1. DIURETICS February, 2012

2. Diuretics Introduction
Diuretics are drugs acting on the kidney
They are drugs that act to increase the flow of urine
The purpose of diuretics is to increase the net loss of water
To achieve this they act on the kidneys at different locations to enhance the excretion of sodium.
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3. Diuretics…
They do this by interfering with one or more of the tubular reabsorptive processes located between the glomerular capsule and junction of the collecting ducts with the ureter
To understand the actions of diuretic agents it is necessary to understand the normal reabsorptive processes that take place after filtration at the glomerular capsules
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4. These processes reduce the filtrate from about 125mL/min to a volume of urine of about 1mL/min, as well as drastically changing the ionic composition.
The regions involved in these processes and the functions performed in each are as follows:
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5. 1. Proximal convoluted tubule
(a) Reabsorption of a substantial portion of the filtered
Na+, accompanied by Cl- and water to maintain
electrochemical and osmotic balance.
(b) Reabsorption of approx. 50% of the filtered K+ accompanied by Cl- and water.
(c) Reabsorption of filtered HCO3-. This involves the production of HCO3- and H+ within the tubular epithelial cells under the influence of cytoplasmic carbonic anhydrase, the transfer of the HCO3-to the peritubular vessels and the exchange of the H+ with Na+ in the filtrate.
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6. Proximal convoluted tubule…
This Na + is transferred to the peritubular fluid, the H+ interacts with HCO3- in the filtrate, catalysed by carbonic anhydrase on the brush border membrane, producing water and CO2 (which may diffuse into the epithelial cells and be used in the production of more HCO3-).
HCO3- reabsorption can take place throughout the nephron but the major site appears to be the proximal tubule.
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7. 2. Descending Limb of the Loop of Henle
The tubular membranes are relatively impermeable to anything other than water, which is removed by osmotic forces
This happens because the interstitial fluid of the medulla is kept hypertonic by the countercurrent concentrating system.
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8. 3. Ascending Limb of the Loop of Henle
Reabsorption of Na+, K+ and Cl- by a co-transport mechanism. The tubule cell membranes are relatively impermeable to water. Thus the rate of absorption of the ions exceeds that of water, leaving a tubule fluid that is hypotonic as it enters the distal tubule.
Ca++ and Mg++ are also reabsorbed in this region
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9. 4. Distal Convoluted Tubule
Reabsorption of Na+, accompanied by Cl-, and further reabsorption of Ca++.
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10. 5. Collecting Duct
Active reabsorption of Na+ in connection with secretion of K+. This ‘exchange’ is increased by aldosterone and by increased delivery of Na+ to the collecting duct.
Reabsorption of water unaccompanied by ions, a process that is regulated by antidiuretic hormone (ADH) released from the posterior pituitary gland. ADH increases the permeability of the tubule cells and normally results in a tubule fluid that is hypertonic relative to the general ECF when it leaves the collecting duct.
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11. Changes in plasma tonicity influence the release of ADH such that more, or less, water is reabsorbed to restore the tonicity to normal
Compounds reducing or blocking these reabsorptive processes for solutes result in the production of an increased volume of urine with increased concentration of one or more ions
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12. Diuretics-
Diuretics are drugs which increase the excretion of sodium and water from the body by an action on the kidney.
Their primary effect is to decrease the reabsorption of sodium and chloride from filtrate, increased water loss being secondary to increased excretion of salt. This can be achieved by-:
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13. Diuretics--- a direct action on the cells of the nephron.
Indirectly modifying the content of the filtrate
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14. Diuretics---
Since a very large proportion of the salt (NaCl) and water which passes into the tubule in the glomerulus is reabsorbed, a small decrease in reabsorption can result in a marked increase in excretion
A summary diagram of the mechanisms and sites of action of various diuretics is shown in the next slides
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15. `
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16. PCT=proximal convoluted tubule TAL=thick ascending loop of Henle
DT= distal tubule
CT=collecting tubule
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17. Simplified diagram of a juxtamedullary nephron and its blood supply
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18. THE DEVELOPMENT OF DIURETIC DRUGS
The diuretics used prior to 1920 were xanthine ( e.g. Theophylline and caffeine) and osmotic diuretics ( e.g. urea ). 
