28. Potassium sparing diuretics, ADH antagonists, osmotic diuretics

Question 1

Where do Potassium-Sparing Diuretics work?

Answer 1

Works on the tubules only

Question 2

List the Vasopressin I and II agonists.

Answer 2

1. Desmopressin: Vasopressin II agonist. Used in diabetes insipidus (no pressor effect).
2. Ornipressin: Vasopressin I selective agonist. Acts as a pressor, given in combo with local anesthetics to inhibit systemic absorption.

Question 3

List the primarily water-excreting diuretics.

Answer 3

1. Osmotic diuretics
2. ADH-antagonists

Question 4

List some osmotic diuretics.

Answer 4

1. Mannitol
2. Glycerol
3. Urea
4. Isosorbide

Question 5

What are the indications of osmotic diuretics?

Answer 5

1. Cerebral edema (and other ↑ ICP cases): suck water from interstitial space. cause severe dehydration.
2. Acute glaucoma attack or (ophthalmological surgery - to ↓ IOP prior to surgery)
3. Acute renal failure: (only early, before anuria) absolutely CI if anuric patient, also CI in cerebral trauma…can worsen cerebral edema.

Question 6

What are the side effects of using osmotic diuretics?

Answer 6

1. Dehydration
2. Pulmonary edema (acutely) – because mannitol rapidly draws water into the extracellular space, by extracting from cells–>edema.
3. Hyponatremia: also from drawing water into EC space.Mannitol also has late hypernatremia due to excessive diuresis without water replacement.
4. Exacerbation of HF due to ↑ EC space

Question 7

List the V2R antagonists.

Answer 7

1. Tolvaptan: V2 receptor antagonist. V2 is in kidney. Used for SIADH.
2. Conivaptan: both vasopressin I and II receptor ATG. V1 is in vessels and causes vasoconstriction.

Question 8

What are the indications of ADH-antagonists?

Answer 8

1. Inappropriate ADH secretion conditions.
2. Refractory edemas: (cirrhosis, nephrosis, HF) - but do not ↓ mortality long-term.

Question 9

What is the mechanism of action of Aldosterone antagonists?

Answer 9

Aldosterone antagonists inhibit aldosterone receptors → ↓ expression of aldosterone-dependent Na/K-ATPase, Na transporters (ENaC), K+ channels on principal cells and H+-ATPase on α-intercalated cells

Question 10

List the Aldosterone antagonist drugs.

Answer 10

1. Spironolactone: non-selective. also acts on progesterone, glucocorticoid, and androgen receptors.
2. Canrenone: spironolactone derivative.
3. Eplerenone: spironolactone derivative. selective for aldosterone receptors.

Question 11

What are the indications for Aldosterone antagonist use?

Answer 11

1. Hyperaldosteronism:
   
   • ​​Primary: Conn
   • Secondary: due to refractory edemas via CHF, nephrotic syndrome, liver cirrhosis; any condition with ↓ intravascular volume
2. Congestive heart failure: Eplerenone is only for CHF in Europe, in the US can also be used for HTN.(Heart Failure - can ↓ myocardial remodeling/fibrosis via ↓ aldosterone effects - ↑ volume, etc.)
3. Hypertension: combo with K-wasting Diuretics - especially eplerenone. should not be combined with ACE-I (would cause hyperkalemia)
4. (Polycystic Ovary Syndrome / Hirsutism - spironolactone blocks 17α-hydroxylase → ↓ testosterone levels)

Question 12

What are the side effects of Aldosterone antagonists?

Answer 12

1. Significant hyperkalemia. esp combo with ACE-I, ARB or BB
2. Metabolic acidosis (non-anion gap, type 4 RTA: ): ↓ aldosterone effect → ↓ H-ATPase activity. (Sketchy: “Type 4 renal tubular acidosis” - only RTA type with hyperkalemia)
3. Anti-androgenic action: antagonize testosterone. in men, long treatment → gynecomastia (due to androgen receptor inhibition) + other endocrine symptoms including: impotence, reduced libido, etc.

Question 13

What are the indications for direct sodium transport blocker use?

Answer 13

1. Hypertension
2. Edema: usually in combo with thiazide
3. Nephrogenic Diabetes Insipidus: specifically lithium-induced NDI; blocks Li entry into collecting duct cells → ↑ clearance of Li.
4. Liddle syndrome (rare AD disorder of overactive ENaC)

NOTE: These drugs are not used so much, sometimes for hypertension. Overall they are not great drugs, hopefully won’t be around much longer.

Question 14

Name the direct sodium transport blockers.

Answer 14

1. Amiloride
2. Triamterene

Question 15

What is the MOA of direct sodium transport blockers?

Answer 15

They inhibit ENaC Sodium transporter in CT principal cells → ↓ Na reabsorption + ↓ K secretion.

Question 16

How are osmotic diuretics metabolized?

Answer 16

They cannot be metabolized..first 2 are sugar-like agents. They remain in nephron, keep water to themselves, flow through nephron and excrete water.

Question 17

List the potassium-sparing diuretics.

Answer 17

1. Aldosterone antagonists: Spironolactone, Eplerenone.
2. Direct Na transporter blockers/ ENaC inhibitors: Amiloride, Triamterene.

Question 18

What is the route of administration of osmotic diuretics?

Answer 18

Given IV infusion (otherwise would cause diarrhea).

Question 19

Are osmotic diuretics strong diuretics?

Answer 19

They are the strongest diuretics! stronger than furosemide.

Question 20

List the ADH antagonists.

Answer 20

1. V2R antagonists: Conivaptan, Tolvaptan
2. Agents that alter ADH activity: Lithium, Demeclocyclin.

Question 21

What is the DOA of aldosterone antagonists?

Answer 21

They are known as “sneaky diuretics” because they take longer to work, but eventually work very well.

Question 22

What are the indications for aldosterone antagonists?

Answer 22

They can treat resistant things like ascites, where furosemide doesn’t work.

Question 23

Are aldosterone antagonist given by themselves or in combination therapy?

Answer 23

1. They are usually not given alone, but with thiazide diuretics (potassium balance).
2. You should be careful with ACE-I combination (hyperkalemia)
3. Don’t combine potassium sparing drugs with diabetics, increase mortality.

Question 24

What are the effects of Aldosterone?

Answer 24

1. Aldosterone activates ENac (Na+ reabsorbed)
2. It causes K+ excretion
3. It also causes H+ excretion

Question 25

What is the MOA of osmotic diuretics?

Answer 25

Act in whole nephron, but strongest in PCT due to free water permeability there (and descending limb). **Proximal sodium reabsorption also decreases.