Vasopressin Receptor Antagonists for the Treatment of Hyponatremia
non-osmotic stimulation of pituitary ADH release and subsequent retention of electrolyte-free water lowers the serum sodium concentration. Infusion of isotonic sodium chloride solution is usually enough to correct hyponatremia. Correction of hypovolemia abolishes the non-osmotic stimulation of ADH release. Electrolyte-free water excretion resumes, often leading to rapid or even over rapid correction of hyponatremia.
Euvolemic hyponatremia presents a unique challenge to clinicians. These patients usually have SIADH. Treatment consists of water restriction when symptoms are mild or absent. However, the efficacy of this treatment is limited and it is seldom well tolerated. Few pharmacological approaches are available. Lithium carbonate was the first agent used for the treatment of hyponatremia. When used for psychiatric illnesses, it can cause nephrogenic diabetes insipidus. Lithium is no longer used for the treatment of hyponatremia mainly because of its slow onset of action, narrow therapeutic window, and potential toxicity.13
in 1975 for the treatment of hyponatremia secondary to SIADH.14
Demeclocycline was first used The exact
mechanism of action is not completely understood, but it likely interferes with the ADH-stimulated adenylate cyclase/cyclic mononucleotide of adenosine (cAMP) pathway, leading to reversible nephrogenic diabetes insipidus in 70 % of cases.15
days. Demeclocycline has been associated with multiple side effects, including nausea, photosensitivity, and nephrotoxicity.14–18 saline is indicated if the severity of clinical symptoms mandate.
Hypertonic
Several considerations have to be taken into account if hypertonic saline is considered for treatment of hyponatremia. If altered mental status, seizures, and coma are present secondary to hyponatremia, infusion of hypertonic saline is indicated. The rate of correction should be guided by the acuity or chronicity of hyponatremia. The rapid initial increase in the serum sodium concentration in order to terminate acute neurologic symptoms is critical. The subsequent rate of correction should be slow, especially in patients with chronic hyponatremia. Caution has to be applied to the rate of correction, and serum sodium should be measured frequently to avoid a too rapid rise in serum sodium. This is of utmost importance in patients with chronic hyponatremia since rapid correction in this setting can be complicated by osmotic demyelination with permanent brain damage or death. In a retrospective study to determine an appropriate rate of correction in patients with severe hyponatremia (serum sodium ≥105 mmol/l), Sterns et al. defined acute hyponatremia as a condition which developed in hospitalized patients or was secondary to psychogenic polydipsia. Chronic hyponatremia in contrast was present at hospital admission. Correction of hyponatremia never led to neurologic complications in patients with acute hyponatremia but occurred in 37 % of patients with chronic hyponatremia. Neurologic sequela only resulted in patients with chronic hyponatremia if the rate of correction exceeded 12 mmol/l during the first 24 hours or 18 mmol/l during the first 48 hours.19 Two more points are important to consider when the treatment decision to use hypertonic saline has been reached. First, often the duration of hyponatremia is not known. Second, evidence is lacking that rapid correction of hyponatremia even in acute hyponatremia is beneficial. Hence an expert panel developed the following treatment guideline: in symptomatic acute hyponatremia a quick increase in the serum sodium concentration by 2–4 mmol/l within one to two hours is critical and appropriate. The subsequent rise should not exceed 10–12 mmol/l maximally during the first day of treatment or preferably should be less.20
US NEPHROLOGY
Patients with cirrhosis and CHF develop hypervolemic hyponatremia, which is characterized by retention of an excess of both salt and water. Since hyponatremia in this setting is almost always chronic, the clinical approach is to restrict electrolyte-free water and salt intake. Improvement of cardiac output in patients suffering from CHF with angiotensin- converting enzyme inhibitors often decreases non-osmotic ADH release and improves hyponatremia. The use of loop diuretics eliminates the medullary concentration gradient and impairs urinary concentration, which in turn decreases retention of electrolyte-free water.21
Most recently, vasopressin receptor antagonists (VRAs) have been introduced to treat hyponatremia. Their use is the focus of this review.
Hyponatremia and Vasopressin Receptor Antagonists
The onset of action usually takes two to three
Antidiuretic Hormone—Physiology and Receptors ADH, or vasopressin, is responsible for the regulation of electrolyte-free water excretion. Neurosecretory cells of the supraoptic and paraventricular magnocellular nuclei of the hypothalamus synthesize this nine-amino-acid hormone. ADH is then transported via axons to the nerve terminals in the posterior pituitary where it resides in vesicles. ADH is secreted into the systemic circulation by a process of exocytosis as osmolarity rises. ADH interacts with its receptor on the basolateral membrane of the collecting duct and increases permeability of water. This leads to a decrease in electrolyte-free water excretion. Non-osmotic stimuli for ADH release involve activation of a parasympathetic pathway in response to acute systemic hemodynamic changes (decreased cardiac filling or decreased arterial pressure), stress, nausea, pain, and hypoxia.22
The physiologic effects of ADH are mediated via three different receptors. Of greatest interest for this review is the binding of ADH to the vasopressin-2 receptor (V2R) in the collecting duct of the distal nephron. Through this interaction, ADH increases the intracellular cAMP concentration. cAMP enables the translocation of preformed aquaporin-2 channels from subapical vesicles into the apical membrane. Increased water permeability results in water flow from the urine into renal tubular cells following its osmotic gradient. Water entry into the plasma is facilitated via constitutively active basolateral membrane aquaporin-3 and -4 channels. This process allows for urinary concentration and water retention. Furthermore, ADH also regulates the expression of aquaporin-2, thereby increasing the number of water channels available for urinary concentration.23
V2R is also expressed in the vascular
endothelium where its activation leads to release of von Willebrand factor. This action is used therapeutically when the ADH analog desmopressin (DDAVP) is used to improve platelet function in patients with uremia or other hemorrhagic diatheses. An additional member of the vasopressin receptor family is vasopressin-1 receptor (V1R). V1R is further subdivided in V1aR and V1bR. New nomenclature has recently evolved to rename V1aR to V1R and V1bR to V3R. Their most important location and physiologic functions are summarized in Table 1.24
The first generation of vasopressin antagonists had the ability to induce excretion of electrolyte-free water by specifically antagonizing
Development of Vasopressin Receptor Antagonists In the 1980s chemical alteration of the ADH agonist DDAVP yielded analogs that had antagonistic properties when tested in anesthetized rats.25
101
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84