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Pharmacology and Therapeutics > 20. Diuretics > Flashcards

20. Diuretics Flashcards

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1
Q

Is the PCT permeable to water?

A

Yes

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2
Q

Which side of the cell are the Na-K-ATPase channels in the PCT?

A

Basal side

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3
Q

From which side of the cell does sodium diffuse into in the PCT?

A

Diffuses into apical side

removed on the other side to maintain conc. grad. which drives Na out of lumen, into blood

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4
Q

What forces cause the movement of water out of the lumen?

A
  • Osmotic force in the kidney

* Oncotic pressure in the blood also draws fluid out of the lumen

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5
Q

What do you have between the endothelial cells in the PCT and how does this affect movement of water/electrolytes?

A
  • Large gap junctions
  • Causes fair amount of movement of water/electrolytes via the paracellular route

(transcellular determined by transporters and channels

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6
Q

Where is carbonic anhydrase located in the PCT?

A

Lumen and cell

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7
Q

Outline the mechanism of bicarbonate reabsorption in the PCT?

A

• Bicarbonate (lumen) reacts with H+ (being pushed out of the cell) => carbonic acid
• Carbonic acid => CO2 + water [Carbonic anhydrase]
• CO2 and water enter the cell and recombine to form carbonic acid [Carbonic anhydrase]
- readily dissociates into HCO3- and H+

  • HCO3- is exported out of cell into interstitium, along with Na+ to balance charges
  • Bicarbonate/Cl exchangers (AE1) also export HCO3-, and Cl channels allow Cl- to escape back out

• H+ is exported out of the cell, into the lumen, and Na+ is brought in through an H+/Na+ antiporter

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8
Q

What is the H+/Na+ antiporter associated with in the PCT?

A

Glucose and amino acids coming out of the lumen

kidney doesn’t want to lose these

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9
Q

What is amino acid and glucose movement always coupled to in the PCT?

A

Sodium movement

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10
Q

What do special transporters in the PCT recognise on the drugs in phase I metabolism?

A

Side chains/group - allows the kidney to move the drug into the lumen of the kidney for excretion

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11
Q

What percentage of the total filtered Na load is reabsorbed back into the blood in the PCT?

A

70%

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12
Q

Is the descending limb permeable to water?

A

Yes (very)

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13
Q

Why does water freely move from the tubule lumen to the interstitium in the descending limb?

A
  • Isotonic on tubular side
  • More hypertonic in the interstitium (due to proteins and sodium)
  • Therefore osmotic pole is apical => basal
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14
Q

Is the ascending limb permeable to water?

A
  • Apical membrane is impermeable

* However, a very small amount leaves via the paracellular route

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15
Q

Do the following ions move across the ascending limb, and how:
• Na+
• Cl-
• K+

A
  • Sodium-chloride-potassium triple transporter on the apical membrane moves them out of the lumen
  • Na-K ATPase on basal membrane maintains the sodium gradient (Na+ out, K+ in)
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16
Q

How do the junctions and mitochondria compare in the descending and ascending LOH?

A

Descending
• Loose tight junctions
• Not many mitochondria (don’t pump ions)

Ascending
• Very tight junctions
• Lots of mitochondria (high metabolic activity)

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17
Q

Why does the Loop of Henle have a countercurrent mechanism?

A
  • Same initial osmolarity in both limbs
  • Salt pumped out from ascending limb (AL) into interstitial space between both limbs
  • AL osmolarity decreases, inter-limb space osmolarity increases
  • Causes water to flow from DL passively into the space
  • Process repeats
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18
Q

Which limb of the LOH is thicker?

A

Ascending limb

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19
Q

Why do we need a countercurrent mechanism?

A
  • Promote water movement from the collecting duct
  • Large conc. gradient of sodium in the interstitium is created
  • Acts as an osmotic gradient for water to move out of the collecting duct => interstitium => blood
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20
Q

Where in the nephron do we start to see the action of aldosterone?

A

As you get from the end of the DCT to the collecting duct

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21
Q

Do we see the involvement of aldosterone and aquaporins in the early DCT?

A

No

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22
Q

How is the reabsorption of Na+ driven in the DCT?

A
  • Na-Cl transporter on the apical membrane (tubular side)

* Na-K-ATPase on basal membrane (ensure maintained conc. grad. and reabsorption into blood)

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23
Q

What transporters are present on the basal side of the cells in the DCT?

