Diuretics

Question 1

Starting off, how do diuretics work?

Answer 1

Act by blocking specific transport functions of the renal tubules, thereby increasing urinary sodium chloride and water losses

Question 2

By definition, diuretics are drugs that increase the rate of urine flow; however; clinically useful diuretics..?

Answer 2

increase the rate of excretion of Na and usually of Cl

–direct toward reducing extracellular fluid volume by decreasing total body NaCl content

Question 3

Through the effects on sodium and water balance, diuretics decrease what?

Answer 3

both blood volume and venous pressure

• -leading to a decrease in cardiac output and fall in arterial pressure
• -decrease in venous pressure reduces capillary hydrostatic pressure, which decreases capillary fluid filtration and promotes capillary fluid reabsorption, thereby reducing edema

Question 4

Next I will go through each portion of the renal tubule in regard to transport mechanism and drug interactions. Starting from the first reabsorptive site in the nephron is the proximal tubule. What is the percents of reabsorption for the various ions?

Answer 4

Na: 65% 
NaHCO2: 85% 
K: 65% 
Water: 60% 
All of the filtered glucose and AA are absorbed

Question 5

Explain the mechanism of Na’K transport in the proximal tubule

Answer 5

1. Na enters the cell from the lumen across the apical membrane and is pumped out (To the blood) across the basolateral cell membrane by the Na/K ATPase
2. Reabsorption of Na and accompanying solutes establishes an osmotic gradient across the proximal tubule epithelium that is the driving force for water reabsorption

Question 6

Can a proximally acting diuretic induce relatively large losses of sodium and water?

Answer 6

no, since most of the excess fluid delivered out of the proximal tubule can be reabsorbed more distally, particularly in the loop of Henle

Question 7

How does the Na/H exchanger work in the proximal tubule?

Answer 7

Na/H exchanger is located in the luminal membrane allows Na to enter the cell from the tubular lumen in exchange for a proton (H) from inside the cell, whist the Na/K ATPase in the basolateral membrane pumps the reabsorbed Na into the interstitium to maintain low intracellular Na concentration.

Question 8

In the proximal tubule the HCO3 permeability of the luminal membrane is low. However, the membrane harbors the enzyme carbonic anhydrase. What does this enzyme do?

Answer 8

The H secreted into the lumen combines with HCO3 to form H2CO3 (Carbonic acid), which is rapidly dehydrated to CO2 and OH by carbonic anhydrase

• -the OH is hydrate to water
• -CO2 freely diffuses into the cytoplasm of the proximal tubular epithelial cell
• -intracellular CO2 is rapidly rehydrate back to H2CO3 by intracellular carbonic anhydrase
• -after dissociation of H2CO3, the H is available for transport by the Na/H exchanger and the HCO3 is transported out of the cell by a basolateral membrane transporter

Question 9

In the proximal tubule what system helps deliver diuretics to the luminal side of the tubule?

Answer 9

Organic acid secretory system

• -the system is saturable and diuretic drugs in the bloodstream compete for transfer with endogenous organic acids, such as uric acid.
• -therefore patients will have excess uric acid in the blood

Question 10

Moving down the nephron to the thick descending loop of henle (TAL), what is the main transport?

Answer 10

Reabsorbs NaCl without accompanying water

• -diluting the tubular fluid
• 23% of the filtered Na+ load by means of the luminal membrane Na/k/2Cl cotransporter, NKCC2
• -Cl exists the cell via a basolateral Cl channel.
• Na exists via the Na/K ATPase

Question 11

Explain the additional repolarization of the cell that is accomplished by the apical K channel ROMK

Answer 11

ROMK

• -recycles back into the lumen the K imported into the cell via NKCC2
• -therefore an overall lumen positive electrical potential is generated which drives the paracellular reabsorption of additional Na along with Ca2+ and Mg2+ from lumen to interstitium

Question 12

Moving down the nephron to the distal convoluted tubule, what is the reabsorption here?

Answer 12

Between 4 to 8% of the filtered NaCl load

• -Na enters the cell via the Na-Cl transporter (NCCT)
• -Basolateral exit of Na is mediated by Na/K ATPase
• -Cl exits by basolateral anion pathway
• -transepithelial reabsorption of luminal calcium and magnesium occurs via ion specific channels

Question 13

Finally the last piece of the nephron is the cortical collecting duct, what is the reabsorption in this part?

Answer 13

Final site of NaCl reabsorption

• -determines the final Na concentration of the urine
• -Luminal Na enters the cells of the cortical collecting duct via the epithelial Na channels, ENac, in the apical membrane
• -K is also secreted into the lumen via ROMK channels to maintain tight control of plasma K concentrations, as well as to minimize the transepithelial potential difference resulting from Na reabsorption.

Question 14

The cells of the cortical collecting duct express vasopressin (ADH) responsive water channels, what does ADH do?

Answer 14

Allowing ADH to control the permeability of the collecting tubule to water
–in the absence of ADH, the collecting tubule is impermeable to water and dilute urine is produced

Question 15

Now lets cover diuretics. First we are going to discuss loop diuretics, the main one used is Furosemide. What does this drug do?

