CLASSIFICATION of DIURETICS

Inhibitors of Na+-Cl symport

(primary site of action is distal convoluted tubule)
Inhibitors of Na+-K+-2Cl symport
(primary site of action is thick ascending limb)
Inhibitors of renal epithelial sodium channels (primary site of action is late
distal tubule and collecting duct)
Antagonists of mineralocorticoid receptors (primary site of action is late distal
tubule and collecting duct)
Osmotic diuretics
(primary site of action is loop of Henle)
Inhibitors of carbonic anhydrase
(primary site of action is proximal tubule)
Miscellaneous agents

Thiazides
1. NaCl reabsorption in distal convoluted tubule and mechanism of diuretic
action of Na+-Cl symport inhibitors. Numbers in parentheses indicate
stoichiometry. S, symporter; CH, ion channel; BL, basolateral membrane; LM,
luminal membrane.
2. Na+ pump in basolateral membrane provide free energy for Na+-Cl
symporter in luminal membrane, which moves Cl into the cell against e-c
gradient. Cl passively exits the baso-lateral membrane via a Cl channel.
3. Thiazides inhibits Na+-Cl symporter by competing for Cl binding site.
4. Mutations in the Na+-Cl symporter cause a form of inherited hypokalemic
alkalosis called Gitelmans syndrome
5. Inhibition of Na+-Cl symporter in the cortical diluting segment attenuates
the ability of the kidney to excrete a dilute urine during water diuresis.

Some thiazides are weak inhibitors of carbonic anhydrase and HCO3 and
phosphate excretion.
Inhibition of Na+-Cl symporter in DCT results in increased Na+ excretion by
5% along with Cl and water (i.e. urine vol. by 5X).
Some thiazides are weak inhibitors of carbonic anhydrase and HCO3 and
phosphate excretion.
K+ excretion is increased.
Mg2+, I & Br excretion increased.
Ca2+, Uric acid excretion is decreased.

NOTES:
1. GFR 125 mL / minute urine 1 mL/min
2. The kidneys have 0.5% of body weight, but consume 7% of total-body oxygen
intake.

3. 65% of filtered solutes are reabsorbed in the proximal tubule.

4. This part (1, 2, 3) is highly permeable to water, and reabsorption is isotonic.
5. The DTL (4) is highly permeable to water, yet its permeability to NaCl and
urea is low.
6. In contrast, the ATL (5) is permeable to NaCl and urea but impermeable to
water.
7. The thick ascending limb TAL(6,7) actively reabsorbs NaCl but is impermeable
to water and urea. (blocked by loop diuretics)
8. Approximately 25% of filtered solutes are reabsorbed in the loop of Henle,
mostly in the TAL with a big reabsorptive capacity.
9. DCT (9, 10, 11) actively transports NaCl and is impermeable to water.
(inhibited by thiazides)
10.TAL and DCT made up the diluting segment of the nephron.
11.The CT system (12, 13, 14) adjusts electrolytes (solutes) under aldosterone
action.
12.Water (solvent) permeability in CT is controlled by ADH.

