Drugs that Act on the Kidneys III

Question 1

What is an example of an osmotic diuretic?

Answer 1

Mannitol IV

Question 2

What are osmotic diuretics?

Answer 2

Membrane impermeant polyhydric alcohols = pharmacologically inert

Question 3

How do osmotic diuretics enter the nephron?

Answer 3

By glomerular filtration = are not reabsorbed

Question 4

What effect do osmotic diuretics have on the filtrate?

Answer 4

Increase the osmolarity = opposes the absorption of water in parts of the nephron that are freely permeable to water

Question 5

Where is the major site of action in the kidneys of osmotic diuretics?

Answer 5

The proximal tubule = area where most iso-osmotic reabsorption of water takes place

Question 6

What is the secondary action of osmotic diuretics in the proximal tubule?

Answer 6

Decrease sodium reabsorption = larger fluid volume decreases sodium concentration and electrochemical gradient for reabsorption

Question 7

What are the uses of osmotic diuretics?

Answer 7

Prevention of acute hypovolaemic renal failure to maintain urine flow
Urgent treatment of acutely raised intracranial and intra-ocular pressure

Question 8

What are the adverse effects of osmotic diuretics?

Answer 8

Transient expansion of blood volume, hyponatraemia

Question 9

How can hyperglycaemia cause osmotic diuresis?

Answer 9

Reabsorptive capacity of proximal tubule for glucose is exceeded = glucose remaining in filtrate retains fluid

Question 10

How can iodine-based radiocontrast dyes cause osmotic diuresis?

Answer 10

Dye filtered at glomerulus but not reabsorbed = constitutes osmotic load

Question 11

What is an example of a carbonic anhydrase inhibitor?

Answer 11

Acetazolamide = increases excretion of HCO3-with Na+, K+ and H2O

Question 12

What do carbonic anhydrase inhibitors cause?

Answer 12

Alkaline diuresis and metabolic acidosis

Question 13

What conditions are carbonic anhydrase inhibitors used to treat?

Answer 13

Glaucoma and following eye surgery
Prophylaxis of altitude sickness
Some forms of infantile epilepsy

Question 14

What are the benefits of alkanising urine?

Answer 14

Relief of dysuria, prevention of weak acid crystallisation, enhanced weak acid excretion

Question 15

What does aldosterone cause in the kidneys?

Answer 15

Enhanced tubular Na+ reabsorption and salt retention

Question 16

What does ADH cause?

Answer 16

Enhanced H2O reabsorption

Question 17

What are the symptoms of diabetes insipidus?

Answer 17

Similar to diabetes = polyuria, thirst, polydipsia

Urine is copious and dilute

Question 18

What is neurogenic diabetes insipidus?

Answer 18

Lack of ADH secretion from posterior pituitary = treated with desmopressin

Question 19

What is desmopressin?

Answer 19

Synthetic analogue of ADH with V2 selectivity

Question 20

What is nephrogenic diabetes insipidus?

Answer 20

Inability of nephron to respond to ADH = rare, caused by recessive and X-linked mutations in AVPR2

Question 21

What are some substances that inhibit the action of ADH?

Answer 21

Lithium, demeclocycline, vaptans

Question 22

What are vaptans?

Answer 22

Act as competitive antagonists of ADH receptors = V1A, V1B, V2

Question 23

What do V1A receptors mediate?

Answer 23

Vasoconstriction

Question 24

What do V2 receptors mediate?

Answer 24

H2O reabsorption in collecting tubule = direct AQP2-containing vesicles to apical membrane

Question 25

What does block of V2 receptors cause?

Answer 25

Excretion of water without accompanying Na+ = raises plasma Na+ concentration

Question 26

What are some indications of vaptan use?

Answer 26

Hypervolaemic hyponatraemia = to reduce preload | Tolvaptan can be used in syndrome of inappropriate ADH to correct hyponatraemia

Question 27

What are some examples of vaptans?

