Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic anhydrase inhibitors also block the carbonic anhydrase present in the eyes and glial cells, resulting in decreased aqueous humor and CSF production, respectively. Acetazolamide is the prototypical CAI. Carbonic anhydrase inhibitors are mainly used for the treatment of altitude sickness, edema in patients with metabolic alkalosis, glaucoma, and, sometimes, as an adjuvant treatment for certain types of epilepsies and increased intracranial pressure. Carbonic anhydrase inhibitors are not used for the treatment of hypertension.

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Chemistry and Pharmacodynamics

Definition

Carbonic anhydrase inhibitors (CAIs) are diuretics that block the carbonic anhydrase enzymes.

  • Drugs in this class include:
    • Acetazolamide (the prototypical CAI)
    • Methazolamide
  • 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

Chemical structure

Acetazolamide is a sulfonamide.

Chemical Structure of Acetazolamide

Chemical structure of acetazolamide

Image: “Acetazolamide” by Ayacop. License: Public Domain

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.
Bicarbonate reabsorption in the proximal tubule

Bicarbonate reabsorption in the proximal tubule
NHE3: Na+-H+ ion exchanger 3
CA-IV: carbonic anhydrase IV
CA-II: carbonic anhydrase II


Image by Lecturio. License: CC BY-NC-SA 4.0

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

Physiologic effects

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

Pharmacokinetics

Table: Pharmacokinetics of carbonic anhydrase inhibitors
DrugAbsorptionDistributionMetabolismExcretion
Acetazolamide
  • Readily absorbed
  • Bioavailability: > 90%
  • Onset of activity:
    • Oral: 1‒2 hours
    • IV: 2‒10 minutes
  • Protein binding: 95%
  • Vd: 0.3 L/kg
Not metabolized
  • In urine, as unchanged drug
  • Half-life: 2.5‒9 hours
Methazolamide
  • Slower absorption compared to acetazolamide
  • Peak activity: 6‒8 hours
  • Protein binding: 55%
  • Vd: 17‒23 L
Slowly within the GI tract
  • Urine (25% as unchanged drug)
  • Half-life: 14 hours
Vd: volume of distribution

Indications

  • 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.
  • Glaucoma
  • 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

Adverse effects

  • Electrolyte and glucose disturbances:
    • Metabolic acidosis
    • Hypokalemia
    • Hyponatremia
    • Hyperglycemia or hypoglycemia
  • Myopia/blurry vision
  • CNS symptoms:
    • Dizziness
    • Headache
    • Drowsiness/fatigue
    • Paresthesias

Contraindications

  • Sulfa allergies
  • Severe liver and/or kidney disease 
  • Adrenocortical insufficiency
  • Hyponatremia
  • Hypokalemia

Precautions

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).

Table: Comparison of diuretics
MedicationMechanismPhysiologic effectIndication
Thiazide diuretic: Hydrochlorothiazide↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl cotransporter
  • ↓ Blood pressure
  • ↓ Edema
  • Hypertension
  • Edema
Loop diuretic: FurosemideInhibits the luminal Na+/K+/Cl cotransporter in the thick ascending limb of the loop of Henle
  • ↓ Edema
  • ↓ Blood pressure
  • Edema/ascites
  • CHF
  • Hypertension
Potassium-sparing diuretic: Spironolactone
  • ↓ Reabsorption of Na through the ENaC channels in the CD
  • Inhibition of aldosterone receptors in the CD
  • ↓ Blood pressure
  • ↓ Edema
  • Does not cause ↑ excretion of K+
  • Anti-androgenic effects
  • CHF
  • Edema/ascites
  • Hypertension
  • Hirsutism in females
  • Primary hyperaldosteronism
Carbonic anhydrase inhibitor: AcetazolamideInhibits 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
  • ↑ Urinary excretion of HCO3 → metabolic acidosis
  • ↓ Intraocular pressure
  • Edema in patients with metabolic alkalosis
  • Altitude sickness
  • ↑ Intraocular pressure
  • Off label: normal pressure hydrocephalus
Osmotic diuretics: Mannitol↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption
  • ↓ Free water
  • ↓ Cerebral blood volume
  • Increased intracranial pressure
  • Increased intraocular pressure
PCT: proximal convoluted tubule
DCT: distal convoluted tubule
CHF: congestive heart failure
Diuretics

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. UpToDate Lexicomp Drug Topic Pages: Acetazolamide; methazolamide. Retrieved June 17, 2021, from
    1. https://www.uptodate.com/contents/acetazolamide-drug-information 
    2. https://www.uptodate.com/contents/methazolamide-drug-information 
  2. 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.
  3. Kassamali, R., Sica, D.A. (2011). Acetazolamide: A forgotten diuretic agent. Cardiol Rev. 19(6), 276‒278. https://pubmed.ncbi.nlm.nih.gov/21983315/
  4. 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/
  5. 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/
  6. Stuart, M.C., Kouimtzi, M., Hill, S.R. (Eds.). (2009). WHO Model Formulary 2008. World Health Organization. p. 439.
  7. World Health Organization. (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
  8. 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/
  9. 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/
  10. Coote, J.H. (1991). Pharmacological control of altitude sickness. Trends Pharmacol Sci. 12(12), 450‒455. https://pubmed.ncbi.nlm.nih.gov/1792688/
  11. 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/
  12. 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/
  13. 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/
  14. 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/

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