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Renal SB > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

what are the drugs that act on the kidneys

A

diuretics
vasopressin receptor agnoists and antagonists
SGLT2
Uricosuric drugs

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2
Q

what are the main functions of diuretics

A

increase urine flow, normally by inhibiting the reabsorption of electrolytes (mainly sodium salts) at various sites in the nephron

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3
Q

what is the golden rule in water balance physiology

A

Where sodium goes water follows

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4
Q

how do diuretics work fundamentally

A

water follows sodium
normally 90% of sodium reabsorbed so water follows
diuretics decrease sodium absorption, decreasing water reabsorption
thus increasing urine flow

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5
Q

how can the volume of urine excreted in due to diuretics be affected

A

where on the nephron is being affected

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6
Q

what are diuretics used to treat

A

conditions where there is an increase in the volume of interstitial fluid i.e. oedema causing tissue swelling

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7
Q

what does oedema result from

A

an imbalance between the rte of formation and absorption of interstitial fluid

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8
Q

what forces dictate fluid movement from the capillary circulation and the interstitial fluid

a.k.a. the Starling forces

A

driving water out of the capillary
- capillary pressure

driving water into the capillary
- capillary osmotic/oncotic pressure

Pressure in interstitial fluid
- does not have much of a driving force

Osmotic/oncotic pressure of the interstitial fluid
- again not much driving force

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9
Q

what is the capillary osmotic pressure derived from

A

plasma proteins

- mainly albumin

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10
Q

what is the formation of interstitial fluid proportional to

A

(Pc - Pi) - (πp - πi)

(osmotic pressure inside the capillary - osmotic pressure outside the capillary i.e. interstitial)

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11
Q

what causes oedema in relation to starling forces

A

increase Pc or decrease πp

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12
Q

what diseases cause this

A

the nephrotic syndrome
congestive heart failure
hepatic cirrhosis with ascites

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13
Q

what will the glomerulus not let pass through and what is it when this goes wrong

A

large plasma protein
- it is kept in the capillaries of the glomerulus

the nephrotic syndrome

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14
Q

what is the nephrotic syndrome

A

disorder of glomerular filtration, allowing protein (largely albumin) to appear in the filtrate (proteinuria)

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15
Q

when is proteinuria normal

A

under conditions of intense exercise

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16
Q

what does the urine look like in proteinuria

A

frothy

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17
Q

what happens as a result of the nephrotic syndrome

A

decreased plasma volume
Decreased πp (oncotic pressure)
increase in formation of interstitial fluid

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18
Q

what does the increase in interstitial fluid cause

A

oedema

↓blood volume
↓ cardiac output

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19
Q

how does a decrease in blood volume and CO eventually lead to oedema

A 
activation of RAAS
>>
Na+ and H20 retention 
>>
↑Pc, ↓ πp (increase in pressure in the capillary and decrease in osmotic pressure)
>>
Oedema
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20
Q

what does congestive heart failure arise from and what does it cause in relation to kidneys

A

from reduced cardiac output.

renal hypoperfusion activates the renin-angiotensin system

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21
Q

how does congestive heart failure cause pulmonary and peripheral oedema

A

Expansion of blood volume contributes to increased venous and capillary pressures which, combined with reduced πp causes oedema

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22
Q

how does hepatic cirrhosis with ascites cause oedema

A

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

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23
Q

what are the major steps of sodium reabsorption

A
  1. Na+ (passive Cl- absorption)
  2. Na+/H+ exchange (blocked by carbonic anhydrase inhibitors)
  3. Na+/K+/2Cl- co-transport (blocked by loop diuretics)
  4. Na+/H+ exchange (blocked by carbonic anhydrase inhibitors)
  5. Na+/Cl- co-transport (blocked by thiazide diuretics)
  6. Na+/K+ exchange (blocked by potassium-sparing diuretics)
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24
Q

where do the steps of sodium reabsorption occur

A

Steps 1 +2 - Proximal convoluted tubule
Step 3 - Thick ascending limb of the loop of Henle
Step 4 + 5 - Distal convoluted tubule
Step 6 - Collecting tube

