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)