Salicylates excretion

When overdosing occurs, gastric lavage is advised and an alkaline, high urine output state should be maintained (see Chapter 59 Management of the Poisoned Patient). Hyperthermia and electrolyte abnormalities should be treated. In severe toxic reactions, ventilatory assistance may be required. Sodium bicarbonate infusions may be employed to alkalinize the urine, which will increase the amount of salicylate excreted. 

Roch-Ramel F, Roth L,ArnowJ, Weiner LM. Salicylate excretion in the rat free flow micropuncture experiments. J Pharmacol Exp Ther 1978 207 737-747. 

Not fully understood. Sulfinpyrazone competes successfully with salicylate for seeretion by the kidney tubules so that salicylate excretion is re-dueed, but the salieylate bloeks the inhibitory effect of sulfinpyrazone on the tubular reabsorption of urie aeid eausing the uric acid to accumulate within the body. ... 

The use of CA inhibitors as diuretics is limited by their propensity to cause metabolic acidosis and hypokalemia. Their use can be indicated in patients with metabolic alkalosis and secondary hyperaldosteronism resulting for example from aggressive use of loop diuretics. Furthermore, CA inhibitors are effective dtugs to produce a relatively alkaline urine for the treatment of cysteine and uric acid stones as well as for the accelerated excretion of salicylates. Perhaps the most common use of CA inhibitors is in the treatment of glaucoma. 

After oral administration, acetylsalicylic acid is rapidly and almost completely absorbed but in the intestinal mucosa it is partly deacetylated to salicylic acid, which also exhibits analgesic activity. The plasma half-life of acetylsalicylic acid is 15 min whereas that of salicylic acid, at low dosages of acetylsalicylic acid, is 2-3 h. Salicylic acid is eliminated more slowly when acetylsalicylic acid is administered at high dose rates because of saturation of the liver enzymes. The metabolites are mainly excreted via the kidney. 

Affecting the rate of drug elimination by increasing urinary pH (eg, the excretion of salicylates is increased, whereas excretion of quinidine and amphetamines is decreased)... 

Figure 20 Urinary excretion data showing the influence of moisture on the percutaneous absorption rate of salicylates. (O) Anhydrous system rate ( ) hydrous system rate. (Reprinted with permission from Ref. 62.)...

Table 5 shows that the ratio of the excretion rate under hydrous condition to that under anhydrous condition decreases with the decreasing water solubility of the salicylate or with the oil/water distribution coefficient. It can be said that the more water soluble compound is aided to a greater degree by the presence of moisture than those of lesser solubility. This trend is, however, not a direct proportionality due to the influence of other physical phenomena such as viscosity, molecular size, and intermolecular bonding. 

Stuer et al. [46] evaluated the presence of the 25 most used pharmaceuticals in the primary health sector in Denmark (e.g., paracetamol, acetyl salicylic acid, diazepam, and ibuprofen). They compared PECs with experimental determinations and they conclude that measured concentrations were in general within a factor of 2-5 of PECs. Carballa et al. [45] also determined PECs for pharmaceuticals (17), musk fragrances (2) and hormones (2) in sewage sludge matrix. For that purpose they used three different approaches (1) extrapolation of the per capita use in Europe to the number of Spanish inhabitants for musk fragrances (2) annual prescription items multiplied by the average daily dose for pharmaceuticals and (3) excretion rates of different groups of population for hormones. They indicated that these PECs fitted with the measured values for half of them (carbamazepine, diazepam, ibuprofen, naproxen, diclofenac, sulfamethoxazole, roxithromycin, erythromycin, and 17a-ethiny I e strad iol). 

In another experiment, the ranking of urinary excretion rates of salicylic acid and four of its derivatives paralleled, both in rabbits and in man, the extent to which the drug was bound to plasma proteins. The most extensively bound salicylate had the longest plasma half-life and the least extensively bound, the shortest (Kl). 

El. Kakemi, K., Arita, T., Yamashina, H., and Konishi, R., Absorption and excretion of drugs X. The effect of the protein binding on the renal excretion rate of salicylic acid derivatives. Yakugaku Zasshi 82, 536-639 (1962). 

Lactation Salicylates are excreted in breast milk in low concentrations. 

Large doses may decrease urinary excretion of phenolsulfonphthalein. Salicylates in the urine result in falsely elevated vanillylmandelic acid (VMA) with most tests, but falsely decrease VMA determinations by the Pisano method. 

Capsules Elimination of free mesalamine and salicylates in feces increased proportionately with the dose. N-acetyl-5-ASA was the primary compound excreted in the urine (19% to 30%). 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

An understanding of absorption, binding, metabolism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, triiodothyronine, valproic acid, sulfafurazole, and salicylic acid. 

Pharmacokinetics Absorption differs between formulations. Protein binding 50%-80%. Bound to serum albumin. Metabolized to salicylate glucuronides and salicyluric acid. Excreted in urine. 

Tubular secretion The active secretory systems can rapidly remove the protein-bound drugs from the blood and transport them into tubular fluid as the drugs that are bound to proteins are not readily available for excretion by filtration. The drugs known to be secreted by organic anion secretory system (i.e. strong acids) are salicylates, chlorothiazide, probenecid, penicillin etc. and cation (i.e. bases) includes catecholamines, choline, histamine, hexamethonium, morphine etc. 

Aspirin (acetylsalicylic acid, Figure 7.9) is a derivative of salicyclic acid, which was first used in 1875 as an antipyretic and antirheumatic. The usual dose for mild pain is 300-600 mg orally. In the treatment of rheumatic diseases, larger doses, 5-8 g daily, are often required. Aspirin is rapidly hydrolysed in the plasma, liver and eiythrocytes to salicylate, which is responsible for some, but not all, of the analgesic activity. Both aspirin and salicylate are excreted in the urine. Excretion is facilitated by alkalinisation of the urine. Metabolism is normally very rapid, but the liver enzymes responsible for metabolism are easily saturated and after multiple doses the terminal half-life may increase from the normal 2-3 h to 10 h. A soluble salt, lysine acetylsalicylic acid, with similar pharmacological properties to aspirin, has been used by parenteral administration for postoperative pain. Aspirin in low doses (80-160 mg daily) is widely used in patients with cardiovascular disease to reduce the incidence of myocardial infarction and strokes. The prophylaxis against thromboembolic disease by low-dose aspirin is due to inhibition of COX-1-generated thromboxane A2 production. Because platelets do not form new enzymes, and COX-1 is irreversibly inhibited by aspirin, inhibition of platelet function lasts for the lifetime of a platelet (8-10 days). 

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