A Textbook of Clinical Pharmacology and Therapeutics

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 acetazolamideis therefore self-limiting. Large doses
cause paraesthesiae, fatigue and dyspepsia. Prolonged use pre-
disposes to renal stone formation due to reduced urinary cit-
rate (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). Furosemideis 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 some-
times produces diuresis, and may prevent the development of
established failure, although this is difficult to prove.
Loop diuretics increase urinary calcium excretion (in con-
trast to thiazides). This is exploited in the treatment of hyper-
calcaemia when furosemideis 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 Naand Ktogether with

2Clions from the lumen (‘NaK2Clcotransport’), see

Figure 36.1.

Pharmacokinetics

Furosemideis 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 iso-

osmotically 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 NaK2Clcotransport mechanism, as opposed to

NaK2Clcotransport at other sites, such as the inner ear.

The luminal site of action of furosemidealso contributes to

diuretic insensitivity in nephrotic syndrome, where heavy

albuminuria results in binding of furosemideto 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 Kreabsorption in the loop
   of Henle and increased delivery of Nato 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
   NaK2Clcotransporter in the ear, which is involved in
   the formation of endolymph.


2. 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 aminoglyco-

side toxicity. Lithiumreabsorption is reduced by loop diuret-

ics 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.

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/Kexchange
  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.