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

DIURETICS 275
Key points
Diuretics
Diuretics are classed by their site of action.
• Thiazides (e.g. bendroflumethiazide) inhibit Na /Cl
reabsorption in the early distal convoluted tubule; they
produce a modest diuresis and are used in particular in
hypertension.
• Loop diuretics (e.g. furosemide) inhibit Na /K /2Cl
cotransporter in the thick ascending limb of Henle’s
loop. They cause a large effect and are used especially
in heart failure and oedematous states.
• Potassium-sparing diuretics inhibit Na /K exchange
in the collecting duct either by competing with
aldosterone (spironolactone), or non-competitively
(e.g. amiloride, triamterene). They cause little diuresis.
Spironolactone improves survival in heart failure and is
used in hyperaldosteronism. These drugs are sometimes
combined with thiazide or loop diuretics to prevent
hypokalaemia.
• Carbonic anhydrase inhibitors (e.g. acetazolamide) inhibit
HCO 3 reabsorption in the proximal tubule. They are weak
diuretics, cause metabolic acidosis and are used to treat
glaucoma, rather than for their action on the kidney.
• Osmotic diuretics (e.g. mannitol) are used in patients
with incipient acute renal failure, and acutely to lower
intra-ocular or intracranial pressure.
concentration falls without accumulation of any unmeasured
anions, giving a non-anion gap metabolic acidosis, as in renal
tubular acidosis. The reduction in plasma bicarbonate leads to a
reduced filtered load of this ion, so less bicarbonate is available
for reabsorption from proximal tubular fluid. The diuretic
effect of acetazolamide is therefore self-limiting. Large doses
cause paraesthesiae, fatigue and dyspepsia. Prolonged use predisposes
to renal stone formation due to reduced urinary citrate
(citrate increases the solubility of calcium in the urine).
Hypersensitivity reactions and blood dyscrasias are a problem,
as with other sulphonamides.
LOOP DIURETICS
Uses
The main clinical use of loop diuretics (e.g. furosemide) is for
heart failure (Chapter 31). Furosemide is also useful in patients
with chronic renal failure who are suffering from fluid overload
and/or hypertension. Large doses may be needed to produce
diuresis in patients with severe renal impairment. In patients
with incipient acute renal failure, intravenous infusion sometimes
produces diuresis, and may prevent the development of
established failure, although this is difficult to prove.
Loop diuretics increase urinary calcium excretion (in contrast
to thiazides). This is exploited in the treatment of hypercalcaemia
when furosemide is given after volume replacement
with 0.9% sodium chloride.
Mechanism of action
Loop diuretics have steep dose–response curves and much
higher maximum effects than thiazide or other diuretics,
being capable of increasing fractional sodium excretion to
as much as 35%. They act from within the tubular fluid to
inhibit a co-transporter in the thick ascending limb of the
loop of Henle which transports Na and K together with
2Cl ions from the lumen (‘Na K 2Cl cotransport’), see
Figure 36.1.
Pharmacokinetics
Furosemide is rapidly and extensively absorbed from the gut.
It is 95% bound to plasma protein and elimination is mainly
via the kidneys, by filtration and proximal tubular secretion.
Approximately two-thirds of water reabsorption occurs isoosmotically
in the proximal convoluted tubule, so furosemide
is substantially concentrated before reaching its site of action
in the thick ascending limb. This accounts for its selectivity for
the renal Na K 2Cl cotransport mechanism, as opposed to
Na K 2Cl cotransport at other sites, such as the inner ear.
The luminal site of action of furosemide also contributes to
diuretic insensitivity in nephrotic syndrome, where heavy
albuminuria results in binding of furosemide to albumin
within the lumen.
Adverse effects
1. Acute renal failure – loop diuretics in high dose cause
massive diuresis. This can abruptly reduce blood volume.
Acute hypovolaemia can precipitate prerenal renal
failure.
2. Hypokalaemia – inhibition of K reabsorption in the loop
of Henle and increased delivery of Na to the distal
nephron (where it can be exchanged for K ) results in
increased urinary potassium loss and hypokalaemia.
3. Hypomagnesaemia.
4. Hyperuricaemia and gout.
5. Otoxicity with hearing loss is associated with excessive
peak plasma concentrations caused by too rapid
intravenous injection. It may be related to inhibition of
Na K 2Cl cotransporter in the ear, which is involved in
the formation of endolymph.
7. Metabolic alkalosis – the increased water and chloride
excretion caused by loop diuretics results in contraction
alkalosis.
8. Idiosyncratic blood dyscrasias occur rarely.
Drug interactions
Loop diuretics increase the nephrotoxicity of first-generation
cephalosporins, e.g. cephaloridine, and increase aminoglycoside
toxicity. Lithium reabsorption is reduced by loop diuretics
and the dose of lithium carbonate often needs to be
reduced.
THIAZIDE DIURETICS
The mechanism, adverse effects, contraindications and
interactions of thiazide diuretics are covered in Chapter 28,
together with their first-line use in hypertension.