Acetazolamide: carbonic anhydrase inhibition and metabolic acidosis
Acetazolamide blocks the enzyme carbonic anhydrase in the proximal tubule (first part of the kidney tubule), so lost bicarbonate can cause metabolic acidosis (too much acid in the blood).
Remember
Blocking carbonic anhydrase makes the kidney lose bicarbonate and sodium together: the sodium loss gives a mild diuresis (an increase in urine volume) and the bicarbonate loss can cause metabolic acidosis.
Acetazolamide is the main diuretic in the carbonic anhydrase inhibition category. Carbonic anhydrase is an enzyme (a protein that speeds up a chemical reaction) on the surface of the cells lining the proximal convoluted tubule, the first twisted part of the nephron after the glomerulus. There it helps the kidney reclaim filtered bicarbonate, the blood's main buffer against acid.
Block the enzyme and bicarbonate stays in the tubule, then is lost in the urine with sodium and water. Less hydrogen ion is then available for the sodium–hydrogen exchanger (a membrane protein that swaps sodium in for hydrogen out), so less sodium is reabsorbed. Water follows the sodium by osmosis, giving a diuresis, which is an increase in urine volume. It is a mild diuresis, because later parts of the nephron take back much of the extra sodium.
The same bicarbonate loss explains the acidosis. With less bicarbonate to react with acid, the blood can become more acidic. This is a metabolic acidosis, a fall in blood pH caused by too little bicarbonate rather than by a lung problem. Chloride is reabsorbed in place of the lost bicarbonate, so the anion gap (the difference between the measured positive and negative ions in the blood) stays normal. The gap rises when lactate or ketones, which are unmeasured acids, build up, but it stays normal when bicarbonate is simply lost.
The lungs usually compensate by breathing faster to blow off carbon dioxide, but that is only compensation, so the main disturbance stays metabolic. Acidosis is a predictable result of how the drug works, so it should be looked out for in anyone taking it, and clinically significant acidosis needs prompt assessment and treatment.
Key facts
- Target
- carbonic anhydrase on the cells lining the proximal convoluted tubule, where it helps reclaim filtered bicarbonate.
- Diuresis
- the diuresis comes from less bicarbonate, sodium and water being reabsorbed, but it is weak, and the acidosis also limits it, so it fades with continuous use.
- Acid–base result
- a metabolic acidosis with a normal anion gap, because chloride is reabsorbed in place of the lost bicarbonate.
- Urine
- becomes alkaline rather than acidic, because bicarbonate is lost in it.
- Compensation
- the lungs usually breathe faster to lower carbon dioxide, so the primary disturbance stays metabolic.
- Monitoring
- acidosis should be looked out for in anyone taking acetazolamide, and clinically significant acidosis needs prompt assessment and treatment.
Exam traps
- A high anion gap acidosis does not fit acetazolamide. It needs unmeasured acids such as lactate or ketones to build up, but here chloride takes the place of the lost bicarbonate and the gap stays normal.
- Metabolic alkalosis (a rise in plasma bicarbonate) points the wrong way. Acetazolamide wastes bicarbonate, so the level in plasma falls and the blood becomes more acidic.
- Respiratory alkalosis (a fall in carbon dioxide caused by overbreathing, or hyperventilation) is not the primary disturbance. The faster breathing is only the lungs compensating for the metabolic acidosis.
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