Recall that the functional unit of the kidney is the nephron, which is divided into several distinct sections.

The Glomerulus, enclosed by Bowman's capsule -- is the site of filtration.  Plasma from afferent arterioles is filtred through the glomerulus into Bowman's capsule, the first step in urine formation.  The filtrate proceeds to the next section for initial urine formation

Proximal Convoluted Tubule (PCT) -- This is a major site of reabsorption for electrolytes (Na, Cl, K), bicarbonate, water, glucose, and amino acids.  Two-thirds to three-quarters of Na, Cl, and water that is to be conserved by the kidney is reabsorbed in the PCT.  This section possesses numerous transport mechanisms and is high in carbonic anhydrase activity, due to the function of bicarbonate conservation.  Other specific carrier proteins (co- and counter-transport mechanisms) that are specific for each segment and diuretic action will be discussed below.  The PCT is relatively permeable to water, due to the presence of numerous gap junctions.

Loop of Henle -- This segment of the nephron plays a major role in the countercurrent exchange/multiplier system of water conservation.  It has the ability to concentrate solutes, increase osmotic pressure, and conserve or excrete water.  It also serves as a sight of Na, K, and Cl conservation.  (NOTE that by the end of the loop, all K that is going to be conserved has been conserved.)  The loop is less permeable to water than the PCT, however, it may still pass from the tubular lumen to interstitial spaces.

Distal Convoluted Tubules (DCT) -- This segment of the nephron has two distinctive portions.  The early DCT is very similar to the ascending limb of the loop of Henle.  It is also called the "diluting segment" due to its ability to reabsorb Na, without passage of water (it is less permeable to water than the loop), thus diluting the urine.   The late portion of the DCT is more similar to the collecting tubules.  This latter portion is impermeable to water except in the presence of ADH (anti-diuretic hormone, vasopressin).  Aldosterone also acts in the DCT.  The actions that occur in the late DCT are very similar to those discussed below for the collecting tubules.

Collecting Tubules (CT) -- This segment is also impermeable to water, except in the presence of ADH.  ADH causes the formation of pores or "water channels" that allow the passage of water from the tubular lumen to the interstitium.  Aldosterone also acts in the CT to increase the activity and number of Na/K ATPase pumps.  This causes Na retention (conservation) with water following osmotically through the ADH pores.

Thiazide and thiazide-type diuretics -- This class includes the true thiazide diuretics (chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, bendroflumethiazide, benzthiazide, cyclothiazide, polythiazide, and trichlormethiazide) and the thiazide-like diuretics, that are structurally dissimilar but possess the same mechanisms and pharmacodynamics (chlorthalidone, indapamide, metolazone, and quinethazone).

Mechanism of Action -- These drugs act in the late portion of the ascending loop of Henle and in the early portion of the DCT.  They specifically act at the Na/Cl co-transport mechanism (symport) where they compete with and block the binding of Cl ion to the transport protein.  Normally, Na is reabsorbed in this portion of the nephron by this symport that is specific for Na and Cl (RECALL that in co- and counter-transport mechanisms BOTH of the ligands must be present and bound to induce the conformational changes allowing transport.).  The thiazides, by inhibiting Cl binding, prevent the reabsorption of Na and, since water will osmotically follow Na, prevent the reabsorption of water (hence the diuretic effect).

Clinical Responses

Potassium -- potassium loss (increased excretion or less retention) occurs with the thiazides by one of three mechanisms.  Recall that the kidney is very good at conserving Na.  With the thiazides, this was prevented in the early portion of the DCT.  Therefore, later in the nephron (the late DCT and CT), a more vigorous attempt to conserve Na will take place.  This is primarily mediated by aldosterone, which reabsorbs Na at the expense of K.  Therefore,
Increased aldosterone activity aids in the potassium loss

Increased aldosterone secretion aids in the potassium loss

Hyochloraemic alkalosis (caused by the loss of Cl through the mechanism of thiazides) also aids in potassium loss.  This is a compensatory action that occurs with alkalosis due to loss of Cl ion.

Regardless of the exact mechanism, thiazide use will cause loss of Na, Cl, and K to some extent.

