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Water and sodium
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
If the patient is not dehydrated and SIADH has been diagnosed, fluid intake restriction to 800–1000 mL/day may be indicated. Administration of demeclocycline, by antagonizing the action of ADH on renal tubules, may also help but may have side effects such as photosensitivity. Recently vasopressin 2 receptor antagonists such as tolvaptan have been used to treat SIADH and hyponatraemia of cardiac failure and cirrhosis.
Diabetes Epidemiology – 1980 and Beyond
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
A rare type of diabetes, though not associated with hyperglycaemia, is diabetes insipidus (DI). It has been called ‘diabetes’ because of the central characteristic of excessive water loss through urination, which is also one of the cardinal signs of uncontrolled diabetes. The excessive loss of water through urination has been attributed to the peptide hormone vasopressin, also known as anti-diuretic hormone (ADH) or arginine vasopressin (AVP). The loss of function or loss of signalling to this hormone is the primary reason for DI. Largely, DI has been classified as central, nephrogenic, dipsogenic and gestational. Vasopressin or ADH, as the name suggests, control the fluid loss through urine. In central DI, there is damage to the hypothalamus or pituitary gland which results in a decrease or loss of ADH production and action. This results in loss of control in the amount of water lost through urine. Nephrogenic DI occurs when the kidneys fail to respond to the normal level of vasopressin; consequently there is excessive water loss. It can occur due to reasons such as chronic kidney disease, mutation in the vasopressin receptors in the kidneys, medications such as lithium, high blood calcium and low potassium in the blood. Since there is supposedly a feedback loop in vasopressin-water intake, dipsogenic DI occurs when there is damage to the thirst signalling located in the hypothalamus. As a result, a large intake of water suppresses vasopressin release which results in increased urine output. It is worth highlighting that gestational DI occurs relatively rarely. Major symptoms of DI include excessive thirst, fatigue and dry skin, while seizures and brain damage due to severe dehydration occur rarely [14]. The level of thirst could be severe enough to consume up to 20 litres of water per day. As a result of this huge water consumption, there is a rapid increase in the amount of urine. Thus, excessive water loss may result in hypovolaemia and electrolyte imbalance. The ADH maintains the water balance in normal individuals by acting on the vasopressin-2-receptor (V2R) upon detecting blood osmolarity and the arterial blood volume. ADH activates V2R present in the basolateral membrane of the principal cells in the renal collecting duct and distal convoluted tubule. This interaction activates protein kinase A (PKA) which results in phosphorylation of aquaporin 2 (AQP2) water channels in the intracellular vesicles. This activation is followed by the translocation of AQP2 vesicles into the cell membrane that exposes the AQP2. The collecting duct becomes water permeable due to AQP2 and concentrates the urine resulting in control of water loss [15].
Vasopressin receptor antagonists: a patent summary (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Ferenc Baska, Éva Bozó, Tamás Patócs
Researchers at the Xuzhou Medical University discovered new benzodiazepine derivatives as novel V2 receptor antagonists for the treatment of autosomal dominant kidney disease [72]. In 2022 they published benzazepine compounds (31, Figure 8) as a potential treatment or prevention of disorders including hypertension, dysmenorrhea, adrenal hyperplasia, chronic congestive heart failure, liver cirrhosis, depression, hyponatremia, or PKD [73]. An in vivo test was performed to determine the antagonistic effect of compounds on arginine vasopressin receptors by inhibiting the action of cAMP using PKD1 knockout mice. Results revealed that these compounds significantly delayed the occurrence and development of PKD compared with tolvaptan and control. In another patent application, benzodiazepine pyrrole compounds (32, Figure 8) are described by Xuzhou Medical University [74]. The compounds are arginine vasopressin V2 receptor antagonists that can be used as pharmacological tools in studying the kinetics of receptor-ligand binding.
Pharmacotherapeutic options in the treatment of nocturia: an update on the current oral drug therapies
Published in Expert Opinion on Pharmacotherapy, 2022
Older patients, especially older women should be started on the lowest effective dose to minimize drug adverse effects such as hypertension and hyponatremia. The higher side effects experienced by female patient could be attributed to the location of the vasopressin V2 receptor gene on the X chromosome [24]. Hyponatremia commonly occurs after the first week of therapy and severe hyponatremia while very rare, can be dangerous if left untreated and can result in seizures, respiratory arrest, coma and death. A recent meta-analysis on three desmopressin clinical trials in nocturia [25] showed the patient’s age, baseline serum sodium level and desmopressin dose as well as concomitant administration of certain drugs such as selective serotonin reuptake inhibitors or tricyclic antidepressants, to be predictors of clinically significant hyponatremia.
A cross-sectional survey of hospitalization and blood tests implementation status in patients who received tolvaptan under 75 years of age using a Japanese claims database
Published in Expert Opinion on Drug Safety, 2021
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Tolvaptan is a nonpeptide orally selective antagonist of the vasopressin V2 receptor that increases dilute urine production in a dose-dependent manner [1]. Tolvaptan is used for the treatment of the following diseases under the Japanese medical insurance [2]: (1) fluid accumulation induced by chronic heart failure (FA-CHF), (2) fluid accumulation induced by liver cirrhosis (FA-LC), (3) autosomal dominant polycystic kidney disease (ADPKD), and (4) hyponatremia-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). In Japan, tolvaptan was first approved in October 2010 for FA-CHF. Then, it was additionally approved for treating FA-LC in September 2013. However, the use of tolvaptan for these indications is not approved in other countries and regions [2–8]. Further, tolvaptan is prescribed at lower doses (7.5 or 15 mg daily) for these indications than for ADPKD (60 mg daily).