The next group of compounds introduced were the carbonic-anhydrase inhibitors. These were developed from the sulphonamides, following on the observation that sulphanilamide caused, as a side-effect, a mild diuresis. 
As a result of further modifications of the original structure, Acetazolamide was introduced in 1950.
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19. Classes of Diuretics i) Thiazides e.g. Bendrofluazide
Hydrochlorothiazide.
ii) Loop diuretics e.g.
Frusemide
Bumetanide
Ethacrynic acid
Piretamide and Torasemide
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20. Classes of Diuretics… iii) Potassium – sparing diuretics Amiloride
Triamterine
Spironolactone ( Aldosterone antagonist)
iv) Osmotic diuretics e.g. Mannitol
v) Carbonic anhydrase inhibitors e.g. Acetazolamide
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21. DIURETICS ACTING DIRECTLY ON CELLS OF THE NEPHRON
Drugs which cause salt loss by an action on cells must obviously affect those parts of the nephron where most of the active and selective solute reabsorption occurs:
The ascending loop of Henle.
The early distal tubule.
The collecting tubules and ducts
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22. LOOP DIURETICS
Loop diuretics are the most powerful of all diuretics, capable of causing % of the sodium in the filtrate to be excreted.
They are termed ‘ High ceiling “ diuretics.
The main example is Frusemide; others are Bumetanide, Piretanide, Torasemide and Ethacrynic acid.
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23. Loop diuretics---
These drugs act primarily on the thick segment of the ascending loop of Henle,
Inhibiting the transport of sodium chloride out of the tubule into the interstitial tissue by inhibiting the Na+/ K+/2Cl- carrier in the luminal membrane. 
Frusemide, Torasemide and Piretanide have a direct inhibiting effect on the carrier, acting on the chloride- binding site.
Ethacrynic acid forms a complex with cysteine, the complex being the active form of the drug.
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24. Loop diuretics---
The reabsorption of solute at this site is the basis for the ability of kidney to concentrate the urine by creating a hypertonic interstitial area in the medulla,
which provides the osmotic force by which water is reabsorbed from the collecting tubules under the influence of the anti-diuretic hormone.
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25. Loop diuretics---
The action of the loop diuretics has the additional effect that more solute is delivered to the distal portions of the nephron where its osmotic pressure further reduces water reabsorption.
Essentially, some of the solute which normally passes into the medullary interstitium and draws water out of the collecting ducts, now remains in the tubular fluid and holds water with it.
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26. Loop diuretics--
As much as 25 % of the glomerular filtrate may pass out of the nephron ( compared with the normal loss of about 1 % ), resulting in a profuse diuresis. 
Loop diuretics appear to have a venodilator action, directly and/ or indirectly through the release of renal factor.
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27. Loop diuretics---
After intravenous administration to patients with acute heart failure, a therapeutically useful vascular effect is seen before the onset of the diuretic effect.
Piretanide, in particular, has general vasodilator actions.
 The increased sodium concentration that reaches the distal tubule results in increased loss of H+ and potassium.
Loop diuretics may thus produce a metabolic alkalosis.
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28. Loop diuretics---
There is an increase in the excretion of calcium and magnesium and a decrease excretion of uric acid. 
The effect on calcium is made use of in the treatment of hypercalcaemia.
Torasemide causes less loss of potassium and calcium.
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29. Pharmacokinetics of loop diuretics
The loop diuretics are readily absorbed from the gastrointestinal tract and may also be given by injection.
They are strongly bound to plasma protein and so do not pass into the glomerular filtrate to any marked degree.
They reach their site of action- the luminal membrane of the cells of thick ascending loop- by being secreted in the proximal convoluted tubule by the organic acid transport mechanism; the fraction thus secreted will pass out in the urine.
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30. P’kinetics of loop diuretics
The fraction not secreted is metabolized in the liver- Bumetanide and Torasemide being metabolised by cytochrome P450 pathways and Frusemide being glucuronidated.
Given orally, they act within 1 hour; given intravenously, they produce a peak effect within 30 minutes.
The half-live are about 90 minutes (longer in renal failure )
-and the duration of action 3-6 hours, except in the case of Torasemide which has a longer duration of action and can therefore be given once a day.
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31. Clinical uses of loop diuretics
In patients with salt and water overload due to-;
Acute pulmonary oedema 
Chronic heart failure.
