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Pharmacology and Therapeutics > 20. Diuretics > Flashcards

20. Diuretics Flashcards

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
Q

What does vasopressin do to the collecting duct?

A
  • Interacts with the V2 receptor
  • Moves aquaporin channels into the apical membrane
  • Provides mechanism for water to move across the cell, into the interstitium
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26
Q

Does the collecting duct have an Na-Cl cotransporter?

A

No

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27
Q

How does aldosterone lead to the transcription of a gene?

A
  • 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
Q

What is Liddle’s syndrome?

A
  • Inherited disease of high BP
  • Mutation in aldosterone activated Na channel
  • Channel is always on => Na retention => hypertension
29
Q

Is there paracellular transport in the collecting duct?

A
  • Very little
  • Very tight epithelium
  • Water has to go through membrane components/aquaporins
30
Q

How do diuretics generally work?

A

• 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
Q

What are the 5 major classes of diuretics?

A
  • 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
Q

Which part of the kidney tubule do osmotic diuretics affects?

A

Whole tubule

33
Q

Where do carbonic anhydrase inhibitors act in the kidney?

A

PCT

34
Q

Where do loop diuretics act in the kidney?

A

Ascending LOH

35
Q

Where do thiazides act in the kidney?

A

DCT

36
Q

Where do potassium-sparing diuretics act in the kidney?

A
  • Late in the DCT

* Collecting duct

37
Q

How does the location of action of a diuretic affects its power?

A
  • 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
Q

Describe the action of osmotic diuretics e.g. mannitol

A
  • 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
Q

When are osmotic diuretics clinically used?

A
  • Pulmonary oedema

* Cerebral oedema

40
Q

Describe the action of carbonic anhydrase inhibitors e.g. acetazolamide

A
  • 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
Q

How does increased delivery of HCO3- to the distal tubule affect K+?

A

Increases K+ loss

42
Q

Describe the action of loop diuretics e.g. frusemide

A
  • 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
Q

How useful are loop diuretics?

A

Most clinically relevant diuretics (30% reduction in water reabsorption, from 99%)

44
Q

What is potassium recycling and where does it occur?

A
  • 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
Q

Which drugs interfere with potassium recycling and what does this lead to?

A
  • 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
Q

Why do loop diuretics particularly decrease the positive lumen potential?

A
  • 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
Q

How do loop diuretics affect K+ in the DCT, as well as Ca2+ and Mg2+ reabsorption?

A
  • Delivery of Na+ to DCT promotes K+ loss (increased Na/K exchange)
  • Loss of K+ recycling also decreases reabsorption of Ca2+ and Mg2+
48
Q

What are loop diuretics clinically used for and what is their main effect?

A

• Oedema (can be due to heart failure)

  • Increase urine volume
  • Na, Cl and K loss (and Ca and Mg)
49
Q

What are the unwanted effects of loop diuretics?

A
  • Hypokalaemia
  • Hypovolaemia and hypotension
  • Metabolic alkalosis
50
Q

Describe the action of thiazide diuretics e.g. bendroflumethiazide

A
  • 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
Q

How do thiazide diuretics affect K+, Mg2+ and Ca2+?

A
  • Loss of all ions

* K+ loss due to increased Na/K exchange

52
Q

When are thiazide diuretics used?

A
  • Cardiac failure
  • Hypertension (hypovolaemic and vasodilation effects)
  • Idiopathic hypercalciuria
  • Nephrogenic diabetes insipidus
53
Q

What are the unwanted effects of thiazide diuretics?

A
  • K+ loss - metabolic alkalosis

* Inhibits insulin secretion

54
Q

What is the major problem with thiazides and loop diuretics?

A
  • 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
Q

How can you overcome the major problem with thaizides and loop diuretics?

A

Administer with ACE inhibitors

56
Q

What are the 2 classes of potassium-sparing diuretics?

A
  • Aldosterone receptor antagonists

* Inhibitors of aldosterone-sensitive Na+ channels

57
Q

How does spironolactone (mineralocorticoid/aldosterone receptor antagonist) work?

A
  • Aldosterone normally increases Na+ reabsorption
  • Spironolactone prevents aldosterone from producing Na channels and Na-K-ATPase
  • This prevents Na+ reabsorption - diuretic
58
Q

How does amiloride (inhibitor of aldosterone-sensitive Na+ channels) work?

A

Blocks the Na+ channel, preventing Na+ from getting into the cell

59
Q

Where do potassium-sparing diuretics act?

A

Late distal tubule

60
Q

How do potassium-sparing diuretics affect H+ and uric acid?

A
  • Increased H+ retention (reduced Na/H exchange)

* Increased loss of uric acid

61
Q

Why are most diuretics not potassium-sparing?

A
  • 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
Q

What is hyperuricaemia and which diuretics is it common with?

A
  • 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
Q

Who are thiazides first line treatments for and why?

A
  • Hypertension in Afro-Caribbean people, and anyone over 55
  • They have salt sensitive hypertension
  • Associated with low renin - no point giving ACEi
64
Q

Why are thiazides preferred over other diuretics in treating hypertension?

A

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
Q

What is the effect of chronic thiazide use?

A
  • Reduced TPR
  • Activation of eNOS in endothelium - vasodilator
  • Ca2+ channel antagonism
  • Opening of Kca channel - smooth muscle
  • Blood pressure reduced
66
Q

How do diuretics treat heart failure and oedema?

A
  • 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
Q

What is the danger with giving the loop diuretic chronically in heart failure?

A
  • 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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