Pharmacology of Diuretics

Question 1

What is the sole purpose of diuretics?

Answer 1

To increase urine volume.
Drugs which increase the excretion of salts (mainly NaCl) and water by the kidneys.

They decrease blood volume and cardiac output. Many diuretics also dilate arteries.

Question 2

Fill in:
The kidneys filter large quantities of —- (4% of the plasma CO), reabsorb those substances that the body must —-, and excrete substances that must be eliminated.

Answer 2

plasma

conserve

Question 3

What does the kidney receive the most of?

Answer 3

Blood flow of any organ.

20% of cardiac output

Question 4

What are the two things that the kidney controls?

Answer 4

What is in the blood and blood volume.

Question 5

How does the kidney work to increase urine volume?

Answer 5

They increase salt and hence water secretion.

They reduce Na+ and Cl- reabsorption in the nephron, decreasing reabsorption of water.

Question 6

How many sodium is usually reabsorbed and what does this mean?

Answer 6

99+% of Na+ and water filtered by the kidneys is normally reabsorbed.

This means a small decrease in % reabsorption will greatly increase urine volume.

Question 7

What are 3 conditions which loop diuretics can treat?

Answer 7

• Heart failure (increased venous pressure due to reduced cardiac function)
• Renal disease (protein lost via kidneys, plasma protein falls)
• Hepatic disease (lover produces less albumin, plasma protein falls)

All of them are due to fluid being retained by oedoma.

Question 8

What type of diuretics treats hypertension?

Answer 8

Thiazide-type diuretics

Question 9

How many litres of blood leaves the vascular system in micro-circulation?

Answer 9

4L (goes into the lymphatic system and back into tissues)

Question 10

What happens to protein concentration in renal disease and what does this cause?

Answer 10

decrease in protein concentration

the gradient causing water to move back into the capillary will decrease causing oedema to occur

Question 11

What two absorption processes are proportionate to each other?

Answer 11

Sodium and water reabsorption.

Question 12

Explain the affects of diuretics on sodium reabsorption

Answer 12

It slightly blocks sodium reabsorption and hence water reabsorption also.
This is what causes blood volume to decrease. Protein in the blood stays the same but the volume it is in decreases so this causes more fluid to be excreted due to diuretics.

Question 13

What proteins regulate sodium and water reabsorption?

Answer 13

Sodium - angiotensin 2 and aldosterone

Water - ADH

Question 14

How much sodium and water is reabsorbed in the proximal tubule?

Answer 14

2/3

Question 15

What molecules are reabsorbed/secreted at the PT?

Answer 15

Reabsorbed = glucose, amino acids, bicarbonate

Secreted = protons and weak acids&bases

Question 16

Explain how the secretion of weak acids and bases occurs at the PT

Answer 16

Pumps do this along the nephron. Between the capillaries and the PT, pumps move the weak a&b into the nephron. Weak acids are filtered and secreted by these pumps also.

Question 17

What are two ways diuretics get into the filtrate?

Answer 17

Pumped out or filtered out.

Question 18

What % of sodium is reabsorbed in the DT?

Answer 18

5-10%

Question 19

What other ion process is sodium absorption linked to?

Answer 19

Potassium secreted

Question 20

In terms of potassium, what happens at the DT and collecting duct?

Answer 20

Net secretion of K+ stimulated by aldosterone.

Question 21

How does ADH work?

Answer 21

Acts in the collecting duct producing aquaporins to cause water absorption. It also allows permeability of urea. A high concentration of urea in medulla which doesn’t build up in the loop of Henle and collecting duct. High conc in medulla increase osmolality to help the water get reabsorbed.

Question 22

Are there any diuretics that work on the PT?

Answer 22

No

Question 23

Where are transport processes for sodium reabsorption found?

Answer 23

Luminal membrane of epithelial cells which line the nephron.

Question 24

What transporter mainly reabsorbs sodium in the PT?

Answer 24

Sodium-hydrogen exchanger

Question 25

What transporter for sodium reabsorption occurs in the loop of Henle? What does this transport

Answer 25

Sodium potassium chloride transporter (NKC22) 1 Na+, 1 K+, 2Ca2+

Question 26

Does the collecting duct have?

Answer 26

No transporter, have tubules instead. One involved in sodium reabsorption and other in potassium secretion.

Question 27

Explain the sodium concentration gradient formed in the loop of Henle

Answer 27

Sodium concentration in cells is lower than in the loop of Henle so this creates a gradient and membrane potential. Energetically favourable for sodium to go into a cell and it drags the other ions with it. Sodium pumped into the interstitial cells and then the capillary to go around the whole body.

Question 28

What is the most important type of diuretic?

Answer 28

Loop diuretics

Question 29

Explain the mechanism behind loop diuretics

Answer 29

Block of the Na+, K+, 2Cl- co-transporter in the thick ascending loop of Henle. This strongly inhibits Na+ reabsorption. The sodium then remains in the nephron. Causes a powerful diuresis because the kidneys lose their capacity to create a hypertonic medullary interstitium needed to drive ADH-induced water reabsorption.