Thiazide diuretics also are the mainstay for treatment of nephrogenic diabetes
insipidus, reducing urine volume by up to 50%. Although it may seem
counterintuitive to treat a disorder of increased urine volume with a diuretic,
thiazides reduce the kidney's ability to excrete free water. They do so by increasing
proximal tubular water reabsorption (secondary to volume contraction) and by
blocking the ability of the distal convoluted tubule to form dilute urine. This latter
effect results in an increase in urine osmolality.
Diabetes Insipidus
Diabetes insipidus is due to either deficient production of ADH (neurogenic or
central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic
diabetes insipidus [NDI]). Administration of supplementary ADH or one of its analogs
is effective only in central diabetes insipidus. Thiazide diuretics can reduce polyuria
and polydipsia in both types of diabetes insipidus. Lithium, used in the treatment of
manic-depressive disorder, is a common cause of NDI, and thiazide diuretics have
been found to be very helpful in treating it. This seemingly paradoxic beneficial
effect of thiazides was previously thought to be mediated through plasma volume
reduction, with an associated fall in GFR, leading to enhanced proximal reabsorption
of NaCl and water and decreased delivery of fluid to the downstream diluting
segments. However, in the case of Li+-induced NDI, it is now known that HCTZ
causes increased osmolality in the inner medulla (papilla) and a partial correction of
the Li+-induced reduction in aquaporin-2 expression. HCTZ also leads to increased
expression of Na+ transporters in the DCT and CCT segments of the nephron. Thus,
the maximum volume of dilute urine that can be produced is significantly reduced in
NDI. Dietary sodium restriction can potentiate the beneficial effects of thiazides on
urine volume in this setting. Serum Li+ levels must be carefully monitored in these
patients, because diuretics may reduce renal clearance of Li+ and raise plasma Li+
levels into the toxic range (see Chapter 29). Lithium-induced polyuria can also be
partially reversed by amiloride, which blocks Li+ entry into collecting duct cells,

much as it blocks Na+ entry. As mentioned above, thiazides are also beneficial in
other forms of nephrogenic diabetes insipidus. It is not yet clear whether this is via
the same mechanism that has been found in Li+-induced NDI.
The thiazides are structurally related to sulphonamides. They act at the luminal
surface of the cortical (proximal) diluting segment of the distal convoluted tubule
and inhibit the Na + /Cl co-transporter (NCC) ( Fig. 14.2 , site 4). This prevents Na
+ and Cl from entering the tubular cell. Several structurally different thiazidelike drugs, such as chlortalidone and indapamide, share this site of action.
Thiazides and related diuretics have a lower efficacy than loop diuretics, achieving a
maximum natriuresis of about 58% of the filtered Na + load, and have shallow
doseresponse curves. The onset of diuresis is slow, but they have a longer duration
of action than loop diuretics, which varies among the drugs; for example,
bendroflumethiazide produces a natriuresis for up to 612h and chlortalidone for
4872h. Thiazide and related diuretics are less effective in renal failure (especially
when the glomerular filtration rate is below 20mLmin 1 ). Thiazide and related
diuretics, unlike the loop diuretics, reduce urinary Ca 2+ loss by inhibiting Ca 2+
transport in the proximal and distal tubules.
Thiazide and related diuretics produce arterial vasodilation during long-term use,
which appears to be the basis of their hypotensive effect ( Ch. 6 ), but the
mechanism of vasodilation is incompletely understood. It may involve direct
inhibition of agonist-induced contraction of vascular smooth muscle cells by Ca 2+
desensitization linked to the Rho kinase pathway, a regulator of actinmyosin crossbridging ( Ch. 1 ). The vasodilator action of these drugs occurs at lower dosages
than are required for significant diuresis.
Pharmacokinetics
The thiazide and related diuretics are fairly well absorbed from the gut and most are
metabolised in the liver. They are highly protein-bound and therefore little is filtered
at the glomerulus. Like the loop diuretics, thiazides act from within the renal tubular
lumen after secretion by organic anion transporters in the proximal tubule.
Thiazides generally have more prolonged durations of action than loop diuretics.
Unwanted effects
Hypokalaemia. Clinically this is more important with thiazides than with loop
diuretics. The greatest reduction in plasma K + usually occurs within 2 weeks of
starting treatment.
Hyponatraemia . Prolonged block by thiazides of Na + /Cl co-transport in the
distal convoluted tubule (where water cannot be reabsorbed) impairs free water
clearance. The combination of a thiazide with amiloride (see below) is particularly
associated with dilutional hyponatraemia (see loop diuretics ).
Hyperuricaemia (see loop diuretics ). Gout occurs infrequently and is less common
in women.

