acid in the proximal tubules following glomerular filtration. It does not inhibit uric acid synthesis (B), stimulate tubular secretion (C), or inhibit the metabolism of purines (D). 

Mechanism of Action An antigout agent that competitively inhibits reabsorption of uric acid at the proximal convoluted tubule. Also, inhibits renal tubular secretion of weak organic acids, such as penicillins. Therapeutic Effect Promotes uric acid excretion, reduces serum uric acid level, and increases plasma levels of penicillins and cephalosporins. 

The answer is e. (Katzung, p 254.) Furosemide affects the reabsorption of uric acid in the proximal tubule. It increases uric acid reabsorption... 

Most diuretics cause hyperuricemia. Increased reabsorption of uric acid (along with other solutes) in the proximal tubule as a consequence of volume depletion is one reason however, diuretics also compete with uric acid for excretory transport mechanisms. There is a small increased risk of acute gout in susceptible subjects (73). In the large outcome trials, about 3-5% of subjects treated with diuretics for hypertension developed clinical gout... 

Drugs that increase uric acid excretion in humans include probenecid, which is effective in the regulation of hyperuricemia and the resolution and prevention of tophi, and sulfinpyrazone, which has similar effects. Both agents are weak organic acids and probably act as competitive inhibitors of tubular reabsorption of uric acid. 

The degradation of purines varies with the species. Actually uric acid is excreted as the principal end product of purine metabolism by very few mammals, of which man is unfortunately one. Most nonuricotelio animals possess the enzyme uricase, which converts uric acid to the much more soluble end product allantoin. Man and certain of the higher apes, as well as fowl and reptiles, do not possess this enzyme, so that they must excrete uric acid as the end product of purine metabolism. Despite the fact that it possesses uricase, as do other dogs, the Dalmatian coach hound is peculiar in that it excretes uric acid. This anomaly results from the absence of tubular reabsorption of uric acid in the kidney (Fll). 

Notwithstanding its obsolescence in the treatment of infectious diseases, probenecid found a very important place in the physician s armamentarium because of its uricosuric activity. Its interference with the reabsorption of uric acid through the renal tubular membrane was an unexpected observation. Probenecid is the first useful synthetic compound for the control of uric acid excretion and the age-old disease, gout. 

Probenecid is used to treat gout because it also inhibits the reabsorption of uric acid by a similar mechanism. See Chapter 7.)... 

Allopurinol Probenecid and sulfinpyrazone Inhibits xanthine oxidase and reduces purine metabolism into uric acid Reduce reabsorption of uric acid in the kidney... 

Probenecid (available on a named-patient basis only) and sulfinpyrazone lower the uric acid level in blood by increasing the amount of uric acid passed in the urine. They do this by competing for the transport mechanism responsible for mbular reabsorption of uric acid in the kidney. 

Because of increases in plasma volume and cardiac output, renal blood flow increases. The GFR ri.ses early in pregnancy, and creatinine clearance may be 150 ml/min or more by. 10 weeks. Serum urea and creatinine concentrations fall. Tubular function alters and. in particular, there is a reduction in the renal threshold for glucose. Glycosuria may be present in up to 70% of pregnancies. Tubular reabsorption of uric acid and amino acids alters, and their excretion in urine increases. 

Sulfinpyrazone, a pyrazolidine derivative, is a potent uricosuric agent which also has antithrombotic and platelet inhibitory effects (see Figure 92). It lacks antiinflammatory and analgesic properties. Sulhnpyrazone inhibits renal tubular reabsorption of uric acid. It reduces renal tubular secretion of other organic anions, e.g., paraaminohippuric acid and salicylic acid, and displaces other organic anions bound extensively to plasma proteins (e.g., sulfonamides, salicylates). It is not intended for the relief of an acute attack of gout. 

Probenecid is a uricosuric agent. It acts at the luminal side of the renal tubular cell to decrease tubular reabsorption of uric acid. It may also increase secretion of uric acid into the urine, via the organic acid secretory system. 

