RENAL TUBULE.
Pharmacology 14c – Diuretics
Anil Chopra
1.
2.
3.
4.
5.
Bowmans capsule
Glomerular
filtration
Proximal
tubule
Distal
tubule
Cortex
Revise the physiology of the
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300
kidney, focusing on the
mechanisms which regulate the
Outer
ionic composition (particularly
medulla
Na+, Cl- and K+), volume and
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600
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0
osmolarity of the urine.
Inner
Loop of Henle
medulla
Define the term diuretic.
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Explain how the following
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groups of diuretic drugs alter the
ionic composition, volume and
Collecting duct
osmolarity of the urine

osmotic diuretics, e.g. mannitol

carbonic anhydrase inhibitors, e.g. acetazolamide

loop diuretics, e.g. furosemide (frusemide)

thiazides, e.g. bendroflumethiaze (bendrofluazide)

potassium sparing diuretics. e.g. amiloride, spironolactone.
Note that loop diuretics, thiazides and K+ sparing diuretics are clinically the
most important groups of diuretics.
For each of the following drugs (a) name the principal conditions for which
they are used clinically, (b) list their main pharmacokinetic properties and (c)
describe and explain where possible their principal adverse effects.
(i)
frusemide
(ii) bendrofluazide
(iii) amiloride
(iv)
spironolactone
 The proximal tubule is the principal site of Na, water and HCO3 absorption
 The ascending limb of the loop of henle is impermeable to water and so acts to
increase the osmolarity of the interstitial fluid – this enables water reabsorption in
the collecting duct
 Water reabsopriton in the collecting duct is under the control of arginine
vasopressin (AVP)
RENAL TUBULE.
 Ca reabsorption in the distal tubule
Bowmans capsule
is under control pf PTH (para
thyroid hormone)
Proximal
tubule
Distal
 Aldosterone controls Na and so
Glomerular
Cortex
tubule
filtration
water reabsorption in the distal
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150
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tubule
 In the distal tubule as Na is
Outer
reabsorbed K is excreted – therefore
medulla
increased water excretion leads to
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0
excess K excretion
Inner
Loop of Henle
medulla
 Differing concentrations of filtrate
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and interstitial fluid is shown on the
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right
 Some things, e.g. drugs are actively
Collecting duct
secreted in the proximal tubule
Diuretics: Drugs that act on the renal tubule to promote the excretion of Na+, Cl- and
H2O. They are used to treat:
- Hypertension
- Salt and water overload
 Acute pulmonary oedema
 Heart Failure
 Liver cirrhosis and ascites
 Nephritic syndrome
 Renal Failure
- Acute hypercalcaemia
RENAL TUBULE.
Bowman’s capsule
Proximal
tubule
Glomerular
filtration
Distal
tubule
1
2
HCO3Na+
65-70%
H2O
5
4
H2O
Na+
Cl-
Na+
Na+
Cl-
Cl-
H2O
H2O
Loop of Henle
3
1
H2O
1
Collecting duct
(1) Osmotic Diuretics
Names
Mannitol
Usage
Prevent acute renal failure by increasing H2O excretion.
Decrease intra-cranial pressure.
Decrease intra-ocular pressure.
Mode of Action
It is pharmacologically inert. It is filtered by the glomerulus but not reabsorbed
resulting in an increase in the osmolarity of the kidney tubule. This results in a
decrease in water reabsorption in the proximal tubule, loop of Henle and collecting
duct.
H2 O
Side Effects
Can result in:
 dehydration
 hyponatraemia
 hypernatraemia
 nausea, vomiting
 pulmonary oedema
(2) Carbonic anhydrase Inhibitors
Names
Acetazolamide
Usage – generally weak diuretics used in:
 Metabolic alkalosis.
 Renal stones
 Decrease intra-ocular pressure in glaucoma.
Mode of Action