 Decreased urinary Ca 2+ excretion. This is in contrast to loop diuretics and the

mechanism is not well understood. This action of thiazides is useful for the
treatment of renal stones due to hypercalciuria. Hypercalcaemia does not usually
occur unless there is another underlying disturbance of Ca 2+ metabolism, such as
hyperparathyroidism.
Glucose intolerance. This is dose-related, with a progressive increase in plasma
glucose over many months. The major cause is prolonged hypokalaemia and the
consequent reduced intracellular K + concentration. This inhibits insulin release and
impairs tissue uptake of glucose in response to insulin. The glucose intolerance
usually reverses over several months if the thiazide is stopped (see Ch. 40 ).
Hyperlipidaemia. There is a dose-related increase in low-density lipoprotein
cholesterol and triglycerides. The long-term effects (>1 year) are small, but there is
a theoretical increased atherogenic risk if high doses of thiazides are used ( Ch.
48 ).
Impotence. This is reported by up to 10% of middle-aged hypertensive men
treated with high doses of thiazides ( Ch. 16 ).
Nocturia and urinary frequency can result from prolonged diuresis.

Clinical Indications & Dosage (Table 155)

The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3)
nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes
insipidus. Use of the thiazides in each of these conditions is described below in
Clinical Pharmacology of Diuretic Agents.
Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes
insipidus.
Previously thought to be mediated through plasma volume reduction, with an
associated fall in GFR, leading to enhanced proximal reabsorption of NaCl and water
and decreased delivery of fluid to the downstream diluting segments.
HCTZ causes increased osmolality in the inner medulla (papilla) and a partial
correction of the Li+-induced reduction in aquaporin-2 expression. HCTZ also leads
to increased expression of Na+ transporters in the DCT and CCT segments of the
nephron. Thus, the maximum volume of dilute urine that can be produced is
significantly reduced in NDI.
Nephrolithiasis
Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+
oxalate. While there are numerous medical conditions (hyperparathyroidism,
hypervitaminosis D, sarcoidosis, malignancies, etc) that cause hypercalciuria, many
patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption.
This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the
DCT and thus reduce the urinary Ca2+ concentration. Fluid intake should be

increased, but salt intake must be reduced, since excess dietary NaCl will
overwhelm the hypocalciuric effect of thiazides.
Toxicity
Hypokalemic Metabolic Alkalosis and Hyperuricemia
These toxicities are similar to those observed with loop diuretics (see previous text
and Table 152).
Impaired Carbohydrate Tolerance
Hyperglycemia may occur in patients who are overtly diabetic or who have even
mildly abnormal glucose tolerance tests. The effect is due to both impaired
pancreatic release of insulin and diminished tissue utilization of glucose.
Hyperglycemia may be partially reversible with correction of hypokalemia.
Hyperlipidemia
Thiazides cause a 515% increase in total serum cholesterol and low-density
lipoproteins (LDLs). These levels may return toward baseline after prolonged use.
Hyponatremia
Hyponatremia is an important adverse effect of thiazide diuretics. It is caused by a
combination of hypovolemia-induced elevation of ADH, reduction in the diluting
capacity of the kidney, and increased thirst. It can be prevented by reducing the
dose of the drug or limiting water intake.
Allergic Reactions
The thiazides are sulfonamides and share cross-reactivity with other members of
this chemical group. Photosensitivity or generalized dermatitis occurs rarely. Serious
allergic reactions are extremely rare but do include hemolytic anemia,
thrombocytopenia, and acute necrotizing pancreatitis.
Other Toxicities
Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase
inhibitors may occur. Impotence has been reported but is probably related to
volume depletion.
Contraindications
Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis,
borderline renal failure, or heart failure (see text that follows).

Furosemide
1. NaCl reabsorption in thick ascending limb and mechanism of diuretic action of
Na+-K+-2Cl symport inhibitors. Numbers in parentheses indicate
stoichiometry. Designated voltages are the potential differences across the
indicated membrane or cell. The mechanisms illustrated here apply to the

2.
3.
4.
5.

medullary, cortical, and postmacular segments of the thick ascending limb. S,

symporter; CH, ion channel; BL, basolateral membrane; LM, luminal
membrane.
Na+ pump in basolateral membrane provide free energy for Na+-K+-2Cl
symporter in luminal membrane, which moves K+ & Cl into the cell.
Luminal membrane (ROMK) K+ channel recycles K+.
Basolateral Cl channel provide an exit for Cl.
Lumen positive potential difference help repel cations (Na+, Ca2+, Mg2+)
into the interstitium.