Other Ions
Calcium retention may occur with thiazide diuretics.  As the patient experiences diuresis and body fluid is lost, extracellular fluid volume (ECFV) decreases.  The kidney will attempt to retain ions so that water will be retained (osmotically).  Since the drug is inhibiting Na retention, Ca ions may be conserved more than normal.  Since this action will DECREASE the amount of Ca in the urine, thiazides may be given to prevent calcium-dependent renal stone formation.

Magnesium may be lost with thiazides.  This probably occurs secondarily to the calcium retention just discussed.  Similar to the relationship between Na and K, Ca and Mg are often exchanged (one divalent cation for another) in non-specific transport processes.

Uric Acid -- Uric acid may also be reabsorbed to a greater extent in patients taking thiazides.  This is probably due to the same mechanisms that contribute to Ca retention (an attempt to increase ECFV).  Greater than 50% of patients taking thiazide diuretics will exhibit some degree of hyperuricaemia.  This is typically of little concern EXCEPT in patients with gouty arthritis.  In those individuals, thiazides may precipitate a gouty attack.

Insulin -- Thiazide diuretics may decrease insulin secretion, decrease insulin efficacy, and increase glycogen breakdown, all of which could worsen diabetes mellitus (thiazide may even expose latent DM).  These effects may disappear after a year on the drug.  The effects will also be lessened by the administration of potassium.  It is likely that these effects are directly due to thiazide-induced hypokalaemia, since potassium is required for insulin mobilisation and action.

Serum Lipids -- Thiazide diuretics may increase circulating levels of LDL, cholesterol, and TG.  These effects also disappear after approximately one year and are also lessened by the administration of potassium.  Again, the effects are a direct result of loss of potassium (which may play a role in inhibiting lipid mobilisation).

Adverse Reactions -- In addition to those discussed above.  These are primarily related to the electrolyte imbalances resulting from the drug's mechanism.

Hyponatraemia and Hypokalaemia -- contribute to cardiac abnormalities, including a prolonged QT interval that could lead to torsade de pointes.  These agents may also accentuate quinidine-induced V tach and V fib.

GI upset and Anorexia

Impotence and decreased libido in males

Blood dyscrasias (due to the sulphur-moieties of the drugs)

Photosensitivity/Skin rash (again, due to the sulphur functional groups)

Thiazides may also exacerbate lithium toxicity in those patients taking lithium.  This is due to Li retention (an acceptable alternative to Na, as far as the kidney is concerned).

Thiazides will increase the risk of digoxin toxicity, due to the hypokalaemia.
 

Miscellaneous -- Although these agents may be used in nephrotic syndrome to prompt some urine production and excretion, they are CONTRAINDICATED in patients with anuria (no urine production at all) due to the potential of irreversible kidney failure.  The exceptions are indapamide and metolazone, both of which may be used cautiously in anuric patients.
In vitro studies have indicated that metolazone, in addition to its thiazide-like inhibition of the Na/Cl antiport in the distal tubules, may inhibit phosphate and sodium reabsorption in the proximal tubules.  Although the effects on sodium were less pronounced than those affecting phosphate transport, this could account for the efficacy of metolazone in the patients with anuria.

Mechanism of Action -- The drugs act similarly to thiazide diuretics.  However they are specific for Cl binding sites on the Na/K/Cl symport that is found in the loop and ascending limb of Henle.  This symport mediates the reabsorption of 1 Na, 1 K, and 2 Cl ions.  By binding to the Cl site, loop diuretics prevent the reabsorption of all three ions and the subsequent lack of reabsorption of four molecules of water by osmosis, hence the diuretic effect.


Clinical Responses

Potassium -- Loops also result in potassium loss, however it is more profound than that seen with thiazides.  This is due to the site and mechanism of action. Recall that this is the final stage for potassium conservation and the drug is inhibiting the last chance for the body to save potassium.  Therefore, in addition to the subsequent loss of potassium in an attempt to conserve sodium (described above for the thiazides), the loops are directly causing potassium loss by inhibiting its reabsorption.  The hypokalaemia is potentially more severe with loops and often require potassium supplementation.

Other Ions -- Similar to thiazides, except that calcium loss may occur.

