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Renal > Drugs that Act on the Kidneys I & II > Flashcards

Drugs that Act on the Kidneys I & II Flashcards

1
Q

What are some drug classes that act on the kidneys?

A

Diuretics, ADH agonists/antagonists, SGLT2 inhibitors, uricosuric drugs, renal failure drugs, drugs that alter pH of urine

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2
Q

What are urocosuric drugs?

A

Drugs that promote the excretion of uric acid into urine

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3
Q

What are the desirable actions that diuretics are most often used for?

A

Increase urine flow by inhibiting electrolyte absorption at the nephron
Enhance excretion of salt and water in oedema

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4
Q

What causes oedema?

A

Results from imbalance between the rate of formation and absorption of interstitial fluid

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5
Q

What is the formation of interstitial fluid proportional to?

A

(Pc-Pi) - (plasma oncotic pressure - interstitial oncotic pressure)

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6
Q

What are some diseases that increase Pc/decrease oncotic plasma pressure and produce oedema?

A

Nephrotic syndrome, congestive heart failure, hepatic cirrhosis with ascites

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7
Q

What does nephrotic syndrome involve?

A

A disorder of glomerular filtration, allowing large proteins (usually albumin) to appear in urine (proteinuria)

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8
Q

How does nephrotic syndrome cause oedema?

A

Decreases plasma oncotic pressure increases interstitial fluid formation = decreased cardiac output and blood volume activates RAAS causing NA+/H2O retention

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9
Q

What causes congestive heart failure?

A

Reduced cardiac output and subsequent renal hypotension that activates RAAS

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10
Q

How does congestive heart failure cause pulmonary and peripheral oedema?

A

Expansion of blood volume contributes to increased venous and capillary pressures which combines with reduced plasma oncotic pressure to cause oedema

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11
Q

How does hepatic cirrhosis with oedema cause oedema?

A

Increased pressure in the hepatic portal vein and decreased albumin production cause loss of fluid into the peritoneal cavity (ascites) and oedema

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12
Q

How does hepatic cirrhosis activate RAAS?

A

Occurs in response to decreased circulating volume

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13
Q

What may happen if a massive dose of diuretics are used to correct oedema?

A

May cause collapse or thrombosis

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14
Q

How is sodium absorbed in the proximal convoluted tubule?

A

Passively along with CL-

Na+/H+ exchanger = blocked by carbonic anhydrase inhibitors

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15
Q

How is sodium absorbed in the thick ascending limb of the loop of Henle?

A

Na+/K+/2Cl- co-transport = blocked by loop diuretics

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16
Q

How is sodium absorbed in the early distal convoluted tubule?

A

Na+/H+ exchange = blocked by carbonic anhydrase inhibitors

Na+/Cl- co-transport = blocked by thiazide diuretics

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17
Q

How is sodium absorbed in the collecting ducts and tubule?

A

Na+/K+ exchange = blocked by K+-sparing diuretics

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18
Q

Where is the site of action of most diuretics?

A

Apical membrane of the tubular cells = if they are hydrophilic they must enter the filtrate to act

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19
Q

How do diuretics enter the filtrate?

A

Glomerular filtration = for drug not bound to large plasma protein
Secretion = two mechanisms exist

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20
Q

What are the two mechanisms that allow the secretion of diuretics into the plasma?

A

Organic anion transporters (OATs) = for acidic drugs

Organic cation transporters (OCTs) = for basic drugs

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21
Q

What does secretion of diuretics into the filtrate result in?

A

The concentration of the diuretic in the filtrate being higher than the blood = contributes to pharmacological selectivity

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22
Q

What do the secretory pathways of both organic anions and organic cations involve?

A

Both apical and basolateral transport processes

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23
Q

What is the specificity of organic anion transporters?

A

Low specificity but high transport rates

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24
Q

What are organic anions exchanged for at the basolateral membrane?

A

Alpha-ketoglutarate = occurs against the concentration gradient, facilitated by OAT (OAT 1, 2, 3)

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25
Q

How does alpha-ketoglutarate enter cells?

