Drugs affecting the kidneys

Question 1

what are diuretic agents

Answer 1

a drug that increases the excretion of both fluids and solutes

Question 2

what is a natriuretic

Answer 2

increases Na+ excretion

Question 3

what is a kaliuretic

Answer 3

increases k+ excretion

Question 4

how to increase excretion of na+ and water by kidney

Answer 4

1. reduce reabsorption of na+ from the filtrate

2. increased water loss secondary to na+ excretion

Question 5

what are the 2 modes of action of diuretics

Answer 5

1. direct action on the cells of the nephron

2. modification of content of the filtrate

Question 6

what are the 2 major applications of diuretic agents

Answer 6

1. reduce circulating fluid volume
2. removal of excess body fluids (oedema)
   - via actions on the kidney

Question 7

name the classes of diuretic agents

Answer 7

1. carbonic anhydrase inhibitors
2. osmotic inhibitors
3. loop diuretics
4. thiazides and thiazide like diuretics
5. potassium sparing diuretics- aldosterone antagonists, non aldosterone antagonists

Question 8

where is the main site of action of carbonic anhydrase inhibitors

Answer 8

proximal tubule

Question 9

what is the main site of action of osmotic diuretics

Answer 9

proximal tubule and descending loop of henle

Question 10

where is the main site of action of loop diuretics

Answer 10

ascending loop of henle

Question 11

what is the main site of action of thiazide diuretics

Answer 11

early distal tubule

Question 12

what is the main site of action of potassium sparing diuretics

Answer 12

late distal tubule and early collecting tubule

Question 13

where do most diuretic agents act

Answer 13

most are secreted into the proximal tubule and therefore produce their actions from the luminal side of the tubule

Question 14

give examples of loop diuretics

Answer 14

furosemide, bumetanide

Question 15

describe the action of loop diuretics

Answer 15

1. most effective diuretics available
2. often called high ceiling diuretics- lead to torrential urine flow
3. inhibit Na+/K+/2Cl- transporters (NKCC2) in the thick ascending limb of loop of henle
   - this reduces reabsorption of Na+, k+ and cl-
4. reduced na+ reabsorption leads to rapid and profound diuresis
5. single dose: increases urine volume from 200-1200ml over 3 hours

Question 16

what are the clinical uses of loop diuretics

Answer 16

1. acute pulmonary oedema
2. chronic heart failure
3. cirrhosis of the liver
4. nephrotic syndrome (reduced urine production)
5. acute renal failure (reduced urine production)

Question 17

what are the unwanted effects of loop diuretics

Answer 17

1. dehydration
2. K+ loss leading to low plasma K+ (hypokalaemia)
3. metabolic alkalosis (due to H+ loss in urine)
4. hypokalaemia can potentiate effects on cardiac glycosides
5. deafness (when used with aminoglycoside antibiotics)

Question 18

describe the sodium potassium exchange in the distal tubule when using loop diuretics

Answer 18

loop diuretics cause increased na+ delivery to the distal tubule

• this is exchanged for k+ in the distal tubule which is excreted in the urine
• this contributes to the hypokalaemia associated with loop diuretics

Question 19

describe how thiazide diuretics work

Answer 19

1. act in the distal tubule to inhibit the na+/cl- transport system
2. cause moderate but sustained na+ excretion with increased water excretion
3. moderately powerful diuresis- but maximum diuresis produced is considerably lower than that produced by loop diuretics
4. well absorbed from GIT and long duration of action- up to 24 hours

Question 20

what is the prototype thiazide diuretic

Answer 20

hydrochlorothiazide

Question 21

give examples of thiazide diuretics

Answer 21

bendroflumethiazide (useful for mild/moderate heart failure)

Question 22

how to thiazide like diuretics differ from thiazide diuretics

Answer 22

similar but have different molecular structures

Question 23

give examples of thiazide like diuretics

Answer 23

indapamide, metolazone

Question 24

what are the clinical uses of thiazide diuretics

Answer 24

1. hypertension
2. oedema
3. mild heart failure

Question 25

what are the unwanted effects of thiazide diuretics

Answer 25

1. plasma k+ depletion (due to urinary k+ loss) 2. metabolic alkalosis (due to urinary h+ loss) 3. increased plasma uric acid- gout 4. hyperglycaemia (increased blood glucose) 5. increased plasma cholesterol (with long term use) 6. male impotence (reversible)

