Mechanism of action of thiazides is by -
Ans. is "a' i.e.. Inhibiting Na+/Cl- symporter in DCT o Thiazide diuretics act by inhibiting Na+/ Cl- reabsorption pump in the distal convoluted tubule, thereby increasing urinary excretion of Na+ and Cl-. This result in reduced ECF and plasma volume, which results in decreased CO.o Na+ absorption at different tubular sites.PT - 65-70%Asc. LH - 20-25%DT - 8-9%CD- 1-2%o Tubular absorption can be divided into four sites.Site I- Proximal tubuleo Four mechanisms of Na4 transport have been defined in this segment -1. Direct entry of Na4 along electrochemical gradient.2. Na+-K+ symport along with active reabsorption of glucose, aminoacids, organic anions and PO4 -33. Exchange with H+ by Na+ /H+ exchanger located in the luminal membrane of proximal tubule (PT) epithelial cells. The PT cells secrete H+ with the help of carbonic anhvdrase. H+ ion exchanges with Na+ present in tubular fluid through Na+-H+ exchanger (antiporter) and forms H2CO3 by combining with HCO3-. This H2CO3 is broken into H2O + CO2 by brush border carbonic anhydrase; both CO2 and H2O diffuse inside the cell and recombine to form H2CO3 with the help of intracellular carbonic anhydrase. This H2CO3 is the source of H+. The dissociated HCO3- in the cell is transported to cortical E.C.F. by basolateral membrane Na+-HCO3- symporter resulting in net reabsorption of NaHCO3.Carbonic anvdrase inhibitors (acetazoiamide) act predominantly in PCTand inhibit NaHCQ3 reabsorption.4. The disroportionately large HCO3-, acetate, PO4-3, passive driving forces for Cl- to diffuse through the paracellular pathway, particularly in the later PT. This takes Na+ and H2O along to maintain electrical neutrality and isotonicity; reabsorption in PT is isotonic.o Osmotic diuretics (mannitol) are solutes which are not absorbed in proximal tubule and therefore retain water:Site 11 Ascending limb of loop of Henleo The thick ascending limb can be distinguished into two distinct portion.1. Medullary portion lined by cuboidal cells.2. Cortical portion lined by flattened cells.o Both portions are relatively impermeable to water but absorb salt actively and thus dilute tubular fluid,o In the medullary portion a distinct luminal membrane carrier transports ions in ratio of Na+-K+-2Cl-. The sodium enters the cell is pumped to ECF by Na+ K+ ATPase at the basolateral membrane,o This Na+ -K+--2Cl= symport is inhibited by loop diuretics (eg-Furosemide)o In addition, a Na+-Cl- symporter moves Cl- down its electrochemical gradient into ECF and carries Na+ along.Site III - cortical diluting segment of loop of Henle and early DTo This segment is also impermeable to H2O and continues to absorb salt through Na+-Cl- symporter.o Thiazide diuretics act at this site.Site IV - late distal tubule and collecting ducto In late DT and CD, Na+ is actively reabsorbed; the cation-anion balance being maintained partly by passive Cl- diffusion and partly by secretion of K+ and H+.o Absorption of Na+ at this site occurs through a specific amiloride sensitive Na+ channel and is controlled to a large extent by aldosterone.o K+- sparing diuretics act at this site.o Collecting tubule is the most important site of K+ secretion by the kidney and the site at which virtually all diuretic induced changes in K+ balance occur - as K+ secretion occurs in exchange of Na+, higher the Na+ load in CD higher will be K+ excretion in urine - Diuretics which act on PCT (maximum absortion of Na+ occurs at PCT) like acetazolamide will cause maximum kaliuresis (K+ excretion in urine),o The principal cells are the major sites of Na+, K+, and water transport, and intercalated cells are the primary sites of H+ secretion.o The collecting tubule is also the site at which the final urine concentration is determined. ADH (vasopressin) controls the permeability of this segment to water by regulating the insertion of preformed wrater channels (aquaporin-2, AQP2) into the apical membrane via a G protein - coupled cAMP - mediated process.o ADH also stimulates the insertion of urea transporter UT1 molecules into the apical membranes of medullary collecting tubule cells. Urea concentration in the medulla plays an important role maintaining the high osmolarity of the medulla and in the concentration of urine.
Inhibiting Na+/Cl- symporter in DCT
Inhibiting Na+/Cl- symporter in PCT
Inhibiting Na+K+2C1- in ascending limb of loop of henle
Inhibiting Na+K+2CI- in descending limb of loop of henle
Diuretic