A-28. Potassium sparing diuretics, ADH antagonists, osmotic diuretics

Question 1

Where do K-sparring diuretics act? How much sodium is reabsorbed? MOA

Answer 1

At the level of the collecting tubules (2-5% of Na reabsorption)
They inhibit luminal Na transporter transcription (ENaC).

Question 2

What are the two ways to inhibit ENaC

Answer 2

1. ) Direct transporter inhibitors (amiloride)

2. ) Aldosterone receptor antagonist (spironolactone)

Question 3

What does increased luminal Na excretion do to the K+ and H+ reabsorption?

Answer 3

1. )It causes the K+ (hyperkalemia) and H+ (metabolic acidosis) to no longer be excreted and are instead reabsorbed.
2. ) Also leads to osmotic diuresis

Question 4

Aldosterone receptor antagonist drugs (2)

Answer 4

Spironolactone and Eplerenone

Question 5

MOA of aldosterone receptor antagonist

Answer 5

1. ) Decreases expression of aldosterone-dependent Na/K ATPase
2. ) Na transporters (ENaC) not formed or formed incorrectly

Question 6

Kinetics of spironolactone and eplerenone

Answer 6

Acts slowly via gene expression modification, several times a day

Question 7

Indications for spironolactone and eplerenone

Answer 7

1.) Primary hyperaldosteronism (conn syndrome)
2.) Secondary hyperaldosteronism (refractory edemas where other diuretics don’t work due to CHF, cirrhosis, nephrotic syndrome; any condition decreasing intravascular volume
3.) Hypertension (especially eplerenone)
-shouldn’t be combined with ACE-I (hyperkalemia)
Other
Heart failure (blocks remodeling via aldosterone)
Polycystic Ovary Syndrome, Hirsuitism ( spironolactone blocks 17alpha-hydroxylase decreasing testosterone levels)

Question 8

Side effects of Spironolactone and Eplerenone

Answer 8

1. ) Non-anion gap Metabolic acidosis
2. ) Hyperkalemia ( especially in combo with ACE-I, ARB, or BB)
3. ) Gynecomastia (only with spironolactone due to androgen receptor inhibition since it acts at progesterone, glucocorticoid, and androgen receptors)
   - Also causes impotence and reduced libido
   - eventually replace with eplerenone when these side effects take effect

Question 9

Direct Na Transporter inhibitor drugs

Answer 9

Amiloride

Triamterene (but not used anymore)

Question 10

MOA of amiloride

Answer 10

Directly inhibits ENaC sodium transporter in CT principal cells to decrease Na reabsorption and decreases K+ secretion

Question 11

What is amiloride combined with to balance out K+ saving effects and avoid hyperkalemia

Answer 11

Take with a thiazide to cause K+ wasting

Question 12

Indications of amiloride

Answer 12

1.) Hypertension
2.) Edema (used in combo with thiazides)
Other
Nephrogenic DI (blocks Li entry into collecting duct cells to increase clearance of Li) and Liddle syndrome (rareAd disorder; overactive ENaC channel)

Question 13

Side effects of K+ Sparring diuretics

Answer 13

Hyperkalemia

Question 14

Where do osmotic diuretics act? How is it given?

Answer 14

The whole nephron but strongest effect in the PCT due to free water permeability there
Given Parenterally (otherwise the patient gets diarrhea)

Question 15

Osmotic diuretic drugs (2)

Answer 15

Mannitol and Glycerin

Question 16

Indications of Mannitol and Glycerin

Answer 16

1.) Acute Renal Failure (only early, before anuria)
2.) Cerebral edema (and other cases of increase ICP cases)
Other
Ophthalmological surgery to decrease IOP prior to surgery

Question 17

Side effects of Mannitol and Glycerin

Answer 17

1. ) Pulmonary edema - Mannitol rapidly distributes in EC space, extracting water from cells leading to edema
2. ) Hyponatremia- Also due to drawing water into EC space
3. ) Exacerbation of Heart Failure- Due to increased EC space
4. ) Late Hypernatremia- Due to excessive diuressis without water replacement

Question 18

Contraindication of Mannitol and glycerin

Answer 18

Cerebral Trauma since can leave cerebral vessels and worsen cerebral edema via osmosis

Question 19

ADH Antagonist (New Diuretics) drugs (2)

Answer 19

1. ) Tolvaptan

2. )Conivaptan

Question 20

Tolvaptan and Conivaptain indications

Answer 20

refractory edemas (cirrhosis, nephrosis, HF)- but do not decrease mortality long term

Question 21

Tolvaptan MOA

Answer 21

Vasopressin II selective which inhibits aquaporin channel formation
Used in polycystic kidney disease in chronic form to slow progresssion of disease

Question 22

Conivaptan

Answer 22

both vasopressin I and II receptors are inhibited so both aquaporin channel formation is blocked (V2) and vasoconstriction and platelet aggregation is blocked (V1)

Question 23

Anti-diuretic drugs (2)

Answer 23

Desmopressin and Ornipressin

Question 24

Desmopressin MOA and indication

Answer 24

Vasopressin II selective agonist (increases aquaporin channel formation)
Decreases amount of urine
Used in diabetes insipidus, nocturia

Question 25

Ornipressin MOA and indication

Answer 25

Vasopressin I selective agonist leading to vasoconstriction and platelet aggregation
Acts as a pressor and is given in combo with local anesthetic to enhance effect and stop diffusion into systemic vascular network