Acidification, urinary

The normal UAG ranges from 0 to 5 mEq/L (mmol/L) and represents the presence of unmeasured urinary anions. In metabolic acidosis, the excretion of NH4+ and concurrent CP should increase markedly if renal acidification is intact. This results in UAG values from -20 to -50 mEq/L (mmol/L). This occurs because the urinary CP concentration now markedly exceeds the urinary Na+ and K+ concentrations. Diagnoses consistent with an excessively negative UAG include proximal (type 2) renal tubular acidosis, diarrhea, or administration of acetazo-lamide or hydrochloric acid (HC1). Excessively positive values of the UAG suggest a distal (type 1) renal tubular acidosis. 

Howden, C. W., Reid, J. L., Omeprazole, a gastric proton pump inhibitor lack of effect on renal handling of electrolyte and urinary acidification, Eur. J. Clin. Pharmacol. 1984, 26, 639-640. 

Glutamine is exported from the muscle and extracted from blood mainly by the kidneys or the gut hepatic uptake of glutamine is relatively low in comparison. In the renal tubular cells, glutamine is deaminated in the processes of urinary acidification (see Figure 8.11) or used by the intestinal cells as a fuel. 

Acidification of urine The point was made earlier that the pH of the fluid in the PCT is approximately 6.8, only slightly below that of blood. In contrast, urinary pH may vary considerably but is usually approximately pH 6. Acidification of the urine occurs mainly in the distal portion of the nephron. 

Renal clearance of cotinine is much less than the glomerular filtration rate (Benowitz et al. 2008b). Since cotinine is not appreciably protein bound, this indicates extensive tnbnlar reabsorption. Renal clearance of cotinine can be enhanced by np to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine becanse it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As is the case for nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. In contrast, 100% of nicotine Ai -oxide and 63% of 3 -hydroxycotinine are excreted unchanged in the urine (Benowitz and Jacob 2001 Park et al. 1993). 

Excretion of drugs will be affected by the pH of the urine. If the urine is acidic, weak bases are ionized and there will be poor re-absorption. With basic urine, weak bases are non-ionized and there is more re-absorption. The pH of the urine can be artificially changed in the range 5-8.5 oral administration of sodium bicarbonate (NaHCOs) increases pH values, whereas ammonium chloride (NH4CI) lowers them. Thus, urinary acidification will accelerate the excretion of weak bases and retard the excretion of weak acids. Making the urine alkaline will facilitate the excretion of weak acids and retard that of weak bases. 

The same considerations hold for acidic molecules, with the important difference that alkalinization of the urine (increased pH) will promote the deprotonization of -COOH groups and thus impede reabsorption. Intentional alteration in urinary pH can be used in intoxications with proton-acceptor substances in order to hasten elimination of the toxin (alkalinization phenobarbi-tal acidification amphetamine). 

Metabolism/Excretion - From 60% to 80% of a dose is metabolized via the liver into several metabolites. Quinidine is excreted unchanged (10% to 50%) in the urine within 24 hours. The elimination half-life ranges from 4 to 10 hours in healthy patients, with a mean of 6 to 7 hours. Urinary acidification facilitates quinidine elimination, and alkalinization retards it. In patients with cirrhosis, the elimination half-life may be prolonged and the volume of distribution increased. 

Urinary pH Flecainide elimination is altered by urinary pH alkalinization decreases, and acidification increases flecainide renal excretion. 

Urinary acidification Low Normal (by 1 mo.) Normal adult activity... 

Is treatment with an antibiotic necessary Symptomatic patients always need treatment. Asymptomatic bacteriuria (=10 bacteria/ml in two separate urine cultures) only needs treatment in pregnancy, in children and in obstructions of the urinary tract. Obstmctions in urinary flow must be treated before an antibiotic is started. There is no clear evidence that hydration or acidification of urine improves the results of antimicrobial therapy. 

B. Proteus species produce urease (A) that produces ammonia and urea, alkalizing urine. Urine requires acidification for effective therapy. Hippuric (B), mandelic, or ascorbic acids or methionine are urinary acidifying agents. The normal acidic urinary environment is disturbed by recurrent Proteus in-... 

Enander, Sundwall, and Sorbo - -- 7 found that either oral or Intramuscular administration of 11 to rats at 500 or 100 mg/kg, respectively, increased by many times the urinary excretion of thiocyanate. From the amount of thlocynanate excreted above the base line, the quantity of hydrogen cyanide produced in metabolism of the oxime was calculated to be 0.1 mg/kg—a little more than one-third the LD50 for rats by lntraperitoneal injection. Urine from rats given 120 ymol of II intramuscularly or 400 pmol by mouth contained 3.9-7.8% N-methylpyridinlum-2-nltrlle methanesulfonate. When this compound was injected Intramuscularly into rats at 90 mg/kg, thiocyanate was excreted in the urine in Increased amounts. Also present in the urine was a metabolic product that yielded cyanide on acidification of the urine, similar to a cyanide-yielding metabolite of II found earlier. 

After being found to be healthy on a thorough physical examination accompanied by a broad range of laboratory examinations, 22 men were used in studies of the renal clearance of I, after intravenous injection at 5 mg/kg under a variety of conditions.161 Alkaliniza-tion of the urine to a pH above 7.5 by administration of bicarbonate and acidification of the urine to a pH below 5.0 by administration of ammonium chloride both reduced urinary excretion of I. When 200 mg of thiamine was Injected intramuscularly 20-30 min before intravenous injection of I, urinary excretion of I during the 5 h after... 

