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LCRS Pharmacology and Therapeutics > Diuretics > Flashcards

Diuretics Flashcards

1
Q

What are diuretics?

A

Drugs that act on the renal tubule to promote the excretion of Na+, Cl- and H2O

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2
Q

Where is a lot of sodium reabsorbed?

A

In the proximal tubule

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3
Q

How dos sodium diffuse into the epithelial cell?

A

On the apical side there are Na+ channels

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4
Q

What happens once sodium is in the epithelial cell?

A

Na+/K+ ATPase pumps sodium out of the cell and into the blood in exchange for K+

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5
Q

What effect does the oncotic pressure exerted by the proteins in the capillaries have?

A

It exerts an important force in drawing water into the capillaries

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6
Q

How much protein is there in the filtrate?

A

None

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7
Q

What is another route of ion and water movement apart from the main one?

A

Paracellular pathway

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8
Q

What is the paracellular pathway dependent on?

A

Gap junctions between cells

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9
Q

Where is there a lot of paracellular pathway in use?

A

Proximal tubule has large gap junctions between cells so there is a fair amount of movement of ions and water via the paracellular pathway

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10
Q

Apart from water and ions, what else is reabsorbed lots in the proximal tubule?

A

Glucose and amino acids

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11
Q

What does reabsorption of glucose and amino acids tend to be coupled with?

A

Sodium reabsorption

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12
Q

What is sodium exchange linked to?

A

Carbonic anhydrase

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13
Q

What does carbonic anhydrase do?

A

It converts CO2 + H2O to HCO3- + H+ (reversible reaction)

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14
Q

What happens after H+ and HCO3- is filtered by the glomerulus into the filtrate?

A

They then interact with membrane bound carbonic anhydrase which converts it to CO2 and H2O

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15
Q

What can CO2 and H2O do?

A

Freely diffuse into the cell

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16
Q

What happens once CO2 and H2o enters the cell?

A

They are acted on by carbonic anhydrase that converts them back to H+ and HCO3-

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17
Q

What happens to the H+ and HCO3- once formed in the cell?

A

The HCO3- ions are reabsorbed into the capillaries along with sodium (Na+/HCO3- co transport)
The H+ is used to drive the Na+/H+ exchanger at the apical membrane

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18
Q

What is the end result of the interaction between sodium exchange and carbonic anhydrase?

A

A lot of sodium, bicarbonate and water reabsorption

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19
Q

How are exogenous agents (drugs) removed by the kidneys?

A

They can be removed through transport proteins that pick up the drugs as they pass through the kidneys and transport them into the lumen

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20
Q

What percentage of filtered fluid is reabsorbed in the PCT?

A

About 65-70%

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21
Q

In the loop of Henle, how do the two limbs differ in permeability?

A

The descending limb is freely permeable to water

Ascending limb is not permeable

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22
Q

How does water transport in the descending limb work?

A

It is very straight forward- water moves straight from the tubule lumen, through the epithelial cells into the interstitium

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23
Q

What is the Na+/K+/2Cl- transporter responsible for?

A

Transporting these three ions into the epithelial cels from the lumen in the ascending limb

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24
Q

Which two channels on the basolateral membrane are responsible for moving Na+/K+/2Cl- into the intersitium?

A

Na+/K+ ATPase
K+/Cl- cotransporter

These are present through the nephron because it maintains the concentration gradient that allows absorption of electrolytes from lumen into the cell