A

Via Na+ dicarboxylate transporter 3 (NaDG3) = works against concentration gradient

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26
Q

How does organic anion cross to the lumen at the apical membrane?

A

Via multidrug resistance proteins 2 and 4 (MRP2/4) and breast cancer resistance protein (BCRP) = primary active transport

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27
Q

How does organic anion cross from the lumen?

A

Via OAT4 in exchange for alpha-ketoglutarate

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28
Q

How do organic cations enter at the basolateral membrane?

A

Mainly by OCT2 = driven by negative potential of cell interior and against a concentration gradient

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29
Q

How do organic cations enter at the lumen of the apical membrane?

A

Enters in rate limiting manner via electroneutral multidrug and toxin extrusion transporters (MATES) and active transport by MDR1

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30
Q

What genetic syndrome mimics the effects of loop diuretics?

A

Bartler syndrome = autosomal recessive mutations in NKCC2, ROMK and ClCKb/barttin

31
Q

What are the two main loop diuretics used?

A

Furosemide and bumetanide

32
Q

How do loop diuretics inhibit the Na+/K+/2Cl- transporter?

A

By binding to the Cl- site

33
Q

What effect does the inhibition of the Na+/K+/2Cl- transporter by loop diuretics have

A

Decreases tonicity of interstitium of the medulla
Prevent dilution of the filtrate in thick ascending limb
Increases Na+ load delivered to distal regions of nephron causing K+ loss
Increases Ca2+ and Mg2+ excretion

34
Q

Why are loop diuretics classed as high ceiling agents?

A

Cause 15-25% of filtered Na+ load to be excreted and have rapid onset following IV administration

35
Q

How are loop diuretics beneficial in treating the pulmonary oedema caused by heart failure?

A

Have additional indirect vasodilator action (before diuresis)

36
Q

What are the pharmacokinetics of loop diuretics?

A

Absorbed from GI tract = subject to variation in CHF
Strongly bind to plasma protein
Enter nephron by OAT mechanism

37
Q

What are some conditions where loop diuretics are used to reduce salt and water overload?

A

Acute pulmonary oedema, chronic heart/kidney failure, hepatic cirrhosis with ascites, nephrotic syndrome (proteinuria may reduce effectiveness)

38
Q

What are some indications for loop diuretic use?

A

To increase urine volume in acute kidney failure

To reduce acute hypercalcaemia

39
Q

When are loop diuretics used to treat hypertension?

A

In patients resistant to other diuretics or anti-hypertensives = usually in presence of renal insufficiency

40
Q

What are the contra-indications to using loop diuretics?

A

Severe hypovolaemia or dehydrating

41
Q

What conditions should loop diuretics be used with caution in?

A

Severe hypokalaemia and or hyponatraemia, hepatic encephalopathy, gout

42
Q

What are the adverse effects of loop diuretics?

A

Causing low electrolyte states = hypokalaemia, metabolic alkalosis, hypocalcaemia, hypomagnesaemia
Hypovolaemia and hypotension (especially elderly)
Hyperuricaemia = may precipitate acute gout
Dose-relate hearing loss

43
Q

What genetic syndrome mimics the effects of thiazide and thiazide-like diuretics?

A

Gitelman syndrome = autosomal recessive mutations in NCC

44
Q

What are some examples of thiazide and thiazide-like diuretics?

A 
Thiazide = bendroflumethiazide
Thiazide-like = chlortalidone, indapamide, metolazone
45
Q

How do thiazide/thiazide-like diuretics inhibit the Na+/Cl- co-transporter?

A

Bind to Cl- site

46
Q

What effect does the inhibition of the Na+/Cl- co-transporter by thiazide/thiazide-like diuretics have?

A

Prevents dilution of filtrate in the early distal convoluted tubule
Increases Na+ load delivered to collecting tubule causing K+ loss
Increases reabsorption of Ca2+

47
Q

How do thiazide/thiazide-like diuretics cause modest diuresis?

A

Cause up to 5% of Na+ to be excreted

48
Q

How are thiazide/thiazide-like diuretics beneficial in the treatment of hypertension?