A
  • Na-K-ATPase

* Potassium + chloride transporters

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24
Q

What does aldosterone (mineralocorticoid) do to the collecting duct?

A
  • Binds to the MR receptor and influences nucleus
  • Increases transcription of Na channels and Na-K-ATPase
  • Therefore, increase the capacity to reabsorb sodium
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25
What does vasopressin do to the collecting duct?
* Interacts with the V2 receptor * Moves aquaporin channels into the apical membrane * Provides mechanism for water to move across the cell, into the interstitium
26
Does the collecting duct have an Na-Cl cotransporter?
No
27
How does aldosterone lead to the transcription of a gene?
* Steroid hormone * Diffuses into cell and binds with steroid hormone intracellular receptors, bound to chaperone proteins * Chaperone protein released from receptor * Dimerisation of steroid hormone-receptor complexes * Enters nucleus * Transcription of desired gene
28
What is Liddle's syndrome?
* Inherited disease of high BP * Mutation in aldosterone activated Na channel * Channel is always on => Na retention => hypertension
29
Is there paracellular transport in the collecting duct?
* Very little * Very tight epithelium * Water has to go through membrane components/aquaporins
30
How do diuretics generally work?
• Inhibit reabsorption of Na and Cl (more excretion of it) - losing more ions to urinemeans that water will follow • Also increase the osmolarity of the tubular fluid - decreased osmotic gradient across epithelia, so less water reabsorbed
31
What are the 5 major classes of diuretics?
* Osmotic diuretics * Carbonic anhydrase inhibitors * Loop diuretics * Thiazides * Potassium-sparing diuretics (osmotic diuretics and carbonic anhydrase inhibitors are not really used for their diuretic effects)
32
Which part of the kidney tubule do osmotic diuretics affects?
Whole tubule
33
Where do carbonic anhydrase inhibitors act in the kidney?
PCT
34
Where do loop diuretics act in the kidney?
Ascending LOH
35
Where do thiazides act in the kidney?
DCT
36
Where do potassium-sparing diuretics act in the kidney?
* Late in the DCT | * Collecting duct
37
How does the location of action of a diuretic affects its power?
* The further along in the nephron, the weaker the diuretic | * There is less sodium present, so less water to be potentially prevented from being reabsorbed
38
Describe the action of osmotic diuretics e.g. mannitol
* Filtered by the glomerulus * Not reabsorbed into blood (pharmacologically inert) - binds to nothing * Increases the osmolarity of tubular fluid, maintained throughout * Therefore, conc. gradient. decreases * Less water leaves the tubule * Decrease in water reabsorption where nephron is freely permeable to water (PCT, DLOH, CD)
39
When are osmotic diuretics clinically used?
* Pulmonary oedema | * Cerebral oedema
40
Describe the action of carbonic anhydrase inhibitors e.g. acetazolamide
* Acts in PCT * Inhibits apical membrane bound and cytoplasmic carbonic anhydrase * Bicarbonate and H+ outside not converted to CO2 and H2O effectively * Less converted back * Less H+ inside the cell * Less Na-H exchange at apical membrane * Less Na+ enters the cell, so less water follows
41
How does increased delivery of HCO3- to the distal tubule affect K+?
Increases K+ loss
42
Describe the action of loop diuretics e.g. frusemide
* Act at the ascending LOH * Target the triple transporter * Prevent Na from moving into the interstitium * Impacts the countercurrent * Na reabsorption impaired, so water reabsorption decreases * Causes massive loss of sodium as well as water
43
How useful are loop diuretics?
Most clinically relevant diuretics (30% reduction in water reabsorption, from 99%)
44
What is potassium recycling and where does it occur?
* In PCT to a degree, and LOH * Potassium is constantly being reabsorbed, but also being lost * It enters the cell and exits again back into the tubule * Replenishes a certain amount of positive charge to the lumen * Contributes to the positive lumen potential * Causes a repulsion within the tubule * Promotes movement of Ca, Na and Mg into the interstitium
45
Which drugs interfere with potassium recycling and what does this lead to?
* Carbonic anhydrase inhibitors and loop diuretics * Potassium movement is reduced * Excess positive charge is diminished * Less Ca, Mg and Na move through the paracellular route and reabsorbed
46
Why do loop diuretics particularly decrease the positive lumen potential?
