Drugs affecting the kidneys- diuretic agents

Question 1

What are diuretic agents?

Answer 1

A drug that increases the excretion of both fluids and solutes

Question 2

Natriuretic

Answer 2

Increases Na+ excretion

Question 3

Kaliuretic

Answer 3

Increases K+ excretion

Question 4

Two major applications of diuretic agents

Answer 4

1. Reduce circulating fluid volume

2. Removal of excess body fluids

Question 5

Site of action of carbonic anhydrase inhibitors

Answer 5

Proximal tubule

Question 6

Site of action of osmotic diuretics

Answer 6

Proximal tubule

Descending loop of henle

Question 7

Site of action of loop diuretics

Answer 7

Ascending loop of henle

Question 8

Site of action of thiazide and thiazide like diuretics

Answer 8

Early distal tubule

Question 9

Site of action of K+-sparing diuretics

• aldosterone antagonists
• non- aldosterone antagonists

Answer 9

Late distal tubule

Early collecting duct

Question 10

Loop diuretics

Answer 10

Most effective

Inhibit Na+/K+/2Cl- transporters in thick ascending limb (reduces reabsorption)

Increased Na+ delivery to DT, exchanged for K+ which is excreted in urine

Reduced Na+ reabsorption leads to rapid and profound diuresis

Question 11

Loop diuretics clinical data

Answer 11

Oral absorption

• diuresis in 60 minutes
• persits for 4-6 hours

IV administation

• diuresis within 5minutes
• persists for 2 hours

IM administration
- diuresis in 30 minutes

Question 12

Clinical uses of loop diuretics

Answer 12

MORE ACUTE CASES

Acute pulmonary oedema

Chronic heart failure

Cirrhosis of the liver

Resistant hypertension

REDUCED URINE PRODUCTION

Nephrotic syndrome

Acute renal failure

Question 13

Unwanted effects of loop diuretics

Answer 13

Dehydration

K+ loss leads to hypokalaemia

Metabolic alkalosis due to H+ loss in urine

Hypokalaemia can potentiate effects of cardiac glycosides

Deafness (when used with aminoglycoside antibiotics)

Question 14

Thiazide diuretics

Answer 14

Act in DT to inhibit apical Na+/Cl- co-transporter

Cause moderate but sustained Na+ excretion with increased water excretion

Moderately powerful diuretics

Well absorbed from GI tract and long duration of action (up to 24 hours)

Question 15

Thiazide diuretics clinical data

Answer 15

Prototype is hydrochlorothiazide

Main is benzoflumethiazide

Question 16

Clinical use of thiazide diuretics

Answer 16

Hypertension

Oedema

Mild heart failure

Question 17

Unwanted effects of thiazide diuretics

Answer 17

Plasma K+ depletion

Metabolic alkalosis

Increased plasma uric acid- gout

Hyperglycaemia

Increased plasma cholesterol (long term use)

Male impotence (reversible)

Question 18

Hypokalaemia

Answer 18

Mild: fatigue, drowsiness, dizziness, muscle weakness

Severe: abnormal heart rhythm, muscle paralysis, death

K+ sparing diuretics

• act on DT to inhibit Na+ reabsorption
• K+ is not secreted into distal tubule

Question 19

Subcategories of K+ sparing diuretics

Answer 19

Aldosterone antagonists

• eplerenone
• spironolactine

Non-aldosterone antagonists

• amiloride
• triamterene

Question 20

Aldosterone antagonists

Answer 20

Sprironolactone metabolised to canrenone

Competitive antagonist of aldosterone- reduce Na+ channel formation

Reduces Na+ absorption from DT

Question 21

Clinical uses of sprionolactone

Answer 21

SHORT TERM

Heart failure

Oedema

Question 22

Unwanted effects of spironolactone

Answer 22

Hyperkalaemia

Metabolic acidosis

GI upsets

Gynaecomastia, menstrual disorders, testicular atrophy

Eplerenone produces less effects

Question 23

Triamterene and Amiloride

Answer 23

Weak diurects- act on DT to inhibit Na+ reabsorption and decrease K+ excretion

Blocks luminal Na+ channel

Main unwanted effects

• hyperkalaemia
• metabolic acidosis
• GI disturbances
• skin rashes

Question 24

Combination of diuretics

Answer 24

Increases diuretic effect

Avoids unwanted effects of hypokalaemia

Question 25

How to avoid hypokalaemia

Answer 25

Loop diuretics with spironolcatone Loop diuretics with amiloride or triamterene Thiazides with sprionolactone Thiazides with amiloride or triamterene Diuretics containing K+

Question 26

Carbonic anhydrase inhibitors

Answer 26

Blocks NaHCO3 reabsorption in PT Causes weak diuresis Used for - glaucoma - epilepsy Unwanted effects - metabolic acidosis - enhances renal stone formation

Question 27

Osmotic diuretics

Answer 27

Main- mannitol - non- reabsorbable solute undergoes glomerular filtration - excretion within 30-60 mins - diuresis in 30-60 mins persists for 6-8 hours Clinical uses - cerebral oedma - glaucoma - cause osmotic diarrhoea - acute renal failure Unwanted effects - increases plasma volume - can't be used in patients with hypertension

Question 28

Water as a diuretic

Answer 28

Process controlled by ADH Increased fluid intake leads to reduced secretion of ADH from posterior pituitary due to reduced plasma osmolality Reduced expression of AQP2 channels on apical surface of DT and collecting duct

Question 29

Potential ADH antagonists

Answer 29

Investigational drugs which inhibit the effects of ADH at collecting tubule Two non- selective agents - lithium (Li+) - demeclocycline

Question 30

Toxicity problem of ADH antagonists

Answer 30

Can cause diabetes insipidus Renal failure Li+ cause tremors, mental confusion, cardiotoxicity, thyroid dysfunction and leukocytosis Demeclocycline shouldn't be used in patients with liver disease

Question 31

Xanthines

Answer 31

Caffeine, theophylline, theobromine Produce weak diuretic effect by increasing cardiac output Possibly also some vasodilation of glomerular afferent arteriole Increased renal and glomerular blood flow, increase GFR and urine output