C H A P T E R 5 1
Diuretic agents
811
the loss of hearing is usually reversible after the drug is
stopped. This may be an effect of electrolyte changes on
the conduction of fragile nerves in the central nervous
system.
Clinically important drug–drug interactions
The risk of ototoxicity increases if loop diuretics are
combined with aminoglycosides or cisplatin. Antico-
agulation effects may increase if these drugs are given
with anticoagulants. There may also be a decreased
loss of sodium and decreased antihypertensive effects if
these drugs are combined with indomethacin, ibupro-
fen, salicylates or other non-steroidal anti-inflammatory
agents; a person receiving this combination should be
monitored closely, and appropriate dose adjustments
should be made.
C
arbonic anhydrase
inhibitors
The carbonic anhydrase inhibitors are relatively mild
diuretics. Available agents include acetazolamide
(
Diamox
) and brinzolamide (
Azopt
).
Therapeutic actions and indications
The enzyme carbonic anhydrase is a catalyst for the for-
mation of sodium bicarbonate, which is stored as the
alkaline reserve in the renal tubule, and for the excre-
tion of hydrogen, which results in a slightly acidic urine.
Diuretics that block the effects of carbonic anhydrase
slow down the movement of hydrogen ions; as a result,
more sodium and bicarbonate are lost in the urine.
These drugs are used as adjuncts to other diuretics when
a more intense diuresis is needed. Most often, carbonic
anhydrase inhibitors are used to treat glaucoma because
the inhibition of carbonic anhydrase results in decreased
secretion of aqueous humour of the eye. See Table 51.2
for usual indications for each of these agents.
Pharmacokinetics
These drugs are rapidly absorbed and widely distrib-
uted. Acetazolamide is available orally and for IV use.
These drugs peak in 2 to 4 hours (15 minutes if given IV)
and have a 6- to 12-hour duration. They are excreted in
urine. Some of these agents have been associated with
fetal abnormalities and they should not be used during
pregnancy. Because of the potential for adverse effects
on the baby, another method of feeding should be used
if one of these drugs is needed during breastfeeding.
Contraindications and cautions
Carbonic anhydrase inhibitors are contraindicated in
individuals with allergy to the drug, to antibacterial
sulfonamides or thiazides
to prevent hypersensitivity
reactions
, or in individuals with chronic non-congestive
angle-closure glaucoma,
which would not be effectively
treated by these drugs
. Routine use during pregnancy
is not appropriate; these drugs should be reserved for
situations in which the mother has pathological reasons
for use, not pregnancy manifestations or complications,
and only if the benefit to the mother clearly outweighs
the risk to the fetus.
Cautious use is recommended in people who have
fluid or electrolyte imbalances, renal or hepatic disease,
adrenocortical insufficiency, respiratory acidosis or
chronic obstructive pulmonary disease,
which could be
exacerbated by the fluid and electrolyte changes caused
by these drugs.
Adverse effects
Adverse effects of carbonic anhydrase inhibitors are
related to the disturbances in acid–base and electrolyte
balances. Metabolic acidosis is a relatively common and
potentially dangerous effect that occurs when bicar-
bonate is lost. Hypokalaemia is also common because
potassium excretion is increased as the tubule loses
potassium in an attempt to retain some of the sodium
that is being excreted. People also complain of par-
aesthesias (tingling) of the extremities, confusion and
drowsiness, all of which are probably related to the
neural effect of the electrolyte changes.
Clinically important drug–drug interactions
There may be an increased excretion of salicylates and
lithium if they are combined with these drugs. Caution
Prototype summary: Acetazolamide
Indications:
Adjunctive treatment of open-angle
glaucoma, secondary glaucoma; preoperative use in
acute angle-closure glaucoma when delay of surgery
is indicated; oedema caused by HF; drug-induced
oedema.
Actions:
Inhibits carbonic anhydrase, which
decreases aqueous humour formation in the eye,
intraocular pressure and hydrogen secretion by the
renal tubules.
Pharmacokinetics:
Route
Onset
Peak
Duration
Oral
1 hour
2–4 hours 6–12 hours
Sustained-
release oral 2 hours 8–12 hours 18–24 hours
IV
1–2 mins 15–18 mins 4–5 hours
T
1/2
:
5 to 6 hours; excreted unchanged in urine.
Adverse effects:
Weakness, fatigue, rash, anorexia,
nausea, urinary frequency, renal calculi, bone
marrow suppression, weight loss.
