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Year 2 - Renal (DP) > Pharmacology > Flashcards

Flashcards in Pharmacology Deck (105):
1

How do diuretics increase urine flow?

Inhibit electrolyte reabsorption:
- Mainly Na+ in nephron
-> So reduced water reabsorption

2

What causes oedema?

Imbalance between:
- Rate of ISF formation
AND
- Rate of ISF absorption

3

What is ISF formation proportional to?

(Pc - Pi) - (πp - πi)
Where:
- Pc is capillary hydrostatic pressure
- Pi is ISF hydrostatic pressure
- πp is capillary oncotic pressure
- πi is ISF oncotic pressure

4

What is the main constituent of πp?

Plasma proteins (Mainly albumin)

5

How does Nephrotic syndrome cause oedema?

Reduces πp

6

How does CHF cause oedema?

Increases Pc

7

How does hepatic cirrhosis cause ascites (intraperitoneal oedema)?

Reduced hepatic blood flow
-> Increased portal system pressure
-> Increased Pc -> Ascites
Reduced albumin production -> Decreased πp

8

How does increased ISF formation lead to further oedema?

1. Blood volume and cardiac output reduced
2. RAAS Activation (as there is renal hypoperfusion)
3. Sodium and water retention
4. Increased blood volume
5. Increased Pc and further decreased πp

9

What sort of oedema does CHF cause?

Pulmonary (+/- peripheral)

10

What drugs block Na+ reabsorption in the PCT?

Carbonic anhydrase inhibitors

11

What drugs block Na+ reabsorption in the Loop of Henle?

Loop diuretics

12

What drugs block Na+ reabsorption in the DCT?

Thiazide diuretics

13

What drugs block Na+ reabsorption in the collecting duct?

Potassium-sparing diuretics

14

Where do most diuretics act, the apical membrane or the basolateral membrane?

Apical

15

What drugs are transported into the filtrate by Organic Anion Transporters (OATs)?

Acidic drugs:
- Thiazides
- Loop diuretics

16

What drugs are transported into the filtrate by Organic Cation Transporters (OATs)?

Basic drugs:
- Triamterene
- Amiloride

17

In regards to OATs, how do organic anions enter the cell at the basolateral membrane?

Diffusion
Exchange for α-ketoglutarate

18

How is the [α-ketoglutarate]i kept high?

Transported into cell via a Na+-dicarboxylate transporter:
- Na+ from Na+/K ATPase

19

How do organic anions enter the lumen at the apical membrane?

Via the Multidrug Resistant Protein 2 (MRP2)
And via OAT4 (in exchange for α-ketoglutarate)

20

Why do thiazides predispose to gout?

Uric acid competes with thiazides at MRP2:
- Increases [Uric acid]p -> Gout

21

How do organic cations move across the basolateral membrane?

Diffusion (if uncharged)
OR
Organic Cation Transporters

22

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

Via MRP1
OR
Organic Cation+/H+ antiporters (OCTN)

23

What transporter do Loop diuretics block in the thick ascending loop of the Loop of Henle? How do they do this?

The Na+/K+/Cl- co-transporter:

24

Put the following steps of the pharmacophysiology of how loop diuretics work:
- Filtrate is less dilute in thick ascending limb of Loop of Henle
- Increased calcium and magnesium excretion
- Reduced tonicity of medullary ISF
- Diuretic binds to Cl- site on NKCC2
- Increased Na+ load in DCT and CD
- Potassium loss

1. Diuretic binds to Cl- site on NKCC2 in TAL of Henle
2. Reduced tonicity of medullary ISF
3. Filtrate is less dilute in thick ascending limb of Loop of Henle
4. Increased Na+ load in DCT and CD
5. Potassium loss
6. Increased calcium and magnesium excretion

25

What percentage of filtered Na+ is excreted on the use of IV loop diuretics?

15-25%

26

Loop diuretics have an indirect vasodilator action which makes them useful in pulmonary oedema. What are the possible mechanisms by how this works?

Increase levels of vasodilating prostaglandins?
Reduce response to Angiotensin II and NA?
Open K+ channels in resistance vessels?
-> Hyperpolarisation
-> Reduced Calcium influx -> Relaxation

27

Loop diuretics are strongly bound to plasma proteins, how does this affect their transport into the nephron lumen?

They rely heavily on OATs

28

True or false; Loop diuretics are poorly absorbed from the GI tract?

False

29

Which of the following is not a major use of loop diuretics:
- Acute pulmonary oedema (IV)
- CHF
- Chronic kidney failure
- Ankle oedema
- Hepatic cirrhosis with ascites
- Nephrotic syndrome

Ankle oedema

30

Why do loop diuretics have a reduced effect in nephrotic syndrome?

