Chemistry and Pharmacodynamics
Carbonic anhydrase inhibitors (CAIs) are diuretics that block the carbonic anhydrase enzymes.
- Drugs in this class include:
- Acetazolamide (the prototypical CAI)
- Carbonic anhydrase enzymes are found in the:
- Proximal convoluted tubules (PCTs) of the kidneys: involved in HCO3– reabsorption
- Eyes: involved in aqueous humor production
- Glial cells in the brain: involved in CSF production
Acetazolamide is a sulfonamide.
Background: HCO3– reabsorption in the proximal tubule
Bicarbonate cannot be directly reabsorbed by the kidneys; it must be converted into CO2 in the lumen and then reconverted to HCO3– once inside the cell. This reaction occurs via the following processes:
- Na+-H+ ion exchanger 3 (NHE3) reabsorbs Na+ and secretes H+.
- The secreted H+ combines with the filtered HCO3– to form H2CO3 in the tubular lumen.
- H2CO3 is converted into H2O and CO2 by apical carbonic anhydrase-IV.
- CO2 diffuses freely across the apical membrane back into the cell.
- Intracellular carbonic anhydrase-II converts CO2 and H2O back into H2CO3.
- H2CO3 then dissociates into H+ and HCO3–:
- H+ is recycled through the process via secretion through NHE3.
- HCO3– is absorbed through the basolateral membrane via:
- Na+-HCO3– cotransporter
- HCO3–-chloride exchanger
- Net effects of the entire process:
- Excretion of H+
- Absorption of HCO3–
- Efficiency: 80% of the filtered HCO3– is reabsorbed in the PCT under normal circumstances.
Mechanism of action of CAIs
- Non-competitively inhibit the carbonic anhydrases (CA-IV and CA-II) that catalyze the carbonic reaction: H2CO3 ⇄ HCO3– + H+ ⇄ CO2 + H2O
- Carbonic anhydrase catalyzes both:
- Dehydration of H2CO3 in the PCT apical lumen
- Hydration of CO2 in the PCT epithelial cells
- Inhibition of carbonic anhydrase:
- Keeps HCO3– in the renal tubules (at maximal safe doses, CAIs inhibit about 45% of total HCO3– reabsorption)
- Prevents secretion of HCO3– into the aqueous humor in the eyes
- Prevents secretion of HCO3– into the CSF in the brain
Use of CAI’s results in:
- ↑ HCO3– excretion leading to:
- Hyperchloremic metabolic acidosis
- Alkalinization of the urine
- ↑ Na+ excretion → water follows Na+ → diuresis:
- Due to reduced activity of the Na+/H+ exchanger
- After several days, compensatory Na+ reabsorption increases in other parts of the nephron → diuresis slows significantly
- ↓ Intraocular pressure (IOP) due to ↓ aqueous humor production
- ↓ Intracranial pressure (ICP) due to ↓ CSF production
|Methazolamide||Slowly within the GI tract|
- Patients with edema who have metabolic alkalosis
- Altitude sickness:
- Hypobaric hypoxia leads to respiratory alkalosis, which requires kidneys to compensate with ↑ HCO3– excretion and/or ↓ H+ excretion
- Acetazolamide leads to ↑ HCO3– excretion, improving acid-base status
- The increased acid load allows the body to take faster, deeper breaths to bring in enough O2 without elevating serum pH.
- Centrencephalic epilepsy (adjuvant therapy, works via an unknown mechanism)
- Additional off-label uses:
- Idiopathic intracranial hypertension and normal pressure hydrocephalus
- Stable, hypercapnic chronic obstructive pulmonary disease (used as a respiratory stimulant)
- Metabolic alkalosis
- Prevention of cystine renal calculi
Adverse Effects and Contraindications
- Electrolyte and glucose disturbances:
- Metabolic acidosis
- Hyperglycemia or hypoglycemia
- Myopia/blurry vision
- CNS symptoms:
- Sulfa allergies
- Severe liver and/or kidney disease
- Adrenocortical insufficiency
Carbonic anhydrase inhibitors should be used with caution in the following populations:
- Patients with respiratory acidosis
- Patients in whom an impairment in mental alertness is not acceptable (e.g., machine operators)
- Diabetes (may alter glucose control)
- Mild-to-moderate liver or kidney disease
- Elderly patients (may be more sensitive to side effects)
- Pregnancy and lactation (data is limited)
Comparison of Medications
Some of the other most common diuretics include thiazide diuretics (e.g., hydrochlorothiazide), loop diuretics (e.g., furosemide), K+-sparing diuretics (e.g., spironolactone), and osmotic diuretics (e.g., mannitol).
