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By Duy Thai
DIURETICS I & II
Uses of diuretcis
• Reducing oedema associated with the following conditions:
1. Congestive heart failure
2. Hepatic failure
3. Pulmonary oedema
4. Cerebral oedema
5. Glomerulonephritis
6. Premenstrual oedema (???)
• Hypertension
Collecting tubule
• 1-3% of Na+ is reabsorbed here
• Na+ is reasbsorbed without Cl-. This results in a net buildup of
negative charges in the tubule lumen. To balance out this
negative charge, K+ or H+ is secreted.
• The amount secreted depends on:
• Volume flow
• Anion present
• Availability of K+ and H+
• Potential difference created by the N+ reabsorption
• Aldosterone acts here to increase water reabsorption
e.g: SPIRONOLACTONE
• Note: Any diuretic which acts before the collecting tubule will result in K loss
+
• In the collecting tubule, the amount of K+ secreted depends on the amount of Na+ arriving.
+ +
Diuretics which block Na reabsorption in the proximal parts of the nephron cause lots of Na to
+ +
arrive at the collecting tubule. The more Na arriving, the more K will be exchanged, and so
+
there is a loss of K from the body.
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1997 Clinical pharmacology
By Duy Thai
• Diuretics which block Na+ reabsorption at the collecting tubule will be preventing this Na+ K+
exchange. Hence, these diuretics will not cause loss of K+. However these diuretics are acting at
the last part of Na+ reabsorption, where only 1 - 3% of Na+ is absorbed. Most of the Na+ has
already been reabsorbed in the more proximal parts of the nephron and so these diurectics are
fairly weak.
Classification of diuretics
1. Water
• The more fluid you put in to your body, the more you will pee out. Not very useful in the
treatment of oedema, because we are trying to minimise the amount of fluid in the body.
2. Acid forming salts
3. Xanthines
• Substances such as tea and coffee may have a diuretic effect
4. Mercurials
• Not used any more since they needed to be injected intramuscularly
• Were a powerful group of diuretcs used extensively for cardiac failure
5. Osmotic
6. Carbonic anhydrase inhibitors
7. Thiazides These will be discussed in more detail below
8. High ceiling (loop diuretcs)
9. K+ sparing
Osmotic diuretics
• Properties:
• Water soluble so that they can be freely filtered by the glomerulus
• Need to be poorly reabsorbed by the tubules, because they exert their effect by remaining in the
tubular lumen
• The drugs are mostly non electrolytes (which are pharmacologically inert)
• Mannitol
• Urea
• Glycerol
• Mechanism of action:
• These agents act on the parts of the nephron which are freely permeable to water (where there is
passive absorption of water) - the proximal tubule, the descending loop of henle and the
collecting tubules
• By remaining in the tubular lumen, these agents cause an increase in colloid osmotic pressure in
the tubular lumen. This results in “suction” of water into the tubular lumen.
• There is also reduced water reabsorption due to renal medullary hyperemia (involves
prostinoids)
• There is impairment of Na+ reabsorption because the diluted solution in the lumen reduces the
Na+ concentration gradient, making it harder for Na+ to be reabsorbed. The Na+ loss which
occurs is not very marked
• Administration and uses
• These agents form the major constituents of IV drips.
• Given IV to maintain kidney function during trauma or surgery
• These situations involve a lot of blood loss, which may cause severe hypotension. This
causes the renal arteries to constrict, possibly leading to renal infarction
• Osmotic diuretics are not useful in conditions associated with Na+ retention
• Glycerol, given orally, is used to reduce intracranial pressure prior to neurosurgery
• Urea, given orally or IV, is used to reduce CSF pressure
• Also used to increase the excretion of drugs in acute poisoning
• Side effects:
• Not many.
• May cause cardiac failure because these agents are also exerting an osmotic pressure in the
blood, which tends to suck fluid out of the cells, increasing blood volume.
