Diuretics I and II

Question 1

Indicate some key properties of diuretics.

what do they do, how, edema, which ions do they regulate

Answer 1

The drugs or agents that cause increase in urinary output – by increasing sodium and water excretion

Specifically, capable of excreting Na+ and Cl-, the major ions present in the extracellular volume.

Increased Sodium levels in the system could lead to edema; diuretics by promoting natriuresis bring down edema.

Diuretics regulate K+, H+, Ca2+, and Mg2+, Cl−, HCO3−, and
H2PO4−,uric acid excretion

Also involved in maintaining hemodynamics

Question 2

Diuretics – Clinical Uses (6)

Answer 2

Edema

High blood pressure/ Hypertension – (by promoting diuresis and natriuresis, diuretics decrease hypervolemia and hypernatremia bringing down the pre-load)

Heart Failure – (reduce edema and congestion)

Renal swelling/inflammation

Hepatic inflammation/ Cirrhosis

Glaucoma

Question 3

Diuretics - Classification

6 classes

Answer 3

1. Carbonic Anhydrase Inhibitors
2. Osmotic Diuretics
3. Loop Diuretics (Na+/K+/Cl- symporter inhibitors)
4. Thiazide / thiazide like (Na+/Cl- symporter inhibitors)
5. K+ sparing diuretics
6. Non-specific cation channel inhibitors or cyclic nucleotide gated channel inhibitors

Question 4

3 Carbonic Anhydrase Inhibitors

common ending?

Answer 4

Acetazolamide, Dichlorphenamide, and Methazolamide

amide ending

Question 5

2 Osmotic Diuretics

Answer 5

Mannitol, Urea

Question 6

4 Loop diuretics

Answer 6

Furosemide, Bumetanide, Ethacrynic acid, and Torsemide

Question 7

5 Thiazide / thiazide like diuretics

Answer 7

Hydrochlorothiazide, Chlorthalidone, Chlorothiazide,
Indapamide and Metolazone

Question 8

4 K+ sparing diuretics

Answer 8

Triamterene, Amiloride, Spironolactone and Eplerenone

Question 9

Properties of Carbonic Anhydrase

major location, specific location of two types, role of CA

Answer 9

CA (enzyme) is prominently present in proximal convoluted
tubule

CA – type IV is present in luminal (brush border) and
basolateral membrane and CA- type II is present in cytoplasm.

CA plays a role in HCO3- reabsorption and acid excretion (H+)

Question 10

What is the function of CA type IV and CA type II?

Answer 10

CA (type IV): rapidly decomposes H2CO3 -→ CO2 + H2O in
the presence of brush bordered CA type IV

CA (type II): CO2 is lipophilic membrane diffusible gas and
reacts with H2O in Cytoplasm by CA (type II) to form H2CO3 (unstable inside cytosol), which again breaks down to HCO3 - and H+

Question 11

What is the function of the sodium hydrogen exchanger (NHE) and what does enhanced NHE activity result in?

Answer 11

The Sodium Hydrogen Exchanger (NHE) tries to
get rid of H+ ion in exchange for Sodium uptake

Enhanced NHE activity always maintains low H+
levels inside cells

Question 12

MOA of Carbonic Anhydrase Inhibitors

Answer 12

Acetazolamide, Dichlorphenamide, and Methazolamide

MOA: Inhibit CA enzymes of both Type II and Type IV. CA inhibitors prevent;

a) CO2 uptake by decreasing H2CO3 break down

b) indirectly decrease the amount of Na+ re-absorbed from luminal fluid

Question 13

Adverse Effects and Contraindications of CA Inhibitors

Answer 13

Adverse Effects:

**1) Systemic Metabolic Acidosis
**
2) Alkalinization of Urine

3) Skin Toxicity, sulfonamide like reactions (all drugs in this class have a sulfonamide moiety), allergic reactions

Contraindications:

Hepatic Cirrhosis: may increase ammonia levels and cause hepatic encephalopathy

Chronic Obstructive Pulmonary Disorder

Question 14

Which diuretics act on the Loop of Henle, and what are their precise locations of action?

Answer 14

Osmotic Diuretics: Thin descending limb

Loop Diuretics: Thick Ascending Limb

Question 15

Osmotic Diuretics - Mannitol: Location of action, MOA, what ions are excreted?

Answer 15

The major site being the loop of Henle and also act on proximal tubule (water permeable membranes)

MOA: By acting as an inert agent mannitol increases osmolarity, promoting water loss in lumen.

Always accompanied by excretion of Na+, K+, Ca2+, Mg2+, Cl−, HCO3−, phosphate (indirect effect due to osmolarity).

Thus, promoting enhanced urine output.

Question 16

Osmotic Diuretics: Adverse Effects and Contraindications

Answer 16

Adverse effects:

dehydration, hyponatremia, with nausea and vomiting.

