Joydeep Ganguly

ANDTHEIR

MECHANISM

DIURETICS

Diuretics These are the drugs which cause a net loss of Na+ and

water in urine. Diuretics are among the most widely prescribed drugs. Application of diuretics to the management of hypertension

& in edema. CLASSIFICATION1. High efficacy diuretics (lnhibitors of Na+-K+-2Cl- cotransport) a) Sulphamoyl derivatives: Furosemide, Bumetanide,

Torasemide b) Phenoxyacetic acid derivatives: Ethacrynic acid c) Organomercurials: Mersalyl

Cont……… 2. Medium efficacy diuretics (lnhibitors of Na+ -Cl- symport)(a) Benzothiadiazines (thiazides): Hydrochlorothiazide, Benzthiazide,

Hydroflumethiazide, Clopamide

(b) Thiazide like (related heterocyclics): Chiorthalidone, Metolazone, Xipamide, Indaoamide.

3. Weak or adjunctive diuretics (a) Carbonic anhydrase inhibitors: Acetazolamide (b) Potassium sparing diuretics: (i) Aldosterone antagonist: spironolactone (ii) Inhibitors of renal epithelial Na+ channel: Triamterene,

Amiloride. (c) Osmotic diuretics: Mannitol, Isosorbide, Glycerol (d) Xanthines: Theophylline

High Ceiling Loop Diuretics (lnhibitors of Na+-K+-2Cl-

Cotransport)

Ion transport in the thick ascending limb of Henle's loop, showing the site of action of loop diuretics

Cont…… The sodium pump (P) is the main primary active transport mechanism,

and Na+, K+ and Cl- enter by a cotransport system (C1). Chloride leaves the cell both through basolateral chloride channels and by an electroneutral K+/Cl- cotransport system (C2). Some K+ returns to the lumen via potassium channels in the apical membrane, and some Na+ is absorbed paracellularly through the zonula occludens.

Furosemide (Frusemide) Prototype drug

•The development of this orally and rapidly acting highly efficacious diuretic •Its maximal natriuretic effect is much greater than that of other classes. The diuretic response goes on increasing with increasing dose: upto 10 L of urine may be produced in a day.

THIAZIDE AIID RELATED DIURETICS (lnhibitors of Na+-Cl- symport)

Salt transport in the distal convoluted tubule, showing the site of action of thiazide diuretics. The sodium pump (P) in the basolateral membrane is the primary active transport mechanism. Sodium and chloride ions enter by an electroneutral cotransport carrier (C1). Exm- Chlorthiazide.

CARBONIC ANHYDRASE INHIBITORS 1. Carbonic anhydrase (CAse) is an enzyme which catalyses the

reversible reaction. H2O + CO2 ↔ H2CO3. 2. Carbonic acid spontaneously ionises. H2CO3 ↔ H+ + HCO3 3. The enzyme is present in renal tubular cell (specially PT)

gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBC. Eg: Acetazolamide.

Sodium is absorbed and hydrogen ion secreted at the luminal surface by an antiport mechanism. Mostbicarbonate in the filtrate is reabsorbed in this way in the proximal tubule. In the distal tubule bicarobonate is added to the plasma and monobasic phosphate or ammonium chloride is added to the urine. Primary active transport mechanism is the sodium pump (P). Dashed line with K+ indicative passive diffusion.

Cont…….

POTASSIUM SPARING DIURETICSThese are either aldosterone antagonist or directly inhibit Na+ channels in DT and CD cellsto indirectly conserve K+. Eg: Spironolactone (Aldosterone antagonist)

OSMOTIC DIURETICS

1. Mannitol is a nonelectrolyte of low molecular weight (182) that is pharmacologically inert

2. Given in large quantities sufficient to raise osmolarity of plasma and tubular fluid.

Mannitol appears to limit tubular water and electrolyte reabsorption in a variety of ways:a. Retains water iso-osmotically in PT, dilutes luminal fluid which

opposes NaCl reabsorptionb. Inhibits transport processes in the thick AscLH by an unknown

mechanism. Quantitatively this appears to be the most important cause of diuresis.

c. Expands extracellular fluid volume (because it does not enter cells, mannitol draws water from the intracellular compartment)-increases g.f.r. and inhibits renin release

Applications of Diuretics:Diuretics are very effective in the treatment of conditions like:- Chronic heart failure Nephrotic syndrome Chronic hepatic diseases Hypertension Pregnancy associated oedema Cirrhosis of the liver Edema.

THANK YOU…