NOTES:

Passive countercurrent multiplier hypothesis of Kokko and Rector (1972)

Active transport of NaCl & K (i) concentrates NaCl in the interstitium of the
outer medulla & (ii) dilutes the tubular fluid.
In the CT, water is extracted only if ADH is present.
Outer medullary CT had a low permeability to urea; therefore urea is
concentrated in the tubular fluid.

Hypertonicity of Medulla

Diffusion of urea out of the inner medullary, which is permeable to urea

hypertonic
High urea concentration in the inner medulla extracts water from the DTL and
concentrates NaCl in the tubular DTL which is impermeable to salt and urea.
ATL is salt permeable, NaCl diffuses out and contributes to the hypertonicity
of the medullary interstitium.

1. Mutations in the genes coding for the Na+-K+-2Clsymporter, the apical K+

channel or the basolateral Cl channel causes Bartters $ (hypokalemic
alkalosis with salt wasting and hypotension).
2. Diuresis powerful diuresis even with low GFR. Onset and duration shorter
than thiazides. Site of action = thick ascending limb (TAL) of the loop of
Henle.
MOA = About 25% of filtered Na+ load is reabsorbed in the TAL, and the
nephron segments past the TAL cannot reabsorb the flood of rejectate exiting
TAL. (Basic physiology)
3. So, inhibition of Na+-K+-2Cl symporter results in profound increase in
urinary excretion of Na+ and Cl, and water. Ca2+, Mg2+ reabsorption is
inhibited due to abolishing of transepithelial potential difference.
4. Furosemide (a sulfonamide), but not bumetanide and piretanide, weakly
inhibit carbonic anhydrase and increase HCO3 and PO4= excretion.
5. All inhibitors of Na+-K+-2Cl symport increase excretion of K+ and titratable
acid, but reduce uric acid excretion.

6. By blocking active NaCl reabsorption in TAL, loop diuretics disturb the

mechanism that produce hypertonicity of medulla, and the kidneys ability to
concentrate urine during hydropenia is eliminated.
7. Also, as TAL is the diluting segment, the ability of kidney to excrete a dilute
urine during water diuresis is impaired.
8. Since vitamin Dinduced intestinal absorption and parathyroid hormoneinduced renal reabsorption of Ca2+ can be increased, loop diuretics do not
generally cause hypocalcemia. However, in disorders that cause
hypercalcemia, Ca2+ excretion can be usefully enhanced by treatment with
loop diuretics combined with saline infusions.
2. Effects on renal haemodynamics
Loop diuretics block tubulo-glomerular feedback (TGF) by inhibiting salt transport
into the macula densa. Therefore, unlike CAIs, loop diuretics do not decrease GFR by
activating TGF.
Loop diuretics stimulate renin release, due to interference with NaCl transport and,
if volume depletion occurs, to reflex activation of SNS and to stimulation of intrarenal baroreceptors. Prostacyclin may mediate renin release.
3. Reduction of BP when given I.V. vasodilation occur before diuresis and RBF is
increased. Left ventricular filling pressure is decreased and benefits patients with
acute pulmonary oedema.
4. Ototoxicity alter electrolyte composition of endolymph in the inner ear by
inhibiting electrolyte transport.
5. Hyperglycemia inhibit insulin release.
Mechanism of action and effects
Loop diuretics, such as furosemide, must be secreted into the proximal kidney
tubule by the tubular organic anion transporters to access their site of action. The
extent of the natriuresis and diuresis is dependent on the rate of delivery of the
drug to the renal tubule via this secretory mechanism. Once these transporters
have been saturated, increasing the dose of the diuretic will not enhance its effect.
Loop diuretics bind to the Na + /K + /2Cl co-transporter complex (NKCC2) at the
luminal border of the thick ascending limb of the loop of Henle, and inhibit Cl
reabsorption. This diminishes the electrochemical gradient across the cell and
reduces Na + reabsorption from the tubular fluid ( Fig. 14.2 , site 3). Loop diuretics
therefore reduce the ability of the kidney to generate the medullary ionic
concentration gradient and impairs generation of concentrated urine in the
collecting duct. Loop diuretics also inhibit tubuloglomerular feedback and the
afferent artery vasoconstriction in response to the increased tubular concentrations
of Na + and Cl . They are powerful, high-ceiling diuretics which can inhibit
reabsorption of up to 25% of the Na + that appears in the glomerular filtrate.
The doseresponse curves of loop diuretics are steep, but the doses required to
achieve maximal inhibition of Na + reabsorption show wide inter-individual

