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RENAL > A. DIURETICS > Flashcards

A. DIURETICS Flashcards

1
Q

when are diuretics used as CV drugs

A
  • chronic heart failure as reduce oedema
  • anti-hypertensives as reduce blood pressure (and BV)

*both due to fluid accumulation

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2
Q

what is the basis of the MoA of diuretics

A
  • increase sodium excretion (natriuresis)
  • Na+ movement followed osmotically by water
  • therefore decrease extracellular/plasma volume
  • increase urine production
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3
Q

what factors determine effectiveness of a diuretic

A
  1. site of action: magnitude of natriuresis (LDs limit 25% reabsorption but TDs only limit 5%)
  2. site of action: increased delivery of Na+ at distal segments, LDs and TDs will cause hypokalaemia and metabolic alkalosis
  3. delivery of diuretic to site of action (lumen): LDs and TDs need to be secreted, affected by renal impairment
  4. size of effect on extracellular volume: decreased EC volume activates RAAs so we get hypokalaemia and metabolic alkalosis to correct for loss of fluid (compensatory mechanisms as body tries to retain water it has)
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4
Q

where do osmotic agents act

A

PCT

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4
Q

where do thiazide diuretics act

A

early part of DCT

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5
Q

where do K+-sparing diuretics act

A

late DCT and CD

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6
Q

where do loop diuretics act

A

thick ascending limb of LoH

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7
Q

example of an osmotic diuretic

A
  • mannitol
  • glucose in hyperglycaemia
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8
Q

characteristics of osmotic diuretics

A
  • pharmacologically inert as don’t activate/inhibit a particular molecular target
  • freely filtered so poorly/not reabsorbed
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9
Q

how do osmotic diuretics work

A
  • increase osmolality of tubular fluid (filtrate) in PCT and LoH as it’s a highly osmotically active molecule
  • reduces passive reabsorption of water and it exits in urine
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10
Q

what is the potency of osmotic diuretics and how does this affect their use

A
  • very potent with a large diuresis effect
  • not used to treat hypertension or peripheral oedema
  • used in a acute medicine (ICU) ie: cerebral oedema as increases osmolality of blood and hence removes fluid from brain
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11
Q

example of loop diuretics

A
  • furosemide
  • bumetanide
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12
Q

characteristics of loop diuretics

A
  • very powerful effect
  • cause 15-25% of filtered Na+ to be excreted (normally <1%) and hence water follows
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13
Q

where do loop diuretics need to be secreted to and how

A
  • tubular lumen (of PCT) via organic anion (week acid) transporter to have access to their SoA
  • they aren’t filtered well as they bind to plasma proteins
  • transporters pull the LD from plasma proteins (AT)
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14
Q

how do loop diuretics work

A
  • block Na+/K+/2Cl- symporter of the thick ascending limb of LoH
    (may block at Cl- binding site)
  • so Na+ reabsorption decreased and process of countercurrent multiplication disrupted
  • reduced hyperosmotic interstitium and as CD moves through the medulla there is reabsorption of water by ADH
  • decreased ability of kidney to concentrate urine
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15
Q

consequences of loop diuretics

A
  • increase in K+ loss
  • loss of transepithelial potential reduces absorption of divalent cations and causes the loss of Ca2+ and Mg2+
    *loops can be used in hypercalcaemia
  • promote renin release, leading to increased AngII activity and aldosterone
16
Q

how do loop diuretics reduce absorption of divalent cations

A
  • don’t lose 2Cl- due to Na+/K+/2Cl- symporter being blocked
  • hence the lumen isn’t slightly +ve, electrochemical gradient is lost and there is a decrease in paracellular diffusion of cations
17
Q

how do loop diuretics promote renin release

A
  • decrease NaCl entry into macula densa tubular cells due to the Na+/K+/2Cl- symporter being blocked
  • renin released from JG granular cells in afferent and efferent arterioles
  • RAAs activated
  • kidney becomes refractory to LDs for some hrs after use due to Na+ and water retention which negates diuretic effects
18
Q

uses of loop diuretics

A
  • chronic heart failure as reduce pulmonary oedema secondary to left ventricular failure and peripheral oedema (right ventricle isn’t working well and bringing blood back up to heart)
  • renal failure to improve diuresis
19
Q

example of thiazide diuretic

A

bendroflumethiazide

20
Q

example of thiazide-related diuretic

A
  • indapamide
  • chlortalidone

(metolazone isn’t a thiazide but in this group as MoA similar)

