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RED - Kidney Pharmacology & Therapeutics > K5; Diuretics > Flashcards

K5; Diuretics Flashcards

1
Q

How are diuretics used?

A

Important cardiovascular drugs:

  • Management of chronic heart failure
  • Anti-hypertensive (third-line)
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2
Q

How do diuretics work?

A
  • Increase Na+ excretion; natriuresis (normally reabsorbed along with water)
  • Na+ movement is thus followed osmotically by water (diuresis)
  • Decreasing extracellular/plasma volume (reduce oedema in CHF etc, reduces BP)
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3
Q

What 4 factors determine the overall effectiveness of a diuretic?

A
  1. ) Where it acts in the nephron (dependent on how much Na+ secretion is enhanced e.g. blocking reabsorption at LoH = 25% excretion)
  2. ) Response of segments not affected directly by the diuretic
  3. ) Delivery of the diuretic to its site of action (within the lumen; diuretics have to gain access to the lumen by getting in to the filtrate = secretion at PCT into the lumen)
  4. ) Size of effect on the extracellular volume (decreasing extracellular volume activates RAAS, releasing renin from granular juxtaglomerular cells of the afferent/efferent arterioles etc, Ang II and aldosterone ‘correct’ change&raquo_space;> the bigger the change in extracellular volume the greater the RAAS activation = compensatory adaptive response means some diuretics have limited window of activity)
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4
Q

What are the classes of different diuretic agents and where do they work?

A
  • Osmotic agents; PCT
  • Loop diuretics; LoH
  • Thiazide diuretics; early DCT
  • K+ sparing diuretics; late DCT and CD
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5
Q

Give examples of osmotic diuretics.

A
  • Mannitol

- Glucose when hyperglycaemic (causes osmotic diuresis; glycosuria etc.)

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6
Q

What are the properties of osmotic diuretics?

A
  • Pharmacologically inert (don’t activate/inhibit a molecular target)
  • Freely filtered (get through glomerular filter easy) and poorly/not reabsorbed
  • Increases osmolality of the tubular fluid/filtrate in PCT and LoH
  • Reduces passive reabsorption of H2O; stays in higher osmolality
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7
Q

When are osmotic diuretics not used (and where are they used)?

A
  • Hypertension
  • Peripheral oedema

Used in:
- Acute medicine e.g. cerebral oedema (increased osmolality removes extracellular fluid from the body and fluid from brain)

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8
Q

What are some examples of loop diuretics and their characteristics?

A

E.g. furosemide, bumetanide

  • ‘High-ceiling’ diuretics due to powerful diuresis ‘torrential’ (10-fold increase in OG urine production)
  • Causes 15-25% of filtered Na+ to be excreted (25% normally reabsorbed at LoH)
  • Water thus accompanies Na+
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9
Q

Where do loop diuretics act and what does this mean for drug delivery?

A
  • On the inside of the thick ascending limb of the LoH
  • Molecular target: blocking Na+/K+/2Cl- symporter
    (may block at the Cl- binding site)
  • Need to be secreted into the tubular lumen (at PCT) via organic anion (weak acid) transporter (as not much is filtered)
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10
Q

What are the consequences of blocking the Na+/K+/2Cl- symporter? (loop diuretics)

A
  • Decrease Na+ reabsorption (thus more is excreted, and water follows); disrupt process of countercurrent multiplication
  • Hyperosmotic interstitium is reduced
  • Decreased ability of the kidney to concentrate urine
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11
Q

What are the other effects of loop diuretics besides its principle Na+/K+/2Cl- symporter blocking effect?

A
  • Causes an increase in K+ loss
  • Loss of transepithelial potential (as not moving 2Cl- across into tubular cell; loss of +10mV P.D.) reducing absorption of divalent cations (paracellularly down their electrochemical gradient) thus causing the loss of Ca2+ and Mg2+ in the urine (thus can be used for hypercalcaemia)
  • Decreased NaCl entry into macula densa (as Na+/K+/2Cl- symporter in macula densa at the top of the ascending limb of the LoH is sensor for NaCl, cells think there’s low NaCl); promotes renin release (from granular cells) thus increasing Ang II activity (compensatory mechanism; RAAs activation, aldosterone enables Na+/water reabsorption) - kidney becomes refractory to loop diuretics for some hours after use
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12
Q

When are loop diuretics used?

A
  • Used in CHF (chronic heart failure); reducing pulmonary oedema (breathlessness) secondary to LVF (Left Ventricular Failure; back pressure thus fluid build-up in lungs etc) and peripheral oedema (particurlarly in RVF)
  • Used in renal failure (impaired Na+ reabsorption etc./filtering = water retention) to improve diuresis
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13
Q

What are some examples of thiazide/thiazide-like diuretics and how potent are they?

A
  • Bendroflumethiazide
  • Thiazide-like: chlortalidone, indapamide
  • Moderately powerful diuretics (5% of filtered Na+ is excreted; not as powerful as loop though)
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14
Q

Where do thiazide diuretics act and how do they get there?

A
  • They block the Na+/Cl- symporter of the early DCT (inhibiting active Na+ reabsorption and accompanying Cl- transport)
  • Need to be secreted into the tubular lumen (at the PCT) via organic anion (weak acid) transporter (not particularly well filtered otherwise)
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15
Q

What is the net effect of a thiazide diuretic?

A
  • Decreased Na+ & Cl- reabsorption
  • Thus NaCl stays within filtrate and water follows, decreasing H2O reabsorption (normally in the late DCT and CD)
  • Increased solute in tubular fluid thus decreasing H2O reabsorption gradient
  • Reducing circulating volume
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16
Q

What are thiazides/thiazide-like diuretics used for?

