Carbonic Anhydrase Inhibitors

Enzyme Properties:

*Major location: luminal proximal tubule membrane
*Activity: catalyzes dehydration of carbonic acid, H2CO3 , required for bicarbonate reabsorption
*blockade of carbonic anhydrase activity -- induces a sodium bicarbonate diuresis, reducing body bicarbonate levels

Carbonic anhydrase inhibitors:
*alkaline diuresis
*hyperchloremic metabolic acidosis
*Prototype: acetazolamide

Acetazolamide:
*well-absorbed orally
*excretion: tubular secretion -- proximal tubule
>>dose reduction in renal insufficiency
*At maximal carbonic anhydrase inhibition: 45% inhibition of bicarbonate reabsorption
>causes significant bicarbonate loss
>hyperchloremic metabolic acidosis
>limited effectiveness because:
bicarbonate depletion increases sodium chloride reabsorption
*reduction in aqueous humor and cerebrospinal fluid production

Clinical Application:
Glaucoma:
*decreases rate of aqueous humor production -- leads to a declining in intraocular pressure
*most common indication for use of carbonic anhydrase inhibitors

Dorzolamide: topical inactive carbonic anhydrase inhibitor.
*no diuretic or systemic metabolic effects
*reduction in intraocular pressure comparable to oral agents

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:some role in *management of epilepsy
*hypokalemic 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 and in electrical potential -- enhances potassium excretion
>>counteracted by potassium chloride administration

Others:
drowsiness, parathesias
accumulation in renal failure (CNS toxicity)
hypersensitivity reactions

Contraindications:
hepatic cirrhosis

Category: Pharmacology Notes