Diuretics

Question 1

PK for diuretics - role of PCT

Answer 1

organic anion transporters on basolateral membrane of PCT allows drug entry from blood –> cell

Question 2

Osmotic diuretics

Answer 2

mannitol
rarely used in clinical practice
Injected into blood, freely filtered
Osmotically active - holds water in urine
more urine produced

Question 3

PCT diuretics

Answer 3

osmotic diuretics

carbonic anhydrase inhibitors

Question 4

Carbonic anhydrase inhibitors

Answer 4

Prototype: acetazolamide
MOA: inhibits CA, reduces amount of sodium and bicarbonate resorption
- sodium retained in lumen leads to downstream loss of potassium
- No bicarbonate resorption - becomes acidotic
- Na/H exchanger pulls sodium into cell and pushes H+ into lumen (driven by Na gradient created by Na/K ATPase)
- H+ ions used to reclaim filtered bicarb from lumen, through action of CA
1) H+ combines with HCO3 –> H2CO3 in filtrate
2) CA converts H2CO3 –> H2O + CO2
3) CO2 enters cell - reverse reaction, generate H+ and HCO3
4) HCO3 moves into blood, H+ recycled back into lumen

• works early in PT, so not as effective on Na handling

Question 5

Loop of Henle diuretics

Answer 5

loop diuretics

Question 6

Loop diuretics

Answer 6

Prototype: furosemide (Lasix)
MOA: inhibits NKCC - less Na, K, Cl reabsorption
- no electrochemical gradient set up to drive paracellular resorption of Ca, Mg (less Cl- in interstitium and less K+ in lumen)
- downstream effects: channels in DT stuck reabsorbing Na, can’t reabsorb K+ and H+, leading to metabolic alkalosis & hypokalemia

Question 7

DCT diuretics

Answer 7

thiazides

Question 8

Thiazide diuretics

Answer 8

Prototype: HCTZ, metolazone (not technically a thiazide but same action, also highly potent)
MOA: inhibits NCC transporter
- more Na and Cl in lumen
- ds effects: metabolic alkalosis and hypokalemia (impaired K/H resorption due to excess Na)
- increased Ca+ reabsorption results in hypercalcemia (can reduce incidence of kidney stones, help in osteoporosis)

Question 9

CD diuretics

Answer 9

aldosterone antagonists (K+ sparing)
ENaC blockers (K+ sparing)

Question 10

Aldosterone antagonists/K+ - sparing diuretics

Answer 10

Prototype: spironolactone, epleronone
MOA: antagonist against mineralocorticoid receptor (MR)
- Normally, aldosterone binds MR, translocates to nucleus and upregulates ENaC and Na/K ATPase
- less Na+ reabsorption, producing natriuresis and diuresis
- less K+ excretion, due to less Na/K ATPase

Question 11

ENaC blockers

Answer 11

Prototype: amiloride, triamterene
MOA: inhibits ENaC, preventing reabsorption of Na from lumen
- diuresis, natriuresis
- less Na reabsorption –> less Na pumped from cell b Na/K ATPase
- more K+ retention

Question 12

CA inhibitor indications

Answer 12

Reduce production of aqueous humor, effective for glaucoma
Increases bicarb excretion –> metabolic alkalosis
Used to treat acute mountain sickness

Question 13

CA inhibitor SE

Answer 13

metabolic acidosis

Kidney stones due to alkaline urine

Question 14

Loop diuretic indications/PK

Answer 14

CHF
edema
HTN

high therapeutic ceiling
Transported through organic anionic transporter (OAT) - need GFR
Other drugs can compete for OAT
Bound to albumin - reduced distribution if hypoalbuminemia
Albuminiuria can cause binding of furosemide to albumin in urine, reducing its effects
short half life

Question 15

Loop diuretic SE

Answer 15

Ototoxicity
Hypokalemia
Metabolic alkalosis (loss of H+)
lose calcium/magnesium
sulfa drug

Question 16

Thiazide diuretic indications

Answer 16

CHF
edema
HTN
increased Ca resorption - osteoporosis, kidney stones

Question 17

SE of thiazides

Answer 17

alkalosis
hyperglycemia
hyperlipidemia
more electrolyte abnormalities than loop diuretics
ds effects: metabolic alkalosis, hypokalemia

Question 18

Thiazides PK

Answer 18

narrow therapeutic range
activitiy in distal end of nephron - little chance to upregulate distal sites (changing electrolyte balance)
slow onset
when added to a full blockade of TALH (+ loop diuretic), get huge vol. of urine loss
requires GFR

Question 19

K+ sparing diuretic indications

Answer 19

hypokalemia
hyperaldosteronism (spironolactone)
aldosterone-aided heart failure (spironolactone)

Question 20

SEs of K+ sparing diuretics

Answer 20

hyperkalemia
metabolic acidosis
spironolactone-specific: gynocomastia, menstrual disorders, testicular atrophy