Uric Acid -- Similar to thiazides.

Lipids and Insulin -- Similar to thiazides, except that the effects may be more pronounced with the loops, due to the additional potassium loss.

Other Effects -- Furosemide may also produce an increase in venous capacitance.  This effect is thought to be prostaglandin mediated (it is known that at least some of the diuretic effects of furosemide are PG-mediated, since NSAID co-administration will reduce the diuretic efficacy of loop diuretics).  The ability of furosemide to cause slight venodilatation may contribute somewhat to its efficacy in the treatment of hypertension and congestive heart failure.
 

Adverse Effects -- Hypokalaemia is the primary concern.  Effects are similar to those for thiazide diuretics (for both hyponatraemia and hypokalaemia) except the effects of K loss will be more profound.  Hypomagnesaemia may contribute to cardiac toxicity (i.e. hypomagnesaemic-related arrhythmias) and hypocalcaemia may contribute to both cardiac and skeletal muscle dysfunction.
 
Ototoxicity -- Loop diuretics may produce ototoxicity.  Although this may occur with chronic oral dosing, it is most often seen with rapid IV bolus injections.  It initially presents as tinnitus and vertigo, but may progress to hearing impairment and deafness.  Ethacrynic acid is the worst offender for ototoxicity.

Ethacrynic acid also may produce a severe watery diarrhoea.

Alkalosis may occur secondary to chloride loss.

Aldosterone Antagonists -- Spironolactone
Mechanism of Action -- Recall that in times of hyponatremia, low blood pressure, or decreased total body water volume, aldosterone is secreted.  It then will bind with intracellular receptors in the late DCT and CT.  The aldosterone-receptor complex then activates that portion of nuclear DNA/RNA that is responsible for the translation, transcription, and synthesis of the proteins that make the renal Na/K ATPase Pump.  Therefore, aldosterone increases the synthesis (and also the activity) of the Na/K pump.  The pump then exchanges tubular Na for cellular K, thus conserving the Na at the expense of K.  Again, water that would normally follow the Na osmotically, will remain in the tubule and be excreted.  Spironolactone competes with aldosterone for its binding site on the intracellular receptor, thus reducing the production of the Na/K pump.  As may be reasoned from this mechanism, the action of spironolactone is at least in part dependent upon the level of aldosterone activity.  (If aldosterone activity is low, spironolactone produces less effect, if activity is high, spironolactone is more effective, as in aldosterone-producing tumours of the adrenal gland.)

 
Clinical Responses
Potassium -- Potassium will be retained with spironolactone, potentially leading to hyperkalaemia.

Other Ions -- May see minimal retention of H, Ca, and Mg ions, in an attempt to increase ECFV.

Uric Acid -- Minimal increases in circulating uric acid, but not as severe as with loops or thiazides.

Lipids & Insulin -- Spironolactone will not alter these, since changes in them are K dependent and no K has been lost.
 

Other Effects -- Spironolactone, due to its steroidal structure, may interfere with steroid synthesis.  It also may act as a partial agonist/antagonists at other steroid receptors.

Adverse Reactions

Electrolyte Imbalance -- The primary concern with spironolactone is hyperkalaemia, which may cause cardiac abnormalities, decrease the efficacy of digoxin, and cause muscle cramping/aches.  Overdoses of spironolactone may cause acidosis, due to H ion retention.

Endocrine Effects -- Due to the activity of spironolactone at the androgen receptor, the following effects may be seen

Gynecomastia and decreased libido in males
Hirsutism, voice deepening, and menstrual irregularities in females
Other Adverse Effects
GI upset
Blood dyscrasias
 
Sodium Channel Inhibitors -- Amiloride, Triamterine
Mechanism of Action -- In addition to the Na/K pump, Na may also be conserved at the expense of K in the late DCT/early CT by simple diffusion through Na and K channels.  Normally, Na concentration is greater in the tubular lumen than intracellularly.  Therefore, the concentration gradient will cause the diffusion of Na from the lumen to the cell, where it may then be taken into the interstitium for conservation.  Since the cell is gaining a monovalent cation, electrochemically it would prefer to loose one as well.  It does this through the loss of K (which has a higher intracellular concentration that luminal concentration) through a K channel.  These agents block the Na channel, preventing its reabsorption (again water will stay in the lumen with it).  Since the cell has NOT gained the Na, it has no need to loose the K and therefore the K is spared.

