The distal convoluted tubule cells also possess a sodium-chloride symporter on the apical side, which passively allows one sodium ion and one chloride ion to diffuse together in from the lumen (where urine is forming) into the cell interior. As sodium is pumped out of the cell by the ATPase, its intracellular concentration falls, and additional sodium begins to diffuse in from the tubule lumen as replacement. The symporter requires chloride to be transported in as well. Water passively follows to maintain isotonicity; excess chloride and potassium passively diffuse out the cell through basolateral channels into the interstitial space, and water accompanies them. The water and chloride, as well as the sodium pumped out by the ATPase, will be absorbed into the bloodstream. Metolazone and the other thiazide diuretics inhibit the function of the sodium-chloride symporter, preventing sodium and chloride, and therefore water too, from leaving the lumen to enter the tubule cell. As a result, water remains in the lumen and is excreted as urine, instead of being reabsorbed into the bloodstream. Since most of the sodium in the lumen has already been reabsorbed by the time the filtrate reaches the distal convoluted tubule, thiazide diuretics have limited effects on water balance and on electrolyte levels. Nevertheless, they can be associated with low sodium levels, volume depletion, and low blood pressure, among other adverse effects. Pharmacokinetics
Metolazone is only available in oral preparations. Approximately 65% of the amount ingested becomes available in the bloodstream.
Kashin–Beck disease (KBD) is a chronic, endemic type of osteochondropathy (disease of the bone) that is mainly distributed from northeastern to southwestern China, including 15 provinces. As of 2011, Tibet has the highest incidence rate of KBD in China. Southeast Siberia and North Korea are other affected areas. KBD usually involves children ages 5–15. To date, more than a million individuals have had KBD. The symptoms of KBD include joint pain, morning stiffness in the joints, disturbances of flexion and extension in the elbows, enlarged inter-phalangeal joints, and limited motion in many joints of the body. Death of cartilage cells in the growth plate and articular surface is the basic pathologic feature; this can result in growth retardation and secondary osteoarthrosis. Histological diagnosis of KBD is particularly difficult; clinical and radiological examinations have proved to be the best means for identifying KBD. Little is known about the early stages of KBD before the visible appearance of the disease becomes evident in the destruction of the joints.This disease has been recognized for over 150 years but its cause has not yet been completely defined. Currently, the accepted potential causes of KBD include mycotoxins present in grain, trace mineral deficiency in nutrition, and high levels of fulvic acid in drinking water. Selenium and iodine have been considered the major deficiencies associated with KBD. Mycotoxins produced by fungi can contaminate grain, which may cause KBD because mycotoxins cause the production of free radicals. T-2 is the mycotoxin implicated with KBD, produced by members of several fungal genera.