Lecture 6: Basic Pharm of Diuretics

Question 1

MOA for carbonic anhydrase inhibitors; where?

Answer 1

• In PCT
• Prevents luminal dehydration of H2CO3 to CO2
• Prevents intracellular rehydration of CO2 to H2CO3
• Decreases HCO3- reabsorption

Question 2

Why does diuretic effect of carbonic anhydrase inhibitors diminish over time?

Answer 2

As the H2CO3 is excreted, the body is not able to produce enough to keep up with excretion and eventually these inhibitors will have nothing to act on.

Question 3

Where are carbonic anhydrase inhibitors most commonly used?

Answer 3

• CSF

- Aqueous humor of the eye (glaucoma)

Question 4

MOA for osmotic agents - mannitol; where do they affect?

Answer 4

PCT, Thin Descending limb, Collecting duct

Is a non-reabsorbable solute that causes a countervailing osmotic force, as water comes into the lumen to try and balance out the concentration of mannitol. This leads to increases urine volume and excessive water loss.

Question 5

Adverse effects of Mannitol?

Answer 5

• ECF volume expansion (complicates CHF)
• Dehydration
• Hyperkalemia
• Hypernatremia

*The Hyperkalemia and natremia arise from the loss of water from the cells which increases the ion concentrations in cells causing ions to diffuse out in attempt to reach equilirbrium

Question 6

Clinical application for osmotic agents (mannitol)?

Answer 6

Reduce intracranial and intraocular pressure

Question 7

MOA for loop diuretics and where in kidney do they affect?

Answer 7

Thick ascending limb

• Inhibit the NKCC2 co-transporter, so Na+, K+, and 2 Cl- are staying in lumen. K+ is not diffusing out of the cell to create membrane potential necessary to reabsorb Mg2+ and Ca2+ via paracellular pathway.

Question 8

Adverse effects of loop diuretics?

Answer 8

• Hypomagensia
• Hypokalemic metabolic alkalosis
• Ototoxicity

Question 9

What causes the hypokalemic metabolic alkalosis w/ loop diuretics?

Answer 9

Increased Na+ delivery to the collecting duct (since it’s not being reabsorbed), promotes the increased excretion of K+. The increased Cl- promotes the excretion of H+

Question 10

What can increase chances of ototoxicity?

Answer 10

Loop diuretic used in conjunction w/ aminoglycosides

Question 11

What are the clinical applications of loop diuretics?

Answer 11

• Edema (acute pulmonary edema)
• Acute hypercalcemia
• Hyperkalemia
• Anion OD
• ARF

Question 12

MOA for Thiazides and where in kidney do they work?

Answer 12

• Distal Convolute tubule
• Inhibit the Na+/Cl- transporter (electrically neutral) which lower intracellular Na+ and enhances Na+/Ca2+ exchange in basolateral membrane, increasing reabsorption of Ca2+

Question 13

Adverse effects of Thiazides?

Answer 13

• Hypokalemic metabolic alkalosis

- Impaired CHO tolerance (bad for diabetics)

Question 14

Clinical application for Thiazides?

Answer 14

• HTN

- Heart failure

Question 15

What are the 2 Aldosterone antagonists; difference; where do they work?

Answer 15

• Collecting Tubules
• Eplerenone (selective)
• Spironolactone (non-selective)

Question 16

MOA for eplerenone (aldosterone antagonist)?

Answer 16

Is selective for the aldosterone (mineralcorticoid) receptor, blocks the receptor, and prevents the aldosterone mediated Na+ reabsorption (ENaC channel) and K+ excretion by inhibiting the Na+-K+ATPase.

Question 17

MOA for spironolactone (aldosterone antagonist)?

Answer 17

Non-selective, acts on other targets such as androgen and progesterone receptors, but will also act on the aldosterone receptor.

Question 18

Adverse effects of Eplerenone?

Answer 18

Hyperkalemia - reduced urinary excretion of K+

Question 19

Adverse effects of Spironolactone?

Answer 19

• Gynecomastia (Off-target effect)

- Hyperkalemia (reduced urinary excretion of K+)

Question 20

Clinical application of aldosterone antagonists (eplerenone and spironolactone)

Answer 20

• Excessive activity on the mineralcorticoid receptors (Conn’s syndrome)
• Hyperaldosteronism (heart failure and nephrotic syndrome)

Question 21

Where does ADH act in the kidney?

Answer 21

In the collecting tubules, acts on V2 receptors (Gs protein-coupled receptors) which increases cAMP mediated increase of AQP2 channels, which increases the permeability of the collecting tubule to water.

Question 22

Which ADH antagonists directly bind to the V2 receptor?

Answer 22

The Vaptans (Conivaptan and Tolvaptan)

Question 23

How does Lithium act as an antagonist to ADH?

Answer 23

Reduces the ADH-induced increases in cAMP after ADH binds its receptor

Question 24

Adverse effects of ADH inhibitors?

Answer 24

• Nephrogenic diabetes insipidus
• Renal failure
• Dry mouth
• Thirst

Question 25

Clinical applications of ADH inhibitors?

Answer 25

• CHF

- SIADH

Question 26

What does adenosine do at the pre-glomerular afferent arteriole?

Answer 26

• Reduces blood flow to the glomerulus (i.e GFR)

- Key signaling molecule in the process of tubuloglomerular feedback

Question 27

What are the modest non-specific adenosine receptor antagonists?

Answer 27

Caffeine and theophylline

Question 28

MOA for adenosine receptor antagonists

Answer 28

• In PCT: interfere with NHE3 (Na+ / H+ exchanger)

- Collecting tubule: interfere collecting tubule K+ secretion

Question 29

Why are adenosine receptor antagonists being highly researched?

Answer 29

They are not K+ wasting , induce diuresis, and stops tubuloglomerular feedback