Anesthesia Pharmacology:  Renal Pharmacology

• Carbonic Anhydrase Inhibitors

  •  The enzyme, carbonic anhydrase exhibits the following characteristics:

    •  Its major location is the luminal proximal tubule membrane.

    •  Carbonic anhydrase catalyzes dehydration of carbonic acid, H₂CO₃ , required for bicarbonate reabsorption

    •  Blockade of carbonic anhydrase activity  induces a sodium bicarbonate diuresis, which reduces body bicarbonate levels

  • Carbonic anhydrase inhibitors are unsubstituted sulfonamides which are bacteriostatic. 

    • These agents promote alkaline diuresis and a hyperchloremic metabolic acidosis.

      • Prototype drug is acetazolamide (Diamox)

  • Acetazolamide: (Diamox) is well absorbed orally and is excreted by tubular secretion, at the proximal tubule.

    • In renal insufficiency a dose reduction is appropriate.

    • At maximal carbonic anhydrase inhibition, a 45% inhibition of bicarbonate reabsorption is observed.

      •  This level of inhibition results in significant bicarbonate loss and a hyperchloremic metabolic acidosis.

      • Acetazolamide (Diamox) administration causes a reduction in aqueous humor and cerebrospinal fluid production

  • Clinical Applications:

    • Glaucoma:

      • Because acetazolamide decreases the rate of aqueous humor production, a decline in intraocular pressure occurs.

      • Management of glaucoma is the most common indication for use of carbonic anhydrase inhibitors.

      • Dorzolamide (Trusopf), another carbonic anhydrase inhibitor exhibits no diuretic or systemic metabolic effect; however, administration of this agent causes a reduction in intraocular pressure.

    • Urinary Alkalinization:

      • Increased uric acid and cystine solubility by alkalinizing the urine (by increasing bicarbonate excretion)

      • For prophylaxis of uric acid renal stones, bicarbonate administration (baking soda) may be required

    • Metabolic Alkalosis:

      • Results from:

        •  Decreased total potassium with reduced vascular volume

        •  High mineralocorticoid levels

        •  These conditions are usually managed by treating the underlying causes; however, in certain clinical settings acetazolamide may assist in correcting alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}

    • Acute Mountain Sickness:

      • Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of all of 3000 meters}; symptoms -- usually mild

      • In serious cases: life-threatening cerebral or pulmonary edema

      • Acetazolamide reduces the rate of CSF formation and decreases cerebral spinal fluid pH.

      • Prophylaxis against acute mountain sickness may be appropriate

    • Other Uses:

      • Dome role in management of epilepsy

      • Hypokalemia periodic paralysis

      • Increase urinary phosphate excretion during severe hyperphosphatemia.

  •   Toxicity

    • Hyperchloremic metabolic acidosis

      • Due to reduction of body bicarbonate stores

    • Renal stones:

      • Bicarbonate loss is associated with:

        • Phosphaturia

        • Hypercalciuria (calcium salts, relatively insoluble at alkaline pH)

    • Renal potassium loss:

      • Increased sodium bicarbonate in the collecting tubule increases the lumen-negative electrical potential -- enhances potassium excretion

        • Counteracted by potassium chloride administration

    • Others:

      • Drowsiness, parathesias

      • Accumulation in renal failure (CNS toxicity)

      • Hypersensitivity reactions

    • Contraindications:

      • Hepatic cirrhosis

        • Urinary alkalinization will decrease ammonium ion trapping, increasing the likelihood of hepatic encephalopathy.