Hepatic cirrhosis complicated by ascites.
Nephrotic syndrome.
Renal failure.
In hypertension, especially if accompanied by renal impairment.
In acute treatment of hypercalcaemia.
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32. Side effects of loop diuretics
Some unwanted effects are common with loop diuretics, and are directly related to their renal actions.
Potassium loss resulting in low plasma potassium ( hypokalaemia ) and metabolic alkalosis due to hydrogen ion excretion are both likely to occur.
Hypokalaemia can be averted or treated by concomitant use of potassium-sparing diuretics or by potassium supplements.
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33. Side effects of loop diuretics
Depletion of magnesium and calcium is common, and in elderly patients, hypovolaemia and hypotension, with collapse due to sudden loss of extracellular fluid volume, can follow the profuse diuresis produced by these agents.
Unwanted effects which are not related to renal actions of the drugs are rare. They include nausea, allergic reactions and infrequently, deafness ( compounded by concomitant use of an aminoglycoside antibiotic ).
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34. Side effects of loop diuretics--
Ethacrynic acid is more likely to cause G.I.T. disturbances and deafness and is consequently less widely used
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35. DIURETICS ACTING ON THE EARLY DISTAL TUBULE-THIAZIDES
The diuretics acting at this site- sometimes referred to the distal convoluted tubule- include the Thiazides and related drugs.
The main thiazide is bendrofluazide, others are hydrochlorothiazide and cyclopenthiazide.
Drugs with similar actions include chlorthalidone, and newer ones such as Indapamide, Xipamide and Metolazone.
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36. Mode of action of Thiazides
They decrease active reabsorption of sodium and accompanying chloride by binding to the chloride site of the electro-neutral Na+/Cl- co-transport system and inhibiting its action. 
They do not have any action on the thick ascending loop of Henle.
Potassium loss with these drugs is significant and can be serious.
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37. Side effects of Thiazides--
Excretion of uric acid and calcium is decreased; that of magnesium is increased
Thiazide diuretics have a paradoxical effect in diabetes insipidus where they reduce the volume of urine.
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38. Side effects of thiazides
They have some extra-renal actions- they produce vasodilatation and can cause hyperglycaemia.
When used in the treatment of hypertension, the initial fall in blood pressure is due to decreased blood volume resulting from diuresis, but later phase seems to be due to a direct action on the blood vessels.
Indapamide is said to lower blood pressure at sub-diuretic doses with less metabolic disturbances.
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39. Pharmacokinetics of Thiazides
The thiazides and related drugs are all effective orally, being well absorbed from the G.I.T.
All are excreted in the urine mainly by tubular secretion mechanisms.
Their tendency to increase plasma uric acid is due to competition with uric acid for tubular secretion mechanism. 
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40. Pharmacokinetics of Thiazides
With the shorter- acting drugs such as Bendrofluazide, Hydrochlorothiazide, chlorothiazide and cyclopenthiazide, onset of action is within 12 hours, maximum effect at about 4-6 hours and duration between 8 and 12 hours.
The longer acting drugs such as Chlorthalidone have a similar onset but longer duration of action and can be given on alternate days.
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41. Clinical uses of Thiazides
In hypertension.
In mild heart failure
 In severe resistant oedema ( metolazone, especially, is used together with loop diuretics)
To prevent recurrent stone formation in idiopathic hypercalciuria.
In nephrogenic diabetes insipidus.
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42. Main side effects of Thiazides
These agents have a fairly large therapeutic index and serious unwanted effects are relatively rare.
The main unwanted effects of thiazides are the result of some of renal actions; a decrease plasma potassium is particularly significant.
Others are metabolic alkalosis, increased plasma uric acid ( with the possibility of gout ) and hyperglycaemia (which could exacerbate diabetes mellitus ).
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43. Other side effects of Thiazides
Indapamide has little obvious effect on potassium, uric acid and glucose excretion. 
Unwanted effects not related to the main renal actions of the thiazides include increased plasma cholesterol ( with long-term use), male impotence ( reversible on stopping the drug ) and,
Infrequently, hypersensitivity reactions ( skin rashes, blood dyscrasiasis and, more rarely still, pancreatitis, acute pulmonary oedema ).
