SURVEY OF OPHTHALMOLOGY VOLUME 23 l NUMBER 3.

NOVEMBER-DECEMBER 1978

REVIEWS IN MEDICINE
PAUL LICHTER, EDITOR

Carbonic Anhydrase Inhibition in

Glaucoma: Hazard or Benefit for the
Chronic Lunger?

EDWARD R. BLOCK, M.D. AND ROBERT A. ROSTAND, M.D.

Division of Pulmonary Medicine, Department of Medicine, University of Florida,

College of Medicine, Gainesville, Florida

Abstract. Carbonic anhydrase inhibitors, of proven value in the longterm manage-

ment of glaucoma, have a number of troublesome side effects, most of which are well-
known. However, their potential hazards to patients with chronic obstructive lung
disease have received little attention. The author reviews the physiological effects of
carbonic anhydrase inhibition on carbon dioxide metabolism and the implications for
the chronic lung patient. The untoward pulmonary complications associated with the
use of carbonic anhydrase inhibitors are of particular importance to ophthalmolo-
gists, since chronic lung disease and glaucoma, both common disorders in the elderly.
frequently coexist in the same patient. (Surv Ophthalmol 23: 169-172, 1978)

Key words. carbonic anhydrase inhibition - chronic obstructive lung disease

* glaucoma

C
arbonic anhydrase inhibitors (CAI) are
of proven value in the longterm manage-
ment of patients with glaucoma.
Unfortunately, their usefulness is often
limited by untoward effects which include
gastrointestinal upset, malaise, anorexia,
weight loss, paresthesias, and loss of libido.
In addition to these troublesome side effects,
administration of CA1 is accompanied by cer-
tain predictable alterations in carbon dioxide
(CO,) metabolism. The inhibition of carbonic
anhydrase implies a resultant impairment in
the in vivo transport of CO, leading to in-
creased CO, gradients between body tissues
and pulmonary alveoli and retention of CO,
in the body.17.22,26These changes are a
necessary corollary to the established impor-
169
tance of this enzyme in the CO,-bicarbonate
system. Most patients are able to adjust to
these CAI-induced alterations in CO,
metabolism by increasing alveolar ventila-
tion and establishing a new steady-state for
CO, production and elimination.22~2s How-
ever, the development of increased CO,
gradients, with or without frank acidosis, is
not without potential hazards in certain
patients, especially those with chronic
obstructive lung disease who may be unable
to increase their alveolar ventilation suf-
ficiently to compensate for these metabolic
changes.
Although the hazards associated with the
use of CA1 in patients with chronic obstruc-
tive lung disease were theorized’ and
170 Surv Ophthalmol 23 (3) November-December
documented to occur3 over twenty years ago,
the warnings seem to have gone un-
recognized. A recent symposium on ocular
therapeutics devoted an entire chapter to
reviewing other problems with CA1 but failed
to even mention potential hazards to patients
with chronic lung disease and glaucoma who
require CAI.“’ In addition, the Physicians’
Desk Reference (31st) edition, 1977) and the
package inserts from the most commonly
prescribed CA1 (acetazolamide, Diamox@;
dichlorphenamide, Daranide@; methazola-
mide, Neptazane@; and ethoxzolamide, Car-
drase@) fail to offer any warning or precau-
tion pertaining to the use of CA1 in chronic
lungers. This is in contrast to our own ex-
perience and the experience of others who
have expressed concern over the use of CA1 in
patients with obstructive airway disease;
therefore, we would like to draw attention to
several “unrecognized” potential complica-
tions. In order to do so, we will review briefly
some of the physiological effects of inhibi-
