Urine proton excretion

Ammonia increases proton excretion by providing a buffer for protons that are transported into the renal tubular fluid (which is transformed into urine as it passes through the tubules of the kidney) (Fig. 42.7). Specific transporters in the membranes of the renal tubular cells transport protons from these cells into the tubular lumen in exchange for Na. The protons in the tubular fluid are buffered by... 

Protonated THAM (with CP or HCO, ) is excreted in the urine at a rate that is slightly higher than creatinine clearance. As such, THAM augments the buffering capacity of the blood without generating excess C02. THAM is less effective in patients with renal failure and toxicities may include hyperkalemia, hypoglycemia, and possible respiratory depression. 

Ammonia buffers protons in the tubules of the kidney to prevent formation of an acidic urine, when the kidney excretes (secretes) protons to control the pH of the blood. 

Urea (H2N-CO-NH2) is the diamide of carbonic acid. In contrast to ammonia, it is neutral and therefore relatively non-toxic. The reason for the lack of basicity is the molecule s mesomeric characteristics. The free electron pairs of the two nitrogen atoms are delocalized over the whole structure, and are therefore no longer able to bind protons. As a small, uncharged molecule, urea is able to cross biological membranes easily. In addition, it is easily transported in the blood and excreted in the urine. 

Approximately 60 mmol of protons are excreted with the urine every day. Buffering systems in the urine catch a large proportion of the H"" ions, so that the urine only becomes weakly acidic (down to about pH 4.8). 

When carbonic anhydrase inhibitors block the enzyme in the kidney, HjCOj formation— and consequently the availability of H3O+ (i.e., protons)—decreases. Since the Na+ ions in the filtrate cannot be exchanged, sodium is excreted, together with large amounts of water, as a result of ion hydration and osmotic effects. The result is diuresis, accompanied by a dramatic increase in urine volume. There is also failure to remove HCOj" ions because there is no H3O+ to form HjCOj, which would decompose to COj -1- HjO. Therefore, the normally slightly acidic urine becomes alkaline. The strong carbonic anhydrase inhibitors also increase K+ excretion, an undesirable effect. 

Ition of the ketone bodies may be as high as 5000 mg/24 hr, and the blood concentration may reach 90 mg/dl (versus less than 3 mg/dL in normal individuals). A frequent symptom of diabetic ketoacidosis is a fruity odor on the breath which result from increased production of acetone. An elevation of the ketone body concentration in the blood results in acidemia. [Note The carboxyl group of a ketone body has a pKa about 4. Therefore, each ketone body loses a proton (H+) as it circulates in the blood, which lowers the pH of the body. Also, excretion of glucose and ketone bodies in the urine results in dehydration of the body. Therefore, the increased number of H+, circulating in a decreased volume of plasma, can cause severe acidosis (ketoacidosis)]. Ketoacidosis may also be seen in cases of fasting (see p. 327). 

The effect of urinary pH on drug ionization also has toxicological implications. For example, in cases of phenobarbital (a weak acid barbiturate) overdose the urine can be alkalinized (the pH elevated) by administering sodium bicarbonate to the patient. The resultant increase in pH shifts the dissociation equilibrium for this weak acid to the right, producing an increase in the proportion of the ionized form, less reabsorption in the kidneys, and more rapid elimination. Conversely, acidifying the urine with ammonium chloride will increase the excretion rate of drugs that are weak bases since they will be more protonated (ionized) and less reabsorbed (more polar, less lipophilic). 

The kidneys will excrete excess acid equivalents in the urine. At acidic pH, LSD will become protonated and therefore no longer slip back across the tubule epithelium into the circulation this will lead to accelerated elimination of LSD. We here have another example of the principle of non-ionic diffusion , which we have previously discussed in the context of drug absorption. 

Ketoconazole is water-soluble at a pH of below 3. Its oral absorption is influenced by the acidity of the stomach contents, and the concomitant administration of histamine H2 receptor antagonists, proton pump inhibitors, antacids, or food affects its absorption. A high carbohydrate meal ingested with ketoconazole reduces total drug absorption, while a high lipid meal increases it. Erratic absorption is particularly apparent in patients with AIDS. Peak serum concentrations are seen within 2-3 hours. The half-life is about 8 hours. CSF penetration is less than 10% (1). Ketoconazole is extensively metabolized in the liver and excreted in the bile in an inactive form less than 1% of the active drug is excreted in the urine. Clearance is not significantly altered by renal dialysis (1). 

THAM, available as a 0.3 N solution, is a highly alkaline, sodium-free organic amine that acts as a proton acceptor to prevent or correct acidosis. Tromethamine combines with hydrogen ions from carbonic acid to form bicarbonate and a cationic buffer. THAM also acts as an osmotic diuretic to increase urine flow, urine pH, and the excretion of fixed acids, CO2, and electrolytes. At pH 7.4, 30% of THAM is not ionized and therefore may penetrate into cells and neutralize acidic anions of the intracellular fluid. Intracellular pH increases have been noted within 1 hour after the infusion of THAM. There is, however, no chnical or physiologic evidence that this action is beneficial, or that THAM is more efficacious than sodium bicarbonate. " ... 

Ammonium ions are major contributors to buffering urinary pH, but not blood pH. Ammonia (NH3) is a base that combines with protons to produce ammonium (NH4 ) ions (NH3 + H -> NH4 ), a reaction that occurs with a pK of 9.25. Ammonia is produced from amino acid catabolism or absorbed through the intestine, and kept at very low concentrations in the blood because it is toxic to neural tissues. Cells in the kidney generate NH4 and excrete it into the urine in proportion to the acidity (proton concentration) of the blood. As the renal tubular cells transport H into the urine, they return bicarbonate anions to the blood. 

Under normal circumstances, approximately 90% of the nitrogen excreted in the urine is in the form of urea. The exact amounts of each component vary, however, depending on dietary protein intake and physiologic state. For instance, NH4 excretion increases during an acidosis because the kidney secretes ammonia to bind protons in the urine. 

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