Clinical Responses
Potassium -- Similar to spironolactone
Other Ions -- Similar to spironolactone, may also see Cl ion loss.
Other Effects
Amiloride may also block Na/H antiports and Na/Ca antiports, also causing Na and water loss.

Triamterine may also directly inhibit the Na/K pump, causing Na/water loss.  It is also a weak folate antagonist and as such may produce blood dyscrasias (anaemias are especially prominent in patients with cirrhosis) and birth defects.

Both drugs will be effective K sparing diuretics regardless of aldosterone activity.

Adverse Reactions
Electrolyte Imbalance -- Hyperkalaemia, similar to spironolactone
GI Upset
Musculoskeletal Disorders -- similar to spironolactone
Dermatological & haemtological -- Triamterine, similar to the thiazides, namely rash/photosensitivity.

Mechanism of Action -- In the PCT, the enzyme carbonic anhydrase plays a major role in acid/base balance and the conservation of bicarbonate ion (through the conversion of carbon dioxide and water to carbonic acid, which then dissociates to the bicarbonate and H ions).  As may be seen in the illustration below, the production of the bicarbonate yields a free H ion.  This is then excreted into the urine via a Na/H antiport (counter-transporter mechanism).  Consequently, with each H ion excreted a Na ion is reabsorbed.  This will ultimately result in the retention of one water molecule for every Na conserved.  CAI will prevent the formation and subsequent ionisation of carbonic acid.  Therefore, no H ion is formed and the Na/H antiport will not cause the reabsorption of Na.  (This action will also ultimately reduce the bicarbonate reabsorption.)

Clinical Responses
Tolerance -- Tolerance develops relatively rapidly to CAI, which limits their usefulness.

Other Responses -- The osmotic effects produced by inhibiting bicarb and H ion formation in the eye will decrease the production of  aqueous humour.  Therefore these agents are useful in the treatment of glaucoma.

Adverse Reactions

Metabolic Acidosis -- This is due primarily to the reduction in bicarbonate formation and the subsequent loss of its buffering capability.  This effect has proven beneficial in treating alkalosis-induced seizures.
CNS Depression -- Drowsiness, Fatigue
Paraesthesias
Dysgeusia
Diarrhoea

Mechanism of Action -- Following injection or absorption of the oral products these agents are distributed on a very limited basis to the body.  In general, they stay in systemic circulation until they are presented to the glomerulus where they are freely filtered into the tubules of the nephron.  They undergo very limited reabsorption and therefore remain in the tubular lumen, thereby creating an osmotic pressure that is greater than the tubular epithelium.  This results in the movement of water osmotically from the cell to the lumen (and from the interstitium to the cell to the lumen), thereby increasing the excretion of water.

Use of Mannitol over other osmotic diuretics -- Mannitol is preferred over the other agents because 1) it is inherently non-toxic, 2) it is freely filtered, 3) it is non-reabsorbable, 4) it is not metabolised, and 5) the other agents may pass into cells to a limited extent.

Adverse Reactions

Cardiovascular Toxicity -- Immediately after injection, the osmotic action of the compounds in the vasculature will cause the osmosis of non-vascular fluids into the vessel, increasing blood volume.  This in turn increases the workload of the heart (increased afterload, peripheral resistance) which may be detrimental.  These agents are contraindicated in patients with congestive heart failure.

Other Complications

Volume depletion
Hypernatraemia - increase Na retention in attempts to retain the water
Hyperkalaemia - same mechanism

Diuretics are useful in a number of conditions that may be related to total body water volume, peripheral resistance, or production of fluids within the body.  General uses for diuretics include hypertension, congestive heart failure, and oedema not associated with cardiac disease.  Additional uses include hyperaldosteronism (spironolactone as noted above), glaucoma (CAI and osmotics), acute mountain sickness (CAI), centrencephalic epilepsy (CAI, as noted above), cerebral oedema (osmotics), and increased intracranial pressure (osmotics).  They may also be useful in early nephrotic syndrome, when urine output is low.  However, as noted above, the use of diuretics is contraindicated in anuria (early total renal failure with no urine output) except for the thiazides indapamide and metolazone and the loop bumetanide, which may be used cautiously.  Loop diuretics are useful in the treatment of hyperkalaemia, as discussed below.  Thiazide diuretics may provide some usefulness in the treatment of nephrogenic diabetes insipidus, as described below.