tion of carbonic anhydrase and the results of
several studies evaluating the use of CA1 as
respiratory stimulants.
Physiological Effects of Carbonic
Anhydrase Inhibition
In the early 1930’s, Roughtonz3 demon-
strated the presence in red blood cells of an
enzyme, carbonic anhydrase, which catalyzed
the reversible hydration and dehydration of
CO, by the following reaction:
CO, + H,O z H,CO, * H++ HCO;
Subsequently, carbonic anhydrase has been
found in many tissues: the renal cortex, gas-
tric mucosa, pancreas, eye, lung, and central
nervous system.lg It is not surprising,
therefore, that CA1 over the past twenty
years have had a wide range of clinical and
therapeutic roles; they have been used for
reduction of intraocular pressure (IOP), alka-
linization of urine, treatment of periodic
paralysis and acute mountain sickness, and
as respiratory stimulants and anticonvul-
sants.‘S~lB
It has been shown that at least 99.9 percent
of kidney and red blood cell carbonic
anhydrase activity must be inhibited before
full physiological effects are observed.1S
Inhibition of renal carbonic anhydrase results
in a prompt, but brief, increase in urine
volume associated with an increase in urine
pH, bicarbonate excretion, and sodium and
potassium excretion. The alkaline urine is ac-
1978 BLOCK, ROSTAND
companied by a decrease in the excretion of
titratable acid and ammonia. As a result, the
concentration of serum bicarbonate falls in
the extracellular fluid and metabolic acidosis
results. Inhibition of red cell carbonic anhy-
drase impairs COZ elimination from the
pulmonary capillary blood leading to the es-
tablishment of a CO, gradient between
arterial blood (and body tissues) and the
pulmonary alveoli and retention of CO, in the
body.
This undesirable effect of CA1 was first
demonstrated by Mithoefer and Davis18 who
administered a single large dose of aceta-
zolamide (50 mg/kg) intravenously to rats in
whom a subcutaneous gas pocket had been
created to permit the measurement of tissue
CO, tension. Thirty minutes after the ad-
ministration of the drug, tissue CO, tension
had risen by 9 mm Hg despite a concomitant
increase in alveolar ventilation and reduction
in alveolar CO, concentration. Similar obser-
vations were made by Carter and Clark4 and
Mithoefer17 in dogs and by Shepard et al (Fed
Proc (abstract): 13: 135,1954) in normal exer-
cising humans and by Strijmme and FogZS
during hyperventilation in humans receiving
smaller oral doses of acetazolamide (lo- 12
mg/kg).
Clinical Studies
While it is not certain at what precise dose
of acetazolamide the elimination of CO, is
compromised in normal humans, the early
studies of Pocidalo et aF2 demonstrated that
oral or intravenous doses of acetazolamide in
excess of 10 mg/kg resulted in a significant
CO, gradient between arterial blood and
pulmonary alveoli. These results were ob-
tained in normal subjects and patients with
emphysema. In normal persons, the increase
in tissue stores of CO, due to inhibition of
carbonic anhydrase will eventually result in a
rise in alveolar minute ventilation. This in-
crease in alveolar ventilation is believed to
result from stimulation of the respiratory
center either directly from an increase in
tissue CO, concentration within the respira-
tory center or indirectly via an increase in hy-
drogen ion concentration. This led several in-
vestigators to explore the clinical use of CA1
as respiratory stimulants in patients with
chronic obstructive lung disease. The results
of these studies are varied and inconsistent.
Ventilation improved in many patients with
chronic obstructive lung disease and
worsened in others, not infrequently leading
REVIEWS IN MEDICINE 171

