Diuretics

Question 1

Furosemide. Describe its pharmacokinetics.

Answer 1

Loop diuretic. Inhibits the Na/K/Cl/Cl.

Oral or IV administration. Renal excretion. Rapid onset of action. Plasma binding.

Question 2

Acetazolamide

Answer 2

Proximal convoluted tubule. Carbonic anhydrase inhibitor. By blocking carbonic anhydrase, Na and HCO3 are trapped in the lumen of the PCT and thus more Na is lost. Since the Na should be exchanged for H+, this proton remains trapped in the cell, leading to a metabolic acidosis. The filtrate will thus be more alkaline.

Acetazolamide is not a potent diuretic. It is also used in the treatment of Glaucoma, AMS, and metabolic alkalosis.

Side effects include metabolic acidosis, drowsiness, CNS depression, paresthesias, and fatigue.

Question 3

Spironolactone

Answer 3

Aldosterone blocker —> ENac channels not in membrane of the CCD principal cells. K sparing.

Question 4

HCTZ

Answer 4

DCT (NaCl channel)

Question 5

Aside from cerebral edema in DKA, for what purposes might one use mannitol? What are two other drugs in this category?

Answer 5

Mannitol is an osmotic diuretic. It cannot be absorbed in the PCT, so it increases the excretion of Na, Cl, and water. Other osmotic diuretics are isosorbide and glycerol, but these are partially absorbed, so less useful.

Mannitol can be used to decrease intraocular pressure in glaucoma, decrease cerebral edema, and in prevention of AKI. Causes an acute rise in the ECF volume. Side effects are headache and nausea. With prolonged use can lead to severe dehydration.

Question 6

Name four loop diuretics.

Answer 6

Furosemide, bumetanide, torsemide, ethacrynic acid.

Lead to excretion of 15-20% of filtered Na. Inhibit resorption of water by inhibiting the K/Na/Cl/Cl pump in the TALH.

Question 7

What are the side effects of loop diuretics?

Answer 7

Hypokalemia
Metabolic alkalosis
Hypocalcemia
Hyponatremia
Hearing loss
Uric acid retention

Question 8

For what would use of loop diuretics be indicated?

Answer 8

Pulmonary edema
Cardiogenic edema
Hepatogenic edema
Hypercalcemia

Rapid onset of action.

Question 9

What type of drug is ethacrynic acid? Describe its pharmacokinetics.

What is unique about it?

Answer 9

Loop diuretic. IV administration. Extensive plasma protein binding. Rapid onset of action. Excretion at the kidney.

The only non-sulfa containing diuretic out there.

Question 10

Torsemide

Answer 10

Loop diuretic. High bioavailability (80-90% vs 40-70 for furosemide, so may be more efficacious in CHF. Also has a longer half life (12-16 hours vs 4-6 for furosemide).

Question 11

Describe the location and function of the macula densa.

Answer 11

The macula densa is a group of specialized cells located at the distal part of the loop of Henle which is in contact with the afferent arteriole leading to the glomerulus. As a part of the juxtaglomerular apparatus, it regulates renin secretion, and therefore angiotensin and aldosterone production.

Question 12

Aldosterone

Answer 12

enhances distal tubular reabsorption of sodium by stimulation of the synthesis and translocation of sodium transporter proteins.

Question 13

Name the thiazide diuretics. Describe how and where they act.

Answer 13

HCTZ, chlorthalidone, metolazone

Na+/Cl- cotransporter in proximal part of distal convoluted tubule, causing moderate diuresis since only about 5% of filtered sodium is reabsorbed in this location. Less efficacious than loop diuretics in producing natriuesis and diuresis.

Antihypertensive effect secondary to decreased plasma volume and decreased CO.

Question 14

Potent thiazide which can increase sodium excretion.

Answer 14

Metolazone

Question 15

For what are thiazide diuretics used?

Answer 15

HTN

Edema (Metolazone)

Question 16

What are the side effects of the thiazide diuretics?

Answer 16

Hypokalemia
Hypomagnesemia
Hyponatremia

Chloremia
Uric acid retention
Hyperglycemia
Hypercalcemia

Question 17

Why is acetazolamide used in AMS? Describe the physiology. (acute mountain sickness?)

