Diuretics

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• Diuretics
• Diuresis increased urine flow
• Diuretics substances which elicit diuresis
• In the kidney, water reabsorption dependent
  primarily on Na reabsorption
• Thus a diuretic is an agent which inhibits
  tubular Na reabsorption (along with Cl-, HCO3-)
  resulting in increased excretion of these ions.

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• Natriuretic effect (enhance secretion of sodium
  and thus
• water)
• Mainly act by decreasing tubular reabsorption at
  one or more sites in nephron
• Diuretics can have effects on
• - Sodium reabsorption
• - Potassium loss
• - Body fluids

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• Effect on sodium reabsorption
• Na reabsorption could be reduced by
• 1. Inhibition of uptake into tubular cells
• 2. Inhibition of reabsorption through the tight
  junctions
• 3. Inhibition of extrusion across the
  basolateral membrane
• Most diuretics in common use act on sodium
  transporters in luminal membranes of cells in
  distal and/or collecting ducts

4

• Mechanism for salt reabsorption
• 1 Na, 2 Cl- and possibly one K enter cell
  together across luminal membrane by co-transport
  process.
• If K required, it leaks back into lumen
• Overall process causes lumen to become positive
• Positive lumen drives out more Na through tight
  junctions (cation permeable)
• Na entering nephron cells pumped out of cells
  across basolateral membrane by sodium pump

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Sodium reabsorption in the early PCT
Lumen (urine)
Peritubular (Blood)
Na
Na
H
K
Na
Glucose, Phosphate, Amino acids,
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Sodium reabsorption in the late PCT
Lumen (urine)
Peritubular (Blood)

Cl-

Na

H

H-Anion
H-Anion


Anion

Cl-
Na


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Sodium reabsorption in the thick ascending limb
of loop of Henle
Lumen (urine)
Peritubular (Blood)
Na
Cl-
2Cl-
K
Na
Na
K
H
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Sodium reabsorption in the DCT
Lumen (urine)
Peritubular (Blood)
Na
Na
K
Cl-
H2O
Cl-
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Sodium transport in the Collecting Duct
Lumen (urine)
Peritubular (Blood)
Na
Na
K
K
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• Except for K-sparing diuretics, all diuretics
  not only increase Na excretion, but also cause
  increased K secretion (unwanted side-effect)
• Diuretics (except osmotic diuretics) are organic
  acids
• Secreted by the PCT secretory mechanism
• Higher concentration within tubule than blood
• Exert their effects from within tubule
• There are several chemical types and several
  possible sites of action for diuretcis within the
  nephron.

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• Diuretics are substances that increase the rate
  of urine output.
• Therefore typically larger volumes of dilute
  urine might be expected to be produced.
• Many diuretics act to block the reabsorption of
  sodium chloride from the tubule.
• Sodium chloride is a solute and as such exerts an
  osmotic effect which reduces the rate of water
  reabsorption from the tubule.
• Consequently if the rate of reabsorption of
  sodium chloride is reduced the volume of urine
  produced increases.
• Diuretics maybe used to aid in the correction of
  fluid accumulation or the effects of fluid
  accumulation such as hypertension.

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• Types Of Diuretics.
• There are a number of different types of
  diuretics.
• Types of diuretics are generally classified
  according to their mode of action.
• Some example of types of diuretics are shown
  below.
• Osmotic diuretics.
• Loop diuretics.
• Thiazide diuretics.
• Carbonic anhydrase diuretics.
• Competitive inhibitors of aldosterone.
• Sodium channel blockers.

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• Osmotic Diuretics.
• Osmotic diuretics generally consist of molecules
  which are small enough to pass through the
  ultrafiltration barrier and enter the nephron.
• However, the molecules that form osmotic
  diuretics either block the reabsorption of
  solutes from the nephron (especially sodium) or
  are not easily absorbed from the nephron
  themselves (mannitol).
• Consequently solutes remain within the filtrate
  and exert an osmotic effect that inhibits the
  reabsorption of water.
• This effect can also be seen if blood plasma
  levels of glucose become very high (e.g. in
  hyperglycaemic episodes experienced by
  individuals with diabetes mellitus). The glucose
  that remains unabsorbed inhibits the reabsorption
  of water and larger volumes of urine are
  typically produced, initially.

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• Loop diuretics
• Loop diuretics include furosemide (Lasix),
  bumetanide
• (Bumex), and torsemide (Demadex).
• They are often described as "high ceiling"
  diuretics
• Due to their high diuretic potential they can
  cause up to
• 20 of the filtered load of NaCl H2O to be
  excreted in
• the urine.
• Act by inhibiting the Na- K-2Cl- cotransporter
  in the
• thick ascending limb of the loop of Henle. They
  also
• interfere with the reabsorption of K , Ca, and
  Mg
• in the loop.