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25
Q

how to diuretics shift oedema

A

increased output of water and salt
blood leaving the kidney is hemoconcentrated (volume reduced)
plasma protein concentration goes up
oncotic pressure goes up
blood goes back to the periphery with greater oncotic pressure
it can suck fluid out of interstitial space and help mobilise oedema

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26
Q

when might a potassium-sparign diuretic be added

A

when a loop diuretic and thiazides are already being used and hypokalaemia needs to be corrected

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27
Q

where is the site of action of many diuretics (thiazides, loop, potassium sparing) and what does this mean

A

apical membrane of the tubular cells
i.e. the membrane facing the lumen
that the diuretic must be in the filtrate to reach its site of action

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28
Q

how can diuretics get into the filtrate

A

glomerular filtration (for drug not bound to plasma protein)

secretion via transport process in the proximal tubule (most important one)

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29
Q

what are the two transport systems that diuretic that can get them into filtrate

A

The organic anion transporters (OATs) – transport acidic drugs (e.g. thiazides and loop agents)

The organic cation transporters (OCTs) – transport basic drugs (e.g. triamterene and amiloride)

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30
Q

what is the principle marker for renal plasma flow

A

PHA

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31
Q

what does secretion result in in relation to diuretics and what does this contribute to

i.e. molecules moving against concentration gradient

A

concentration of diuretic in the filtrate being higher than that in blood

contributes to pharmacological selectivity i.e. only work in the kidney which we need

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32
Q

how can OA- enter the cells in OATs and where does it happen

A

by either diffusion (only a little), or in exchange for α-ketoglutarate (α-KG)
at basolateral membrane

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33
Q

how is α-KG transported in the cell

A

(against a concentration gradient) via a Na+-dicarboxylate transporter

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34
Q

how does the OA- enter the lumen at the apical membrane

A

via either leaving on multidrug resistance protein 2 (MRP2), or in exchange for α-KG via OAT4

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35
Q

where is the sodium and potassium channel always found

A

the BASOLATERAL membrane

NEVER the apical

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36
Q

how can sodium move into the cell and what is it coupled with

A

via the NaDC

coupled with α-ketoglutarate (α-KG)

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37
Q

what does NaDC allow

A

build up of α-ketoglutarate (α-KG) inside the cell

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38
Q

how can α-ketoglutarate (α-KG) go back into the interstitial fluid

A

in exchange for organic ions

how organic ions get into the tubular cell

39
Q

what is a problem with using a thiazide diuretic

A

it competes with uric acid for transport at OATs causing plasma urate increase predisposing to gout

40
Q

how can Organic cations (OC+) get into the cell at the basolateral membrane

A 
either by diffusion (if they are uncharged)
or OCT 
(both driven by negative potential of cell interior and against a concentration gradient)
41
Q

how does OC+ exit the apical membrane and enter the lumen

A

by facilitated diffusion via multidrug resistance protein 1 (MRP1)
OR
in exchange for hydrogren ions on an antiporters system (OCTN)

42
Q

what does the antiporter system allow

A

allows protons from the tubular fluid to come back into the cell in exchange for organic cation going out of the cell

43
Q

what does the antiporter system mean for sodium reabsorption

A

sodium comes in
proton goes out
some proton come back in
allow OC+ to be placed in the lumen

44
Q

MOA of loop diuretic

A
  • drives direction of sodium, potassium and chloride all in the same direction out of the lumen
  • goes into the cytoplasm of the tubular cell
  • ratio is 1 sodium to 1 potassium to 2 chlorides (2 +ve ions and 2 -ve ions so electroneutral process)
  • sodium exported across membrane through the Na+/K+ ATPase and adds sodium to the interstitium
  • potassium can be move out the cell on K+/Cl- co-transporter OR can leak back into the lumen via potassium channel
  • some of the chloride moves out of the K+/Cl- co-transporter AND some leaves basolateral membrane via a Chloride ion channel
45
Q

where do loop diuretics work and what do they work on

A

in the thick ascending limb of the loop of Henle

work on Triple transporter (Na+/K+/2Cl- co-transporter; NKCC2)