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25
Which limb of the loop of Henle can reabsorb Na+?
Ascending
26
What happens to the interstitial after sodium transport into it?
It becomes hypertonic and fluid in ascending limb becomes hypotonic
27
What effect does the medullary interstitium becoming hypertonic have?
It will draw more water from descending limb so fluid in descending limb will become more hypertonic because you're removing water but sodium is being retained
28
What is the end result of the transport in loop of Henle?
You have very concentrated interstitium
29
Why is the countercurrent effect called countercurrent?
Capillaries that pass through this pass in the opposite direction to the flow of fluid
30
What happens to a lot of fluid in the interstitium?
It will end up in the capillaries
31
What does the interstitium have a profound effect on as it becomes more concentrated?
The collecting duct which is incredibly permeable to water under the influence of vasopressin
32
What is the effect of the interstitium on collecting duct very important for?
Making sure that we don't lose too much fluid
33
In the early distal tubule, what happens to any sodium left in the filtrate?
It will be transported by the Na+/Cl- transporter i the apical membrane and eventually it will get to the capillaries
34
What becomes important as you move to the late distal tubule?
Aldosterone and aquaporins
35
What are aldosterone and vasopressin very important in?
Mediating collecting duct function
36
What is aldosterone and what does it do?
A steroid which binds to mineralocorticoid receptors in the cell and acts via the nucleus to increase production of Na+ channels and Na+/K+ ATPase
37
What does aldosterone stimulate?
The production and insertion of the machinery that is required for sodium reabsorption in the collecting duct (provided that the concentration gradient is maintained by Na+/K+ ATPase_
38
What does vasopressin do?
Stimulates and assembles AQP2 (aquaporin 2) molecules that allow water to follow the sodium
39
How do the majority of diuretics work?
They inhibit the reabsorption of Na+ and Cl- i.e. increase excretion They increase the osmolarity of tubular fluid i.e. decrease the osmotic gradient across the epithelia
40
What are the 5 main classes of diuretic drugs?
Osmotic diuretics e.g. Mannitol Carbonic anhydrase inhibitors e.g. Acetazolamide Loop diuretics e.g. Frusemide Thiazide diuretics e.g. Bendrofluazide Potassium-sparing diuretics e.g. Amiloride, spironolactone
41
What sort of diuretics aren't classically used as diuretics (not used for that purpose clinically)?
Osmotic diuretics and carbonic anhydrase inhibitors
42
Where do diuretics work?
Throughout the nephron
43
How do osmotic diuretics e.g. Mannitol work?
They are pharmacologically inert- all it does is increase the osmolarity of the plasma and kidney filtrate- it is filtered by the glomerulus but is not reabsorbed Increasing the osmolarity of the filtrate will mean that less water leaves the lumen and is reabsorbed
44
What are osmotic diuretics clinically used for?
They are used to raise plasma osmolarity to draw out fluid from cells and tissues
45
How do carbonic anhydrase inhibitors (e.g. acetazolamide) work?
It blocks carbonic anhydrase which will prevent H+ and HCO3- from entering the epithelial cells form the lumen so there will be less Na+/H+ exchange so bicarbonate remains in the lumen and less sodium is reabsorbed (via Na+/H+ exchanger). As there is more sodium in the lumen, water remains in the lumen thus increasing the urine volume
46
What do loop diuretics act on?
Na+/K+/2Cl triple transporter in the ascending limb of the loop of Henle
47
How do loop diuretics work?
They target the Na+/K+/2Cl transporter which means that sodium reabsorption in ascending limb of loop of Henle is greatly impaired so more sodium is retained in the lumen
48
How powerful are loop diuretics?
They are very powerful and can promote 15-20% fluid loss
49
What else do loop diuretics remove?
Potassium recycling
50
What is potassium recycling?
You have K+ being reabsorbed via the triple transporter It is also exchanged for Na+ by the Na+/K+ protein on the basolateral membrane. This potassium then diffuses back out of the cell into the lumen
51
What does potassium recycling lead to?
It means that there is always a certain amount of potassium that is driving other positive ions across the cell via the paracellular pathway There is positive lumen potential that drives positive ions across the epithelium via the paracellular pathway
52
What effect do loop diuretics have by blocking potassium recycling?
They interfere with the positive lumen potential so you tend to lose some other positive ions in the urine as well- Ca2+ and Mg2+ in the urine because they aren't being driven via the paracellular route into the interstitium
53
What is the main effect of loop diuretics?
Large increase in urine volume and Na+,Cl= and K+ loss
54
What is the main use of loop diuretics?
Oedema
55
What are the unwanted effects of loop diuretics?
Hypovolaemia and hypotension K+ loss (and Ca2+ and Mg+) Metabolic alkalosis
56
What do thiazide diuretics act on?
Distal tubule
57
Why are thiazide diuretics not as powerful as loop diuretics?
The distal tubule is only responsible for about 5-10% of fluid
58
How do thiazide diuretics work?
They bind to and block the Na+/Cl- cotransporter so more Na+ and Cl- is lost in the urine If used at high dose they can cause 5-10% fluid loss
59
What is the main effect of thiazide diuretics?
Moderate increase in urine volume and increase in Na+, Cl- and K+ loss (and Mg2+ loss)
60
What are thiazide diuretics used for?
Cardiac failure Hypertension (due to decrease in blood volume) Idiopathic hypercalciuria Nephrogenic diabetes insipidus
61
What are the unwanted effects of thiazide diuretics?
K+ loss- metabolic alkalosis | Inhibits insulin secretion
62
What is the problems with loop and thiazide diuretics related to?
Release of renin by macula densa cells
63
Why is there a problem with diuretics and macula densa cells?
The protein on the apical membrane of the macula densa cells is the same as the ones seen in the loop of Henle- loop diuretics block this and prevent entry of sodium into the macula densa cells
64
Where are macula densa cells found?
Distal tubule
65
What happens after a diuretic has been used for a long time?
It has caused a fair amount of Na+ and Cl- loss so will eventually reduce concentration of Na+ in the tubular fluid because the amount in the blood decreases so amount being filtered reduces so amount reaching macula densa decreases
66
What is a decrease in Na+ reaching macula densa a stimulus for?
Renin secretion which will then stimulate increase in Na+ reabsorption This is a general principle for all diuretics that they stimulate renin secretion
67
Why is the renin secretion a problem?
Because you're trying to reduce Na+ and fluid reabsorption and hence reduce blood pressure but you're activating a system that is going to cause vasoconstriction and promote aldosterone production which will increase Na+ reabsorption- negates the effect of droogs
68
How is the effect of renin secretion commonly avoided?
ACE inhibitors are administered with diuretics
69
Where do potassium sparing diuretics (amiloride and spironolactone) act?
In the late distal tubule and collecting duct
70
What are the classes of potassium sparing diuretics?
Aldosterone receptor antagonists e.g. spironolactone | Inhibitors of aldosterone-sensitive Na+ channels
71
What is spironolactone?
Mineralocorticoid receptor antagonist so prevents aldosterone from having its effect of increasing Na+ reabsorption so there is a decrease in Na+ and a diuretic effect
72
What is the main effect of potassium sparing diuretics?
Small increase in urine volume and loss of Na+
73
What is spironolactone used for?
Hypertension and heart failure | Hyperaldosteronism
74
What are the unwanted effects of potassium sparing diuretics?
Hyperkalaemia- metabolic acidosis | Can cause gynaecomastia, menstrual disorders and testicular atrophy

LCRS Pharmacology and Therapeutics (33 decks)

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