Diuretics II

Question 1

What are some K-sparing diuretics? Structure?

Answer 1

Triametrene [Dyrenium] & Amiloride [Midamor]organic bases and are not structurally related to aldosterone.

Question 2

How do K sparing diuretics work?

Answer 2

They block ENaC sodium channels to inhibit Na reabsorption in DCT and CD

Question 3

What are the effects of K sparing diuretics?

Answer 3

•Increase Urinary excretion of Na+ (weak effect).•inhibit the secretion of K+ and H+ (K-sparring)

Question 4

Clinical uses of K sparing diuretics?

Answer 4

•Diuretics. Combined with HCTZ [Dyazide] to increase their effectiveness and decrease K+ excretion.

Question 5

Side effects of K sparing diuretics?

Answer 5

-Hyperkalemia, -Megaloblastic anemia in patients with cirrhosisTriamterene rarely forms kidney stones

Question 6

Responses to diuretics (thiazides in particular) are seen at lower doses, which produce a small but optimal natriuretic effect; higher doses should be avoided because of increase risk of side effects.

Answer 6

Responses to diuretics (thiazides in particular) are seen at lower doses, which produce a small but optimal natriuretic effect; higher doses should be avoided because of increase risk of side effects.The antihypertensive effect of thiazides plateaus at 25mg of HCTZ.A single morning dose of HCTZ will provide sustained effect, while reducing K+ wastage during the nighttime.

Question 7

T or F. Most popular drugs for treatment of mild or moderate hypertension.

Answer 7

T.

Question 8

What diuretics may be effective in patients with impaired renal function?

Answer 8

Metolazone and indapamide However, most of these compounds are usually ineffective when GFR lower than 30 mL/min and/or serumcreatinine above 2.5 mg/dL.

Question 9

T or F. Patients with “volume dependent” hypertension (notably African Americans and elderly, with low renin levels) show better responses.

Answer 9

T.

Question 10

A poor response to thiazides may reflect what?

Answer 10

Either an overwhelmingload of dietary sodium or impaired renal capacity to excrete sodium

Question 11

When are loop diuretics used?

Answer 11

More efficient diuretics than the thiazides. Used in patientswith severe hypertension unresponsive to thiazides,especially with renal insufficiency, cardiac failure or cirrhosis.Due to their high efficacy, these diuretics (furosemide inparticular) is administered I.V. in acute pulmonary edema.

Question 12

Why do loop diuretics require more monitoring than thiazides?

Answer 12

They cause excessive natriuresis leading to more side effects thanthiazides. Therefore, they require more frequent monitoring.

Question 13

What is a common cause of diuretic resistance?

Answer 13

Co-administration of NSAID (such as aspirin, Motrin.) with loop diuretics

Question 14

When are K+ sparing diuretics particularly useful?

Answer 14

Useful in patients at risk of K+ depletion and in patients with hyperuricemia.

Question 15

Spironolactone is the diuretic of choice in what disease?

Answer 15

cirrhosis and canbe titrated up to 400 mg/day in very rare cases. If GFR is

Question 16

Other uses of spirolactone?

Answer 16

Equipotent to Thiazides as antihypertensives, useful toenhance the natriuretic effects of other diuretics.Available combination formulations include:Spironolactone+Hydrochlorothiazide; Triameterene+Hydrochlorothiazide = [Dyazide] a very popularantihypertensive diuretic.

Question 17

Contraindications for spirolactone?

Answer 17

They are contraindicated in significant renal insufficiencyGFR

Question 18

When is ADH released?

Answer 18

•Elevation in plasma osmolarity > 280 mOsm/Kg.•Depletion of extracellular volume•Other: pain, nausea hypoxia

Question 19

What does ADH bindings to the VI receptor cause?

Answer 19

Binding of vasopressin to V1R activates Gq-PLC-IP3 pathway and mobilizes Ca2+ causing vasoconstriction of vascular smooth muscle

Question 20

Where are ADH V2 receptors located?

Answer 20

in principal cells in renal collecting ducts (CD)

Question 21

What does ADH bindings to the V2 receptor cause?

Answer 21

activates Gs-cAMP, PKA.• PKA increases rate of insertion of water channel containing vesicles (WCV’s) into the apical membrane of CD.• PKA phosphorylates the water forming channel aquaporin- 2, which are then inserted as tetramers into the apical membrane.• Aquaporin channels increase the permeability of CD to water.• PKA also phosphorylates the urea transporter (termedVRUT or UT1), and increases the permeability of CD to urea.• This in concert with the TALH and the multiplierconcentrates urine, up to 4 times the osmolarity of plasma.

