Carbonic anhydrase inhibitors Domina Petric MD Introduction Carbonic

Carbonic anhydrase inhibitors Domina Petric, MD

Introduction �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 H 2 CO 3 to CO 2 at the luminal membrane � rehydration of CO 2 to H 2 CO 3 in the cytoplasm

Introduction By blocking carbonic anhydrase, inhibitors blunt Na. HCO 3 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 p. H from the HCO 3 - 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 S 2 segment: dosing must be reduced in renal insufficiency.

Pharmacodynamics Inhibition of carbonic anhydrase activity profoundly depresses HCO 3 - reabsorption in the PCT. At its maximal safe dosage, 85% of the HCO 3 - reabsorptive capacity of the superficial PCT is inhibited. Some HCO 3 - can still be absorbed at other nephron sites so the overall effect is about 45% inhibition of whole kidney HCO 3 - reabsorption.

Pharmacodynamics �Carbonic anhydrase inhibition causes significant HCO 3 - losses and may lead to hyperchloremic metabolic acidosis. �The diuretic efficacy of acetazolamide decreases significantly with use over several days because HCO 3 - depletion leads to enhanced Na. Cl reabsorption by the remainder of the nephron.

Changes in urinary electrolyte patterns and body p. H in response to diuretic drugs Group Urinary electrolytes Na. Cl Na. HCO 3 K+ Carbonic anhydrase inhibitors Loop agents + ++++ 0 + Thiazides ++ + + Loop agents plus thiazides +++++ + ++ K+ sparing agents + + - Body p. H ↓ ↑ ↑ ↑ ↓

Pharmacodynamics �The major clinical applications of acetazolamide involve carbonic anhydrasedependent HCO 3 - and fluid transport at sites other than the kidney. �The ciliary body of the eye secretes HCO 3 from the blood into the aqueous humor. �Formation of cerebrospinal fluid by the choroid plexus involves HCO 3 - 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 Dichlorphenamide Methazolamide Usual oral dosage 50 mg 1 -3 times daily 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 p. H from 7, 0 -7, 5 with carbonic anhydrase inhibitors. �In the case of uric acid, p. H needs to be raised only to 6, 0 -6, 5.

Urinary alkalinization �In the absence of HCO 3 - administration, these effects of acetazolamide last only 2 -3 days. �Prolonged therapy requires oral HCO 3 administration. �Excessive urinary alkalinization can lead to stone formation from calcium salts. �Urine p. H 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 lifethreatening.

Acute mountain sickness �Acetazolamide decreases cerebrospinal fluid formation and cerebrospinal fluid p. H, 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 HCO 3 - 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 p. H. �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 HCO 3 -), 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 NH 4+ by converting it to rapidly reabsorbed NH 3. This may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis.

ADENOSINE A 1 RECEPTOR ANTAGONISTS

Adenosine receptor antagonists These drugs interfere with the activation of NHE 3 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.

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