There is protein in the tubules so the diuretics bind to them

31

Which of the following is not an adverse effect of loop diuretics:
- Hypokalaemia
- Impaired glucose tolerance
- Metabolic alkalosis
- Hypovolaemia and Hypotension
- Hypocalcaemia and Hypomagnesaemia
- Hyperuricaemia

Impaired glucose tolerance

32

How can hypokalaemia be prevented when diuretics are used?

K+ supplement
OR
Add a K+-sparing diuretic

33

What drugs have increased toxicity when a patient is hypokalaemic?

Digoxin
Class III antidysrhythmic drugs:
- Amiodarone and Sotalol

34

How can diuretics cause metabolic alkalosis?

H+ secretion is increased in the collecting ducts

35

What do thiazide diuretics block?

Na+/Cl- co-transporter in the early DCT

36

What are the two best examples of thiazide diuretics?

Bendroflumethiazide
Hydrochlorothiazide

37

What are the two best examples of thiazide-like diuretics?

Metolazone
Indapamide

38

Put the following steps of the pharmacophysiology of how thiazide diuretics work:
- Prevent dilution in early DCT
- Increased Na+ load in late DCT
- Increased calcium reabsorption
- Inhibit Na+/Cl- carrier by binding to Cl- site
- Potassium loss

1. Inhibit Na+/Cl- carrier by binding to Cl- site
2. Prevent dilution in early DCT
3. Increased Na+ load in late DCT
4. Potassium loss
5. Increased calcium reabsorption

39

What percentage of filtered Na+ do thiazides cause to be excreted?

~5%

40

How do thiazide diuretics enter the PCT?

Via OATs

41

Which of the following is not a use for thiazide diuretics:
- Hypertension
- Mild CHF
- Nephrolithiasis
- Chronic hepatitis
- Nephrogenic Diabetes Insipidus
- Severe pulmonary oedema

Chronic hepatitis

42

True or false; Thiazide diuretics can cause erectile dysfunction?

True

43

True of false; Thiazide diuretics do not affect glucose tolerance?

Fale - They impair it

44

What does aldosterone do in the late DCT and collecting duct?

Increases the synthesis of Na+/K+ ATPase via increased gene transcription
Increases the synthesis of a protein that activates Epithelial Na+ Channel on the apical membrane:
- Makes them open more frequently
These result in Na+ and water retention and K+ excretion

45

How does ADH work in the collecting ducts?

Acts via GPCRs to increase the number of aquaporins to allow more water reabsorption

46

What channels excrete K+ into the lumen at the apical membrane?

Renal outer medullary K+ channels (ROMK)

47

What causes the lumen to become more negative?

Increased Na+ reabsorption:
- Depolarizes basolateral vs apical membrane
-> As Cl- reabsorption

48

As the lumen becomes more negative, how is this corrected?

Increased K+ driving force:
-Increased K+ secretion to balance charge
-> H+ secretion also increased

49

How do Amiloride and Triamterene work?

Block apical ENaC:
- Reduces Na+ reabsorption
- Lumen is less negative
- Reduced K+ secretion
-> As charge doesn't need balanced

50

How do Spironolactone and Eplerenone work?

Compete with intracellular aldosterone receptors:
- Reduces ENaC activating protein synthesis
- Reduces Na+/K+ ATPase synthesis
-> Both cause reduced K+ excretion

51

What is spironolactone metabolised to that has the most diuretice action?

Canrenone

52

How do spironolactone and eplerenone gain access to the cells of the DCT and collecting duct?

Via basolateral membrane:
- They are lipophilic

53

What is the GI absorption like for Triamterene and Amiloride?

Triamterene -> Good
Amiloride -> Poor

54

When are aldostereone antagonists indicated?

CHF
Conn's
Resistant hypertension
Secondary hyperaldosteronism (in hepatic cirrhosis)

55

What type of diuretic is Mannitol?

An osmotic diuretic

56

What is the structure of Mannitol?

A membrane impermeant polyhydric alcohol

57

True or false, osmotic diuretics are pharmacologically inert?

True

58

How does Mannitol enter the nephron?

By glomerular filtration

59

Are osmotic diuretics reabsorbed?

No

60

How do osmotic diuretics work?

Increase filtrate osmolarity which results in the opposition of water reabsorption

61

Where is the primary site of action of Mannitol and why is this the primary site?

PCT:
- Most iso-osmotic water reabsorption

62

What is a secondary effect of Mannitol?

Reduces Na+ reabsorption in PCT

63

What type of renal failure can mannitol prevent?

Acute hypovolaemic renal failure

64

Apart from renal failure, when else is mannitol used? How does it help these states?

