A Textbook of Clinical Pharmacology and Therapeutics

Uses

Thiazides are used in:

1. hypertension (Chapter 28)
   2.mild cardiac failure (Chapter 31);
   3.resistant oedema – thiazides or related drugs (e.g.
   metolazone) are extremely potent when combined with a
   loop diuretic;
   4.prevention of stones – thiazides reduce urinary calcium
   excretion and thus help to prevent urinary stone
   formation in patients with idiopathic hypercalciuria;
   5.diabetes insipidus – paradoxically, thiazides reduce urinary
   volume in diabetes insipidus by preventing the formation
   of hypotonic fluid in the distal tubule; they are therefore
   sometimes used to treat nephrogenic diabetes insipidus.

POTASSIUM-SPARING DIURETICS

Some diuretics inhibit distal Na/Ktubular exchange (Figure
36.1), causing potassium retention at the same time as natri-
uresis. They fall into two categories:

1. competitive antagonists, structurally related to
   aldosterone: spironolactone,eplerenone;
   2.Na/Kexchange antagonists that do not compete with
   aldosterone: amiloride,triamterene.

These are not potent diuretics, since only a small fraction of the
filtered Nais reabsorbed by this mechanism, but spironolac-
toneprolongs survival in heart failure (Chapter 31) and is use-
ful when there is hyperaldosteronism, whether primary
(Conn’s syndrome, resistant hypertension) or secondary (e.g.
in cirrhosis with ascites). High doses of spironolactonecauses
gynaecomastia and breast tenderness in men and menstrual
irregularity in women – oestrogenic side effects. Eplerenoneis
more selective and lacks these oestrogenic effects. It is much
more expensive but has been shown to improve survival fol-
lowing myocardial infarction (Chapter 29).
Amilorideandtriamterenealso inhibit Na/Kexchange,
but not by competition with aldosterone. They are marketed as
combination tablets with loop or thiazide diuretics as a means
of avoiding hypokalaemia. Hypokalaemia is important if drugs
such as digoxin(Chapters 31 and 32) or sotalol(Chapter 32)
are co-prescribed, because their toxicity is increased by
hypokalaemia. Conversely K-retaining diuretics predispose to
hyperkalaemia if used with ACEI or sartans in patients with
renal impairment.

OSMOTIC DIURETICS

Use and mechanism of action

Osmotic diuretics undergo glomerular filtration but are poorly
reabsorbed from the renal tubular fluid. Their main diuretic
action is exerted on the proximal tubule. This section of the
tubule is freely permeable to water, and under normal circum-
stances sodium is actively reabsorbed accompanied by an

276 NEPHROLOGICAL AND RELATED ASPECTS

Key points

Salt overload and diuretics

• Several diseases are associated with retention of excess
  salt and water, including:
  
  
  • heart failure;
  
  
  • renal failure;
  
  
  • nephrotic syndrome;
  
  
  • cirrhosis.
  
  
  
  


• Treatment involves restriction of dietary salt and
  administration of diuretics to increase salt excretion.


• The main classes of diuretics for these indications are:
  
  
  • thiazides;
  
  
  • loop diuretics;
    –K-sparing diuretics.
  
  
  
  


• In addition to treating salt/water overload, diuretics are
  also used in:
  
  
  • systemic hypertension;
  
  
  • glaucoma (carbonic anhydrase inhibitors);
  
  
  • acute reduction of intracranial or intra-ocular
    pressure (osmotic diuretics);
  
  
  • hypercalcaemia (furosemide);
  
  
  • nephrogenic diabetes insipidus (thiazides).
  
  
  
  

isoosmotic quantity of water. The presence of a substantial

quantity of a poorly absorbable solute opposes this, because as

water is reabsorbed the concentration and hence the osmotic

activity of the solute increases. Osmotic diuretics (e.g. manni-

tol) also interfere with the establishment of the medullary

osmotic gradient which is necessary for the formation of con-

centrated urine. Mannitolis poorly absorbed from the intes-

tine and is given intravenously in gram quantities.

Unlike other diuretics, osmotic diuretics increase the plasma

volume (by increasing the entry of water to the circulation as a

result of increasing intravascular osmolarity), so they are unsuit-

able for the treatment of most causes of oedema, especially car-

diac failure. It is possible that, if used early in the course of

incipient acute renal failure, osmotic diuretics may stave off the

occurrence of acute tubular necrosis by increasing tubular fluid

flow and washing away material that would otherwise plug the

tubules. Osmotic diuretics are mainly used for reasons uncon-

nected with their ability to cause diuresis. Because they do not

enter cells or some anatomical areas, such as the eye and brain,

they cause water to leave cells down the osmotic gradient. This

‘dehydrating’ action is used in two circumstances:

1. reduction of intra-ocular pressure: pre-operatively for
   urgent reduction of intra-ocular pressure and in closed-
   angle glaucoma;
   2.emergency reduction of intracranial pressure.

SIADH: OVERHYDRATION

Overhydration without excess salt is much less common than

salt and water overload, but occurs when antidiuretic hor-

mone (ADH) is secreted inappropriately (e.g. by a neoplasm

or following head injury or neurosurgery), giving rise to the

syndrome of inappropriate secretion of ADH (SIADH). This