DIURETICS

DIURETICS

Diuretics are drugs that promote the output of urine excreted by kidney.

Diuretics mainly promotes the excretion of the sodium ions(Na+),chloride ions(Cl-) or bicarbonate ions(HCO3-) and water from the body, the net result being increase the urine flow. The excretion by kidney is dependent on glamerular filtration, tubular reabsorption and tubular secretion.

These drugs also act by decreasing tubular reabsorption, a process that involves the active transport of electrolytes and other solutes from tubular urine to the tubular cells and then to the extra cellular fluid and increase glamerular filtration. But the diuretics do not affect the glamerular filtration rate or the action of anti diuretic hormone (ADH) on the distal portion of the nephron.

Diuretics are very effective on the treatment of cardiac edema (extra vascular accumulation of fluid in tissues), specifically with congestive heart failure and also employed for various disorders such as nephrotic syndrome, diabetes insipidus, hyper tension, nutritional edema, edema of pregnancy, cirrhosis of liver and also lower the intracellular and cerebrospinal fluid pressure.

CLASSIFICATION

I. Carbonic anhydrase inhibitors (Site-I Diuretics)
Acetazolamide, Methazolamide, Dichlorphenamide, Disulfamide, Ethoxzolamide.

II. Thiazide and Thiazide like Diuretics (Site-III Diuretics)

Chlorthiazide, Benzthiazide, Hydrochlorothiazide, Hydroflumethiazide, Bendroflumethiazide, Trichlormethiazide, Methyclothiazide, Polythiazide, Cyclothiazide, Mefruside, Clopamide, Xipamide, Indapamide, Quinethazone, Metolazone, Clorexolone, Chlortalidone.

III. High ceiling or Loop Diuretics (Site-II Diuretics)
1. Organo mercurials – Chlormerodine mercury, Meralluride, Mercaptomerin, Merethoxylline

procaine, Mersalyl.
2. 5-Sulpamoyl & 3-Amino Benzoic acid derivatives- Bumetanide, Furosemide,
3. 4-Amino-3-pyridine sulphonyl ureas- Torsemide, Triflocin.
4. Phenoxy acetic acids- Ethacrynicacid.

IV. Potassium sparing Diuretics (Site-IV Diuretics)
1. Aldosteron inhibitors – Spiranolactone, Metyrapone
2. 2,4,7-Triamino-6-aryl pteridines – Triamterene
3. Pyrazinoyl Guanidines – Amiloride. HCl.

V. Xanthine Derivatives -

Caffeine, Theophylline. Theobromine.

VI. Miscelleneous -
Mannitol, Potassium acetate, Sodium acid phosphate, Urea.

I. Carbonic anhydrase inhibitors (Site-I Diuretics)

Structure Activity Relationship for CAI

1. The free sulfamoyl nitrogen is important for diuretic activity. The mono and Di substituents at SO2NH2 abolish the activity.


2. Substitution of the methyl group on one of the ring nitrogen (Methazolamide) retains the activity.


3. The heterocyclic sulphonamides have highest lipid/water partition coefficient and lowest pKa values have greatest CA inhibitory and diuretic activity.


4. The benzene meta sulphonamide derivatives have activity only when substituted with chlorine or methyl groups.

Mechanism of action of CAI

Carbonic anhydrase found in many sites such as renal cortex, eye, CNS, gastric mucosa, and pancreas. This enzyme catalyses the reversible hydration of CO2 to carbonic acid.
CO2 + H2O --------H+ + HCO3-

The diuretics inhibit the Carbonic anhydrase enzyme at the proximal convoluted tubules cause reduction in H+ ions for Na+-H+ exchange CO2 reabsorption from glamerular filtrate is suppressed and HCO3- excretion is increased and facilitates K+ secretion.

Due to decreased Na+ reabsorption, the Na+-H+ exchange in distal convoluted tubule increases cause loss of K+ in urine. To maintain ionic balance Cl- is retained by kidney and decreased diuresis. So they are weak diuretics.

