Diuretics

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Diuretics
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Why do we want to know about diuretics?

• What do kidneys do?
• What can go wrong?
• Interventions that can be used
• how do they work?
• Effects, side effects

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Functions of the kidney?

• Excretion of waste products
• regulation of salt and electrolyte content
• and volume of extra -cellular fluid
• acid -base balance

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How?

• Several hundred litres of plasma filtered/day
• filtrate - very little protein/protein bound
  substances
• 99 of sodium is reabsorbed, some substances
  secreted
• 1.5 litres voided as urine
• Diuretics increase salt and water excretion

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Why diuretics?

• important group of drugs employed for their
  effects on the kidney to enhance salt and water
  excretion (only when needed)
• when used heart failure, other causes of salt
  and water retention (renal failure, liver
  failure), hypertension

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Variety of compounds with diuretic activity

• Xanthines - theophylline, caffeine
• osmotic diuretics - urea
• carbonic-anhydrase inhibitors
• thiazides
• loop diuretics
• aldosterone antagonists
• potassium sparing diuretics

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How do they work?

• Direct effect on cells of the nephron..
• where most of the active and selective solute
  reabsorption occurs
• ascending loop of Henle
• early distal tubule
• collecting tubules and ducts
• OR
• modifying the content of the filtrate by their
  presence

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Loop diuretics (Rang and Dale p361-363)

• Frusemide, bumetanide, piretanide
• act on thick segment of ascending loop
• inhibit NaCl transport OUT of tubule by
  inhibiting Na/K/2Cl- carrier (co-transporter)
  in luminal membrane ( acting on chloride binding
  site)
• Reduces the hypertonic interstitial area in the
  medull, so reducing water re-absorption
• increases Na solute concentration in the distal
  tubule which is exchanged for K and H
  (hypokalemia and alkalosis)
• Can increase the excreted sodium from 1 to 15
  of filtrate
• Also reduce peripheral vascular resistance

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Loop diuretics

• Kinetics
• oral and IV preparations
• bound to plasma protein, secreted into tubule
• metabolised by the liver ( P450)
• act within 1 hour
• half life about 90 minutes longer in renal
  failure
• duration - 3-6 hours (Lasts Six Hours Lasix)

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Loop diuretics

• Effects
• pass urine in large amounts!
• Side effects
• electrolyte depletion
• Hypovolemia
• other reactions rare
• Main Use
• Heart failure particularly acute left
  ventricular failure
• Hepatic cirrhosis
• Nephrotic syndrome
• Renal failure

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thiazide diuretics

• bendrofluazide, hydrochlorothiazide, indapamide
• act on distal convoluted tubule
• bind to chloride site of Na/Cl cotransport
  system and inhibit action
• decrease active Na resorption
• decrease water resorption
• changes in Ca, magnesium and uric acid

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thiazide diuretcis

• kinetics
• rapidly absorbed orally
• secreted into the tubule
• maximal effect 4- 6 hours, duration 8-12 hours

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thiazide diuretics

• effects
• increase urine output
• side effects
• electrolyte disturbances
• increased cholesterol
• impotence
• hypersensitivity reactions (rare)
• Main uses
• hypertension
• mild heart failure

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aldosterone antagonists

• spirololactone
• inhibits action of aldosterone (intracellular
  receptor binding anatagonism), increases sodium
  and decreases potassium secretion
• kinetics
• well absorbed orally, active metabolite half life
  of 16 hours
• effects
• limited diuresis
• Main uses heart failure and cirrhosis
• side effects
• Hyperkalemia, estrogen like effects

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other potassium sparing diuretics

• Triamterene, amiloride
• act on collecting ducts
• inhibit Na resorption, decrease potassium
  excretion
• effects
• limited diuresis
• side effects
• electrolyte disturbances

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clinical choices

• Uses
• cardiac failure
• hypertension
• fluid overload
• NOT for everyone with oedema (eg from venous
  insufficiency)
• acute versus chronic
• evidence of benefit

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references

• Rang Dale, 5th edition
• Cardiovascular Therapeutic Guidelines
• Australian Medicines Handbook