A

Possess additional vasodilator action

49
Q

What are the pharmacokinetics of thiazide/thiazide-like diuretics?

A

Well absorbed from GI tract

Enter nephron via OAT mechanism

50
Q

What are thiazide/thiazide-like diuretics widely used for?

A

Treatment of mild heart failure and hypertension = indapamide or chlortalidone

51
Q

What are some indications for thiazide/thiazide-like diuretic use?

A

Severe resistant oedema, nephrogenic diabetes insipidus, renal stone disease

52
Q

What are the contra-indications and cautions of thiazide/thiazide-like diuretic use?

A 
Contra-indication = hypokalaemia
Cautions = hyponatraemia, gout
53
Q

What are the adverse effects of thiazide/thiazide-like diuretics?

A

Hypokalaemia, metabolic alkalosis, hypovolaemia and hypotension, hypomagnesaemia, hyperuricaemia, erectile dysfunction, impaired glucose tolerance in diabetes

54
Q

What receptor type does aldosterone act via?

A

Cytoplasmic receptors

55
Q

What effect does aldosterone binding have?

A

Increases synthesis of CAP1 that activates ENa channel
Increases expression of ENa channel
Increases abundance of Na+/K+-ATPase
Relatively rapidly increases expression of ENa channel via serum glucocorticoid-stimulated kinase (Sgk1)

56
Q

What channels secrete K+ into the urine in the collecting tubule?

A

ROMK and BK

57
Q

How do loop and thiazide diuretics enhance Na+ reabsorption?

A

By increasing Na+ load

58
Q

What effect does the increased Na+ reabsorption by thiazide and loop diuretics have on the lumen?

A

Causes resulting charge separation and depolarises the luminal membrane compared to the basolateral membrane

59
Q

What does the depolarisation of the lumen due to thiazide or loop diuretic use cause?

A

Increases the driving force of K+ across the luminal membrane = leads to enhanced secretion of K+, Sgk1 increases ROMK number in apical membrane

60
Q

What eventually causes hypokalaemia due to loop or thiazide diuretic use?

A

Secreted K+ is washed away by increased urinary flow rate that also indirectly activates ROMK channel

61
Q

What are some examples of potassium sparing diuretics?

A

Amiloride and triamterene = block apical sodium channel and decrease Na+ reabsorption
Spironolactone and eplerenone = compete with aldosterone for binding to intracellular receptors

62
Q

Why do spironolactone and eplerenone have limited diuretic action?

A

They are modulated by aldosterone levels

63
Q

What is the action of spironolactone and eplerenone?

A

Competitively antagonise the action of aldosterone at cytoplasmic receptors = gain access to cytoplasm via basolateral membrane

64
Q

What effect do spironolactone and eplerenone have on electrolytes?

A

Increase excretion of Na+ and decrease excretion of K+

65
Q

What is spironolactone metabolised to?

A

Rapidly metabolised to canrenone = accounts for most of action of the drug

66
Q

Are spironolactone and eplerenone well absorbed from the GI tract?

A

Yes

67
Q

What is the action of amiloride and triamterene?

A

Block luminal sodium channels in the collecting tubule = similar effect on electrolyte flux to spironolactone

68
Q

How do amiloride and triamterene enter the nephron?

A

Via the OCT system in the proximal tubule

69
Q

Are amiloride and triamterene well absorbed from the GI tract?

A

Triamterene is, but amiloride isn’t

70
Q

What is the major indication for potassium sparing agents?

A

In conjunction with other agents that cause potassium loss = cause hyperkalaemia when given alone

71
Q

How do potassium sparing agents potentiate the actions of loop and thiazide diuretics?

A

Block the action of aldosterone

72
Q

What are some conditions treated by potassium sparing agents?

A

Heart failure, Conn’s syndrome, resistant essential hypertension, secondary hyperaldosteronism (caused by hepatic cirrhosis with ascites)

73
Q

What are the contra-indications for potassium sparing agents use?

A

Severe renal impairment, hyperkalaemia, Addison’s disease (aldosterone blockers)

Renal (36 decks)

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