Diuretic pharmacology lecture Flashcards
Prototype carbonic anhydrase inhibitor
Acetazolamide
dorzolamide, brinzolamide, methazolamide
Location carbonic anhydrase
-mainly at the proximal tubule (both in the cytoplasm and lumen)
Function of CA in lumen
-CA reversibly catalyzes the conversion of H2CO3 to CO2 and H2O (this is a critical step in the reabsorption of bicarbonate)
CO2 is highly lipophilic so crosses the PT membrane and readily reacts with H2O within the cell
Function of CA in cytoplasm of PT cell
-CA catalyzes the formation of H2CO3 from CO2 and H2O
Net effect of CA
- allows for recycling of H+ into the lumen in exchange for Na+
- Na+ and HCO3- are transported across the basolateral membrane along with HCO3-
Net effect of CAIs
-net effect is Na+ and HCO3- reabsorption resulting in loss of Na+ and HCO3- in the urine
Pharmacokinetic issues
- acetazolamide is cleared by the kidneys
- dosing should be adjusted in renal impairment
Indications for use of CAIs
- glaucoma
- metabolic alkalosis
- acute mountain sickness (altitude sickness)
Contraindications for use CAIs
-no major contraindications
Side effects of CAIs
1) Metabolic acidosis
2) Renal stones
3) Hypokalemia
Cause of metabolic acidosis by CAI
-due to reduction in bicarbonate stores
Cause of renal stones by CAI
- Calcium salts become insoluble in alkaline urine –> leads to precipitation of calcium phosphate and hence stone development
- chronic use of CAI may also reduce excretion of solubilizing factors
Cause of hypokalemia by CAI
- leads to increased Na+ in the tubule
- when this Na+ is inevitably reabsobed at distal segments on the nephron K+ is excreted
Countering the effects of diuretic actions
-because CAI acts so early on in the nephron the diuretic actions of it are countered by a number of sites for Na+ reabsorption that appear distally in the tubule
Hx of acetazolamide
- was one of the first diuretics
- derived from the ab sulfanilamide after it was discovered that this antibiotic produced both a diuresis and metabolic acidosis as a side effect
How do CAI work in the treatment of glaucoma (their main use)
- in glaucoma get increased intraocular pressure (IOP)
- CA located in the ciliary processes of the eye results in the formation of HCO3- in acqueous humor
- decrease rate of formation HCO3- in humor to reduce IOP
Protypes potassium sparing diuretics
1) Aldosterone antagonist= spironolactone (also eplerenone)
2) epithelial sodium channel (ENaC) blockers: Triamterene, Amiloride
Why hypokalemia associated with many diuretics
- diuretics = enhanced Na+ in the lumen of the nephron
- high Na+ concentration in the tubule lead to compensatory reabsorption of Na+ in exchange for K+ excretion in the distal nephron
- leads to hypokalemia associated with many diuretics
Goal of K+ sparring diuretics
-prevent the reabsorption of Na+ and subsequent loss of K+ in the late distal tubule/early collecting duct of the nephron
What is exchange of Na+ for K+ in the distal nephron mediated by?
The epithelial Na+ channel (ENaC) on the luminal side of the membrane
-Na+/K+-ATPase pump on the basolateral membrane (side opposite the lumen of the tubule)
Function of basolateral Na+/K+-ATPase pump
Creates a gradient for the entry of Na+ into the cell from the ENac on the luminal side of the membrane
MOA of potassium sparing diuretics
- actively pumps Na+ ut of the cell into the interstitium in exchange for a K+ ion
- the Na+ that is lost from the cell is replaced by another Na+ ion which enters passively through ENaC
- the K+ that entered the cell exits into the lumen of the tubule through a K+ channel
- K+ sparring diuretic inhibts this exchange of Na+ for K+ by inhibiting ENaC alone or both ENaC and the Na+/K+-ATPase pump
Spirolactone -MOA
- acts as an antagonist at the receptor that aldosterone binds to
- normally aldosterone binds to mineralocorticoid receptor MR