variation. Because they have a short duration of action, there is partial

compensation for the natriuresis by subsequent rebound Na + uptake from the
tubular fluid after their action has finished. Loop diuretics remain effective even in
advanced renal failure, but larger doses are necessary to deliver an effective
concentration of drug to the remaining renal tubules as the reduced tubular
secretion results in greater metabolism of the drug in the liver.
When injected intravenously, furosemide releases vasodilator prostaglandins, such
as prostacyclin, into the circulation and produces a short-lived venodilation. Pooling
of blood in these capacitance vessels reduces central blood volume, which can be
useful in the treatment of acute left ventricular failure ( Ch. 7 ). Loop diuretics also
produce arterial vasodilation (see thiazide diuretics), but because of their short
duration of action they are not widely used to treat hypertension, except in renal
failure when their diuretic action can be useful.
Pharmacokinetics
Furosemide is incompletely and erratically absorbed from the gut, with considerable
inter-individual variation. Bumetanide is more completely and reliably absorbed.
Furosemide and bumetanide can also be given intravenously. Natriuresis and
diuresis begin about 30min after an oral dose and last up to 6h; intravenous
injection produces a more rapid effect, with an onset of diuresis within minutes.
Loop diuretics are partially metabolised in the liver. They are highly protein bound in
plasma and little drug is filtered at the glomerulus. Renal failure impairs the delivery
of drug to the tubular fluid, since the ability of the kidney to secrete organic anions
is reduced and other substrates compete with the diuretic for the organic anionic
transporters.
Unwanted effects
Excessive salt and water depletion can cause intravascular volume depletion,
hypotension and renal impairment.
Dilutional hyponatraemia can arise from excessive Na + loss that exceeds water
loss. Hyponatraemia is far less common than with thiazide diuretics. Stimulation of
ADH secretion in response to plasma volume contraction also contributes to
hyponatraemia by promoting reabsorption of water from the collecting duct.
Hyponatraemia can present with lethargy, impaired consciousness and eventually
coma and seizures.
Hypokalaemia is dose-related, but less severe than with diuretics such as
thiazides which have a longer duration of action (see below). It arises from
increased urinary K + loss from the distal part of the distal renal tubule. There are
several contributory mechanisms:
loop diuretics increase the delivery of Na + to the distal convoluted tubule, so
there is enhanced Na + reabsorption at this site. This creates a negative luminal
gradient that promotes K + diffusion into the tubular lumen,