|Thiazide diuretic: Hydrochlorothiazide||↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl– cotransporter|
|Loop diuretic: Furosemide||Inhibits the luminal Na+/K+/Cl– cotransporter in the thick ascending limb of the loop of Henle|
|Potassium-sparing diuretic: Spironolactone|
|Carbonic anhydrase inhibitor: Acetazolamide||Inhibits both the hydration of CO2 in the PCT epithelial cells and the dehydration of H2CO3 in the PCT lumen; results in ↑ HCO3– and Na+ excretion|
|Osmotic diuretics: Mannitol||↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption|
DCT: distal convoluted tubule
CHF: congestive heart failure
- UpToDate Lexicomp Drug Topic Pages: Acetazolamide; methazolamide. Retrieved June 17, 2021, from
- Ives, H.E. (2012). Diuretic agents. In Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.) Basic and Clinical Pharmacology, 12th Ed. pp. 256‒258.
- Kassamali, R., Sica, D.A. (2011). Acetazolamide: A forgotten diuretic agent. Cardiol Rev. 19(6), 276‒278. https://pubmed.ncbi.nlm.nih.gov/21983315/
- Van Berkel, M.A., Elefritz, J.L. (2018). Evaluating off-label uses of acetazolamide. Am J Health Syst Pharm. 75(8), 524‒531. https://pubmed.ncbi.nlm.nih.gov/29626002/
- Smith, S.V., Friedman, D.I. (2017). The idiopathic intracranial hypertension treatment trial: A review of the outcomes. Headache. 57(8). 1303–1310. https://pubmed.ncbi.nlm.nih.gov/28758206/
- Stuart, M.C., Kouimtzi, M., Hill, S.R. (Eds.). (2009). WHO Model Formulary 2008. World Health Organization. p. 439.
- World Health Organization. (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
- Low, E.V., et al. (2012). Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: Systematic review and meta-analysis. BMJ. 345, e6779. https://pubmed.ncbi.nlm.nih.gov/23081689/
- Saito, H., et al. (2011). Adverse effects of intravenous acetazolamide administration for evaluation of cerebrovascular reactivity using brain perfusion single-photon emission computed tomography in patients with major cerebral artery steno-occlusive diseases. Neurol Med Chir (Tokyo). 51(7), 479‒483. https://pubmed.ncbi.nlm.nih.gov/21785240/
- Coote, J.H. (1991). Pharmacological control of altitude sickness. Trends Pharmacol Sci. 12(12), 450‒455. https://pubmed.ncbi.nlm.nih.gov/1792688/
- Katayama, F., Miura, H., Takanashi, S. (2002). Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies. Brain Dev. 24(3), 150‒154. https://pubmed.ncbi.nlm.nih.gov/11934510/
- Zaidi, F.H., Kinnear, P.E. (2004). Acetazolamide, alternate carbonic anhydrase inhibitors, and hypoglycemic agents: Comparing enzymatic with diuresis induced metabolic acidosis following intraocular surgery in diabetes. Br J Ophthalmol. 88(5), 714‒715. https://pubmed.ncbi.nlm.nih.gov/15090429/
- Moviat, M., et al. (2006). Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients. Crit Care. 10(1), R14. https://pubmed.ncbi.nlm.nih.gov/16420662/
- Platt, D., Griggs, R.C. (2012). Use of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Arch Neurol. 69(4), 527‒529. https://pubmed.ncbi.nlm.nih.gov/22158718/