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44. Side effects of Thiazides--
In cases of hepatic failure, thiazides can precipitate encephalopathy.
An unusual but potentially serious unwanted effect is hyponatraemia
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45. Potassium –sparing diuretics - Spironolactone
Spironolactone has a limited diuretic action.
It is an antagonist of aldosterone, a mineralo corticoid-competing for intracellular aldosterone receptors in the cells of the distal tubule.
The Spironolactone-receptor complex does not apparently attach to the DNA, and the subsequent processes of transcription, translation and production of mediator protein (s) – do not occur. 
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46. Spironolactone…
The result is an inhibition of the sodium-retaining action of aldosterone and a concomitant decrease in its potassium-secreting effect.
Spironolactone has subsidiary actions in decreasing hydrogen ion secretion and also uric acid excretion.
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47. P’kinetics of spironolactone
Spironolactone is well absorbed from the G.I.T.
Its plasma half-life is only 10 minutes but its active metabolite, canrenone, has a plasma half-life of 16 hours.
The action of spironolactone is believed to be largely but not entirely due to canrenone.
The onset of action is very slow, taking several days to develop.
Potassium canrenoate is given parenterally.
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48. Uses of Spironolactone
With potassium-losing diuretics to prevent potassium loss ( spironolactone is used less frequently than amiloride or triamterene because it is poorly tolerated ).
Spironolactone is used-;
In primary hyperaldosteronism ( Conn’s syndrome ) which is rare.
In secondary hyperaldosteronism due to hepatic cirrhosis complicated by ascites.
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49. Side effects of Spironolactone
Gastro-intestinal upsets occur fairly frequently.
If spironolactone is used on its own it will cause hyperkalaemia and possibly metabolic acidosis.
Actions on steroid receptor in tissues than the kidney can result in gynaecomastia, menstrual disorders and testicular atrophy.
 Peptic ulceration has been reported.
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50. POTASSIUM SPARING DIURETICS-TRIAMTERENE (TM) AND AMILORIDE (AM)
Like spironolactone, triamterene and amiloride have a limited diuretic efficacy.
They act on the collecting tubules and collecting ducts, inhibiting sodium reabsorption and decreasing potassium excretion.
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51. Mode of actions of TRIAMTERENE(TM) AND AMILORIDE(AM)
Amiloride blocks the luminal sodium channels by which aldosterone produces its main effect, making less sodium available for transport across the basolateral membrane.
Triamterene probably has a similar action.
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52. TRIAMTERENE(TM) AND AMILORIDE(AM) ---
Both are mild uricosuric, i.e. they promote the excretion of uric acid. 
The main importance of these diuretics lies in their potassium sparing ability.
They can be given with potassium-losing diuretics like thiazides in order to maintain potassium balance
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53. P’KINETICS OF TM & AM Triamterene is well absorbed in the G.I.T.
Its onset of action is within 2 hours and its duration of action 12 to16 hours.
It is rapidly metabolized in the liver and partly excreted unchanged in the urine.
Amiloride is poorly absorbed and has a slower onset, with a peak action at 6 hours and a duration of action of about 24 hours.
Most of the drug is excreted unchanged in the urine.
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54. Side effects of AM & TM
The main unwanted effect is related to the pharmacological action of the drugs-hyperkalaemia, which can be dangerous.
Metabolic acidosis can occur, as can skin rashes.
G.I.T. disturbances have been reported but are infrequent.
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55. DIURETICS WHICH ACT INDIRECTLY BY MODIFYING THE CONTENT OF THE FILTRATE
Diuretics which act indirectly by modifying the content of the filtrate do so by increasing either the osmolarity or the sodium load
E.g. OSMOTIC DIURETICS:
 osmotic diuretics are pharmacologically inert substances ( e.g. Mannitol ) which are filtered in the glomerulus but incompletely reabsorbed or not reabsorbed at all by the nephron
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56. Osmotic diuretics--
They can be given in amounts sufficiently large for them to constitute an appreciable fraction of plasma osmolarity.
 Within the nephron, their main effect is exerted on those parts of the nephron which are freely permeable to water- the proximal tubule, descending limb of the loop and the collecting tubules
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57. Osmotic diuretics--
Passive water reabsorption is reduced by the presence of the non-reabsorb-able solute within the tubule; consequently a larger volume of fluid remains within the proximal tubule
This has a secondary effect of reducing sodium reabsorption, since the sodium concentration within the proximal tubule is lower than it otherwise would be, and this alters the electrochemical gradient for reabsorption. 
