Vasopressins clearance

In normal human subjects, ANP infusion for one hour causes increased absolute and fractional sodium excretion, urine flow, GFR, and water clearance (53—55). As shown in many in vitro and in vivo animal studies, ANP achieves this by direct effect on the sodium reabsorption in the inner medullary collecting duct, ie, by reducing vasopressin-dependent free-water and sodium reabsorption leading to diuresis and by indirect effect through increased hemodynamic force upon the kidney. ANP inhibits the release of renin and aldosterone resulting in the decreased plasma renin activity and aldosterone concentration (56,57). 

Profound hyponatremia due to reduced free water clearance is a predictable dose-related effect of vasopressin (17). This is a particular risk in patients who are unconscious or who have disturbed thirst sensation (SEDA-22, 487). 

Polydipsia and polyuria are frequent but reversible concomitants of lithium treatment, occurring at therapeutic serum concentrations. The principal physiologic lesion involved is loss of the ability of the collecting tubule to conserve water under the influence of antidiuretic hormone, resulting in excessive free water clearance (nephrogenic diabetes insipidus). Lithium-induced diabetes insipidus is resistant to vasopressin but responds to amiloride. 

Water is present in a free (non-osmotically bound) state and as a chemically bound hydrate solid structure. The clearance of free water is controlled by vasopressin it is calculated from the volume of urine/minute minus the osmolal clearance. A normal daily fluid intake of 1,700-2,200 ml (25-30 ml/kg BW) in addition to some 300 ml oxidation water is balanced by a fluid discharge of approximately 1,500 ml as urine, about 100 ml in stools, roughly 600 ml as perspiration and some 400 ml as expired air. (s. fig. 16.1)... 

Terlipressin, a prodrug converted into lysine vasopressin, has been used recently in septic shock patients." This drug has a half-hfe of 6 hours and acts via vascular receptors aud reual tubular V2 receptors. In one report, terlipressin 1 mg was given intravenously to 15 patients with norepinephrine-resistant septic shock."" Terhpressin was shown to increase MAP at 30 minutes, which lasted for 24 hours. Despite a decrease in cardiac output, terlipressin increased gastric mucosal perfusion, urine output, and creatinine clearance. These preliminary findings suggest that a clinical trial should be conducted that evaluates mortality, in addition to hemodynamic effects. 

Kidney and liver. The kidney and the liver play the major role in the clearance of oxytocin and vasopressin from the circulation. Liver extracts inactivate oxytocin by a two-stage process. The first step consists in the reduction of the disulfide bond with the simultaneous oxidation of reduced gluthathione, the reductive cleavage of oxytocin being coupled to the oxidation of NADPH as follows ... 

However, compounds of the type 89 were reported to have low solubility and relatively high log D. This resulted in replacement of the 3,4-difluorobenzaldehyde with 2-methyloxazole-4-aldehyde in the U-4CR. Compound 92 (GSJC221149A) has been noted to have nanomolar affinity for the oxytocin receptor with > 1400-fold selectivity over the closely related vasopressin receptors. Compound 92 (Figure 7.3) has also shown to have a good rat pharmacokinetic profile and low human microsomal clearance and inhibits oxytocin-induced contraction in vivo in the anesthetized rat... 

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