Carbonic anhydrase inhibitors Domina Petric, MD

Introduction In the PCT carbonic anhydrase catalyzes: 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 By blocking carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and cause diuresis. The prototypical carbonic anhydrase inhibitor is ACETAZOLAMIDE.

Pharmacokinetics 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.

Pharmacodynamics 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 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.

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

Pharmacodynamics 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.

Clinical indications and dosage

Glaucoma 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: Drug Usual oral dosage Dichlorphenamide 50 mg 1-3 times daily Methazolamide 50-100 mg 2-3 times daily

Urinary alkalinization 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 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.

Metabolic alkalosis 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 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.

Acute mountain sickness 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 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.

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

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

toxicity

Hyperchloremic metabolic acidosis 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.

Renal stones 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 potassium wasting 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.

Other toxicities 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.

Contraindications 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.

Adenosine a1 receptor antagonists

Adenosine receptor antagonists 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.

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