Question 30

What is the purpose of the sodium left in the medulla that is not reabsorbed?

Answer 30

The sodium which is being reabsorbed is going back into the blood and the rest of it remains in the medulla where it helps to create a high osmolality which ADH uses for water reabsorption.

Question 31

Give the 6 points on the Na+ transport on the thick ascending limb of loop of Henle

Answer 31

1. Na+ pump on basal surface 2. Electroneutral Na+:K+:2Cl- cotransporter at luminal surface, inhibited by loop diuretics 3. Na+ removed by Na+-K+ pump & some by Na-HC03- transporter 4. Cl- diffuses out via CLCN channels 5. K+ diffuses back via ROMK channels at luminal surface, so can re-enter the cell 6. Tight junction impermeable to H20, but allows diffusion of cations (e.g. Ca2+ and Mg2+) driven by positive potential

Question 32

What way does potassium move into the cell?

Answer 32

Higher potassium concentration in the cell than in the nephron lumen so K+ goes through the ROMK channels out of the cells. It moves 2 positive and 2 negatives charges into the cell so the potential is not affected. K+ diffuses through the channel, creates a potential in which the lumen of the nephron is positive to the cell and the interstitial fluid. This pushes the negative ions into the interstitium to help the reabsorption of all these cations (especially potassium and magnesium).

Question 33

What is the main use of loop diuretics? What happens to calcium and magnesium by loop diuretics?

Answer 33

Oedematous conditions (heart failure, hepatic cirrhosis). Blocking calcium and magnesium transporter to prevent a membrane potential so less reabsorption of Ca and Mg occur. This can lead to too low concentrations of these.

Question 34

What are the adverse effects of loop diuretics?

Answer 34

- hypokalaemia (low plasma K+) due to increased Na+-K+ exchange in collecting tubule. - metabolic alkalosis (decreased plasma volume = contraction alkalosis) This makes the concentration of bicarbonate go up if plasma volume decreases - depletion of calcium and magnesium ions (decreased potential gradient across TAL - less reabsorption, use for hypercalcaemia) - obtoxicity (deafness) because of the Cl- handling part of NKCC2 resembles a Cl- channel in the inner ear - hypovolaemia (blood volume is reduced too much which causes circulatory shock)

Question 35

What is normal plasma K+?

Answer 35

4mmol

Question 36

Explain the mechanism behind thiazide-type diuretics? What are the adverse effects?

Answer 36

``` Block NCCT (sodium-calcium co-transporter). Block Na+, Cl- co-transport in the distal convoluted tubule, reduce plasma volume, venous return, cardiac output. Also, reduce total peripheral resistance by an unknown mechanism. ``` Hypokalaemia (too low potassium levels), hyperglyceamia (too high glucose), hyperuriceamia (excess of uric acid in blood)

Question 37

What are the 5 points about sodium transport pathways in the distal tubule?

Answer 37

1. Na+ pump on basal surface 2. Electroneutral Na+:Cl- (NCCT) cotransporter at luminal surface, inhibited by thiazide diuretics 3. Na+ pumps exchanges Na+ for K+ and Cl- diffuses out via channels 4. K+ diffuses back through channels on the basolateral surface 5. Both here and the in the loop of Henle, K+ transport across the epithelium is not dependant on Na+ reabsorption

Question 38

Explain how diuretics leads to K+ loss

Answer 38

By reducing Na+ reabsorption, thiazides and loop diuretics increase delivery of Na+ and fluid to the collecting duct. This increases Na+ uptake and secretion of K+ and H+ in the collecting tubule. The K+ secretion can cause hypokalaemia, and the H+ secretion can cause metabolic alkalosis. Hypokalaemia can be prevented by combining loop/thiazide diuretics with a K+ sparing diuretic or by giving K+ supplements.

Question 39

Explain the sodium pump creating a flow of Na+ and K+

Answer 39

Sodium pump creating a gradient so sodium flows in from the lumen of nephron into the cells. Creates a membrane potential, depolarises the cell and lots of potassium in cells means K+ is then driven out of the nephron and then excreted. Another cell has a transporter which exchanges potassium for H+, more K+ means more H+ out the cell and into the urine.

Question 40

What two things block sodium reabsorption?

Answer 40

- Blocking Na+ channels | - Blocks affects of aldosterone so less proteins expressed

Question 41

Explain the K+ sparing diuretics 1 - give the two examples

Answer 41

Block sodium channel or the expression of the sodium channels. Low efficacy due to action in late distal tubule and collecting duct. Amiloride: block collecting tubule Na+ channels, thus block Na+ reabsorption and K+ secretion. Spironolactone: aldosterone antagonist (blocks aldosterone receptor), competes for receptor Pro-drug.

Question 42

Give details on K+ sparing diuretics 2

Answer 42

Not usually used as the sole diuretic since they cause only limited diuresis and have a tendency to cause hyperkalaemia due to inhibition of K+ secretion. Used with loop or thiazide diuretics to enhance diuresis and prevent hypokalaemia.