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LCRS Pharma > Diuretics > Flashcards

Diuretics Flashcards

1
Q

what are the main channels in the PCT on the basal side (into blood)?

A

basal Na+/K+ ATPases (into interstitum)

there are also Na+/HCO3- co-transporters on this side

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2
Q

what is the function of the basal Na+/K+-ATPases?

A

maintain the sodium gradient across the cell so it can keep coming from the tubule

NB basal is closest to the interstitium

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3
Q

what creates the oncotic pressure in the interstitum?

A

movement of protein and sodium

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4
Q

how is bicarbonate taken in at the PCT from the tubule?

A

bicarbonate is converted to water and CO2 by carbonic anhydrase in the lumen.
These products can cross into the cell and are converted to bicarbonate (and H+) by intracellular carbonic anhydrase

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5
Q

where are drugs exported out of?

A

the PCT

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6
Q

how much sodium is reabsorbed at the PCT?

A

65-70% of Na+ reabsorbed.

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7
Q

what occurs at the descending limb (DL) of the Loop of Henle (LoH)?

A
  • only H2O reabsorption via AQP molecules
  • impermeable to ions
    i. e. it is permeable to water
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8
Q

what occurs the AL of LoH?

A
  • ions like sodium can move out
  • impermeable to water
  • interstitial becomes hypertonic (more ions)
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9
Q

what is the purpose of the AL of LoH being impermeable?

A

to establish the counter current flow so there is water reabsorption at the collecting ducts

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10
Q

what is the main transporter in the AL of LoH?

A 
Triple transporter (Na, Cl, K)
sodium and chloride are mainly reabsorbed

sodium can move in paracellularly

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11
Q

how is the countercurrent flow established?

A
  1. Loop is filled with isotonic fluid.
  2. Na+ is pumped out of the ascending limb into the interstitium. Fluid in ascending limb decreases in osmolarity (ion loss)
  3. Concentrated interstitium (with more sodium) pulls water from descending limb. Fluid in descending limb increases in osmolarity (more ions left in it- becomes concentrated)
  4. More fluid flows into the tubule and shifts the descending limb fluid into the ascending limb.
  5. Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity.
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12
Q

what is the main transporter in the early DCT?

A

Na+/Cl- co-transporter.

Draws more ions into the interstitium

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13
Q

how does water reabsorption occur in the early DCT?

A
  • Impermeable to free water reabsorption (no gap junctions available)
  • mediated mainly by selective AQP2 channels under VP control
  • much more common in late DCT than early
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14
Q

what 2 things occur in the late DCT and collecting duct?

A
  • Aldosterone induces Na+-channel production (amiloride target)
  • VP induces AQP2 synthesis dependant on blood osmolarity
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15
Q

what AQPs are expressed basally (towards blood) in the collecting duct?

A

AQP3/4 constitutively expressed on basal membrane

AQP2 from the tubule

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16
Q

how does water reabsorption occur in the late DCT and collecting duct?

why is water not freely re-uptaken?

A
  • Impermeable to free water re-uptake
  • therefore mediated by channels
  • osmolarity increases deeper into the medulla so any free absorption would ruin the gradient as water would pass back into the tubular fluid.
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17
Q

what are the main effects of diuretics?

A

o Inhibiting the reabsorption of Na+ and Cl- (less water moves out of tubules)

o Increasing the osmolarity of the tubular fluid (more water enters tubules)
– decrease osmotic gradient (i.e. osmotic diuretics).

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18
Q

what are the 5 main classes of diuretics? which 3 are used clinically usually?

A 
o Osmotic diuretic
- Mannitol
o Carbonic anhydrase inhibitors
- Acetazolamide.
o Loop diuretics
- Furosemide (Frusemide)
o Thiazides
- Bendroflumethiazide (Bendrofluazide)
o Potassium-sparing diuretics
-Amiloride, Spironolactone.

loop diuretics, thiazides and potassium sparing diuretics are mainly used

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19
Q

what is the effect of osmotic diuretics like mannitol?

A

increased tubule osmolarity:

Reduce water re-uptake at any part of the nephron that enables water re-absorption

20
Q

what properties of mannitol allow it to carry out its function?

A

Pharmacologically inert and is not reabsorbed after being filtered.

Only action is to decrease the osmotic gradient by raising the osmolarity of the tubular fluid (it contributes to it)

this interferes with the counter current flow

21
Q

where do carbonic anhydrase inhibitors like acetozolamide act?

A

PCT

22
Q

what is the action of acetozolamide?

A

by inhibiting the carbonic anhydrase, it can:
o Increase bicarbonate in the tubular fluid.
o Increase the pH of the cell as LESS H+ ions are made from CO2 and H2O
o Less Na+ is taken back up by the Na+/H+-anti-porter.

23
Q

what are the actions of carbonic anhydrase inhibitors?

A
  • inhibition of carbonic anhydrase leads to a reduction of H+ in the PCT
    [remember CA: CO2+H2O–> H+ and HCO3-]
  • pH increases in PCT as less H+ is produced
  • therefore less Na+ exchanges with the little H+ produced in PCT

knock on effects:

  • inhibit Na+ and HCO3- reabsorption in PCT to blood
  • increase tubular fluid osmolarity (more Na+) –> decrease water reabsorption.
  • Other effects increase delivery of HCO3- to DCT (CA is birectional) and increase K+ loss.
24
Q

where does furosemide act?

