VPT 311: General and Systemic Veterinary Pharmacology (2+1)

CARBONIC ANHYDRASE INHIBITORS

• Bicarbonates penetrate the luminal membrane only very slowly, and its absorption in the proximal tubule is heavily dependent on the presence of an enzyme ‘carbonic anhydrase’.
• This is a zinc containing enzyme whose function is to speed up the attainment of equilibrium of the reaction:

CO₂ + H₂O –> H₂CO₃

• Role of carbonic anhydrase in diuresis is that it is capable of accelerating this reaction in either direction.
  

• This enzyme is found within the proximal tubule cells and in association with their luminal brush border.
• The activating step in the process of bicarbonate absorption is the secretion of H⁺ into the tubule lumen, which is largely responsible for the favourable electrical gradient down which Na⁺ diffuses into the cell.
• This H⁺ is derived from the dissociation of carbonic acid, whose supply is facilitated by the presence of carbonic anhydrase.
• The carbonic anhydrase inhibitors interfere with the absorption of bicarbonate from the proximal tubule, by reducing the supply of H⁺ to the membrane pump and by reducing the rate of absorption of carbonic acid from the lumen.
• Filtered bicarbonate is thus trapped in the urine together with an electrically equal amount of Na⁺ and an osmotically equivalent amount of water.
• These drugs cause an increased excretion of bicarbonate with accompanying sodium, potassium and water excretion resulting in an increased flow of alkaline urine and mild metabolic acidosis.
• They are poor diuretics because there is compensatory reabsorption of Na⁺ is the segments further down the nephron.
• These drugs are used in glaucoma and in some types of epilepsy.
• Their action results in a depletion of extracellular bicarbonate and their effect is self limiting as the blood bicarbonate level falls.
• Side effects are drowsiness, numbness and tingling of the face and extremities (due to metabolic acidosis) and disturbances of vision.
• This group of drug is rarely used as diuretics.
• Acetazolamide used as a carbonic anhydrase inhibitor is a derivative of a sulphonamide but does not possess any antibacterial action.
• Acetazolamide is a non-competitive, irreversible inhibitor of carbonic anhydrase.