Question 26

what is indapamide currently used for

Answer 26

currently the preferred thiazide diuretic for the treatment of resistant hypertension due to lower incidence of unwanted effects

Question 27

what are the symptoms of mild hypokalaemia

Answer 27

fatigue, drowsiness, dizziness, muscle weakness

Question 28

what are the symptoms of severe hypokalaemia

Answer 28

abnormal heart rhythm, muscle paralysis, death

Question 29

how can the issue of hypokalaemia be avoided in the use of diuretics

Answer 29

potassium sparing diuretics can be used

Question 30

give examples of aldosterone antagonist potassium sparing diuretics

Answer 30

spironolactone and eplerenone

Question 31

give examples of non aldosterone antagonist potassium sparing diuretics

Answer 31

amiloride and triamterene

Question 32

describe how aldosterone antagonists work

Answer 32

1. spironolactone metabolised to canrenone- active metabolite - a competitive antagonist of aldosterone receptor 2. reduces na+ channel formation and its absorption from distal tubule 3. limited diuretic action (not as potent as loop diuretics or thiazides) 4. as mechanism depends on protein expression in distal tubular cells, so effects may take several days to develop

Question 33

what are the clinical uses of spironolactone

Answer 33

1. heart failure 2. oedema 3. primary hyperaldosteronism 4. secondary hyperaldosteronism

Question 34

what are the unwanted effects of aldosterone antagonists

Answer 34

1. hyperkalaemia (increased plasma k+ levels) 2. metabolic acidosis (due to increased plasma h+) 3. GI upsets 4. menstrual disorders, testicular atrophy 5. eplerenone produces less unwanted effects than spironolactone

Question 35

describe the use of non aldosterone antagonists

Answer 35

1. weak diuretics- act on distal tubule to inhibit na+ reabsorption and decrease k+ excretion 2. blocks luminal na+ channel by which aldosterone produces its main effects 3. of little therapeutic use alone but useful in combination with potassium depleting diuretics as they limit hypokalaemia

Question 36

what are the unwanted effects of non aldosterone antagonists

Answer 36

hyperkalaemia, metabolic acidosis, GI disturbances, skin rashes

Question 37

explain why diuretics are sometimes used in combination

Answer 37

1. to increase diuretic effect- some patients don't respond well to one type of diuretic - combinations of diuretics with different sites of action can sometimes provide a synergistic action 2. to avoid the unwanted effects of hypokalaemia - combinations of loop/thiazides with potassium sparing diuretics - diuretic preparations containing k+

Question 38

give examples of diuretic combinations designed to minimise hypokalaemia

Answer 38

1. loop diuretics with spironolactone 2. loop diuretics with amiloride or triamterene 3. thiazides with spironolactone 4. thiazides with amiloride or triamterene 5. diuretics with k+: eg. furosemide and K+

Question 39

describe how water can act as a diuretic

Answer 39

1. the most simple diuretic 2. under normal conditions, increased water intake leads to increase in volume of urine excreted 3. process is controlled by antidiuretic hormone (regulates water balance) - normally some ADH is present in circulation, maintaining urine volume at approx 1.5L/day 4. increased fluid intake leads to reduced secretion of ADH from the posterior pituitary due to reduction in plasma osmolality 5. reduced expression of AQP2 receptors on apical surface of distal tubules and collecting duct cells means more water excretion

Question 40

does water as a diuretic increase excretion of na+

Answer 40

there is no increased excretion of na+ | - AQP2 channel moves water only

Question 41

what are potential ADH antagonists

Answer 41

investigational drugs which inhibit the effects of ADH at the collecting tubule - 2 non selective agents: Lithium and democlocycline

Question 42

what unwanted effects have been identified in potential ADH antagonists

Answer 42

1. can cause diabetes inspidus 2. renal failure reported 3. Li+ can cause tremors, mental confusion, cardio toxicity, thyroid dysfunction and leukocytosis 4. democlocycline shouldn't be used in patients with liver disease

Question 43

give examples of xanthines

Answer 43

caffeine, theophylline, theobromine

Question 44

describe the effects of xanthines

Answer 44

1. commonly found in tea and coffee 2. produce their weak diuretic effect by increasing cardiac output and causing renal vasodilation 3. results in increased renal blood flow which increases glomerular filtration rate and urine output 4. rarely used clinically due to gastric irritant effects