Carbonic anhydrase inhibitors work by inhibiting the carbonic anhydrase enzyme in the proximal convoluted tubule. This decreases bicarbonate reabsorption leading to increased urine output and loss of bicarbonate in the urine. The prototypical drug is acetazolamide. It is well absorbed orally and increases urine pH within 30 minutes. The drug is excreted by the kidney so dosage must be reduced in renal failure. It inhibits bicarbonate reabsorption throughout the nephron leading to metabolic acidosis. Major uses include glaucoma, urinary alkalinization for stones, acute mountain sickness, and metabolic alkalosis. Toxicities include acidosis, hypokal

1. Domina Petric, MD
Carbonic anhydrase inhibitors

2.  Carbonic anhydrase is present in many nephron sites.
 Predominant location is the epithelial cells of the
proximal convoluted tubule (PCT).
In the PCT carbonic anhydrase catalyzes:
 dehydration of H2CO3 to CO2 at the luminal
membrane
 rehydration of CO2 to H2CO3 in the
cytoplasm
Introduction

3. By blocking carbonic anhydrase,
inhibitors blunt NaHCO3 reabsorption
and cause diuresis.
The prototypical carbonic anhydrase
inhibitor is ACETAZOLAMIDE.
Introduction

4.  The carbonic anhydrase inhibitors are well
absorbed after oral administration.
An increase in urine pH from the HCO3
- diuresis is:
 apparent within 30 minutes
 maximal at 2 hours
 persists for 12 hours after a single dose
Excretion of the drug is by secretion in the proximal
tubule S2 segment: dosing must be reduced in
renal insufficiency.
Pharmacokinetics

5. Inhibition of carbonic anhydrase activity profoundly
depresses HCO3
- reabsorption in the PCT.
At its maximal safe dosage, 85% of the HCO3
- reabsorptive
capacity of the superficial PCT is inhibited.
Some HCO3
- can still be absorbed at other nephron sites so
the overall effect is about 45% inhibition of whole kidney
HCO3
- reabsorption.
Pharmacodynamics

6.  Carbonic anhydrase inhibition causes
significant HCO3
- losses and may lead to
hyperchloremic metabolic acidosis.
 The diuretic efficacy of acetazolamide
decreases significantly with use over several
days because HCO3
- depletion leads to
enhanced NaCl reabsorption by the
remainder of the nephron.
Pharmacodynamics

7. Group Urinary electrolytes
NaCl NaHCO3 K+
Body pH
Carbonic anhydrase
inhibitors
+ +++ + ↓
Loop agents ++++ 0 + ↑
Thiazides ++ + + ↑
Loop agents plus thiazides +++++ + ++ ↑
K+ sparing agents + + - ↓
Changes in urinary electrolyte patterns and
body pH in response to diuretic drugs

8.  The major clinical applications of
acetazolamide involve carbonic anhydrase-
dependent HCO3
- and fluid transport at sites
other than the kidney.
 The ciliary body of the eye secretes HCO3
-
from the blood into the aqueous humor.
 Formation of cerebrospinal fluid by the
choroid plexus involves HCO3
- secretion.
Pharmacodynamics

9. CLINICAL INDICATIONS AND DOSAGE

10.  The reduction of aqueous humor formation by
carbonic anhydrase inhibitors decreases the
intraocular pressure.
 Topically active agents reduce intraocular pressure
without producing renal or systemic effects:
dorzolamide, brinzolamide.
 Peroral agents:
Glaucoma
Drug Usual oral dosage
Dichlorphenamide 50 mg 1-3 times daily
Methazolamide 50-100 mg 2-3 times daily

11.  Uric acid and cystine are relatively insoluble:
formation of stones in acidic urine.
 Cystinuria is a disorder of cystine reabsorption.
 Solubility of cystine can be enhanced by
increasing urinary pH from 7,0-7,5 with
carbonic anhydrase inhibitors.
 In the case of uric acid, pH needs to be raised
only to 6,0-6,5.
Urinary alkalinization