Diabetes insipidous is characterised by copious amounts of urine output.  It may originate from one of two sources, and results in massive fluid loss.

Central diabetes insipidous -- is caused by either lack of synthesis or secretion of antidiuretic hormone (ADH, vasopressin).  ADH acts in the late DCT and CT to open channels which allow water to be conserved.  It is one of the primary necessary components of the countercurrent system for the conservation of water (in the absence of ADH, a very dilute urine is produced and water is excreted in great quantities).  Central DI is treated with vasopressin (injectable) or more commonly with vasopressin analogues (Desmopressin, DDAVP or deamino-D-argininevasopressin, intranasal or injectable, or lypressin).  These agents may produce as side effects tremor, sweating, vertigo, nausea & vomiting, and facial flushing.  Signs of toxicity include extensions of the side effects plus water intoxication.

Nephrogenic diabetes insipidous -- In this condition, ADH is synthesised and excreted by the brain but the kidney is resistant to its effects (there could be some defect in the receptor or second messenger system).  This condition may be congenital or the result of hypercalcaemia, hypokalaemia, or a consequence of drug toxicity (lithium and demeclocycline).

The exact type of DI is diagnosed by a challenge dose of desmopressin.  If the dose causes urine output to fall, the patient has central DI, if no change occurs, the patient has nephrogenic DI.

Amiloride -- The drug of choice in lithium-induced nephrogenic DI.  Amiloride will block the uptake of Li by the Na channel (Na channel blockade), thus inhibiting the effects of lithium.

Thiazide Diuretics -- While it may seem contradictory to administer a diuretic to a patient who has too much urine output, there is a pharmacodynamic basis that explains the usefulness of these agents in nephrogenic DI.  The natriuresis (Na loss) that occurs as a result of thiazide therapy will decrease ECFV (as already discussed).  This, in turn, causes a compensatory increase in NaCl reabsorption (again, as previously discussed) in the proximal tubule (before the area affected by DI) with water following (recall that the PCT is permeable to water).  There is then less water in the DCT where thiazides will inhibit Na/water reabsorption.  This allows a greater amount of water reabsorption than would occur normally in patients with DI.  This therapy is especially good if the patient is also placed on a low Na diet (further necessitating the importance of Na reabsorption).  Thiazide/Na restriction may result in a 50% decrease in urine output, which is considered good in these patients.

As noted above, both hypo- and hyper-kalaemia may result from specific diuretic agents, either of which may lead to life-threatening cardiac abnormalities.  Therefore in both instances, intervention should be made to correct the metabolic imbalance.

In cases of hypokalaemia, the simple administration of potassium will reverse the condition.

However the treatment of hyperkalaemia is more difficult.

Loop diuretics (which result in a relatively high degree of potassium loss) may be used to lower mild hyperkalaemia.

If the situation is more life-threatening, sodium polystyrene sulphonate (Kayexalate) may be used.  Sodium polystyrene sulphonate is a cationic binding (exchange) resin.  This agent exerts its activity mainly in the large intestine, where the sodium ions on the molecule are replace with potassium.  The agent produces variable results, exchanging approximately 1 mEq of potassium/gram of drug.  It may produce constipation and/or faecal impaction (this may be avoided by the co-administration of sorbitol, which may be used as the vehicle for the resin).  It may be given orally or rectally. Caution should be used in those patients sensitive to increases in sodium (since it is liberated from the resin and may be absorbed) such as those with severe hypertension or congestive heart failure.

Other treatments of hyperkalaemia include parenteral calcium (to counter the cardiac effects), sodium bicarbonate or glucose and insulin (to cause a shift of intracellular potassium), or dialysis.