A

Loop diuretic :
Acts on the ascending limb of the LoH on the triple transporter (Na,Cl,K)

very powerful

25
Q

what does furosemide do?

A

loop diuretic: Inhibit the triple transporter.

Impacts the countercurrent effect.

26
Q

what is the effect of inhibiting the triple transporter (by furosemide)?

A

action of loop diuretic:

  • Results in K+ and Na+ loss
  • as well as loss of Ca2+ and Mg2+ (due to loss of K+ recycling as the positive lumen potential is lost)

K+ is lost eventually later down the stream to Na+

27
Q

how does furosemide decrease paracellular transport of ions?

A
  • small leak of potassium back into the tubule from the cell physiologically (called K+ recycling)
  • furosemide inhibits this so less positive luminal pressure
  • less paracellular transport of ions including Mg2+, Ca2+
28
Q

where do thiazides like bendroflumethiazide act?

A

Act on the early DCT

not as powerful as loop diuretics

29
Q

what does bendroflumethiazide do?

A

it is a thiazide: inhibit Na+/Cl- co-transporter in the early DCT

30
Q

what is the effect of inhibition of the Na+/Cl- co-transporter?

A

done by thiazides:

  • Results in K+ and Mg2+ loss and Ca2+ re-absorption
  • Na+ may not be lost but exchanged in the late DCT with potassium so K is lost
31
Q

why do loop diuretics not prevent the loss in K+?

A

Na+ moves further down to the DCT where its needs to be reabsorbed at the expense of K+

32
Q

what does the macula densa cell detect?

A

detects the tubular concentration of Na+ in the late ascending thick limb of the LoH.

33
Q

what effect diuretics have on the renin system?

A

Loop diuretics and thiazides reduce the sodium reaching the macula densa so this will increase renin secretion to promote sodium reabsorption and fluid retention

therefore diuretics would promote renin secretion

34
Q

what diuretics has the greatest effect on renin secretion?

A

Loop diuretics would have the greatest effect as they retain more sodium in the tubule
Effects result in resistance to chronic use diuretics

35
Q

what are the potassium sparing diuretic drugs?

A

1) Spironolactone
– aldosterone receptor antagonist and Na/K ATPase inhibitor

2) Amiloride
– aldosterone-sensitive Na+ channel inhibitor (lumen channel)

antagonise aldosterone actions
not powerful

36
Q

what is the effect of potassium sparing diuretic?

A
  • inhibition of aldosterone action means fewer sodium channels are made for the reabsorption of sodium in the early DCT
  • increased H+ retention due to the effects of decreased Na+/H+ exchange.
  • K+ is retained as it is not exchanged for Na+
37
Q

what are the side effects of diuretics?

A 
 Hypovolaemia 
– loop diuretics and thiazides.
 Hyponatraemia 
– loop diuretics and thiazides.
 Hypokalaemia 
– loop diuretics and thiazides.
 Metabolic alkalosis 
– loop diuretics and thiazides.
 Hyperuricaemia
 – loop diuretics and thiazides. Loop diuretics have a more powerful effect of all.
 Hyperkalaemia
 – K+-sparing diuretics due to less Na/K exchange 
 Metabolic acidosis 
 – carbonic anhydrase inhibitors.
38
Q

why do diuretics cause hyperuricaemia?

A

Hyperuricaemia is excess urea in the blood

Diuretic drugs use the OAT (organic anion transporter) to get into the tubule and compete with uric acid in the blood so uric acid increases in the blood

39
Q

what drug is used as the first line of treatment for hypertension in many countries?

A

Thiazides

40
Q

in which particular demographic are thiazides particularly useful?

A

the salt sensitive group

  • those aged 55+
  • those of Afro Caribbean origin at any age
41
Q

what are the two phases of response to thiazides?

A
  • intially diuretic (4-6 weeks)

- then vasodilatory with chronic use (decreased TPR due to NO production)

42
Q

what are the initial and later diuretic responses to thiazides?

A 
o	Initial (4-6 weeks) – reduction of BP due to reduction of blood volume.
o	After 4-6 weeks – plasma volume restored due to tolerance.
43
Q

what effect does chronic use of thiazides have?

A

reduction of TPR:

  • due to activation of eNOS, Ca2+-channel antagonism and opening of K[Ca]-channels
  • this leads to NO production (vasodilator) ,less calcium influx and hyperpolarisation.
44
Q

which drug is useful in acute reduction of congestion in HF presenting with oedema due to fluid retention?

A

Loop diuretics

Spironolactone (worsening HF)

45
Q

what is the negative effect of using loop diuretics in HF?

A

will increase renin secretion (due to reduced sodium load into macula dense) leading to cardiac remodelling.

46
Q

what effect does chronic use of loop diuretics have in association with in HF and oedema treatment?

how can this effect be reduced?

A

problem of resistance and RAS activation.

effect reduced with the additional use of K+ sparing diuretics to stop the rebound activation of RAS to reduce water and sodium retention

LCRS Pharma (32 decks)

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