Diuretics

• Five classes of diuretics

  • osmotic
  • carbonic anhydrase inhibitors
  • loop
  • thiazides
  • potassium-sparing
• Main indications for diuretics

  • oedema
  • congestive heart failure
  • hypertension
• most diuretics inhibit reabsorption of sodium at different levels of the renal tubule system. more sodium excreted = more water excreted
• Sometimes combinations of diuretics with different mechanisms are used (synergistic effect)
• Mannitol

  • pharmacologically inert
  • increases plasma osmolarity
  • filtered at glomerulus and poorly reabsorbed
  • increases osmotic pressure in glomerular filtrate
  • decreases H2O reabsorption from nephron
• Mannitol is an osmotic diuretic
• Uses of mannitol

  • forced diuresis e.g. in poisoning
  • acute glaucoma
  • cerebral oedema
  • slow IV infusion of 5 - 20 % solution
• Mannitol needs to be delivered by slow IV infusion, as you want to pull tissue from around the cells, rather than dehydrating the cells themselves
• NaCl or glucose cannot be used as osmotic diuretics as they are reabsorbed in the kidneys
• Acetazolamide is a carbonic anhydrase inhibitor
• Acetazolamide suppresses H+ production and thus reduces Na+/H+ exchange - less Na+ reabsorption. It increases excretion of HCO3- causing mildly alkaline urine, and metabolic acidosis.
• Use of carbonic anhydrase inhibitors

  • glaucoma
  • inhibits CA in eyes to reduce the formation of aqueous humour
  • adjunct therapy in metabolic alkalosis
  • prophylaxis of altitude sickness
• Adverse effects of carbonic anhydrase inhibitors

  • dizziness and light headedness
  • blurred vision
  • loss of appetite and stomach upset
• The effects of acetazolamide are self-limiting, because if the acid-base equilibrium is disrupted too much, other mechanisms will be used to generate H+ ions, and therefore the effects will be nullified.
• A healthy student attended a travel clinic in preparation for an expedition to the Himalayas. The GP prescribed acetazolamide tablets to protect against acute mountain sickness (headache, fatigue, dizziness). Why do you get this at high altitudes and how does acetazolamide help?

  Low oxygen = hyperventilation = more CO2 exhaled from lungs = respiratory alkalosis.

  Acetazolamide causes metabolic acidosis and this compensates for the alkalosis.
• Furosemide is a loop diuretic
• Furosemide

  • main action is to inhibit Na+/K+/2Cl- cotransporter
  • cause 15-25% of filtered Na+ to be excreted
  • result in increased osmotic pressure in filtrate delivered to distal tubule (decreases water reabsorption)
• Uses of furosemide

  • heart failure - chronic or acute (pulmonary oedema)
  • hypertension
  • hepatic cirrhosis complicated by ascites
  • nephrotic syndrome
  • renal failure
• Unwanted effects of furosemide (directly related to renal action)

  • hypovolaemia/hypotension - excessive Na+ loss and diuresis
  • Hypokalaemia - K+ loss
  • Metabolic or contraction alkalosis - increase plasma [HCO3-]
• Unwanted effects of furosemide unrelated to renal action

  • dose-related hearing loss
  • allergic reactions: rashes, bone marrow depression
• A 64 year old man with known congestive heart failure is admitted to the A+E with signs of acute pulmonary oedema. He is immediately treated with oxygen by face-mask, morphine for respiratory distress, nitrates as vasodilators to reduce the preload as well as a bolus of diuretics intravenously to stimulate diuresis. Which is the diuretic of choice to be used in this clinical condition (furosemide/mannitol)?

  Furosemide because it acts quickly and eliminates large volumes of urine. Mannitol can cross into the alveoli and worsen pulmonary oedema.
• Thiazides act in the DCT
• Carbonic anhydrase inhibitors act in the PCT
• Hydrochlorathiazide

  • action is to block Na+/Cl- cotransporter
  • results in higher osmolarity of urine and decreased water reabsorption
  • effect is self-limiting
  • lower blood volume leads to renin secretion, angiotensin formation and aldosterone secretion (limitation of effect of thiazides)
• Hydrochlorathiazide is a thiazide diuretic
• Uses of thiazide diuretics

  • long term use
  • congestive heart failure
  • hypertension
• Unwanted effects of thiazides related to renal action

  • hypokalaemia, metabolic alkalosis
  • hypercalcaemia
  • hypomagnesaemia
  • hyponatraemia
• Unwanted effects of thiazides unrelated to renal action

  • hyperuricaemia precipitating gout (thiazide competes with uric acid for tubular secretion)
  • hyperglycaemia (impaired pancreatic release of insulin and diminished tissue utilisation of glucose)
  • higher plasma cholesterol level
• Loop diuretics act on the ascending limb of the loop of Henle
• K+ sparing diuretics act at the collecting duct
• ENaC blocker triamterene and amiloride

  • directly block epithelial Na+ channel in distal tubule, collecting tubules and collecting ducts (limited diuretic efficiency)
  • used in conjunction with loop and thiazide diuretics to maintain K+ balance
• Unwanted effects of ENaC blockers

  • hyperkalaemia
  • GI disturbance
  • idiosycratic reactions: rashes
• Aldosterone antagonist spironolactone

  • used in conjunction with loop and thiazide diuretics to maintain K+ balance
  • adjunct therapy in heart failure
  • hyperaldosteronism
  • primary (Conn's syndrome)
  • secondary (due to hepatic cirrhosis)
• Unwanted effects of spironolactone

  • hyperkalaemia (can be fatal if ACE inhibitor, angiotensin receptor antagonist or B-blocker are prescribed)
  • gastrointestinal disturbance
  • menstrual disorders or testicular atrophy (acting on progesterone or androgen receptors)
• A 55 year old woman with known hypertension has been treated with furosemide and hydrochlorathiazide for peripheral oedema. At a regular check up the GP finds she still has ankle oedema. Blood work shows K+ 2.8 mEq/L. Should the GP increase the thiazide dose or add spironolactone?

  Add spironolactone - there is still ankle oedema, so you want to add another drug, but the potassium is low, so you want to specify a potassiumsparing diuretic.
• A patient with congestive heart failure becomes refractory to a loop diuretic even if the normal doses were progressively increased 5 fold. Blood work shows K+ 4.0 mEq/L. What do you do next?

  • increase furosemide 10fold
  • add thiazide
  • add spironolactone

  Add spironolactone because the potassium is low.
• Antihypertensives all have antiproteinuric effects and therefore are very valuable for use in chronic kidney disease
• Enalapril action - inhibit production of angiotensin II
• Enalapril use

  • high blood pressure
  • especially useful in reducing oedema resulting from heart failure
  • Chronic renal failure - antiproteinuric and protective effect
• Enalapril unwanted effects

  • headache
  • cough
  • dizziness
  • hyperkalaemia