Passive reabsorption

Any drug known to be largely excreted by the kidney that has a body half-life of less than 2 hours is probably eliminated, at least in part, by tubular secretion. Some drugs can be secreted and have long half-lives, however, because of extensive passive reabsorption in distal segments of the nephron (see Passive Diffusion, earlier in the chapter). Several pharmacologically active drugs, both anions and cations, known to be secreted are listed in Table 4.5. 

A) Drugs that are ionized in the renal tubule are more likely to undergo passive reabsorption than those that are unionized... 

The most important function of the proximal tubular cell is the conservation of filtered Na+ and the reabsorption of water. The PCT is also the main site of FICO-3 reabsorption. This is achieved by the transfer of Na+ and FICO-3 from the tubular lumen into the cell and then into the extracellular fluid (ECF) accompanied by the passive reabsorption of approximately 70% of the filtered water via the tight junctions between the tubular cells. The presence of the enzyme carbonic anhydrase in the cytoplasm and luminal epithelium of the cells of the PCT allows the kidney to eliminate FI+ while simultaneously retaining FICO-3. 

Passive reabsorption of lipid-soluble, un-lonized drug which has been concentrated so that the Intraluminal concentration is greater than that in the perivascular space. 

Four factors contribute to the ability to concentrate urine (1) Active reabsorption of Na+, K+, and CF without water reabsorption by the thick ascending limb of the loop of Henle results in interstitial hypertonicity and hypoosmotic tubular fluid. (2) Selective permeability to water, but not small electrolytes, in the descending thin limb of the loop of Henle allows passive reabsorption of water, facilitated by interstitial hypertonicity. (3) Relatively low medullary blood flow maintains medullary hypertonicity, allowing continued elaboration of concentrated urine. (4) In the presence of ADH, the distal tubule and collecting ducts are permeable to water so that water may diffuse out of the tubular lumen into the medullary, and papillary inter-stitium. Because of the ability of the thick ascending limb of the loop of Henle to move solutes but not water into the medullary interstitium, the medullary, and papillary interstitium are hyperosmotic and hypertonic compared to plasma and cortical interstitium (Figure 29.5). 

Although diastereoisomers, both quinine and quinidine, have similar physical properties (Fig. 18). In clinical studies, the renal clearance of quinidine was fourfold greater than that of quinine (57). No stereoselective differences in plasma protein binding were observed. The renal filtration and passive reabsorption of these two diastereoisomers should be similar since the compounds have similar octanol-water partition coefficients and pKa values (57). Therefore, stereoselective active renal secretion may be the mechanism responsible for the observed differences in the renal clearances of quinine and quinidine. 

Passive reabsorption is driven by the progressive reabsorption of tubular fluid along the nephron. To penetrate the membranes of the tubular epithelium, whose main constituents are lipids, compounds should be liposoluble. As ionized compounds are in general hydrophilic, only the undissociated molecules of weak bases and acids will be rapidly reabsorbed by simple diffusion [15]. Consequently determinants for the rate of reabsorption are the pKa of the organic acid or base, the urinary pH, and the liposolubility of the undissociated base or acid. Another important determinant... 

Figure 10.4 (a) A highly simplified diagram of a kidney tubule to illustrate the filtration and secretion of drugs from the blood into the tubular filtrate, and their subsequent reabsorption or loss in the urine, (b) Schematic representation of the influence of urinary pH on the passive reabsorption of a weak acid and a weak base from the urine in the renal tubules at a high pH the passive reabsorption of the weak base and the excretion of the weak acid are enhanced, while at a low pH values the reabsorption of the weak acid and the excretion of the weak base ore enhanced. 

Salicylate and its metabolites are rapidly and almost completely excreted in the urine by glomerular filtration and by renal tubular secretion. Passive reabsorption of salicylate occurs in the distal tubules. Salicylate elimination is saturable and characterized by Michaelis-Menton kinetics where the elimination half-life is dependent on the dose. Since the pRa of salicylic acid is 3, its renal clearance is greatly influenced by changes in urinary pH. Increasing urinary pH can significantly increase the overall salicylate elimination rate via ion trapping. 