Contraindications:

Strictly prohibited in: Hepatic or Renal Insufficiency

Heart Failure or Pulmonary Congestion

Question 17

What are high ceiling diuretics?

Answer 17

Loop Diuretics

Question 18

Where do Loop diuretics act and what do they inhibit?

Answer 18

Site of action is thick ascending limb of loop of Henle

Na+K+2Cl- symport Inhibitors-

Question 19

Loop Diuretics: MOA

Answer 19

MOA-Inhibitors of Na+-K+-2Cl− symport. This class bind to the Na+-K+-2Cl− symporter in the thick ascending limb.

The potential difference across the epithelial cells is reduced due to inhibition Na+-K+-2Cl− symporter (mainly due to Cl- linhibition) and this could also lead to decreased Ca2+ and Mg2+ reabsorption.

Question 20

Loop Diuretics: Adverse Effects

electrolyte, bp, ear

Answer 20

Acute and severe effects:

Hyponatremia, hypokalemia,
hypotension and collapse.

Hypotension is due to sympathetic reflex leading to RAAS pathway activation

Loop diuretics may cause Ototoxicity characterized by tinnitus, deafness and hearing loss. (An effect due to interference of ionic conductance in stria vascularis of cochlear region)

Question 21

Drug-Drug Interaction of loop diuretics

5

Answer 21

Probenecid competitively inhibits Organic anion transport system mediated secretion of Furosemide.

Aminoglycosides, NSAIDs, paclitaxel and cisplatin increases Ototoxicity when co-administered with loop diuretics

Co-administration with digitalis glycosides may cause arrhythmias

Increase plasma Lithium levels and toxicity

causes nephrotoxicity with Amphotericin B

Question 22

Thiazide / thiazide like diuretics: MOA, and the 5 drugs

What differentiates them from loop diuretics

Answer 22

Hydrochlorothiazide, Chlorthalidone, Chlorothiazide, Indapamide, and Metolazone

MOA - Inhibits Na+-Cl− symporter of Distal Convoluted Tubule.

Minimal effect on GFR , and Renin release/RAAS activation because they act at site past macula densa – which differentiate them from loopdiuretics

Question 23

Adverse Effects of Thiazide Diuretics

Answer 23

Thiazide diuretics may cause magnesium deficiency, mostly in geriatric population

Most importantly cause fluid and electrolyte imbalance,
especially hyponatremia, hypotension, hypokalemia,
hypochloremia

Erectile dysfunction

Question 24

Thiazide diuretics: Drug-drug interactions

Answer 24

A potentially lethal drug interaction - Thiazides vs Quindine (also class of QT interval prolonging drugs) -> causes polymorphic ventricular tachycardia (torsades de pointes) a fatal ventricular fibrillation.

Question 25

What are the 2 parts of the collecting duct?

Answer 25

1. Cortical collecting duct 2. Inner medullary collecting duct

Question 26

Function of principal cells, and what diuretics act on them?

Answer 26

Principal cells reabsorb water, and Na+ but promote K+ secretion Principal cells are the site of action of aldosterone, and also K+-sparing diuretics.

Question 27

What maintains lumenal electric neutrality after ENaC mediated Na+ reabsorption leaves the lumen negatively charged?

Answer 27

K+ from principal cells or H+ from type A intercalated cells are secreted back into the lumen

Question 28

Which 2 diuretics act directly on Epithelial Na+ Channels (ENaC)?

Answer 28

Triamterene and Amiloride

Question 29

Which 2 reduce ENaC membrane expression?

Answer 29

Spironolactone and Eplerenone (mineralocorticoid receptor antagonists)

Question 30

Triamterene and Amiloride – MOA

Answer 30

Inihibit/block ENaC, located in the late distal convoluted tubule and collecting duct. By inhibiting ENaC, they spare K+ loss.

Question 31

Adverse effects of Amiloride and Triamterene and contraindications

Answer 31

**Hyperkalemia** Along with drugs like **Trimethoprim, NSAIDs and ACE Inhibitors**, increase the incidence of hyperkalemia Contraindicated in geriatric patients, renal insufficiency and also in **hypoaldosteronism**

Question 32

MOA: Aldosterone- (Mineralocorticoid Receptor Ligand) induced Na+ uptake

Answer 32

MOA- Following entrance into the cell, Aldosterone forms a complex with its high affinity receptor, MR. Aldosterone-MR complex enters nucleus and binds to responsive elements in DNA to activate the target genes and proteins collectively called Aldosterone induced proteins (AIP). ENaC is one of the aldosterone induced proteins.

