Diuretics

What is diuretic? Classify diuretics?A diuretic is defined as a chemical that increases the rate of urine formation. By increasing the urine flow rate, diuretic usage leads to the increased excretion of electrolytes and water from the body. The primary action of most diuretics is the direct inhibition of sodium transport from the nephron.

Classification of diureticso On the basis of potency

Very potent diuretics (High ceiling diuretics)E.g. Furosemide, Bumetanide etc.

Moderately potent diureticsE.g. Thiazide and Thiazide like diuretics such as Chlorthiazide, Benzothiazide etc.

Weak diuretics Osmotic diuretics (e.g. Mannitol, glucose, sucrose etc.) Potassium sparing diuretics (e.g. Spironolactone, ameloride etc.) CA inhibitors (e.g. Acetazolamide, Dichlorphenamide, Methazolamide etc.)

o On the basis of the anatomical site of action Site 1 diuretics: diuretics acting at the convoluted and straight portions of the proximal tubule.

They are- CA inhibitors (e.g. Acetazolamide, Methazolamide etc.) Site 2 diuretics: diuretics acting at the thick ascending limb of Henle’s loop. They are- Loop

diuretics or High ceiling diuretics (e.g. Furosemide, Bumetanide etc.) Site 3 diuretics: diuretics acting at the distal convoluted tubule of the nephron. They are-

Thiazide or Thiazide like diuretics (e.g. Chlorthiazide, Benzothiazide etc.) Site 4 diuretics: diuretics acting at the connecting tubule (the terminal portion of the distal

convoluted tubule) and the cortical collecting tubule. They are- Potassium sparing diuretics (e.g. Ameloride, Spironolactone etc.)

Chemistry of site 1 diuretics

The common molecular motif → Unsubstituted Sulphonamide moiety. Agents these classes with clinical utility are:

1. Acetazolamide2. Methazolamide

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Mechanism action of site 1 diuretics

The proximal tubule has a tremendous reabsorption capacity. Proximal tubule responsible for the reabsorption of 65-70% of sodium, chloride, water and calcium,

80-90% of the bicarbonate, phosphate and ureate are reabsorb from proximal tubule and 100% of the glucose, amino acid, low molecular weight protein are absorbed.

The Na+ - K+ ATPase are located on the antiluminal membrane of the proximal tubule cells, catalyzes the counter transport of intracellular sodium ions into the interstitium and extracellular potassium ions into the proximal tubule cells.

2K+ enter the cell and 3 Na+ out from the cell. This activity creates a deficit of intracellular sodium in proximal tubule.

The sodium reabsorption at site 1 involves CA which is located in the cytoplasm and on the brush border of the proximal tubule cell.

The hydrogen ions that are secreted into luminal fluid reacts with the filtered bicarbonate ions to generate CA

The CA decomposed and from CO2 and water.

The CO2 diffuse into the proximal tubule cells and is countered back to bicarbonate.

Drug which are used as site 1 diuretics, they inhibit the Na+ - K+ ATPase system and hampered the Na+ reabsorption along with the membrane.

Chemistry of site 2 diuretics

Diuretics in this class have extremely diverse chemical structures. Agents of this class with clinical utility are:-1. Furosemide (a 5-sulfamol-2-aminobenzoic acid).2. Bumetanide (a 5-sulfamol-3-aminobenzoic acid).3. Ethacrynic acid (a phenoxyacetic acid derivative).

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Mechanism of action of site 2 diuretics

When the luminal fluid enters the thick ascending limb of Henle’s loop, it comes into contact with tubular cells that are impermeable to water and possess a capacious luminal membrane bound transport system for sodium.

The major driving force for the reabsorption of sodium is the creation of an intracellular deficit of sodium by the antiluminal membrane bound Na+ - K+ ATPase.

The electroneutral sodium/potassium/chloride co transport system located on the luminal membrane of thick ascending limb in a ratio of 1 Na+:1 K+: 2Cl-.

The chloride ion enters the interstitium through chloride channels in the antiluminal membrane, by transport with potassium ions.

The luminal potassium that accompanies sodium and chloride into the thick ascending limb cells recycles passively downhill back into the luminal fluid.

The potassium that enters the thick ascending limb cells recycles back into the interstitium by antiluminal membrane bound sodium-potassium ATPase.

Then the transport of three positively charged sodium ions and six negatively charged chloride ions from the luminal fluid into the interstitium.

Positive luminal environment that drives more cations such as Na+, K+, Ca+2, Mg+2 from lumen into the interstitium

Diuretic agents that block sodium reabsorption in the thick ascending limb by inhibition of the luminal membrane bound 1 Na+/ 1 K+/ 2 Cl- cotransport system include Furosemide, Bumetanide and a number of miscellaneous agents.

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