46
Q

what is a problem with MOA of loop diuretics

A

it is an electroneutral reaction but there is an uncompensated leak of potassium back into the lumen
- adds positive charge into the lumen

47
Q

what are the principle loop diuretics drugs

A

furosemide and Bumetanide

48
Q

where is the site of action of a loop diuretic drugs and there effect

A

Inhibit the Na+/K+/2Cl- carrier by binding to the Cl- site and thus:

  • Decrease the tonicity of the interstitium of the medulla
  • Prevent dilution of the filtrate in the thick ascending limb
  • Increase the load of Na+ delivered to distal regions of the nephron (causing K+ loss)
  • Increase excretion of Ca2+ and Mg2+
49
Q

what extra effect do loop diuretics have that is helpful in heart failure

A

indirect venodilator action

  • blood return to heart reduces
  • helps shift pulmonary oedema
50
Q

when are loop diuretics used

A

To reduce salt and water overload associated with - HF, pulmonary oedema, chronic kidney failure

increase urine volume in acute kidney failure

Tx hypertension when in conjunction w/ renal failure

reduce acute hypercalcaemia

51
Q

side effects of loop diuretics

A

Potassium loss producing low serum potassium levels (hypokalaemia)

shift in acid-base towards alkaline side (metabolic alkalosis)

Decreased volume of circulating fluid (hypovolaemia) and hypotension

Depletion of calcium and magnesium

Increased plasma uric acid (hyperuricaemia) i.e. gout

52
Q

what causes metabolic acidosis as a side effect of loop diuretics

A

increased H+ secretion from intercalated cells in collecting tubule

53
Q

where do work Thiazide diuretics

A

distal tubule of loop of Henle

54
Q

MOA of thiazide diuretics and effects of this

A

Inhibit the Na+/Cl- carrier by binding to the Cl- site and thus:

  • Prevent the dilution of filtrate in the early distal tubule
  • Increase the load of Na+ delivered to the collecting tubule (causing K+ loss)
  • Increase reabsorption of Ca2+
55
Q

principle drugs of thiazide diuretics

A

Bendroflumethiazide

Hydrochlorothiazide

56
Q

what additional effect do thiazide diuretics contain

A

indirect, vasodilator action

- makes them suitable to use in conjunction to treat hypertension

57
Q

what are thiazide diuretics used to treat

A

mild heart failure
hypertension
severe resistant oedema (w/ loop diuretic)
Renal stone disease

58
Q

side effects of thiazide diuretics

A 
Hypokalaemia 
Metabolic alkalosis
Hypovolaemia and hypotension
Depletion of magnesium (NOT CALCIUM)
Hyperuricaemia i.e. gout
Male sexual dysfunction
Impaired glucose tolerance
59
Q

where does potassium loss in loop and thiazide diuretics occur

A

late distal and collecting tubule

60
Q

how does potassium loss in loop and thiazide diuretics occur

A

1 - Increased Na+ load produces enhanced reabsorption of Na+

2 - Resulting charge separation makes lumen more negative and depolarizes the lumenal vs. basolateral membrane

3 - Increased driving force on K+ across the lumenal membrane leads to enhanced secretion of K+.

4 - Secreted K+ ‘washed away’ by increased urinary flow rate

5 - development of hypokalaemia (and metabolic alkalosis)

61
Q

MOA of potassium sparing diuretics - Amiloride and Triamterene

A

Block the apical sodium channel and decrease sodium reabsorption

62
Q

MOA of potassium sparing diuretics - Spironolactone and Eplerenone

A

Compete with aldosterone for binding to intracellular receptors causing:

1 - decreased gene expression and reduced synthesis of a protein mediator that activates Na+ channels in the apical membrane
2 - decreased numbers of Na+/K+ATPase pumps in the basolateral membrane

63
Q

what do Spironolactone and Eplerenone competitively antagonise and where do they gain access to cytoplasm