Low doses (1 or 2 g/day) can decrease urate excretion and elevate plasma urate concentrations intermediate doses (2 or 3 g/day) may not alter urate excretion large doses (more than 5 g/day) induce uricosuria and lower plasma urate levels. However, such large doses are tolerated poorly. Even small doses of salicylate can block the effects 0/probenecid and other uricosuric agents that decrease tubular reabsorption of uric acid. 

EFFECTS ON URINARY EXCRETION Since the late distal tubule and collecting duct have limited capacity to reabsorb solutes, blockade of Na+ channels in this part of the nephron only mildly increases the excretion rates of Na and Ck ( 2% of filtered load). Blockade of Na channels hyperpolarizes the luminal membrane, reducing the lumen-negative transepithelial voltage. Since the lumen-negative potential difference normally opposes cation reabsorption and facilitates cation secretion, attenuation of the lumen-negative voltage decreases the excretion rates of K+, H+, Ca +, and Mg +. Volume contraction may increase reabsorption of uric acid in the proximal tubule hence chronic administration of amiloride and triamterene may decrease uric acid excretion. Amiloride and triamterene have little or no effect on renal hemodynamics and do not alter TGF. 

Effects Uricosuric drugs act primarily in the kidney and inhibit the secretion of a large number of other weak acids (eg, penicillin, methotrexate) in addition to inhibiting the reabsorption of uric acid. 

Probenecid (e.g., Benemid) Inhibits renal reabsorption of uric acid. Tophaceous gout. To enhance the duration of penicillin (Fig. 7.13) May exacerbate gout attacks. Otherwise well tolerated. ... 

Oligoanuric acute renal failure has been described in patients on phenylbuta-zone ". A pathogenetic mechanism reponsible is the inhibition of the tubular reabsorption of uric acid, which results in hyperuricosuria, uric acid crystallization and, eventually, urethral obstruction. Another form of this syndrome, in which there is no evidence of hyperuricaemia, is felt to be an idiosyncratic reaction. The biopsy picture is consistent with acute tubular necrosis. ... 

Weinman, E.J., G. Eknoyan, W.N. Suki The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J. Clin. Invest. 55 283-291 (1975). 

In most patients with gout, the flow of plasma in the kidney, the glomerular filtration rate, and the renal clearance are normal, and no excess urates are found. Some investigators have claimed that gout is associated with abnormal tubular reabsorption of uric acid (93% in patients with gout versus 91% in normal individuals), leading to an absolute increase in total uric acid reabsorption and an accumulation of uric acid in the blood. 

The treatment of the chronic gouty patient aims at maintaining the lowest possible blood uric acid level. This can be achieved either by preventing reabsorption of uric acid in the proximal tubules or by blocking uric acid biosynthesis through normal metabolic pathways. 

When GFR is normal, hyperuricemia of most gouty patients is not due to augmented tubular reabsorption of uric acid (either presecretory or postsecretory reabsorption), but to diminished tubular secretion of urate. 

Urinary uric acid is thought to be derived from two sources uric acid filtered at the glomerulus and incompletely reabsorbed, and uric acid secreted by the renal tubules. The magnitude of the decrease in urinary uric acid which follows administration of pyrazinamide has been widely accepted as an estimate of the secretory component of urinary uric acid. This estimate is dependent upon the assumption that the site of uric acid reabsorption in the renal tubule is proximal to the site of its secretion. Recently, we have reported that total urinary uric acid excretion increases when urine flow rate increases, and have suggested that this was the result of decreased distal tiibular reabsorption of uric acid. 

If renal tubular reabsorption of uric acid in man occurs at a site distal to the secretion site, part of what is secreted cam be reabsorbed downstream. Under these circumstances, the amount of uric acid in the urine that is attributed to secretion is really that which is secreted and escapes reabsorption. 

Probenecid and salicylate decrease urate binding to serum proteins. However, since reabsorption of uric acid is thought to be almost complete at physiologic filtered loads, small changes in filtered urate load should have little or no effect on urate excretion. 

The present findings suggest that renal tubular reabsorption of uric acid occurs at least in part at a site in the tubule... 

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