Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Alkali citrates, substances dissolving urinary concrements, ATC: G04BC01
Salts of strong bases with weak acids are suitable for alkalinization (neutralisation therapy) and the acid component is assumed to be metabolisable. The base excess resulting from the remaining alkali ions is eliminated via the kidneys and produces an increase in urine pH. The citrate ion from alkali citrates undergoes almost complete oxidative metabolic breakdown to CO2 or bicarbonate. Overall the excretion of citrate is increased which antagonizes formation of urinary calculi.
Neutralisation or alkalinization of the urine can be achieved by oral administration of alkali citrates, the response being dose-dependent.
1 g of potassium sodium hydrogen citrate (8.8 mmol alkali) causes the urine pH to increase by 0.2 – 0.3 units. As a result dissociation rate increases and hence the solubility of uric acid. Litholysis of uric acid calculi is radiologically demonstrated.
Serum concentration of bicarbonate (negatively charged base excess) is, among others, the regulator of citrate excretion. Negatively charged base excess induces alkalosis via change of intracellular pH.
Alkalosis inhibits tubular metabolism of citrate in the kidney that results in reduced absorption of citrate and increased citrate excretion.
Alkalosis at the same time has an influence on calcium flux and reduces urinary calcium excretion.
These mechanisms, namely alkalisation of urine, increased excretion of citrate and reduced excretion of calcium, lead to a decrease of the activity product of calcium oxalate, as citrate in weak alkalotic milieu forms stable complexes with calcium (antagonism of supersaturation of lithogenic constituents).
Furthermore, the citrate ion must be regarded as the most effective physiological inhibitor of calcium oxalate- (and calcium phosphate-) crystallisation and aggregation of these crystals.
Evidence of usefulness of alkalisation is hampered in ensuing kinds of illness, which lack in systematic trials. Theoretical considerations as well as observations in single cases speak for a therapeutic effect:
- Cystinuria and cystine calculus formation: Alkalisation of urine increases solubility of cystine.
Urinary pH should arrive at values between 7.5 and 8.5.
- Treatment with cytostatics: Alkalisation of urine in order to eliminate the rise in uric acid makes sense during a treatment with cytostatics. This is in line with the prophylaxis of uric acid stones. In addition, a protective effect of alkalotic urinary pH is claimed because of reduced agressivity of cytostatic metabolites (e.g. oxazaphosphorin cytostatics) and the increased solubility of cytostatic and its metabolites (e.g. methotrexate) respectively. Urinary pH should be regulated to a value of 7.0 at least.
- In porphyria cutanea tarda, an uroporphyrinogen decarboxylase deficiency exists which metabolises uroporphyrinogen to coproporphyrinogen. The objective of metabolic alkalisation is to prevent back diffusion of coproporphyrin through renal tubuli so that the coproporphyrin clearance rises. As a result of the increased coproporphyrinogen excretion, the synthesis of coproporphyrinogen from uroporphyrinogen is believed to increase and is consequently accompanied by a decrease in circulating uroporphyrin. Urinary pH should meet a value of 7.2 - 7.5.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Citrate undergoes almost complete metabolic breakdown. Only 1.5 % to 2% of the original dose appears unchanged in the urine.
Ingestion of 10 g potassium sodium hydrogen citrate yields approximately 36 mmol of citrate; this is equivalent to less than 2 % of the daily turnover of citrate involved in energy metabolism within the body.
After a one-day intake of potassium sodium hydrogen citrate the equivalent amounts of sodium and potassium are quantitatively excreted via the kidneys within 24 - 48 hours. During long-term administration, the daily excretion of sodium and potassium is in equilibrium with the daily intake.
No significant changes in blood gases or in serum electrolytes have been observed. This indicates that by virtue of renal regulation of alkalinization, the acid-base balance of the body remains intact and that, provided renal function is adequate, any possibility of accumulation of sodium or potassium can be excluded.