A

the action of aldosterone at cytoplasmic aldosterone receptors

can access via the basolateral membrane

64
Q

what actions do Spironolactone and Eplerenone have

A

increase excretion of Sodium

decrease excretion of potassium

65
Q

what actions do Amiloride and Triamterene have and how do they get into the nephron

A

Block lumenal sodium channels in the collecting tubules.

enter nephron via the organic cation transport system in the proximal tubule

66
Q

what are the clinical indications of potassium sparing diuretics

A

is in conjunction with other agents that cause potassium loss

67
Q

what happens when potassium sparing diuretics by themselves

A

hyperkalaemia

68
Q

what are potassium sparing diuretics also known as

A

Aldosterone antagonists

69
Q

what are Aldosterone antagonists used in treatment for

A

Heart failure
Primary hyperaldosteronism (Conn’s syndrome)
Resistant essential hypertension
Secondary hyperaldosteronism (due to hepatic cirrhosis with ascites)

70
Q

where is the major site of action of osmotic diuretics

A

proximal tubule

enter nephron nephron by glomerular filtration but are not reabsorbed

71
Q

what is an osmotic diuretic

A

a type of diuretic that inhibits the reabsorption of water and sodium

e.g. mannitol

72
Q

MOA of osmotic diuretic

A

increase the osmolality of the filtrate

decrease sodium reabsorption in the proximal tubule

73
Q

when are osmotic diuretics used

A
  • prevention of acute hypovolaemic renal failure

- raised inter cranial and intraocular pressure

74
Q

what do carbonic anhydrase inhibitors do and what is an example of one

A

ncrease excretion of HCO3- with Na+, K+ and H2O

e.g. acetazolamide

75
Q

what are carbonic anhydrase inhibitors used in

A

glaucoma and following eye surgery

prophylaxis of altitude sickness

76
Q

what is aldosterone effects on the collecting tubule when it is secreted from the adrenal cortex

A

enhanced tubular sodium reabsorption and salt retention

77
Q

what is ADH effects on the collecting tubule when it is secreted from the posterior pituitary

A

enhanced water absorption

78
Q

what are the two types of diabetes insipidus

A

neurogenic diabetes insipidus
- lack of ADH secretion from the posterior pituitary

nephrogenic diabetes insipidus - - inability of the nephron to respond to ADH

79
Q

how is neurogenic diabetes insipidus treated

A

Desmopressin

80
Q

what is the function of vaptans

A

act as competitive antagonists of vasopressin receptors

81
Q

what are the 3 vasopressin receptors and what do they do

A

V1A receptors mediate vasoconstriction

V1B not important

V2 mediate H2O reabsorption in collecting tubule

82
Q

what happens when V2 receptors are blocked

A

excretion of water without accompanying sodium

thus raises plasma sodium concentration

83
Q

when are vaptans used

A

Tolvaptan used in the Tx of SIADH

84
Q

how does reabsorption happened in the proximal tubule via SGLT2

A

secondary active transport (apical membrane) and facilitated diffusion (basolateral membrane)

85
Q

how does SGLT2 transport glucose

A

coupling it to Na+ influx glucose

86
Q

what does inhibition of SGLT2 result in

A

glucosuria
decreases HbA1 c
weight loss

87
Q

examples of SGLT2 inhibitors

A

Canagliflozin

dapagliflozin

88
Q

what are the major prostaglandins synthesised by the kidneys

A

PGE2 - medulla

PGI2 - glomeruli

89
Q

what do the prostaglandins of the kidney do and when are they synthesised

A

act as vasodilators

synthesised in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin

90
Q

how do prostaglandins work on the GFR

A
  • vasodilate the afferent arteriole
  • renin released leading to angiotensin II that vasoconstrictor the efferent arteriole
  • filtration pressure increases
91
Q

how can NSAIDs precipitate acute renal failure

A

inhibit COX and can greatly decrease GFR in conditions where renal blood flow is dependant upon vasodilator prostaglandins
e.g. HF, liver cirrhosis

92
Q

what 3 drugs in combination can cause acute renal failure

A

ACEI (or ARB), diuretic and NSAID

93
Q

how is uric acid formed

A

catabolism of purines

Renal SB (15 decks)

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