21
Q

where do thiazides and related diuretics need to be secreted to and how

A
  • tubular lumen (of PCT) via organic anion (week acid) transporter to have access to their SoA
  • they aren’t filtered well as they bind to plasma proteins (to circulate in body)
  • transporters pull the LD from plasma proteins (AT)
22
Q

characteristics of thiazides and related diuretics

A
  • moderately powerful diuretics
  • cause ~5% of filtered Na+ to be excreted (small effect)
23
Q

how do thiazides and related diuretics work

A
  • block Na+/Cl- symporter of early DCT
  • inhibit active Na+ reabsorption and accompanying Cl- transport
  • and hence decrease water reabsorption gradient in late DCT and CD
24
Q

why are thiazides and related drugs used as 2nd line drugs in hypertension

A
  • decrease BV so decrease BP
  • after some time, direct vascular effects may be more important

*also used in mild-moderate heart failure

25
Q

what diuretics are effective in renal impairment

A
  • loop diuretics as more potent (moderate-severe)
  • thiazides are renally secreted to act on DCT, thiazides are deemed ineffective in moderate renal impairment as not much can get into the lumen (except metolazone)
26
Q

what are the 2 consequences of loop diuretics and thiazides (ie secondary causes)

A
  • hypokalaemia
  • metabolic alkalosis
27
Q

how is hypokalaemia caused due to LDs and TDs

A
  • kaliuresis due to K+ loss
    1. due to activation of RAAs: Na+ retention and K+ loss
    caused by aldosterone and some via AngII
  1. increased Na+ delivery to late DCT and CD (P-cells) due to Na+ reabsorption inhibited in LoH and early DCT so there is a greater gradient for reabsorption of Na+ into tubular cells and this promotes a greater K+ loss as lumen becomes more electro-ve
28
Q

how does activation of the RAAs cause hypokalaemia

A
  1. decrease Na+ in ECF (increased Na+ loss) sensed by JG cells
  2. volume depletion, low BV due to diuresis (diuretic hypovolaemia) sensed by JG cells
  3. loop diuretics block NaCl entry into macula densa cells and they block Na+/K+/2Cl- symporter (macula densa cells are the molecular player in sensing NaCl in filtrate)
29
Q

how can you reduce risk of hypokalaemia in anti-hypertensive therapy

A
  • combine thiazides with beta-blockers (which inhibit renin release) or ACEIs (potential side-effect is hyperkalaemia)
30
Q

why is hypokalaemia a major clinical problem

A
  • more negative membrane potential causing:
  • cardiac arrhythmias
  • reduced activity of Na+/K+ ATPase pump (potentiates the action of digoxin which inhibits Na+/K+ ATPase in heart failure), so hypokalaemia and digoxin increases inhibition of ATPase
31
Q

how is metabolic alkalosis caused due to LDs and TDs

A
  1. increased Na+ delivery to late DCT & CD leads to
    enhanced Na+ reabsorption which is associated with H+ secretion/loss due to lumen being electro-ve
  2. activation of RAAs with decreased ECF volume leads to aldosterone activity and increased H+ loss

decreased urinary pH
increased blood pH

32
Q

what type of drugs are potassium-sparing diuretics

A
  • aldosterone receptor antagonists (aka mineralocorticoid receptor antagonists)
  • Na+ channel blockers

*can be used in combination with K+-losing agents to reduce K+ loss (ACEIs can cause hyperkalaemia so may be used to negate the effects of K+-losing agent)

33
Q

what is the potency of potassium sparing diuretics

A

weak

34
Q

example of aldosterone receptor antagonists

A
  • spironolactone
  • eplerenone
35
Q

how do aldosterone receptor antagonists work

A
  • antagonise aldosterone (mineralocorticoid) receptors - prevent upregulation/insertion of Na+/K+ ATPase and ENaC
36
Q

when are aldosterone receptor antagonists used

A
  • primary/secondary hyperaldosteronism
  • oedema and ascites associated with liver failure
  • low-dose spironolactone used in heart failure to block the actions of aldosterone on the heart
37
Q

examples of sodium channel blockers

A
  • amiloride
  • triamterene
38
Q

how do Na+ channel blockers work

A
  • block apical ENaC in late DCT and CD in P-cells
  • Na+ no longer retained at expense of K+
  • decreased Na+ and water reabsorption
  • decreased K+ excretion

RENAL (13 decks)

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