Pharmacology of drugs acting on urinary system
Diuretics (natriuretics) are drugs which cause a net loss of Na+ and water in urine. However, Na+ balance is soon restored, even with continuing diuretic action, by compensatory homeostatic
mechanisms of the body, albeit with a certain degree of persisting Na+ deficit and reduction in extracellular fluid volume.
Based on the diuretic action of calomel, organomercurials given by injection were introduced in the 1920s and dominated for nearly 40 years. The CAse inhibitors were developed in the 1950s from the observation that early sulfonamides caused acidosis and mild diuresis. The first modern orally active diuretic chlorothiazide was produced in 1957, and by early 1960s its congeners (thiazide diuretics) were already in common use. Availability of furosemide and ethacrynic acid by mid 1960s revolutionized the pattern of diuretic use. The aldosterone antagonist and other K+ sparing diuretics spironolactone and triamterene/amiloride were developed in parallel to these.
Diuretics are among the most widely prescribed drugs. Application of diuretics in the management of hypertension has outstripped their
use in edema. Availability of diuretics has also had a major impact on the understanding of renal physiology.
1. High efficacy diuretics (Inhibitors of Na+- K+-2Cl¯ cotransport)
Sulphamoyl derivatives Furosemide, Bumetanide, Torasemide
2. Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport)
(a) Benzothiadiazines (thiazides)
(b) Thiazide like (related heterocyclics)
Chlorthalidone, Metolazone, Xipamide,
3. Weak or adjunctive diuretics
(a) Carbonic anhydrase inhibitors
(b) Potassium sparing diuretics
(i) Aldosterone antagonist:
(ii) Inhibitors of renal epithelial Na+
channel: Triamterene, Amiloride.
(c) Osmotic diuretics
Mannitol, Isosorbide, Glycerol
Other high ceiling diuretics, viz. ethacrynic acid and organomercurials (mersalyl) are only historical.
HIGH CEILING (LOOP) DIURETICS
(Inhibitors of Na+ -K+ -2Cl¯ Cotransport)
Furosemide (Frusemide) Prototype drug
The development of this rapidly acting highly efficacious oral diuretic was a breakthrough. 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. It is active even in patients with relatively severe renal failure.
The onset of action is prompt (i.v. 2–5 min., i.m. 10–20 min., oral 20–40 min.) and duration short (3–6 hours).
The major site of action is the thick AscLH (therefore called loop diuretics) where furosemide inhibits Na+- K+-2Cl¯
cotransport A minor component of action on PT has also been indicated. It is secreted in PT by organic anion
transport and reaches AscLH where it acts from luminal side of the membrane. The corticomedullary osmotic gradient is abolished and positive as well as negative free water clearance is
blocked. K+ excretion is increased mainly due to high Na+ load reaching DT. However, at equinatri uretic doses, K+ loss is less than that with thiazides.