A
  • Third-line drugs for hypertension (A + C + D; > 55 years)

- Used in mild/moderate heart failure (move to loop with advanced; greater oedema)

17
Q

When are thiazides not suitable?

A
  • In renal impairment; may have decreased capacity to secrete in the PCT
  • Limited secretion = less likely for thiazides to gain access to the tubular lumen and act at the early DCT (loop diuretics still effective in renal failure due to potent agent)
18
Q

What are the main adverse effects associated with loop diuretics/thiazides?

A
  • Hypokalaemia

- Metabolic acidosis

19
Q

How does hypokalaemia develop with loop/thiazide diuretic use?

A

K+ loss in the urine (kaliuresis):

  1. ) Activation of RAAs; aldosterone secretion (and some Ang II activity) stimulates Na+ reabsorption (and thus water) and accompanying K+ loss (K+ excretion; increases expression of K+ channels in P cells of Late DCT/CD)
  2. ) Increased Na+ delivery to late DCT, promoting K+ loss
20
Q

How do loop/thiazide diuretics inadvertently stimulate RAAs?

A
  • Decreased Na+ in ECF (extracellular fluid, activating renin release)
  • Volume depletion; decrease in blood volume from diuresis “diuretic hypovolameia’
  • Loop diuretics block NaCl entry (blocking Na+/K+/2Cl- symporter) into macula densa cells stimulating renin release from granular cells
21
Q

How does increased Na+ delivery to the late DCT/CD bring about K+ loss? (loop/thiazide diuretics)

A
  • Increased Na+ means increased Na+ entry to the tubular cell (down its electrochemical gradient; created by the Na+/K+ ATPase on the basolateral membrane)
  • Lumen becomes more electronegative as a result (loss of positive Na), encouraging greater K+ secretion via its K+ channel down its electrochemical gradient
22
Q

What is kaliuresis?

A

Increased potassium in the urine

23
Q

How can thiazide/loop diuretic induced hypokalemia be countered in antihypertensive therapy?

A
  • Combining thiazides with beta-blockers (blocking β-receptors on granular cells inhibiting renin release)
  • Or with ACEis (inhibiting Ang I > Ang II in RAAs bringing about a hyperkalaemic effect)
24
Q

What is the clinical issue with hypokalaemia?

A
  • More negative membrane potential (cells are less excitable)
  • Thus can lead to cardiac arrhythmias
  • Reduces activity of Na+/K+ ATPase pump (particularly in myocytes) potentiating the action of digoxin
25
Q

How do loop/thiazide diuretics lead to metabolic alkalosis?

A
  • Due to the increased Na+ delivery to the late DCT/CD which leads to enhanced Na+ reabsorption; associated with H+ secretion/loss
  • As (more) electronegative lumen encourages loss of H+ from I cells (where K+ is being lost from P cells, and Na+ is being reabsorbed)
  • Greater loss of H+ ions means losing acid in acid-base balance (decreased urine pH) = alkalosis (increased blood pH)
  • Also via activation of RAAs (from decreased ECF volume); leads to aldosterone activity acting on plasma membrane receptors increasing H+ secretion (H+ ATPases?)
26
Q

What are the types of potassium-sparing diuretics and their potency?

A
  • Aldosterone receptor antagonists
  • Na+ channel blockers
  • Weak diuretics; but can reduce K+ loss if given with K+-losing agents (loop/thiazide)
27
Q

What antihypertensive(s) negate the effect of potassium-sparing agents?

A

ACEis; cause hyperkaleamia so may negate K+ sparing effect.

28
Q

Give examples of aldosterone receptor antagonists and explain their actions.

A
  • Antagonises aldosterone receptors; preventing upregulation/insertion of Na+ pumps (Na+/K+ ATPase) and channels (ENaC)
  • Blocking mineralocorticoid receptor means there’s no switching on of gene expression
29
Q

When is aldosterone used?

A
  • Used in primary/secondary hyperaldosteronism
  • In oedema/ascites (fluid build up in the peritoneal cavity) associated with liver failure
  • Low-dose spironolactone used in CHF to block actions of aldosterone on the heart
30
Q

How do sodium channel blockers work? Give examples.

A
  • Block apical epithelial Na+ channels (ENaC; simple selective Na+ channel) in the late DCT (P cells) and CD
  • Results in decreased Na+ reabsorption and K+ excretion too
    E..g. amiloride, triamterene
31
Q

How are ACEi (and ATRA) associated with renoprotection?

A
  • Microvascular complications prevalent in diabetes; renal nephropathy (a leading cause of chronic renal failure)
  • ACEis appear to slow renal damage and are advocated in diabetic nephropathy (even in absence of hypertension)
  • Blocking inappropriate RAAs activation
32
Q

What are the key counselling points for diuretics?

A
  • Best taken in the morning (don’t want to disrupt sleep)
  • Patients will experience an increase in urine production (up to 10x with loop; warn patients)
  • Advise patients to avoid excess salt in the diet (hinders diuretic efficacy in kidney)
  • May cause postural hypertension (from loss of fluid) esp. in elderly
  • Thiazides (and loop diuretics less so) may uncover/worsen diabetes
  • Thiazides and loop diuretics may worsen gout
  • NSAIDs may reduce the effects of loop diuretics (NSAIDs reduce production of (renal) PGs that maintain good renal blood flow)
  • Electrolytes should be monitored (may be excess losses)

RED - Kidney Pharmacology & Therapeutics (5 decks)

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