Diuretic pharmacology lecture

Question 1

Prototype carbonic anhydrase inhibitor

Answer 1

Acetazolamide

dorzolamide, brinzolamide, methazolamide

Question 2

Location carbonic anhydrase

Answer 2

-mainly at the proximal tubule (both in the cytoplasm and lumen)

Question 3

Function of CA in lumen

Answer 3

-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

Question 4

Function of CA in cytoplasm of PT cell

Answer 4

-CA catalyzes the formation of H2CO3 from CO2 and H2O

Question 5

Net effect of CA

Answer 5

• allows for recycling of H+ into the lumen in exchange for Na+
• Na+ and HCO3- are transported across the basolateral membrane along with HCO3-

Question 6

Net effect of CAIs

Answer 6

-net effect is Na+ and HCO3- reabsorption resulting in loss of Na+ and HCO3- in the urine

Question 7

Pharmacokinetic issues

Answer 7

• acetazolamide is cleared by the kidneys

- dosing should be adjusted in renal impairment

Question 8

Indications for use of CAIs

Answer 8

• glaucoma
• metabolic alkalosis
• acute mountain sickness (altitude sickness)

Question 9

Contraindications for use CAIs

Answer 9

-no major contraindications

Question 10

Side effects of CAIs

Answer 10

1) Metabolic acidosis
2) Renal stones
3) Hypokalemia

Question 11

Cause of metabolic acidosis by CAI

Answer 11

-due to reduction in bicarbonate stores

Question 12

Cause of renal stones by CAI

Answer 12

• 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

Question 13

Cause of hypokalemia by CAI

Answer 13

• leads to increased Na+ in the tubule

- when this Na+ is inevitably reabsobed at distal segments on the nephron K+ is excreted

Question 14

Countering the effects of diuretic actions

Answer 14

-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

Question 15

Hx of acetazolamide

Answer 15

• 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

Question 16

How do CAI work in the treatment of glaucoma (their main use)

Answer 16

• 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

Question 17

Protypes potassium sparing diuretics

Answer 17

1) Aldosterone antagonist= spironolactone (also eplerenone)

2) epithelial sodium channel (ENaC) blockers: Triamterene, Amiloride

Question 18

Why hypokalemia associated with many diuretics

Answer 18

• 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

Question 19

Goal of K+ sparring diuretics

Answer 19

-prevent the reabsorption of Na+ and subsequent loss of K+ in the late distal tubule/early collecting duct of the nephron

Question 20

What is exchange of Na+ for K+ in the distal nephron mediated by?

Answer 20

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)

Question 21

Function of basolateral Na+/K+-ATPase pump

Answer 21

Creates a gradient for the entry of Na+ into the cell from the ENac on the luminal side of the membrane

Question 22

MOA of potassium sparing diuretics

Answer 22

• 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

Question 23

Spirolactone -MOA

Answer 23

• acts as an antagonist at the receptor that aldosterone binds to
• normally aldosterone binds to mineralocorticoid receptor MR