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• Sodium chloride transport inhibited by loop
  diuretics
• - frusomide, bumetanide, ethacrynic acid
• These block sodium-chloride cotransporter from
  luminal side
• Act on thick ascending limb specifically since
• - Na transport exclusively due to
  co-transporters in this region whist Na
  transport can be by other methods in other parts
  of nephron
• - These diuretics more effective since they are
  secreted into proximal tubule so concentrations
  much higher than in plasma

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• Loop diuretics are indicated in the treatment of
• following conditions
• Fluid overload / oedema Congestive heart
  failure, acute pulmonary oedema, hepatic ascites,
  nephrotic syndrome, renal failure, etc
• Hypertension, especially when accompanied by
  renal impairment
• Acute treatment of hypercalcemia.

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• Thiazide Thiazide-like Diuretics
• Include chlorothiazide, hydrochlorothiazide
  (HCTZ),
• benzthiazide, cyclothiazide, indapamide,
• chlorthalidone, bendroflumethizide, metolazone,
  etc
• Exert their diuretic effect by inhibiting the Na
  - Cl-
• cotransport in the early distal convoluted
  tubules.
• They elicit a weaker diuretic response compared
  to the
• loop diuretics as illustrated by the
  dose-response
• curve.
• Increase the loss of K and Mg2, but reduce Ca2
• excretion (may cause hypercalcemia).

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of filtered Na load excreted
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• They are indicated for
• Hypertension (1st line therapy for mild to
  moderate HTN). They also exert a vasodilatory
  effect. In fact, on chronic use, their diuretic
  effect may become insignificant due to a
  compensatory increase in fractional Na
  reabsorption in the proximal tubules. However,
  their vasodilatory action persists and may
  account for most of their beneficial effect in
  the management of chronic hypertension.
• Mild heart failure
• In combination with loop diuretics, for severe,
  resistant oedema (especially metolazone)

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• 4. Idiopathic hypercalciuria
• 5. Nephrogenic diabetes insipidus (DI). They
  prevent the urine from being diluted further in
  the distal convoluted tubules. This alleviates
  the hypernatremia that accompanies DI.

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• Potassium-Sparing Diuretics
• They include amiloride, triamterene, and
• spironolactone.
• They are weak diuretics that exert their action
  mainly
• on the collecting ducts.
• Amiloride and triamterene act by blocking the Na
• channels in the luminal membrane of the principal
  cells
• of the cortical collecting ducts. This reduces
  the Na
• entry through the luminal membrane and hence the
  net
• reabsorption of NaCl.
• Spironolactone (Aldactone) is a competitive
• aldosterone antagonist at the cytosolic receptor
  level.

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• Potassium-sparing diuretics are used in the
  following
• To prevent hypokalemia induced by loop or
  thiazide diuretics
• 2dary hyperaldosteronism due to hepatic cirrhosis
  ascites.
• Primary hyperaldosteronism (Conn's syndrome)

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• Potassium-sparing diuretics
• Spironolactone
• Act as antagonists to aldosterone, competes with
  aldosterone for receptor sites in DCT (see fig)
• Results in decreased Na reabsorption in DCT
• Promotes Na and water loss
• Decreased Na reabsorption balanced by K
  retention at this site (and H).
• Used in combination with diuretic e.g.. frusomide

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CH2OH
Aldosterone
CO
HCO
HO
Spironolactone
CH3
O
O
CH3
CH3
O
SCOCH3
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• Triamterene and Amiloride
• Similar effect to spironolactone by reducing Na
  absorption and H/K secretion in DCT
• Independent of aldosterone
• Have little diuretic effect
• Used in conjunction with diuretics
• In low doses blocks entry of Na into tubule
  cells across luminal membrane
• Decrease availability of Na to Na-K-ATPase at
  basal cell membrane
• Called Na channel blockers

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• Carbonic Anhydrase Inhibitors
• Weak diuretics
• Used clinically to correct acid-base disturbances
  (alkalosis) rather than for diuretic action
• Acetazolamide (Diamox)
• In PCT HCO3- absorbed form tubule
• Carbonic Anhydrase (enzyme) present in proximal
  tubule cells
• Inhibition of CA inhibits HCO3- absorption from
  tubule
• Presence in lumen of HCO3- reduces Na
  reabsorption