Question 22

What is the difference between central and nephrogenic DI?

Answer 22

Impaired water conservation caused by:• Inadequate AVP secretion (Central DI)• insufficient kidney AVP response (nephrogenic DI).

Question 23

What are some causes of central DI?

Answer 23

• Head injury, surgery or trauma in the pituitary or hypothalamus, tumors, CNS ischemia etc.• Autosomal dominant (chrom 20) cause a gradual loss of AVP.

Question 24

What are some causes of nephrogenic DI?

Answer 24

• Acquired: obstructive renal disease, Drugs: Lithium, clozapine.• Genetic: X-linked caused by gene encoding V2R that result in frame shift, truncated receptor or single amino acid mutations.

Question 25

What are the symptoms of Central and Nephrogenic DI?

Answer 25

•Excrete large volumes or dilute urine.•Drink a lot of water (polydipsia)

Question 26

How is Central DI distinguished from nephrogenic DI?

Answer 26

by the administration of a V2R agonist (such as desmopressin), which will increase urine osmolarity in patients with centralDI but not nephrogenic DI.

Question 27

How is Demopressin given for the treatment for central DI? Does it have V1 action?

Answer 27

Administered nasally (10 μg/whiff), IV, or oral tablet.minimal V1 action

Question 28

What else is Demopressin used to treat?

Answer 28

•Also used in bleeding disorders, given IV. or nasally to increase circulating levels of factor VIII and von Willebrand factor via extrarenal V2 receptors•Used also in nocturnal enurisis (bed wetting in children).

Question 29

How is nephrogenic DI treated?

Answer 29

• Maintain adequate water intake.• Thiazide Diuretics: might reduce polyuria by ~50%.• Cause mild depletion of extracellular water and sodium.• Compensatory renal mechanisms increase thereabsorptive capacities of the proximal convolutedtubule, reducing the volume of (filtrate, i.e. water)delivered to the distal tubule.

Question 30

What are some V1 receptor agonists? How is it given?

Answer 30

Terlipressin [Glypressin]: Restricted use.Administered IV and has less side effects than vasopressin.

Question 31

What are the clinical uses of V1 receptor agonists?

Answer 31

Given IV to treat: -post operative ileus, -reduce bleeding in esophageal varices, and to-reduce bleeding during acute hemorrhagic gastritis.

Question 32

What is SIADH?

Answer 32

Excessive production of ADH resulting in impairedwater excretion and plasma Hypoosmolarity (Hyponatremia).

Question 33

What are some drugs that cause SIADH?

Answer 33

• Psychotropics: SSRI, haloperidol & tricyclic anti depressants.• Sulfonylureas: chloropropamide.• Vinca Alkaloids: (Vincristine and vinblastine).

Question 34

When is SIADH treated?

Answer 34

• Patient is asymptomatic if plasma osmolarity is 125-132 mM and Water restriction is enough.• Generally treatment is ignited when plasma Na+ falls below 120 mM

Question 35

How is SIADH treated?

Answer 35

• Water restriction, IV hypertonic saline is used with extreme care in severe or acute SYMPTOMATIC hyponatremia.• Loop diuretics (interfere with kidney concentrating ability)• Demeclocycline: antagonizes ADH at V2 receptors.• Vaptans

Question 36

What are some other water retaining conditions?

Answer 36

• In CHF, cirrhosis, or nephrotic syndrome, effective blood volume is reduced; hypovolemia exacerbated by diuretics.• Hypovolemia stimulates AVP release; patients may becomehyponatremic owing to vasopressin-mediated retention of water.• Orally active V2 R antagonists provides a new therapeuticstrategy in patients with SIADH and hyponatremia in patients with heart failure, liver cirrhosis, and nephrotic syndrome.

Question 37

What is Tolvaptan?

Answer 37

ADH receptor antagonist that is 29X more selective for the V2R than the V1aR.

Question 38

When is Tolvaptan used?

Answer 38

Significant hypervolemic and euvolemic hyponatremia[serum sodium

Question 39

Metabolism of Tolvaptan?

Answer 39

completely metabolized by CYP3.

Question 40

Side effects of Tolvaptan?

Answer 40

Hyperglycemia, GI disturbances and clotting problems.

Question 41

What is Conivaptan? What is it used for?

Answer 41

• Less selective for the V2R than tolvaptan.• Given IV for acute treatment of hyponatremia in hospital setting only.

Question 42

Side effects of Conivaptan?

Answer 42

Numerous side effects: such as infusion site reaction.• Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.

Question 43

Metabolism of Conivaptan?

Answer 43

Metabolized by CYP3A4.