These act on the proximal tubule to prevent the reabsorption of HCO3- and Na+. This
is results in less water being reabsorbed due to the low osmolarity of the proximal
tubule cells and the intersitium. The high concentration of HCO3- in the distal tubule
will also cause a reduction in K+ loss. Urine is therefore very alkaline.
Side Effects
 Hypokalaemia
 Metabolic acidosis
 Self limiting action
(3) Loop Diuretics
Names - Frusemide
Usage – powerful diuretics used in:
 Oedema – Heart failure, pulmonary, renal, hepatic, cerebral
 Moderate Hypertension - Piretanide
 Hypercalcaemia
 Hyperkalaemia
Mode of Action
It prevents the reabsorbtion of sodium and chloride ions in the ascending loop of
Henle and is associated with a decrease in Ca2+ and Mg2+ reabsorption. This results
in a lower osmolarity of the interstitium and hence less water will be reabsorbed in the
descending limb and collecting duct. The increased Na+ in the distal tubule causes
large K+ loss due to the Na+ / K+ exchange pump. Its overall effect excretion of a large
amount of H20, Na+, Ca2+ and K+.
Side Effects and Pharmacokinetics
 Administration – IV or oral
 Distribution – strongly bound to plasma proteins
 Clearance – secreted into tubular fluid, excreted unchanged
 T1/2 = 1-2hrs, duration of action longer - lasts 3-6hrs
 Hypovolaemia & Hypotension
 K+ loss (Ca2+/Mg2+), Metabolic Alkalosis
 Hypokalaemia
(4) Thiazides
Names
Bendrofluazide (bendroflumethiazide)
Usage
 Cardiac failure
 Hypertension – initially decrease blood volume/long-term = vasodilation
 Severe resistant oedema
 Idiopathic hypercalciuria - stone formation
 Nephrogenic diabetes insipidus (paradoxical)
Mode of Action
They inhibit Na+ and Cl- absorption in the early part of the distal tubule and so
increase magnesium Mg2+ loss and Ca2+ reabsorption. This results in a decrease in
water reabsorption in the collecting duct and therefore a moderate increase in urine
volume and Na+, Cl- & K+ loss (Mg2+ loss).
Other actions of thiazides:
 Vasodilation – due to opening of K channels
 Inhibition of insulin secretion (diabetogenic) –
due to opening of K channels
 Diazoxide a non-diuretic thiazide has marked
vasodilatory and diabetogenic actions
 Inhibition of uric acid secretion into the proximal
tubule
Side Effects and Pharmacokinetics
 Inhibits insulin secretion which can result in
diabetes mellitus.
 The K+ loss can result in metabolic alkalosis.
 Uric acid retention – gout
 Hypokalaemia
MECHANISM OF THIAZIDE ACTION
Tubule lumen
Interstitium
3Na+
ATPase
Na+
Cl-
2K+
ClK+
-
Thiazides
» Admintration – well absorbed orally
» Distribution – most bind to plasma proteins
» Clearance – competes with uric acid for secretion into proximal tubule, excreted
unchanged in urine
» Onset of action 1-2hrs, duration of action 12-24hrs
(5) Potassium Sparing Drugs
Names
Spironolactone, amiloride
Usage
Amiloride is used with other diuretics that result in K+ loss.
Spironolactone is used in hyperaldosteronism (primary and secondary).
Mode of Action
They block aldosterone from binding to its receptor and amiloride inhibits the
aldosterone sensitive Na+ channels, both resulting in an increase in Na+ loss, and K+
reabsorption. The osmolarity of the tubular fluid decreases causing decreased water
reabsorption in the collecting duct. It also increases uric acid loss.
Side Effects
Hyperkalaemia, Metabolic Acidosis
Spironolactone – Gynaecomastia, Menstrual disorders, Testicular Atrophy
Diuretic
Oral
Onset
Duration
Excretion
Other
Osmotic diuretics i.v.
0.5h
1.5-3h
Glom. Fil.
Carbonic
Anhydrase
Inhibitors
Good
0.5h
12h
Tubular
Secretion
Loop diuretic
Good
1h
4-6h
Tubular
secretion
50%
unchanged
50% metab.
Thiazides
Good
1-2h
8-12h
24h
Tubular
secretion
Compete with
uric acid
Spironolactone
Good
Days
Canrenone
Glom. Fil.
Compete with
uric acid
Amiloride
Poor
6h
24h
Tubular
secretion
Unchanged in
urine