12.  In the absence of HCO3
- administration, these
effects of acetazolamide last only 2-3 days.
 Prolonged therapy requires oral HCO3
-
administration.
 Excessive urinary alkalinization can lead to
stone formation from calcium salts.
 Urine pH should be followed during treatment
with acetazolamide.
Urinary alkalinization

13.  Metabolic alkalosis is generally treated by
correction of abnormalities in total body K+,
intravascular volume or mineralocorticoid
levels.
 When the alkalosis is due to excessive use of
diuretics in patients with severe heart
failure, replacement of intravascular volume
may be contraindicated.
Metabolic alkalosis

14. Acetazolamide can be useful in correcting the
alkalosis as well as producing a small additional
diuresis for correction of volume overload.
Acetazolamide can also be used to rapidly correct
the metabolic alkalosis that follows the correction
of respiratory acidosis.
Metabolic alkalosis

15.  Mountain travelers who rapidly ascend
above 3000 m may experience weakness,
dizziness, insomnia, headache and nausea.
 Symptoms are usually mild and last for a
few days.
 In more serious cases, rapidly progressing
pulmonary or cerebral edema can be life-
threatening.
Acute mountain sickness

16.  Acetazolamide decreases cerebrospinal fluid
formation and cerebrospinal fluid pH, which
increases ventilation.
 Acetazolamide diminishes symptoms of
mountain sickness.
 This mild metabolic central and
cerebrospinal fluid acidosis is also useful in
the treatment of sleep apnea.
Acute mountain sickness

17. Carbonic anhydrase
inhibitors have been used
as adjuvants in the
treatment of epilepsy and in
some forms of hypokalemic
periodic paralysis.
Other uses

18.  These drugs are also useful in treating
patients with cerebrospinal fluid (CSF)
leakage (tumor, head trauma, idiopathic).
 By reducing the rate of CSF formation and
intracranial pressure, carbonic anhydrase
inhibitors can significantly slow the rate of
CSF leakage.
Other uses

19. These drugs increase
urinary phosphate
excretion during severe
hyperphosphatemia.
Other uses

20. TOXICITY

21. Acidosis results from chronic reduction of body
HCO3
- stores by carbonic anhydrase inhibitors.
Acidosis limits the diuretic efficacy of these
drugs to 2 or 3 days.
It persists as long as the drug is continued.
Hyperchloremic metabolic acidosis

22.  Phosphaturia and hypercalciuria occur during the
bicarbonic response to inhibitors of carbonic
anhydrase.
 Renal excretion of solubilizing factors (citrate)
may also decline with chronic use.
 Calcium salts are relatively insoluble at alkaline pH.
 The potential for renal stone formation from
calcium salts is enhanced.
Renal stones

23.  Potassium wasting can occur because the increased
sodium, presented to the collecting tubule
(together with HCO3
-), is partially reabsorbed.
 That increases the lumen-negative electrical
potential in that segment and enhances potassium
secretion.
 Treatment/prevention: simultaneous
administration of potassium chloride or a
potassium-sparing diuretic.
Renal potassium wasting

24.  Drowsiness and paresthesias: following
large doses of acetazolamide.
 Carbonic anhydrase inhibitors may
accumulate in patients with renal failure:
nervous system toxicity.
 Hypersensitivity reactions: fever, rashes,
bone marrow suppression and interstitial
nephritis.
Other toxicities

25. Carbonic anhydrase inhibitor-induced alkalinization
of the urine decreases urinary excretion of NH4
+ by
converting it to rapidly reabsorbed NH3.
This may contribute to the development of
hyperammonemia and hepatic encephalopathy in
patients with cirrhosis.
Contraindications

26. ADENOSINE A1 RECEPTOR
ANTAGONISTS

27. These drugs interfere with the activation of NHE3 in the PCT and
the adenosine-mediated enhancement of collecting tubule K+
secretion.
Caffeine and theophylline are weak diuretics because of their
modest and nonspecific inhibition of adenosine receptors.
Adenosine receptor antagonists are under study.
Adenosine receptor antagonists

28. Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
Literature