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58. Osmotic diuretics--
Therefore, the main effect of osmotic diuretics is to increase the amount of water excreted, with a relatively smaller increase in sodium excretion.
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59. Osmotic diuretics--
Hence, they are not useful in treating conditions associated with sodium retention, but have much more limited therapeutic applications
These include for acutely raised intracranial or intraocular pressure and for prevention of acute renal failure.
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60. Osmotic diuretics--
In this latter condition, the glomerular filtration rate is reduced, and absorption of salt and water in the proximal tubule becomes almost complete, so that more distal parts of the nephron virtually dry up, and urine flow ceases.
Retention of fluid within the proximal tubule by administration of an osmotic diuretic limits these effects.
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61. Osmotic diuretics--
The treatment of acutely raised intracranial pressure ( cerebral oedema ) and raised intraocular pressure ( glaucoma ) relies on the increased in plasma osmolarity by solutes that do not enter the brain or eye; this results in extraction of water from these compartments.
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62. Osmotic diuretics
It has nothing to do with the kidney; indeed the effect is lost as soon as the osmotic diuretic appears in the urine.
Osmotic diuretics are usually given intravenously.
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63. Side effects of osmotic diuretics
Include transient expansion of the extracellular fluid volume and hyponatraemia due to abstraction of water from the intracellular compartment. (in patients who are unable to form urine, this could cause cardiac failure or pulmonary oedema or both).
Headache, nausea and vomiting can occur.
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64. DIURETICS ACTING ON PROXIMAL TUBULE
CARBONIC ANHYDRASE INHIBITORS-- cause increase excretion of bicarbonate with accompanying sodium, potassium and water, resulting in an increased flow of an alkaline urine and mild metabolic acidosis.
These agents, though not now used as diuretics, may be used in the treatment of glaucoma to reduce the formation of aqueous humor, and also in some unusual types of epilepsy. Example are Acetazolamide and Dichlorphenamide.
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65. Mode of action
Their main action results in a depletion of extracellular bicarbonate and their effect is self-limiting as the blood bicarbonate falls
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66. DRUGS WHICH ALTER THE URINARY pH: AGENTS WHICH INCREASE THE URINARY pH
Sodium or Potassium citrate or other salts ( acetate, lactate ) are metabolized and the cations are excreted with bicarbonate to give alkaline urine.
This may have some anti-bacterial effects, as well as decreasing irritation or inflammation in the urinary tract.
Alkalinisation is important in preventing certain drugs, such as some sulphonamides, from crystallizing out in the urine; it also decreases the formation of uric acid and cystein stones. 
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67. ….. AGENTS WHICH INCREASE THE URINARY pH
It is possible to increase the excretion of drugs that are weak acids (e.g. salicylates and some barbiturates) by alkalinising the urine.
Sodium bicarbonate given intravenously is used in patients with salicylate overdose
NB: Na+ overload can be dangerous in cardiac failure and that overload with either Na+ or K+ can be harmful in renal insufficiency.
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68. AGENTS WHICH DECREASE URINARY pH
A decrease in urinary pH can be produced with Ammonium chloride but this is now rarely if ever used clinically except in a specialized test for renal tubular acidosis.
The ammonia is metabolized to urea in the liver, leaving chloride and hydrogen ion.
The chloride displaces bicarbonate (which is dissipated by conversion to carbonic acid then to CO2 and H2O).
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69. DRUGS WHICH ALTER THE URINARY pH: AGENTS WHICH INCREASE THE URINARY pH
so that a hyperchloraemic acidosis results.
 The chloride, with accompanying sodium, appears in the glomerular filtrate and passes out in the urine with an osmotic equivalent of water, causing a mild diuresis.
 Then the base-conserving mechanisms come into play, the tubules secrete hydrogen ions in exchange for sodium, ammonia is generated and acid urine ( containing ammonium chloride ) is excreted.
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70. Exercise Describe the normal physiological function of the nephron.
What are diuretics? Giving examples classify the diuretics.
Describe the site of action, actions, clinical uses and side effects of diuretic agents.
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