Question 33

Aldosterone effect on serum and glucocorticoid stimulated kinase activity (SGK1)

Answer 33

Aldosterone also increases serum and glucocorticoid stimulated kinase activity (SGK1) SGK1 by phosphorylating NEDD4/2 proteins prevents a NEDD4/2 mediated ubiquitination and lysosomal degradation of ENaC. As a result, there is more ENaC in the membrane and more Na+ uptake

Question 34

MR Antagonists- Spironolactone, Eplerenone MOA:

Answer 34

MR antagonists prevent aldosterone induced increased expression of ENaC mRNA and protein. MR antagonists also prevent aldosterone mediated NEDD4/2 inhibition by SGK1 promoting ENaC ubiquitination and lysosomal degradation decreasing the membrane localization of ENaC

Question 35

Adverse effects of MR antagonists which drug has less known adverse effects

Answer 35

➢Hyperkalemia ➢ Because of their ability to interfere with other steroid receptors they cause gynecomastia, impotence, decreased libido, hirsutism, and menstrual irregularities – **Eplerenone is MR specific antagonist** with reduced non-specific effects

Question 36

What are the 4 Natriuretic Peptides and where are they produced?

Answer 36

Atrial natriuretic peptide (ANP), and Brain natriuretic peptide (BNP)- produced by heart in response to stretch and stress, C-type natriuretic peptide (CNP) by the endothelium and kidneys, and Urodilatin in urine

Question 37

What channel do Natriuretic peptides act on, and what ions do they allow to pass?

Answer 37

Cyclic nucleotide gated cation (CNGC) channel allows Na+, K+, and NH4 + entry and is controlled by cyclic GMP

Question 38

What are the names of the recombinant natriuretic peptides?

Answer 38

Human recombinant ANP (carperitide, available only in Asian subcontinent) BNP (Nesiritide- a recombinant peptide known to inhibit CNGC function

Question 39

Natriuretic Peptides: MOA receptors / what do they inhibit / prevent exit of what ion

Answer 39

Mechanism of Action:- The natriuretic peptides bind to the natriuretic peptide receptors (NPR- A and B isoforms). This binding triggers the conversion of GTP to cyclic GMP. Cyclic GMP and PKG both inhibits the CNG Channel directly PKG also prevent Na+ exit via the Na+, K+-ATPase (interstitial space).

Question 40

Natriuretic Peptides: Adverse effects, Contraindications and drug interactions type of insufficiency, increase serum levels, increase in hypotension risk

Answer 40

Renal insufficiency and mortality have been reported with some short term studies Increase in serum creatinine levels. Oral ACE inhibitors may enhance the hypotension risks

Question 41

Where is ADH produced, what is it released in response to

Answer 41

Based on the stimulus, AVP is primarily synthesized in CNS, but also synthesized in heart and adrenal glands When the blood osmolality increases, the osmoreceptors of the hypothalamus stimulate the synthesis of prohormone (VP) which then gets activated in posterior pituitary to release 8-AVP/ADH (active) from the secretory granules.

Question 42

Vasopression: MOA | What are V2 receptors

Answer 42

They act through V1a, V1b, and V2 receptors. V2 is the major receptor in renal tissue specifically, in the principal cells of collecting duct and thick ascending limb The antidiuretic hormone, 8- Arginine Vasopressin (8-AVP) causes a rise in cAMP and PKA leading to translocation of Aquaporin 2 on membrane surface to imbibe/import more water -through a G Protein mediated signaling mechanism

Question 43

Vasopression / ADH Drug Interactions

Answer 43

➢Inhibitors of vasopressin secretion include atrial natriuretic peptide, γ- aminobutyric acid, and opioids ➢ Nonsteroidal anti-inflammatory drugs (NSAIDs) particularly indomethacin, and drugs like Carbamazepine and Chlorpropamide increase antidiuretic effects of vasopressin ➢Lithium is of particular importance because of its use in the treatment of manic-depressive disorders inhibits vasopressin effects.

Question 44

Name 2 Vasopressin Agonists and some clinical indications

Answer 44

8 Arginine Vasopressin (AVP) Naturally Occurring – In mammals and humans ➢ Synthetic peptides –V 2 selective agonist – Desmopressin also termed Deamino AVP. ➢ Desmopressin has 3000(times) greater anti-diuretic function than the natural hormone ➢Clinical indications - Diabetes insipidus and Nocturia

Question 45

What are the Vasopression Receptor Antagonists and their respective receptors? common ending

Answer 45

1) V2 specific antagonists: Mozavaptan, Tolvaptan and Lixivaptan 2) V1a / V2 antagonists: Conivaptan common ending: vaptan

Question 46

What are Vasopressin Receptor Antagonists used to treat?

Answer 46

Used for hypervolemic hyponatremia- due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) or due to euvolemic hyponatremia Clinically also used in polycystic kidney disease

Question 47

V2 Receptor Antagonists- adverse effects and drug interactions

Answer 47

➢ **Tolvaptan and Mozavaptan** comes with a boxed warning - **causes demyelination disorders**. -It could also result in coma and death especially in patients with compromised hepatic function, an effect due to rapid correction of hyponatremia. ➢Only administered in a hospital setting. ➢ Tolvaptan and Conivaptan are metabolized by CYP3A4, so CYP3A4 inhibitors like ketoconazole, indinavir and clarithromycin should be avoided.