Review of Renal Physiology
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
Also, recall that the body in general and the kidney specifically exerts
an endogenous control of its own function. The release of renin will
cause the formation of angiotensin II, which prompts the release of aldosterone,
which causes the release of ADH, where these hormones may produce the effects
described above. Atrial natriuretic peptide (ANP, atriopeptin) is
secreted from the atrium of the heart in response to stretch receptors
stimulated by overfilling of the chamber. This is interpreted as
too great a blood volume. ANP then prompts the kidney to stop the
conservation of Na (increase Na excretion) so that water will follow osmotically,
thus reducing blood volume.
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).
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
Regardless of the exact mechanism, thiazide use will cause loss of Na,
Cl, and K to some extent.
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.
Loop Diuretics -- Furosemide, Torsemide, Ethacrynic Acid, Bumetanide
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.
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.
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.
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
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.
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.
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.
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.
Potassium Sparing Diuretics
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
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
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
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
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.)
Carbonic Anhydrase Inhibitors (CAI) -- Acetazolamide, Methazolamide,
Dichlorphenamide, Dorzolamide (ophthalmic only)
Osmotic Diuretics -- Glycerin (Oral), Mannitol (Parenteral), Urea
(Parenteral), Isosorbide (Oral)
Sodium Channel Inhibitors -- Amiloride, Triamterine
Potassium -- Potassium will be retained with spironolactone, potentially
leading to hyperkalaemia.
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.
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.
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
Other Adverse Effects
Hirsutism, voice deepening, and menstrual irregularities in females
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
Potassium -- Similar to spironolactone
Other Ions -- Similar to spironolactone, may also see Cl ion loss.
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
Electrolyte Imbalance -- Hyperkalaemia, similar to spironolactone
Musculoskeletal Disorders -- similar to spironolactone
Dermatological & haemtological -- Triamterine, similar to the thiazides,
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.
An Overview of Diuretic Therapy
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.
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.
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
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.
There also exists a condition referred to as syndrome of inappropriate
of ADH (SIADH). In this condition, the reverse of diabetes insipidous,
too much ADH is secreted and acts upon the kidney, resulting in decreased
urine output and increases in total body water volume. This may be
treated with non-specific ADH antagonists lithium and demeclocyline (noted
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
In cases of hypokalaemia, the simple administration of potassium will
reverse the condition.
Go To Next Section (Anaemias)
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.