T3 L6: Diuretic agents

• What are diuretic agents?

  any compound that increases the volume of urine excreted from body

  (both fluids and solutes)

  Natriuretic: increase Na+ excretion

  Kaliuretic: increase K+ excretion

  Most diuretics reduce reabsorption of Na from filtrate → increased water loss
• What are 'aquaretic agents'?

  New diuretics that increase urine excretion without increasing Na+ excretion
• What are the two modes of action of diuretics?

  1. Direct action on cells of the nephron (more common)
  2. Modification of content of filtrate
• What are the two major applications of diuretic agents?

  1. Reduce circulating fluid volume
  2. Removal of excess body fluid (oedema)
• What part of the nephron doe the majority of fluid reabsorption take place in?

  proximal tubule (70%)
• What are the classes of diuretic agents and their main site of action?


  • Carbonic Anhydrase inhibitors: proximal tubule
  • Osmotic diuretics: Proximal tubule & descending LOH
  • Loop diuretics: Ascending LOH
  • Thiazide: Early distal tubule
  • Potassium-sparing diuretics (aldosterone antagonists & non-aldosterone antagonists): Late distal tubule & early collecting tubule

  
• Where are most diuretic agents secreted into and where to they produce actions?

  secreted into proximal tubule

  produce actions from luminal (urine) side of tubule
• What are Loop diuretics?

  most effective diuretics available

  'high-ceiling diuretics' → 'torrential urine flow'

  mechanism: inhibit NKCC2 (Na/K/Cl/Cl transporters) in ascending LOH → reduce reabsorption of Na, K, Cl → rapid diuresis

  
• What are the unwanted effects of loop diuretics?

  dehydration

  hypokalaemia: K loss leading to low plasma K

  metabolic alkalosis: due to H+ loss in urine

  deafness (when used with aminoglycoside antibiotics)
• What are the clinical uses of loop diuretics?

  • acute pulmonary oedema
  • Chronic heart failure (used for more acute cases)
  • Cirrhosis of liver
  • resistant hypertension
  • nephrotic syndrome (reduced urine production - oliguria)
  • acute kidney injury
• What are the effects of loop diuretics on Na-K exchange in DT?

  inhibit Na/K/Cl/Cl→ less Na reabsorbed into blood → cause increased Na delivery to distal tubule → exchanged for K in DT → excreted in urine → hypokalaemia

  
• What are Thiazide diuretics?

  act in distal tubule

  inhibit apical Na/Cl co-transporter

  cause moderate but sustained Na excretion with increased water excretion

  moderately powerful diuresis: but maximum diuresis produced considerably lower than that by loop diuretics

  Pros: well absorbed from GI tract and long duration of action

  
• What are the unwanted effects of thiazide diuretics?

  plasma K depletion (due to urinary K loss)

  metabolic alkalosis (due to urinary H+ loss)

  Increased plasma uric acid - gout

  Hyperglycaemia

  Increased plasma cholesterol (with long-term use)

  Male impotence
• What is Indapamide?

  thiazide diuretics

  currently preferred diuretic for resistant hypertension

  due to lower incidence of unwanted effects
• What are the clinical uses of Thiazide diuretics?

  hypertension

  oedema (generally used for less acute conditions)

  mild heart failure
• How can hypokalaemia be a problem of thiazide and loop diuretic use?

  due to increased loss of K+ in urine

  • Mild hypokalaemia: fatigue, drowsiness, dizziness, muscle weakness
  • Severe hypokalaemia: abnormal heart rhythm, muscle paralysis, death
• What are Potassium-sparing diuretics good for?

  act on distal tubules to inhibit Na reabsorption

  diuresis without losing K+ in urine, hence avoids hypokalaemia

  Two subcategories:

  1. Aldosterone antagonists
  2. Non-aldosterone antagonists
• What are potassium-sparing diuretics?

  eg Spironolactone and Epleronone

  competitive antagonist of aldosterone receptor

  reduces Na channel formation and its absorption from distal tubule

  • limited diuretic action
  • mechanism depends on reduction of protein expression, so effects take several days to develop

  
• What are the clinical uses of Spionolactone?

  heart failure

  oedema

  (short term use)

  can also be used for resistant hypertension; however concerns over long-term use due to possible incidence of cancer
• What are the unwanted effects of Spironolactone?

  hyperkalaemia - needs to be monitored regularly

  metabolic acidosis

  GI upsets

  gynaecomastita, menstrual disorders, testicular atrophy

  (eplerenone produces less unwanted effects)
• What are Triamterene and Amiloride?

  weak diuretics

  act on distal tubule to inhibit Na+ reabsorption and decrease K+ excretion

  blocks luminal Na channel (where aldosterone acts)

  aldosterone can't produce main effects

  of little use alone, but useful in combination with potassium-depleting diuretics

  Main unwanted effect: hyperkalaemia, metabolic acidosis, GI disturbances, skin rashes

  
• Why are diuretics used in combination?

  • to increase diuretic effect
  • avoid unwanted effects of hypokalaemia
• Diuretic combinations: how to avoid hypokalaemia?

  loop diuretics with spironolactone: Lasilactone

  Loop diuretics with amiloride or tramterene: Co-amilofruse

  Thiazides with spironolactone: Co-flumactone

  Thiazides with amiloride or triamterene: Co-amilozide

  Diuretics containing K+: Burinex K
• What are carbonic anhydrase inhibitors and what is an example?

  eg Azetozolamide

  blocks sodium bicarbonate reabsorption in PT

  weak diuresis

  used for: glaucoma, epilepsy

  unwanted effects: metabolic acidosis, enhance renal stone formation due to alkaline urine
• What are osmotic diuretics and what is an example?

  eg Mannitol

  non-reabsorbable solute which undergoes glomerular filtration

  excreted within 30-60mins

  Clinical uses: raised intercranial pressure (cerebral oedema), intraoccular pressure (glaucoma), acute renal failure, 'osmotic diarrhoea' to eliminate toxins

  Unwanted effects: presence in blood exerts osmotic pressure → increased plasma volume

  so can't be used in patients with HYPERTENSION
• How is water as a diuretic?

  most simple diuretic is water

  increased water intake → increase in volume of urine excreted

  controlled by ADH:

  increased fluid intake → reduced plasma osmolarity →ADH secretion → reduced AQP2 expression → more water excretion

  can be affected by alcohol, nicotine
• Why is water actualy an 'aquaretic'?

  there is no increased excretion of Na+ when water acts as a diuretic

  as AQP2 channels move water only
• What are ADH antagonists?

  Possible new diuretic agents

  which inhibit effects of ADH at collecting duct

  Two non-selective agents: Lithium and demeclocycline
• What are the potential problems involving ADH antagonists as possible diuretic agents?

  Toxicity:

  1. Can cause diabetes insipidus
  2. Renal failure reported for both Li and demeclocycline
  3. Li can cause tremors, mental confusion, cardiotoxicity, thyroid dysfunction and leukocytosis
  4. Demeclocycline shouldn't be used in patients with liver disease
• What are ADH antagonists and V2 receptor antagonists?

  potential new diuretic agents in development
• What are Xanthines?

  eg: caffeine

  commonly found in tea and coffee

  produce weak diuretic effect by increasing cardiac output

  possibly also vasodilatation of glomerular afferent arteriole

  result: increased renal and glomerular blood flow → increases GFR & urine output

  rarely used clinically due to gastric irritant effects