Ammonium chloride increases urinary volume with acidification of urine. The excretion of amphetamine is decreased in relatively alkaline urine and has proved useful in the treatment of amphetamine intoxication. ... 

Ionisation determines the partitioning of drugs across membranes. Unionised molecules can easily cross and reach an equilibrium across a membrane, while the ionised form cannot cross. When the pH is different in the compartments separated by the membrane the total (ionised + unionised) concentration will be different on each side. An acidic drug will become concentrated in a compartment with a high pH and a basic drug in one with a low pH. This is known as ion-trapping, and occurs in the stomach, kidneys, and across the placenta. Urinary acidification accelerates the excretion of weak bases, such as pethidine, while alkalinisation increases the excretion of acidic drugs, such as aspirin. As an example consider pethidine (pKa 8.6) with an unbound plasma concentration of 100 (arbitrary units). At pH 7.4 only 6% of the pethidine will be unionised so that at equilibrium the concentration of unionised pethidine in the urine will be 6 units. In urine at pH 6.5 only 0.8% of the pethidine will be unionised so that the total concentration in the urine will be 744 units. 

The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites, which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. 

Previously popular but of unproved value, forced diuresis may cause volume overload and electrolyte abnormalities and is not recommended. Renal elimination of a few toxins can be enhanced by alteration of urinary pH. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication. 

Ascorbic acid is the main endogenous precursor of oxalic acid and in healthy persons up to 30% of urinary oxalate can originate from ascorbate. Ascorbate is extremely unstable in neutral and alkaline solutions and degrades to oxalate nonenzymatically [6]. Acidification to pH 1-2 is required to prevent deposition of insoluble Ca-oxalate. 

Large individual variations in the urine excretion of methadone are observed depending on urine volume and pH, the dose and rate of metabolism. Acidification of the urine may increase the urinary output of methadone from 5 to 22%.37 Typically, following a 5-mg oral dose, methadone and EDDP account for 5% of the dose in the 24-h urine. In those individuals on maintenance therapy, methadone may account for 5 to 50% of the dose in the 24-h urine and EDDP may account for 3 to 25% of the dose. (S)- and (R)-methadone and EDDP have been reported in saliva38 and methadone and (S)- and (R)-methadone in human breast mi Ik.39 40... 

A 70-year-old woman with a 2-year history of primary biliary cirrhosis confirmed by histological and immunological criteria took colestyramine sachets twice daily for 2 months and developed lethargy, confusion, and drowsiness (3). She had signs of chronic liver disease, portal hypertension, and hepatic encephalopathy. Laboratory investigations confirmed a metabolic acidosis (pH 7.15) and hyperchloremia. Multiple cultures failed to reveal sepsis, and a urinary pH of 4.85 together with tests of renal acidification excluded renal tubular acidosis. No other cause was found and she responded to 600 mmol of sodium bicarbonate intravenously over 36 hours. 

Sometimes, we may want to use a f-test in a way that differs from our previous approach. Say, for example, we are considering the use of urinary acidification to hasten the clearance of amphetamine from patients who have overdosed. An initial trial in rabbits is used to test the general principal. One group of rabbits receives ammonium chloride to induce a lower urinary pH and another group acts as controls. All rabbits receive a test dose of radio-labelled drug, the clearance of which is studied over a few hours. In this case, the question posed should be is there an increase in clearance rather than the standard is there a difference in clearance The former constitutes a one-sided question. 

Table 10.1 shows a set of results for an investigation of the effects of urinary acidification on the clearance of amphetamine. We could test this set of results using two different approaches ... 

Table 10.1 Clearance (ml/min/kg) of an amphetamine with and without urinary acidification...

Table 10.2 Generic output from a one-sided two-sample t-test for higher clearances with urinary acidification...

FLECAINIDE AMMONIUM CHLORIDE Urinary acidification l flecainide levels Flecainide excretion is T in the presence of an acidic urine flecainide exists in predominantly ionic form, which is less readily reabsorbed from the renal tubules Watch for a poor response to flecainide... 

Disposition in the Body. Readily and almost completely absorbed after oral administration, but extensively metabolised to polar and non-polar metabolites bioavailability about 35%. The major metabolites are monodesmethyl- and didesmethylchlor-pheniramine. About 35% of a single dose is excreted in the urine in 48 hours the 24-hour excretion of unchanged drug accounts for about 3 to 10% of the dose but this is increased by acidification of the urine and increased urinary flow, and decreased when the urine is alkaline more non-polar metabolites appear to be excreted after intravenous than after oral administration. After daily oral administration, about 20% of a dose is excreted in the 24-hour urine as unchanged drug, 20% as monodesmethylchlor-pheniramine, and 5% as didesmethylchlorpheniramine. Less than 1% of a dose is eliminated in the faeces. 

Acute poisoning is manifested by excitement and peripheral sympathomimetic effects convulsiorrs may occur also, in acute or chronic overuse, a state resembling hyperactive paranoid schizophrenia with hallucinations develops. Hyperthermia occurs with cardiac arrhythmias, vascular collapse and death. Treatment is chlorpromazine with added antihypertensive, e.g. labetalol, if necessary these provide sedation and a- and P-adrenoceptor blockade (not a P-blocker alone), rendering unnecessary the enhancement of elimination by urinary acidification. 

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