Answer 27

``` Conivaptan = V1A and V2 antagonist Tovaptan = V2 antagonist ```

Question 28

Where does reabsorption of glucose occur?

Answer 28

In the proximal tubule of the kidney mediated by SGLT1 and SGLT2

Question 29

When does glucose appear in the urine?

Answer 29

Reabsorption normally 100% = glucose only appears in urine if filtrate concentration of glucose exceeds renal threshold (about 11 mmol/l)

Question 30

Where are SGLT1 and SGLT2 expressed?

Answer 30

``` SGLT1 = by enterocytes and the kidneys SGLT2 = almost exclusively confined to the proximal tubule ```

Question 31

What effect do drugs that selectively block SGLT2 have?

Answer 31

Only have an effect on renal reabsorption of glucose

Question 32

How much glucose is reabsorbed by SGLT1 and SGLT2?

Answer 32

``` SGLT2 = S1 segment, reabsorbs up to 90% SGLT1 = S2 and 3 segments, reabsorbs up to 10% ```

Question 33

How is glucose reabsorbed in the proximal tubule?

Answer 33

By secondary active transport and the apical membrane and facilitated diffusion at the basolateral membrane

Question 34

How do SGLT1 and SGLT2 transport glucose against a concentration gradient?

Answer 34

By coupling it to Na+ influx

Question 35

What is the transport stoichiometry of SGLT1 and SGLT2?

Answer 35

``` SGLT1 = 2Na+:1 glucose, high affinity, low capacity SGLT2 = 1Na+:1 glucose, low affinity, high capacity ```

Question 36

What does SGLT2 inhibition result in?

Answer 36

Glucosuria

Question 37

What are some examples of SGLT2 inhibitors?

Answer 37

Canagliflozin, dapagliflozin, empagliflozin

Question 38

What are the effects of SGLT2 inhibitors?

Answer 38

Excretion of glucose, decrease in HBA1c, weight loss | Adverse effects = genital bacterial and fungal infections

Question 39

What are prostaglandins?

Answer 39

Part of prostanoid family = formed from fatty acid arachidonic acid by COX 1 and 2

Question 40

What are some features of prostaglandins?

Answer 40

Act as vasodilators and are natriuretic | Synthesised in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin

Question 41

What are the two major prostaglandins synthesised by the kidney?

Answer 41

``` PGE2 = medulla PGI2 = glomeruli ```

Question 42

What effect do prostaglandins have in normal conditions?

Answer 42

Have very little effect on renal blood flow or GFR

Question 43

Under what conditions do prostaglandins cause compensatory vasodilation?

Answer 43

During decrease effective arterial blood volume or vasoconstriction

Question 44

How do prostaglandins affect GFR?

Answer 44

Direct vasodilator effect upon afferent arteriole Releases renin leading to increased levels of angiotensin II Vasoconstricts efferent arteriole (increases filtration pressure)

Question 45

Why can NSAIDs cause acute renal failure in conditions where renal blood flow is dependent on prostaglandin compensatory action ?

Answer 45

Inhibit COX so may reduce prostaglandins = occurs in liver cirrhosis, heart failure and nephrotic syndrome

Question 46

What is three drugs make up the "triple whammy" effect that may cause acute renal failure in conditions dependent on compensation by prostaglandins?

Answer 46

ACE inhibitors/ARBs, diuretics and NSAIDs

Question 47

What is uric acid formed as a result of?

Answer 47

Purine synthesis

Question 48

What does elevated plasma urate predispose to?

Answer 48

Gout

Question 49

What are some examples of uricosuric agents?

Answer 49

Probenecid and sulfinpyrazole = may help treat gout by blocking absorption of urate in proximal tubule

Question 50

What are the points of action of uricosuric agents?

Answer 50

Urate secretion = blocked by low sub-therapeutic doses | Urate secretion and reabsorption = blocked by therapeutic doses, net effect is enhanced excretion