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

274 NEPHROLOGICAL AND RELATED ASPECTS
CIRRHOSIS
Fluid retention in cirrhosis usually takes the form of ascites,
portal hypertension leading to loss of fluid into the peritoneal
cavity, although dependent oedema also occurs. Other important
factors are hypoalbuminaemia (caused by failure of synthesis
by the diseased liver) and hyperaldosteronism (due to
activation of volume receptors and reduced hepatic aldosterone
catabolism). Transplantation may be appropriate in cases where
the underlying pathology (e.g. alcoholism) is judged to have
been cured or (as in some rare inherited metabolic disorders)
will not recur in a donor liver. Nevertheless, symptomatic treatment
is all that is available for most patients.
Diet is important. Protein is restricted in the presence of
hepatic encephalopathy, and should be of high quality to provide
an adequate supply of essential amino acids. High energy
intake from carbohydrate minimizes catabolism of body protein.
Salt restriction is combined with moderate water restriction
monitored by daily weighing. Excessive diuresis may
precipitate renal failure: loss of approximately 0.5 kg body
weight (as fluid) daily is ideal.
Thiazides or loop diuretics exacerbate potassium depletion
and alkalosis and can precipitate hepatic encephalopathy.
Amiloride or spironolactone are used in this setting (see
below), combined subsequently with loop diuretics if
necessary.
DIURETICS
Many diuretics block sodium ion reabsorption from renal tubular
fluid (Figure 36.1). This causes natriuresis (i.e. increased
excretion of sodium ions), so diuretics are used to treat patients
with volume overload. Some diuretics have additional distinct
therapeutic roles because of additional effects on the kidney
(e.g. the use of furosemide to treat hypercalcaemia or the use of
thiazide diuretics to treat nephrogenic diabetes insipidus) or
elsewhere in the body (e.g. mannitol for cerebral oedema).
CARBONIC ANHYDRASE INHIBITORS
Acetazolamide, a sulphonamide, is a non-competitive inhibitor
of carbonic anhydrase. Carbonic anhydrase plays an important
part in bicarbonate reabsorption from the proximal tubule
(Figure 36.1). Consequently, acetazolamide inhibits reabsorption
of sodium bicarbonate, resulting in an alkaline diuresis
with loss of sodium and bicarbonate in the urine. Since chloride
(rather than bicarbonate) is the preponderant anion in the
plasma (and hence in glomerular filtrate), carbonic anhydrase
inhibitors influence only a small fraction of sodium reabsorption
and are thus weak diuretics.
Uses
More importantly than its diuretic effect, acetazolamide
inhibits carbonic anhydrase in the eye and thereby decreases
the rate of secretion of the aqueous humour and lowers intraocular
pressure. Treatment of glaucoma is currently the major
use of acetazolamide. Dorzolamide is a topical carbonic
anhydrase inhibitor for use in glaucoma (Chapter 52).
Carbonic anhydrase in the choroid plexus participates in the
formation of cerebrospinal fluid and acetazolamide has been
used in the management of benign intracranial hypertension.
Acetazolamide is used in the prevention of mountain sickness,
since it permits rapid acclimatization to altitude (which
entails renal compensation for respiratory alkalosis caused by
hyperventilation) by facilitating bicarbonate excretion. Urinary
alkalinization with acetazolamide has been used in the treatment
of children with cysteine stones due to cysteinuria, as
cysteine is more soluble at alkaline than at acid pH. (Many of
these uses are unlicensed.)
Unwanted effects
As a consequence of increased urinary elimination of bicarbonate
during acetazolamide treatment, the plasma bicarbonate
Glomerulus
NaHCO 3
−
Filtration
Carbonic
anhydrase
inhibitors
Na +
(65–70%)
Proximal
convoluted tubule
Cortex
medulla
Distal
convoluted
tubule
(~5%)
Na + CI –
− (1–2%)
Na +
K + H +
(~25%)
Thiazides
Na + K +
2CI –
H 2 0
−
K +
sparing
diuretics
Collecting
duct
H 2 O
Loop
of Henle
−
Loop
diuretics
Urine
excretion
thick ascending limb of Loop of Henle
Figure 36.1: Sites of action of different
diuretics in the nephron.