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1997 Clinical pharmacology
By Duy Thai
NaHCO3
Blood
+
Na
HCO3- + H+
… H+ + HCO3-
H2CO3 „
• CA H2CO3
ƒ CA
H2O + CO2 CO2 + H2O
‚
• Mechanism of action of the carbonic anhydrase inhibitors:
• Prevents the absorption of HCO3- in the lumen by
preventing the breakdown of H2CO3 by carbonic anhydrase
• Acetazolaminde is a non competitive, irreversible inhibitor
of carbonic anhydrase
• Since there is no production of H+ by the tubule cell (see
step 4), Na+ cannot be reabsorbed.
• The mechanism of Na+ reabsorption in the proximal tubule is via counter exchange with
H+
• The net result is:
• HCO3 retained in the lumen
-
• These ions create an osmotic effect, which draws water out into the lumen
• The diuresis is not great because there is compensatory reabsorption of Na is the segments
+
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1997 Clinical pharmacology
By Duy Thai
Thiazides
• In the search for more potent carbonic anhydrase inhibitors, other drug classes were discovered.
• Thiazides were one of these
• Most thiazides are weak inhibitors of CA, but this is not the basis of their action
• They became more effective as a diuretic but less effective as a CA inhibitor
• Mechanism of action:
• Acts at the distal tubule (hence they are medium acting diuretics)
• There is a small amount of compensatory reabsorption of Na+ at the collecting duct
• However, most of the Na+ is already absorbed in the earlier parts of the nephron.
• In the distal tubule, Na+ is reabsorbed via a Na+ Cl- co transport
• Thiazides inhibit this cotransport mechanism, thus preventing Na+ from being reabsobed
1. Inhibition of aldosterone
• Drug:
• Spironolactone
• Mechanism of action:
• Aldosterone (a steroid hormone) enters tubular cells and binds to a mineralocorticoid
receptor in the cytoplasm.
• This hormone receptor complex binds to a response element on the DNA.
• Binding results in the expression of aldosterone induced proteins:
• Activation of silent Na+ channels/pumps
• Alters the cycling of the channels and pumps
• Increased expression of channels and pumps
• Altered permeability of the tight junction (zonula occludens)
• All the above effects result in an increase in Na+ conductance (reabsorption) and
secretion of K+ (One of the complications of excess aldosterone secretion is
hypokalemia)
• Spironolactone binds to the mineralocorticoid receptor and prevents aldosterone from
binding.
• The half life of spironolactone is 10 minutes, but the action of it is much longer. This is
explained by the fact that spironolactone acts via an acive metabolite.
• Spironolactone is metabolised in the liver to canrenone (half life 12-16 hours)
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1997 Clinical pharmacology
By Duy Thai
Alkalinising agents
• Mechanism of action
• Sodium or potassium citrate is metabolised to form a stable cation (Na or K ) and a labile anion
+ +
(citrate)
• Citrate is taken up for use by the TCA. The Na or K is excreted with the most common anion
+ +
-
(HCO3 )
• Hence, you will have an alkaline urine
• Administration and use:
• Increased action of antibacterials, especially sulphonamides.
• Sulphonamides are generally insoluble in acid urine. They may thus precipitate out and
crystallise. Therefore, to increase solubility, the urine is made more alkaline.
• Increase the excretion of acidic drugs
• e.g. Aspirin, salicylates, barbituates
Acidifying agents
• Mechanism of action:
• Ammonium chloride (NH4Cl) is given and metabolised in the liver to NH4 and Cl
+ -
• The base conserving mechanisms secrete H+ and NH4+ into the urine
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1997 Clinical pharmacology
By Duy Thai
• Uses:
• Increase action of antibacterials
• Increase excretion of basic drugs
• e.g. Pethidine, amphetamine
Uricosuric agents
• Diuretics which utilise the organic acid transport mechanism (thiazides and high ceiling) to be secreted
into the tubular lumen to become active also have the problem of causing uric acid retention (because
uric acid excretion uses the same mechanism)
• Hyperuricemia can develop, leading to secondary gout
• There are 2 sorts of gout:
• Primary gout:
• Due to increased uric acid synthesis
• Secondary gout:
• Result of a disease process where there is excessive protein breakdown (e.g.
leukemia, lymphomas)
• Drugs which compete for uric acid excretion
• Salicylates, alcohol, diuretics
• Indacrinone
• The - isomer is diuretic and uricosuric
• The + isomer is uricosuric
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