Increased ICP
Increased IOP
Increased plasma osmolality extracts water from these components

65

What type of drug is Acetazolomide?

Carbonic Anhydrase inhibitor

66

What does Acetazolomide do?

Increases the excretion of:
- Bicarbonate
- Na+
- K+
- Water

67

What does Acetazolomide result in due to the effect it has on urine excretion?

Alkaline diuresis:
- Relieve dysuria
Metabolic acidosis

68

How does Acetazolomide work in the treatment of glaucoma and post-ocular surgery?

Reduces IOP by reducing aqueous humour production

69

What ekse can Acetazolomide be used to treat?

Altitude sickness prophylaxis
Infantile epilepsy

70

What causes Neurogenic DI?

Lack of ADH secretion from posterior pituitary

71

How is Neurogenic DI treated?

Desmopressin:
- V₂-Selective GPCR
-> Avoids increased BP associated with V₁

72

What causes Nephrogenic DI?

Nephrons become insensitive to ADH:
- Usually due to recessive/X-linked mutations
-> In V₂ receptor

73

How is Nephrogenic DI treated?

It can't be

74

What drugs inhibit ADH?

Lithium
Demeclocycline
'Vaptans'

75

How do 'Vaptans' work?

Competitive antagonists of ADH receptors (V₁ₐ, V₁ᵇ and V₂)

76

What does activation of V₁ₐ receptors cause?

Vasoconstriction

77

What does activation of V₂ receptors cause?

Water reabsorption

78

Where does the activation of V₂ receptors have its affects and how?

In collecting duct:
Aquaporin-containg vesicles directed to apical membrane

79

What happens if V₂ receptors are blocked?

Increased water excretion
No Na+ accompanies the water so increased [Na+]p

80

What are some examples of 'Vaptans' and what receptors do they block?

Conivaptan (V₁ₐ and V₂)
Tolvaptan (V₂)

81

When might 'Vaptans' be used?

CHF
Most value in Hypervolaemic Hyponatraemia by reducing preload

82

What channels is glucose absorbed through in the PCT?

SGLT1 + 2

83

When is glycosuria present?

If [Glucose]filtrate >11mmol/L

84

Where is SGLT1 expressed?

Intestines and kidneys

85

Where is SGLT2 expressed?

Almost exclusively in the nephron PCT

86

Describe the process and features of glucose reabsorption by SGLT2?

S1 segment
90% of reabsorption
Low affinity
High capacity

87

Describe the process and features of glucose reabsorption by SGLT1?

S2/3 segment
10% of reabsorption
High affinity
Low capacity

88

How is glucose reabsorbed at the apical membrane?

Secondary active transport

89

How is glucose reabsorbed at the basolateral membrane?

Facilitated diffusion

90

What is the stoichiometry of each SGLT receptor?

SGLT1 -> 2 Na+ : 1 Glucose
SGLT2 -> 1 Na+ : 1 Glucose

91

What does SGLT2 inhibition result in?

Glycosuria

92

What are some examples of SGLT2 inhibitors?

Canagliflozin
Dapagliflozin
Empagliflozin

93

What effects do SGLT2 inhibitors have in T2DM?

Glucose excretion
Reduces HbA1c
Reduces weight

94

What are some side effects of SGLT2 inhibitors?

Glycosuria -> Increases bacterial and fungal UTI risk

95

Where is PGE₂ formed?

Renal medulla

96

Where is PGI₂ (Prostacyclin) formed?

Glomeruli

97

What are the functions of prostaglandins?

Vasodilate
Natriuretic

98

Which of the following does not result in prostaglandin synthesis:
- Ischaemia
- Mechanical trauma
- Angiotensin II
- Hyperkalaemia
- ADH
- Bradykinin

Hyperkalaemia

99

How much of an effect do prostaglandins have on RBF and GFR in normal people?

Very little

100

When do prostaglandins become more important?

In vasoconstriction
If there is a decrease in effective arterial BP

101

How do prostaglandins affect GFR?

1. Direct vasodilator effect on afferent arteriole
2. Increase renin release -> Increased Ang II levels -> Efferent arteriole vasoconstricts -> Increased filtration pressure
3. Both increase GFR

102

How do NSAIDs precipitate acute renal failure?

Inhibit COX so decrease prostaglandin synthesis

103

When especially do NSAIDs reduce GFR?

In conditions were renal blood flow depends on prostaglandins:
- Liver cirrhosis
- CHF
- Nephrotic syndrome

104

What drug combination can be bad?

ACEi + Diuretic + NSAIDs

105

What do Probenecid and Sulfinpyrazole do?

Block reabsorption of urate in PCT