Alkalinisation, urinary

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. 

Urinary pH significantly affects the activity of nitrofurantoin, with loss of potency as the urine becomes more alkaline. For this reason, women with lower UTI who are prescribed nitrofurantoin should be advised not to take alkalinising agents such as potassium citrate (Effercitrate). 

Urinary alkalinisation increases the urine elimination of certain poisons by shifting the urine pH above 7.5 [1,21,79]. It is achieved by intravenous injection of a sodium bicarbonate solution. Raised pH of urine facilitates elimination of acidic drugs such as salicylates and barbiturates as they become ionised. The rate of reabsorption of an ionised drug into the blood is significantly lower than that of a non-ionised drug [1, 79]. In all cases however AC administration is more efficient than urinary alkalinisation [1,80]. It should be also kept in mind that WBI and urinary alkalinisation are relatively slow procedures which may cause delay with AC administration. 

A study in 6 healthy subjects found that the cumulative 72-hour urinary excretion of unchanged dextropropoxyphene was increased sixfold by acidification of the urine with oral ammonium chloride and reduced by 95% by alkalinisation with sodium bicarbonate the half-life of dextropropoxyphene was also shortened by ammonium chloride. The excretion of the active metabolite norpropoxyphene was much less dependent on urinary pH. However, the cumulative excretion of dextropropoxyphene and norpropoxyphene, even into acidic urine, accounted for less than 25% of the dose during 72 hours. ... 

The effect of urinary pH on the clearance of methadone is an established interaction, but of uncertain importance. Be alert for any evidence of reduced methadone effects in patients whose urine becomes acidic because they are taking large doses of ammonium chloride. Lowering the urinary pH to 5 with ammonium chloride to increase the clearance can also be used to treat toxicity. Theoretically, urinary alkalinisers such as sodium bicarbonate and acetazolamide may increase the effect of methadone. 

The urinary excretion of amfetamines is increased by urinary acidifiers (ammonium chloride) and reduced by urinary alkalinisers (sodium bicarbonate). 

A well established and well understood interaction but reports of problems in practice seem rare. The interaction has been exploited to increase the clearance of amfetamines in cases of overdose by acidifying the urine with ammonium chloride. Conversely it can represent an undesirable interaction if therapeutic doses of amfetamines are excreted too rapidly. Care is needed to ensure that amfetamine toxicity does not develop if the urine is made alkaline with sodium bicarbonate or another urinary alkaliniser, acetazolamide. 

Urinary alkalinisers can reduce the loss of diethylcarbamazine in the urine, whereas urinary acidifiers can increase the loss. The clinical importance of this is unknown. 

Urinary alkalinisers can increase the retention of quinine in man, and antacids can reduce the absorption of quinine in animals. None of these interactions appears to be of general clinical importance. 

Large changes in urinary pH caused by acidifying or alkalinising drugs can have a marked effect on the plasma levels of mexiletine in some patients. 

Although changes in urinary pH can affect the amount of mexiletine lost in the urine, the effect of diet or the concurrent use of alkalinisers (sodium bicarbonate, acetazolamide) or acidifiers (ammonium chloride etc.) on the plasma concentrations of mexiletine does not appear to be predictable. There appear to be no reports of adverse interactions but concurrent use should be monitored. The UK manufacturer of mexiletine recommends that the concomitant use of drugs that markedly acidify or alkalinise the urine should be avoided. ... 

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. 

An established interaction, which can be exploited. Should erythromycin be used to treat urinary tract infections its efficacy can be maximised by making the urine alkaline (for example with acetazolamide or sodium bicarbonate). Treatment with urinary acidifiers will minimise the activity of the erythromycin for urinary tract infections and should be avoided. There is no evidence that the efficacy of erythromycin in other infections is affected by urinary acidifiers or alkalinisers. 

Zinner SH, Sabath LD, Casey JI, Finland M. Erythromycin and alkalinisation of tiie urine in the treatment of urinary-tract infections due to gram-negative bacilli. L(mcet( 91V) i, 1267-8. 

Urinary alkalinisers (e.g. potassium or sodium citrate) and those antacids that can raise the urinary pH above 5.5 should not be used during treatment with methenamine because they inhibit its activation. 

Vitamin C 1 g three times daily was found to have no effect on the urinary excretion of methotrexate 45 mg given intravenously to a woman with breast cancer, despite the urine becoming more acidic at pH 5.9 (compare Methotrexate + Urinary alkalinisers , p.654). She was also receiving oral cyclophosphamide, propranolol, amitriptyline, perphenazine and prochlorperazine. No special precautions appear to be necessary. 

Pseudoephedrine and related drugs + Urinary acidifiers or alkalinisers... 

The interaction between ephedrine or pseudoephedrine and urinary alkalinisers are established but reports of adverse reactions in patients appear to be rare. Be aware that any increase in the adverse effects of these drugs (tremor, anxiety, insomnia, tachycardia, etc.) could be due to drug retention brought about by this interaction. Acetazolamide makes the urine alkaline and would be expected to interact with ephedrine and pseudoephedrine in the same way as sodium bicarbonate. 

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