Diuretics

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Chapter: Medicinal Chemistry : Diuretics

Diuretics increase the rate of urine flow and sodium excretion, and are used to adjust the volume or composition of body fluids in a variety of clinical situations, including hypertension, heart failure, renal failure, nephritic syndrome, and cirrhosis.


Diuretics

INTRODUCTION

Diuretics increase the rate of urine flow and sodium excretion, and are used to adjust the volume or composition of body fluids in a variety of clinical situations, including hypertension, heart failure, renal failure, nephritic syndrome, and cirrhosis. The normal fluid filtration in human body is 180 litres, and about 1.5 litres of urine is formed in 24 hrs.

The diuretics act primarily by inhibiting tubular reabsorption; just 1% decrease in tubular reabsorption would produce more than double urine output. The action depends upon the drug by acting on various symport and antiport present in the nephron. All the transports depend on the basolateral membrane porters, especially in tubular reabsorption, which is divided into four sites:

  1. Proximal tubule (PT)

  2. Ascending limb of loop of henle (AscLH)

  3. Cortical diluting segment of loop of henle

  4. Distal tubule (DT)

  5. Collecting duct


Proximal tubule: Transport of Na+ and K+ coupled with active reabsorption of glucose, aminoacids, other organic anions, and PO43– are transported through specific symporters. The exchange with H+ happens in the PT cells, which secrete H+ with the help of carbonic anhydrase (CAse). H+ ion exchanges with Na+-H+ antiporter located in the luminal membrane and forms H2CO3 by combining with HCO3. This H2CO3 is broken into H2O +  CO2 by brush border CAse; both H2O and CO2 diffuse inside the cell and recombine to form H2CO3 with H+.

The dissociated HCO3 in the cell is transported to cortical extracellular fluid (ECF) by basolateral membrane, Na+-HCO3 symporter resulting in the net reabsorption of NaHCO3 . The HCO3 acetate, PO amino acid, and other anion reabsorption produces a passive driving force for Cl to diffuse through the para-cellular pathway.

Ascending limb of loop of Henle: In the medullary portion, a distinct terminal membrane carrier transports ions in the stoichiometric ratio of Na+–K+–2Cl and is nonelectrogenic. The Na+ that enters the cell is pumped to the ECF by Na+K+ ATPase at the basolateral membrane. In addition, a Na+-Cl symporter moves Cldown its electrochemical gradient in the ECF and moves Na+ along.

Cortical diluting segment of loop of Henle: Absorbs salt through Na+–Cl symport.

Distal tubule and collecting duct: In DT and collecting duct Na+ is again actively reabsorbed; the cation-anion balance being maintained partly by passive Cl diffusion and partly by secretion of K+ and H+. Absorption of Na+ at this site occurs through a specific amiloride sensitive Na+ channel, and is controlled to a large extent by aldosterone. The luminal membrane provides an active secretory pump for H+, which is again governed by the movement of Na+ in reverse diffusion.

These are the processes of renal physiology for the reabsorption of water and minerals into the body. Blocking of the symporters and antiports with various drugs provides the diuretic effect according to the site of action.


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