A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

276 NEPHROLOGICAL AND RELATED ASPECTS
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 /K tubular exchange (Figure
36.1), causing potassium retention at the same time as natriuresis.
They fall into two categories:
1. competitive antagonists, structurally related to
aldosterone: spironolactone, eplerenone;
2. Na /K exchange antagonists that do not compete with
aldosterone: amiloride, triamterene.
These are not potent diuretics, since only a small fraction of the
filtered Na is reabsorbed by this mechanism, but spironolactone
prolongs survival in heart failure (Chapter 31) and is useful
when there is hyperaldosteronism, whether primary
(Conn’s syndrome, resistant hypertension) or secondary (e.g.
in cirrhosis with ascites). High doses of spironolactone causes
gynaecomastia and breast tenderness in men and menstrual
irregularity in women – oestrogenic side effects. Eplerenone is
more selective and lacks these oestrogenic effects. It is much
more expensive but has been shown to improve survival following
myocardial infarction (Chapter 29).
Amiloride and triamterene also inhibit Na /K exchange,
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 circumstances
sodium is actively reabsorbed accompanied by an
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. mannitol)
also interfere with the establishment of the medullary
osmotic gradient which is necessary for the formation of concentrated
urine. Mannitol is poorly absorbed from the intestine
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 unsuitable
for the treatment of most causes of oedema, especially cardiac
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 unconnected
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 closedangle
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 hormone
(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