V2-vasopressin receptor antagonists—mechanism of effect and clinical implications in hyponatraemia (1999)

ment of hyponatraemia; vasopressin; vasopressin CHF, liver cirrhosis receptor antagonists tice. Its clinical relevance is related to both the symp- Spontaneous thirst and Increased Increased toms it causes and the state of cardiovascular fluid intake dysfunction it indicates. Hyponatraemic patients may suVer from lethargy, diYculty of concentration, dis- PRA, plasma renin activity; AII, angiotensin II; Aldo, (aldosterone; orientation, muscular cramps, grand mal seizures, and Et, endothelin-1; NA, noradrenaline); aincreased in relation to the even coma. It is important to know that these symp- prevailing plasma osmolality. toms are more related to the rate of decrease of serum sodium concentration than to the absolute level of a than approximately 800 ml per day) vasopressin excess hyponatraemia reached. This surprising observation is will lead to water retention. Consequently, dilution of related to the phenomenon of osmotic unloading of all fluid compartments sets in, including dilution of cells, which causes adaptation of cell volume to the intravascular compartment leading to hyponatrae- any given degree of hyponatraemia within 2-4 days. mia. When daily fluid intake is limited to approxi- Osmotic reloading will have to occur during correction mately 800 cc, however, obligatory fluid losses via of hyponatraemia. Since this will take a similar amount kidney, GI-tract, and lungs will match intake and the of time to be completed, the rate of correction of water balance will become negative. Physicians often hyponatraemia should not be in excess of 0.5 mmol/l/h. approach hyponatraemia as if it was a primary disorder If chronic hyponatraemia is corrected too fast, i.e. at of sodium deficiency. A vast body of published obser- a rate exceeding 0.5 mmol/l/h, and if it reaches hyper- vations documents that this is an erroneous interpreta- natraemic levels, the patient will be at risk of brain tion. Hyponatraemia is almost always a condition of damage. In the literature, the occurrence of central water excess. Therefore the above interpretation may pontine myelinolysis has been well documented in such lead to deleterious therapeutic measures. circumstances. The causes of the non-osmotic vasopressin release in hyponatraemia have been studied intensively. In pre-renal hyponatraemia it was found that barorecep- Pathophysiological significance of hyponatraemia tor activation in the large central arteries is the culprit. The low arterial blood pressure typically present in the Hyponatraemia is encountered in the advanced stages advanced stages of heart failure, liver cirrhosis and of congestive heart failure (CHF ), liver cirrhosis, and volume contraction provides the stimulus to such baro- volume contraction ('prerenal pattern') as well as in receptor activation. In SIADH-type hyponatraemia, the syndrome of inappropriate antidiuretic hormone the stimuli of non-osmotic vasopressin release are not secretion ('SIADH-pattern', Table 1). Hyponatraemia precisely known. These may originate either from is a disorder of vasopressin excess, caused by non- tumour cells or from the hypothalamus. osmotic vasopressin release. Vasopressin increases water reabsorption by the kidney. When such patients Significance of hydro-osmotic V2-vasopressin drink higher than minimal amounts of water (more receptors