Diuretics: Carbonic anhydrase inhibitors
general properties of carbonic anhydrase
Weak diuretics
chemical structure
prototype
other
organic acid with an aminosulfonic acid group
acetazolamide
brinzolamide / methazolamide / dichlorphenamide
MOA
carbonic anhydrase : H2CO3 ↔ H2O + CO2 (dehydration of carbonic acid & hydration of CO2)
Site of action
Proximal tubule (lumen and cytoplasm)
In the lumen
H+ is secreted from the cell across the luminal membrane by Na+-H+ exchanger / HCO3- is filtered at the glomeruli
Sponataneous reaction (association):
H+ + HCO3- → H2CO3
CA-catalyzed reaction (dehydration)
H2CO3 → H2O + CO2 then CO2 is diffused into the cell
In the cell
CA-catalyzed reaction (hydration)
H2O + CO2 → H2CO3
spontaneous reaction (dissociation)
H2CO3 → H+ + HCO3
H+: goes to luminal membrane for recycling Æ Na+-H+ exchanger (secretion of H+)
HCO3- : goes to basolateral membrane Æ Na+-HCO3- symporter (reabsorption of Na+ and HCO3-)
net result of CA and CA inhibitors
net result of CA and CA inhibitors
secretion of H+
reabsorption of Na
reabsorption of HCO3-
net result of CA inhibitors
retention of H+ (secretion of H+↓)
excretion of Na+ (reabsorption of Na+↓)
excretion of HCO3- (reabsorption of HCO3-↓)
Effects of acetazolamide as the prototype of carbonic anhydrase
In the kidney
NaHCO3 reabsorption↓
weak diuresis (NaHCO3 –rich alkaline urine is excreted)
but urinary loss of HCO3- depletes extracellular HCO3- Æ less HCO3- is filtered in the glomeruli Æ diuretic effect becomes limited (weak diuretics)
H+ secretion↓
metabolic acidosis in blood
in the eye (in the ciliary process, proximal tubular cells), CA forms bicarbonate from CO2 (H2O + CO2 → H2CO3→ H+ + HCO3-)
secretion of bicarbonate contributes to formation of the aqueous humor
so, acetazolamide can decrease aqueous humor production -> used in open-angled glaucoma by decreasing intraocular pressure
in RBC (like proximal tubule), CA forms forms bicarbonate from CO2 (H2O + CO2 → H2CO3→ H+ + HCO3-)
this is how CO2 is transported by RBC to the lung in the form of bicarbonate (90% of CA is in the RBC)
so, acetazolamide
increase CO2 in tissue (including CNS)
in CNS, CO2 exerts a weak general anesthetic effect -> somnolence / paresthesia / antiepileptic effect
Pharmacokinetics of acetazolamide
GI absorption & oral bioavailability
Complete
Distribution
high plasma protein binding(97%) + poor lipid solubility -> low Vd (0.25l/kg
elimination
excreted unchanged in urine by the tubular secretion mechanism for organic acid (basolateral OAT1 / apical OAT4 & MRP4)
T1/2 : 6-9 hours
Side effect
somnolence and paresthesia (by CO2 in the brain)
formation of Ca3(PO4)2 – containing calculi in the urinary tract
because acetazolamide increases phosphate excretion into urine (unknown reason) and increase phosphate ionization (due to production of alkaline urine)
drug interactions
alkalinizing of the tubular fluid by CA inhibitors
promote tubular reabsorption of weakly basic drugs (e.g. amphetamine) -> delaying elimination
decrease tubular reabsorption of weakly acidic drugs (e.g. salicylic acid / aspirin) -> promoting excretion
Indications
rarely used as diuretics
they are weak diuretics (used together with other diuretics)
open-angled glaucoma
acetazolamide (oral / i.v.)
brinzolamide (topically)
epilepsy
altitude sickness
acetazolamide (250mg twice a day)