Answer 17

Formation of aqueous humor and CSF is dependent on HCO3 transport. Systemic administration slows progression of pulmonary or cerebral edema via decrease in formation and pH of cerebrospinal fluid.

Question 18

Why are the loop diuretics associated with magnesium and calcium wasting? Describe the mechanism.

Answer 18

Although the K/Cl/Cl/Na cotransporter is electrically neutral, normal action leads to excess intracellular K+ which then leaks back into the lumen creating a lumen positive potential. This potential then drives the reabsorption of cations Mg++ and Ca++.

Question 19

What is the duration of effect (not half life) for the loop diuretics?

Answer 19

2-3 hrs for furosemide
4-6 hrs for torsemide
6 hours for bumetanide

Question 20

Name three diuretics that work at the PCT.

Answer 20

Acetazolamide
Dorzolamide
Brinzolamide

Question 21

What transporters are present in the PCT?

Answer 21

Na/H exchanger (Na moves from lumen into cell, H+ excreted into the lumen)

(Also a Cl- [out of lumen] for Base- exchanger not sure of the significance of this one)

Question 22

What transporter is present in the DCT? What other important process occurs in the DCT?

Answer 22

Na/Cl Cotransporter. (Lumenal) Ca++ passes across the lumen through a channel.

Site of active Ca++ reabsorption (across the basolateral membrane) via a Na+/Ca++ exchanger. This process is regulated by parathyroid hormone (PTH). This exchanger is not present at the loop of Henle and results in important differences in calcium excretion effects between diuretic classes.

In contrast to loop diuretics, thiazides increase reabsorption of Ca++ (lowering of intracellular
Na+ drives Ca++ exchanger. (Think about it…you’ll get it).

Question 23

What transporters are located in the principal cell in the collecting duct?

In the intercalated cells?

Answer 23

Principal cells: ENaC (inward Na channel, regulated by aldosterone. Outward K+ channel.

[The driving force for Na+ entry into cell exceeds that for K+ exit so lumen becomes negative, driving Cl- into cells and K+ into urine. Thus, K+ excretion is coupled to Na+ reabsorption and ALL diuretics that cause a greater delivery of Na+ (and greater tubular flow) to this site will enhance K+ excretion.]

Question 24

Diuretics that block the ENaC channel (____ or ____) or antagonize the aldosterone receptor (____ or _____) will decrease Na+ reabsorption and decrease K+ excretion.

(inward Na channel, regulated by aldosterone. Outward K+ channel.

Answer 24

triamterene and amiloride

spironolactone - eplerenone

Question 25

_____, through effects on gene transcription, increases the number and activity of both Na+ (ENaC) and K+ membrane channels

Answer 25

Aldosterone

Question 26

Spironolactone / Eplerenone work as?

Answer 26

Competitive antagonist at aldosterone receptor, binds to cytosolic receptor preventing enhancement of protein synthesis.

[Blocks aldosterone effect at collecting tubule, thus Na+ is not reabsorbed, lumen potential becomes more positive, thus less K+ and H+ ions move into urine. Promotes only moderate increase in Na+ excretion]

Question 27

Triamterene / Amiloride work as?

Answer 27

Direct effect to block the Na+-channels on collecting duct lumen to decrease Na+ reabsorption (and thus decreases coupled K+ secretion)

Question 28

What side effect is seen with spironolactone that is not seen with eplerenone?

Answer 28

Endocrine abnormalities (gynecomastia) with spironolactone via block of androgen receptor
(10%). NOT seen with eplerenone which is more selective for aldosterone receptors.

Question 29

Synthesis: What classes of diuretic increase uric acid retention?

Answer 29

Thiazides, loop diuretics

Question 30

Synthesis: Which class of drugs is HCO3- wasting?

Answer 30

CA inhibitors.

Question 31

Synthesis: Which class of drugs wastes Mg?

Answer 31

Loop diuretics.

Question 32

Synthesis: Are loop diuretics Ca sparing or wasting? Thiazides?

Answer 32

Loop diureics are Ca wasting.

Thiazides are Ca sparing.

Question 33

Synthesis: Which classes of drugs are K+ wasting? Sparing?

Answer 33

Loop, carbonic anhydrase inhibitors, and thiazides are K+ wasting.

Aldosterone antagonists and Na channel blockers are K+ sparing.