to respiratory acidosis and failure, and the disease and acute respiratory failure. Orally
response in any given lung patient was unpre- administered acetazolamide (500-1000 mg
As a result, this total dose) resulted in prompt bicarbonate
dictable. 3,6.8.9,12,15,20.21,~~,28
mode of therapy gradually fell into disuse. diuresis leading to a reduction in arterial CO,
Fortunately, most people who receive CA1 tension and improvement in oxygenation.
are able to manifest an adequate ventilatory Whether these results will be confirmed in
response to compensate for the development larger numbers of chronic lung patients with
of increased CO, gradients and the reduced mixed respiratory acidosis-metabolic alka-
rate of conversion of bicarbonate to (and losis and whether the use of CA1 will be
from) CO,.24 That this is not always the case shown to be more beneficial and less hazard-
in patients with chronic obstructive lung dis- ous than potassium chloride administration
ease has been alluded to above and is well alone in correcting the metabolic alkalosis in
documented in the literature.3*7~9~11~15~21~z4~zsthese patients are important and, as yet, un-
The incidence of respiratory decompensa- answered questions. Until the answers to
tion and clinical deterioration in lung patients these questions are known, we would caution
treated with CA1 is probably quite low, in- against the use of CA1 in all patients with
creasing with increasing severity of the lung severe chronic obstructive lung disease in
disease, but the exact frequency is not known. whom the development of increased CO,
Naimark et UP’ reported clinical deteriora- gradients and/or frank acidosis might
tion in one of fifteen patients with severe precipitate the development of acute respira-
chronic lung disease and acute respiratory in- tory failure.
sufficiency who were receiving dichlorphena-
mide, 200 mg/day, for 1.5 to 30 weeks.
Wishart and Isaacs,28 Bell et aP and Dorris et
a18 suggest that the incidence may even be Summary
higher, especially in those patients with severe The untoward pulmonary complications
chronic obstructive lung disease; these are associated with the use of CA1 are of par-
patients who have a one-second forced expira- ticular importance to ophthalmologists, since
tory volume of less than 1.0 L and/or chronic lung disease and glaucoma are com-
elevated arterial blood CO, tension and who mon disorders in the elderly and frequently
are unable to increase their work of breath- coexist in the same patient. Mild to moderate
ing, and hence alveolar ventilation, to com- degrees of chronic lung disease would appear
pensate for alterations in CO, metabolism to pose no special problems or contraindica-
and/or acidosis. Such patients will eventually tions to the use of CAI, but this is not the case
tire, retain CO, and develop respiratory with severe chronic obstructive lung disease
acidosis and failure. as defined earlier (one second forced expira-
Recently, Bear et al2 suggested that tory volume I 1.Oliter with or without hyper-
patients with chronic obstructive lung disease carbia).
who have a mixed respiratory acidosis and When the use of CA1 is deemed essential to
metabolic alkalosis may represent a “select” the management of glaucoma in patients with
subgroup of chronic lung patients who will severe chronic obstructive lung disease, it
favorably and predictably respond to CAI. would seem prudent to use the lowest effec-
Their results with acetazolamide in a small tive dose which will lower IOP without com-
number of patients with respiratory acidosis plete inhibition of renal or red blood cell car-
and chloride-sensitive metabolic alkalosis bonic anhydrase activity. In this regard,
(due to diuretic and/or corticosteroid Maren et alI4 have recently demonstrated a
therapy) were encouraging and were based on significant lowering of IOP with no renal loss
the observation that uncorrected metabolic of bicarbonate or development of acidosis in
alkalosis is a respiratory depressant in man.5 patients and volunteers treated with metha-
Thus, correction of the metabolic alkalosis zolamide 25 mg orally every 12 hours.
might be expected to (and did in the 8 patients Although the magnitude of the lowered IOP
reported by Bear et aC) improve ventilation was slightly less than that which follows pres-
and clinical oxygenation. Further evidence to ent schedules of methazolamide or of
support this possibility has been reported by acetazolamide, such a dose regimen may be
Miller and Berns16 who used acetazolamide to preferred in patients with severe underlying
treat diuretic-induced metabolic alkalosis in chronic obstructive lung disease who require
two patients with chronic obstructive lung therapy with CAI.
172 Surv Ophthalmol 23 (3) November-December 1978
Acknowledgment
The authors would like to thank Dr. Thomas H.
Maren for his encouragement and meticulous
review of this manuscript.
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Reprint requests should be addressed to Edward
R. Block, M.D., Division of Pulmonary Medicine,
Department of Medicine, University of Florida,
Box J-225, J. Hillis Miller Health Center,
Gainesville, Florida 32610