Answer 15

Selectively inhibit NaCl reabsorption in the thick ascending Loop of Henle
–by inhibiting luminal Na/K/2Cl cotransporter (NKCC2)

Question 16

Loop diuretic agents are the most efficacious diuretic agents and are sometimes called high ceiling diuretics, why?

Answer 16

1. Large NaCl absorptive capacity of the TAL
2. Nephron segments past the thick ascending limb do not possess the reabsorptive capacity to rescue the flood of rejectate exiting the thick ascending limb.

Question 17

By inhibiting the reabsorption of the NaCl, loop diuretics also?

Answer 17

Diminish the lumen positive potential that comes from K recycling
–this positive potential normally drives divalent cation reabsorption in the loop, and by reducing this potential, loop diuretics cause an increase in Mg and Ca excretion

Question 18

All loop diuretics increase the urinary excretion of K, which predisposes the patient to what?

Answer 18

Hypokalmeia

Metabolic Alkalosis

Question 19

Loop diuretics are used in the management of edema associated with what?

Answer 19

Heart failure
Hepatic
Renal Disease

Question 20

With all that quickly review the adverse effects of loop diuretics.

Answer 20

Most common are fluid and electrolyte imbalance

1. Ototoxicity: manifests as tinnitus, hearing impairment, deafness, vertigo, and a sense of fullness
2. Hyperuricemia: precipitate gout in some patients
3. Acute hypovolemia: depletion of total body Na
4. K depletion: Increased delivery of Na to the distal tubule, particularly when combined with activation of the renin system, leads to increased urinary excretion of K and H
5. Hypomagnesemia and Hypocalcemia: avoid in postmenopausal women
6. Other effects: hypersensitivity, hyperglycemia, hyperlipidemia, photosensitivity, parasthesias, bone marrow depression and GI disturbances

Question 21

Next we will discuss thiazide diuretics, Hydrochlorothiazide, Chlorthalidone, Metolazone. What is the action of thiazides?

Answer 21

Inhibit NaCl reabsorption in the distal convoluted tubule by blocking the Na/Cl cotranspoter (NCCT)

Question 22

Thiazides can increase the excretion of K and acid. What effect is had on calcium?

Answer 22

Increase the reabsorption of calcium

–useful in the treatment of recurrent kidney stones

Question 23

What are thiazides used in management for?

Answer 23

1. HTN
2. Tx of edema due to heart failure
3. Hypercalciuria
4. Premenstrual edema
5. Diabetes insipidus

Question 24

Thiazides are a first line treatment for what?

Answer 24

First line antihypertensive drug in black/elderly patients who do not respond to ACEI’s or ARBs

Question 25

Thiazides have a long half life so what does this mean?

Answer 25

can take 1-3 weeks to produce a stable drop in blood pressure

Question 26

What are the adverse effects of Thiazides?

Answer 26

1. Hypokalemia 2. Hyponatremia 3. Volume depletion: can cause orthostatic hypotension 4. Hyperuricemia: competition for the organic secretory pathway 5. Hypercalcemia 6. Hyperglycemia: decrease glucose tolerance and latent DM may be unmasked during therapy 7. Hyperlipidemia: increase LDL cholesterol, total cholesterol and total TAGs 8. Hypersensitivity: photosensitivity or generalized dermatitis occurs

Question 27

Moving on to the potassium sparing diuretics which are Aldosterone Antagonists: Spironolactone and Eplerenone. What is their role?

Answer 27

Prevent K secretion by antagonizing the effects of aldosterone at the late distal and cortical collecting tubules - -Aldosterone causes retention of salt and water and increases the excretion of K and H - -these drugs competitively inhibit the binding of aldosterone to its receptors

Question 28

Spironolactone is used primarily in the management of edema associated with?

Answer 28

Excessive aldosterone excretion or with congestive heart failure --severe HF is managed in order to increase survival and reduce hospitalization when added to standard therapy

Question 29

What are the adverse effects of Potassium Sparing diuretics (Spironolactone)?

Answer 29

1. Gastric Upset and Peptic Ulcers 2. Endocrine effects: can have antagonist effects at other steroid receptors 3. Hyperkalemia: reduce urinary excretion of K 4. Hypercholoremic Metabolic Acidosis: inhibiting H secretion with K causes acidosis 5. Other effects: drowsiness, lethargy, ataxia, confusion 6. Gynecomastia

Question 30

The next set of drugs are Potassium Sparing Diuretics- Inhibitors of Renal Epithelial Na Channels: Amiloride and Triamterene. What is their action?

Answer 30

Small increases in NaCl excretion and usually are employed for their antikaliuretic actions to offset the effects of other diuretics that increase K excretion. --ENaC is inhibited and K secretion is inhibited

Question 31

What are the adverse effects of Amiloride and Triamterene?

Answer 31

1. Hyperkalemia 2. Hyponatremia Triamterene also can reduce glucose tolerance and induce photosensitization and has been associated with interstitial nephritis and renal stones