A Textbook of Clinical Pharmacology and Therapeutics

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 import-
ant factors are hypoalbuminaemia (caused by failure of synthe-
sis 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 treat-
ment 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 pro-
vide an adequate supply of essential amino acids. High energy
intake from carbohydrate minimizes catabolism of body pro-
tein. Salt restriction is combined with moderate water restric-
tion 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.
Amilorideor spironolactoneare used in this setting (see
below), combined subsequently with loop diuretics if
necessary.

DIURETICS

Many diuretics block sodium ion reabsorption from renal tubu-
lar 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 furosemideto treat hypercalcaemia or the use of

thiazide diuretics to treat nephrogenic diabetes insipidus) or

elsewhere in the body (e.g. mannitolfor 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, acetazolamideinhibits reabsorp-

tion 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 reabsorp-

tion 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 intra-

ocular pressure. Treatment of glaucoma is currently the major

use of acetazolamide.Dorzolamideis 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 acetazolamidehas been

used in the management of benign intracranial hypertension.

Acetazolamideis used in the prevention of mountain sick-

ness, since it permits rapid acclimatization to altitude (which

entails renal compensation for respiratory alkalosis caused by

hyperventilation) by facilitating bicarbonate excretion. Urinary

alkalinization with acetazolamidehas been used in the treat-

ment 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 bicarbon-

ate during acetazolamidetreatment, the plasma bicarbonate

274 NEPHROLOGICAL AND RELATED ASPECTS

thick ascending limb of Loop of Henle

K+

sparing

diuretics

Collecting

duct

H 20

Urine

excretion

K+H+

NaHCO 3

Na+

(65–70%)

Proximal

convoluted tubule

H 2 O

Loop

of Henle

Loop

diuretics

Distal

convoluted

tubule

Cortex

medulla

Carbonic

anhydrase

inhibitors

Glomerulus

Filtration

Thiazides

(~5%)

Na+CI–

2CI–

(~25%)

Na+K+

(1–2%)

−

−

−

−

Na+

Figure 36.1:Sites of action of different

diuretics in the nephron.