II. Thiazide and Thiazide like Diuretics (Site-III Diuretics)

Synthesis of Hydrochlorthiazide

Structure Activity Relationship for Thiazides

1. Thiazides having benzothiadiazine 1,1-dioxide with weakly acidic character is important for good activity.


2. Presence of electron withdrawing group at C-6 is necessity for good diuretic activity. Substitution of chlorine at C-6 has good activity.


3. Substitution of CF3 group has more lipid soluble and larger diuretic action than Chloro compound.
4. Presence of electron releasing groups like methyl or methoxy at C-6 reduces the diuretic activity.


5. Removal or replacement of sulphonamide at C-7 reduces the diuretic activity.


6. Saturation of double bond between 3&4 having 10 times more diuretic activity than unsaturated analogue.


7. Introduction of lipophilic groups such as aralkyl, halo alkyl, thioether enhances the diuretic activity and increase the duration of action.


8. Alkyl substitution at N2 lowers the polarity and enhances the duration of action.

Mechanism of action of Thiazides.
These drugs blocks the reabsorption of Na+, Cl- exchange in the distal convoluted tubule by inhibiting the luminal membrane-bound Na+/ Cl- co transport system.

As a result of these drugs act on site-III, alter the renal excretion rate of important ions other than sodium. Inhibition of sodium reabsorption at site-III ultimately results in the delivery of more of the filtered load of sodium at a faster rate to site-IV.

So there is an enhanced exchange of luminal fluid sodium for the principal cell potassium and an increase in the urinary excretion rate of potassium follows.
Long term use of these agents leads to reduction in calcium excretion.

III. High ceiling or Loop Diuretics (Site-II Diuretics)

Structure Activity Relationship for Loop diuretics

1. 5-sulfomoyl and 2-aminobenzoicacid group is required for good diuretic activity.



2. Substitution at 1st position must be acidic for good diuretic activity.


3. The activating group at 4th position can be Cl or CF3 group increases the activity.


4. Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted at 4th position decreases diuretic activity.



5. Furfuryl,benzyl and thienyl methyl group at 2-position increases the activity.

Mechanism of action of Loop Diuretics

1. The diuretics inhibit the Na+/K+/ Cl- cotransport system located in the luminal membrane of cells in the limb of Henle’s loop.
2. The carboxylate moity is responsible for their competing with Cl- for the Cl- binding site on Na+/K+/ Cl- cotransport system.
3. These drugs inhibits the reabsorption of 20-25% of the filtered load sodium at site-II with in minutes and the net result is that when Na+&Cl- are not reabsorbed at site –II. So large amount of water, sodium and chloride are excreted.
4. These diuretics increase the flow rate of luminal fluid past the macula densa cells, the expected reduction in GFR does not occur.
5. These drugs blocks the reabsorption of K+at site-II by inhibiting the Na+/K+/ Cl- cotransport complex.
6. These may induce the renal excretion up to 20-30% of the filtered load calcium.

IV. Potassium sparing Diuretics (Site-IV Diuretics)

Mechanism of action of Spiranolactone

It inhibits the reabsorption of 2-3% of the filtered load sodium at site-IV by competitively inhibiting the action of aldosterones.

So the passage of luminal fluid sodium in to and potassium, Hydrogen ions out of the late distal convoluted tubule and the early collecting tubule cell is enhanced. So they enhance the water, sodium and chloride excretion.

Mechanism of action of Triamterene& Amiloride
These drugs plugs the sodium channels in the luminal membrane of the principal cell at site-IV and there by inhibits the electrogenic entry of 2-3% of the filtered load sodium in these cells.

It decrease the antiluminal membrane bound Na+/K+-ATP ase activity, leads to decrease in cellular extusion of sodium and in the cellular uptake of potassium at site-IV.