Here too, species differences are reported, but this parameter is accessible to in vitro studies. Both protein-binding and passive reabsorption, factors that determine the rate of renal excretion, are related to the partition coefficients of the compounds119,12°. The half-life of various non- or poorly metabolized sulfanilamides is strongly dependent on the partition coefficient, as can be seen from Fig. 13121. ... 

Chloride ions in food are almost completely absorbed from the intestinal tract. They are filtered from plasma at the glomeruh and passively reabsorbed, along with Nap in the proximal tubules. In the thick ascending limb of the loop of Henle, Cl is actively reabsorbed by the chloride pump, whose action promotes passive reabsorption of Nah Loop diuretics such as furosemide and ethacrynic acid inhibit the chloride pump. Surplus CP is excreted in the urine and is also lost in the sweat, especially in hot environments. 

Only nonionized forms undergo active secretion and active or passive reabsorption. 

For example, at low and high rates of urine flow, the minimal and maximal values of the may vary from 30% to 60% of the glomerular filtration rate. This occurs because various tubular segments are permeable to urea and allow passive reabsorption to occur under conditions of antidiuresis. The fractional excretion of urea (FE ,pa) is calculated as [(urine urea/ plasma urea)/(urine creatinine/plasma creatinine) x... 

The major processes involved in renal excretion are glomerular filtration, active tubular secretion, and passive reabsorption. Overall, renal excretion results from the net contributions of these three processes ... 

By extracting water from intracellular compartments, osmotic diuretics expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release. These effects increase RBF, and the increase in renal medullary blood flow removes NaCl and urea from the renal medulla, thus reducing medullary tonicity. Under some circumstances, prostaglandins may contribute to the renal vasodilation and medullary washout induced by osmotic diuretics. A reduction in medullary tonicity causes a decrease in the extraction of water from the DTL, which limits the concentration of NaCl in the tubular fluid entering the ATL. This latter effect diminishes the passive reabsorption of NaCl in the ATL. In addition, osmotic diuretics may also interfere with transport processes in the TAL. 

There are no methods known to accelerate the active transport of poisons into urine, and enhancement of glomerular filtration is not a practical means to facilitate elimination of toxicants. However, passive reabsorption from the tubular lumen can be altered. Diuretics inhibit reabsorption by decreasing the concentration gradient of the drug from the lumen to the tubular cell and by increasing flow through the tubule. Furosemide is used most often, but osmotic diuretics also are employed ("see Chapter 28). Forced diuresis should be used with caution, especially in patients with renal, cardiac, or pulmonary complications. 

Actions Blocks reabsorption of sodium and chloride in the loop of Henie = prevents the passive reabsorption of water = diuresis Uses CHF, fluid volume overload, pulmonary edema, HTN... 

Stereoselectivity in renal clearance may arise as a result of either selectivity in protein binding, influencing glomerular filtration and passive reabsorption, or active secretion or reabsorption. Enantioselectivity in renal clearance has been reported for a number of drugs, and in the majority of instances the selectivity is relatively modest, with enantiomeric ratios between 1.0 and 3.0 (Table 4). In the case of the diastereoisomers quinine and quinidine, the diiference is about fourfold, with values of 24.7 and 99 mLmin in man, respectively [128]. 

Tocainide is a weak base so that its loss in the urine will be affected by the pH of the urine. Alkalinisation of the urine increases the number of non-ionised molecules available for passive reabsorption, thereby reducing the urinary loss and raising the serum levels. 

Renal excretion is particularly important. Glomerular filtration removes imbound low molecular weight compounds and active secretion and passive reabsorption processes occur throughout the kidney tubules depending on a drug s ability to cross lipid... 

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