* Interfere with Cl- reabsorption into cell * Normally 2Cl- brought in with Na+ and K+ * More Cl- in lumen * Less repulsion between positive ions in lumen
47
How do loop diuretics affect K+ in the DCT, as well as Ca2+ and Mg2+ reabsorption?
* Delivery of Na+ to DCT promotes K+ loss (increased Na/K exchange) * Loss of K+ recycling also decreases reabsorption of Ca2+ and Mg2+
48
What are loop diuretics clinically used for and what is their main effect?
• Oedema (can be due to heart failure) * Increase urine volume * Na, Cl and K loss (and Ca and Mg)
49
What are the unwanted effects of loop diuretics?
* Hypokalaemia * Hypovolaemia and hypotension * Metabolic alkalosis
50
Describe the action of thiazide diuretics e.g. bendroflumethiazide
* Act in the DCT (so only 5-10% water/sodium loss) * Target Na-Cl cotransport on the apical side * Inhibit Na+ and Cl- reabsorption in the early distal tubule * Increased tubular fluid osmolarity => decreased water reabsorption in collecting duct
51
How do thiazide diuretics affect K+, Mg2+ and Ca2+?
* Loss of all ions | * K+ loss due to increased Na/K exchange
52
When are thiazide diuretics used?
* Cardiac failure * Hypertension (hypovolaemic and vasodilation effects) * Idiopathic hypercalciuria * Nephrogenic diabetes insipidus
53
What are the unwanted effects of thiazide diuretics?
* K+ loss - metabolic alkalosis | * Inhibits insulin secretion
54
What is the major problem with thiazides and loop diuretics?
* Same proteins on the macula densa cells (in DCT) are blocked (triple transporter), preventing entry of sodium * Diuretics also independently cause hyponatraemia over time * Low [Na+] stimulates renin secretion * Diuretics also directly promote renin secretion * Renin increases aldosterone, which promotes reabsorption => problem
55
How can you overcome the major problem with thaizides and loop diuretics?
Administer with ACE inhibitors
56
What are the 2 classes of potassium-sparing diuretics?
* Aldosterone receptor antagonists | * Inhibitors of aldosterone-sensitive Na+ channels
57
How does spironolactone (mineralocorticoid/aldosterone receptor antagonist) work?
* Aldosterone normally increases Na+ reabsorption * Spironolactone prevents aldosterone from producing Na channels and Na-K-ATPase * This prevents Na+ reabsorption - diuretic
58
How does amiloride (inhibitor of aldosterone-sensitive Na+ channels) work?
Blocks the Na+ channel, preventing Na+ from getting into the cell
59
Where do potassium-sparing diuretics act?
Late distal tubule
60
How do potassium-sparing diuretics affect H+ and uric acid?
* Increased H+ retention (reduced Na/H exchange) | * Increased loss of uric acid
61
Why are most diuretics not potassium-sparing?
* Other diuretics increase [Na+] reaching the collecting duct * This leads to increased Na/K exchange in the collecting duct (some sodium ironically brought back into interstitial space) * Results in loss of K+ in the urine
62
What is hyperuricaemia and which diuretics is it common with?
* Build up of uric acid * Common with loop and thiazide diuretics * They affect the transporters (basal side) that move uric acid into the lumen (which is usually exchanged with organic ions) * Associated with gout
63
Who are thiazides first line treatments for and why?
* Hypertension in Afro-Caribbean people, and anyone over 55 * They have salt sensitive hypertension * Associated with low renin - no point giving ACEi
64
Why are thiazides preferred over other diuretics in treating hypertension?
Good initial response (4-6 weeks), due to decreased plasma volume (However, plasma volume is then restored and diuretic effect is lost - linked to renin secretion)
65
What is the effect of chronic thiazide use?
* Reduced TPR * Activation of eNOS in endothelium - vasodilator * Ca2+ channel antagonism * Opening of Kca channel - smooth muscle * Blood pressure reduced
66
How do diuretics treat heart failure and oedema?
* Heart failure => less CO * Activation of RAS => Na+ and water retention * Increased TPR => heart works harder, more problems, fluid retention • Loop diuretics promote Na and water loss to reduce work the heart has to do (• IV furosemide works within 30mins)
67
What is the danger with giving the loop diuretic chronically in heart failure?
* Rebound increase in RAS due to detection of low [Na+] at macula densa * ACEi or potassium-sparing diuretic can help (PSD can stop aldosterone competing with loop diuretic)

Pharmacology and Therapeutics (33 decks)

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