 the dilute urine increases the K + gradient across the tubular membrane, which
also favours K + diffusion into the tubular lumen,
diuretic-induced hypovolaemia stimulates release of renin and aldosterone.
Aldosterone further enhances Na + reabsorption in the distal tubule at the expense
of increased K + excretion.
Obligatory urinary loss of Cl with the K + creates a mild metabolic alkalosis in the
plasma. To counteract the alkalosis, H + is shifted out of cells in exchange for
intracellular accumulation of K + , which exacerbates the hypokalaemia.
The diuretic most commonly used for congestive heart failure is a loop
diuretic like furosemide, which is administered IV, in a dosage of 40 mg,
followed if necessary by oral administration, 2080 mg/24 h.
1. Acute pulmonary oedema
2. Acute cerebral oedema
3. Hypertensive crisis
4. Congestive heart failure
5. Oedema of cardiac, renal and hepatic origin.
6. Refractory oedema (with thiazide or K-sparing agents and high dose)
7. Oliguria in early renal failure
8. Induction of forced diuresis in drug overdose
9. Hypercalcemia
10.Hyperkalemia.
Toxicity
Hypokalemic Metabolic Alkalosis
By inhibiting salt reabsorption in the TAL, loop diuretics increase Na+ delivery to the
collecting duct. Increased delivery leads to increased secretion of K+ and H+ by the
duct, causing hypokalemic metabolic alkalosis (Table 152). This toxicity is a
function of the magnitude of the diuresis and can be reversed by K+ replacement
and correction of hypovolemia.

Ototoxicity
Loop diuretics occasionally cause dose-related hearing loss that is usually
reversible. It is most common in patients who have diminished renal function or who
are also receiving other ototoxic agents such as aminoglycoside antibiotics.
Hyperuricemia
Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is
caused by hypovolemia-associated enhancement of uric acid reabsorption in the
proximal tubule. It may be prevented by using lower doses to avoid development of
hypovolemia.
Hypomagnesemia

Magnesium depletion is a predictable consequence of the chronic use of loop agents

and occurs most often in patients with dietary magnesium deficiency. It can be
reversed by administration of oral magnesium preparations.
Allergic and Other Reactions
All loop diuretics, with the exception of ethacrynic acid, are sulfonamides. Therefore,
skin rash, eosinophilia, and less often, interstitial nephritis are occasional adverse
effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal.
Allergic reactions are much less common with ethacrynic acid.
Because Henle's loop is indirectly responsible for water reabsorption by the
downstream collecting duct, loop diuretics can cause severe dehydration.
Hyponatremia is less common than with the thiazides (see below), but patients who
increase water intake in response to hypovolemia-induced thirst can become
severely hyponatremic with loop agents. Loop agents can cause hypercalciuria,
which can lead to mild hypocalcemia and secondary hyperparathyroidism. On the
other hand, loop agents can have the opposite effect (hypercalcemia) in volumedepleted patients who have anotherpreviously occultcause for hypercalcemia,
such as metastatic breast or squamous cell lung carcinoma.
Contraindications
Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in
patients who are sensitive to other sulfonamides, but this appears to be very rare.
Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal
failure, or heart failure.
>>>Large doses of the cephalosporin antibiotic, cephaloridine, produce acute
proximal tubular necrosis in humans and in laboratory animals. Cephaloridine is
actively transported into the proximal tubular cell by an organic anion transport
system while transport across the lumenal membrane into tubular fluid appears
restricted. High intracellular concentrations of cephaloridine are attained in the
proximal tubular cell which are critical to the development of nephrotoxicity. There
is substantial evidence indicating that oxidative stress plays a major role in
cephaloridine nephrotoxicity. Cephaloridine depletes reduced glutathione, increases
oxidized glutathione and induces lipid peroxidation in renal cortical tissue. The
molecular mechanisms mediating cephaloridine-induced oxidative stress are not
well understood. Inhibition in gluconeogenesis is a relatively early biochemical
effect of cephaloridine and is independent of lipid peroxidation. Furthermore,
cephaloridine inhibits gluconeogenesis in both target (kidney) and non-target (liver)
organs of cephaloridine toxicity. Since glucose is not a major fuel of proximal tubular
cells, it is unlikely that cephaloridine-induced tubular necrosis is mediated by the
effects of this drug on glucose synthesis.

K-Sparing Diuretics: Amiloride & Triamterene

1. Na+ reabsorption in late distal tubule and collecting duct and mechanism of
diuretic action of epithelial Na+-channel inhibitors. Cl reabsorption (not
shown) occurs both paracellularly and transcellularly, and the precise
mechanism of Cl transport appears to be species-specific. Numbers in
parentheses indicate stoichiometry. Designated voltages are the potential
differences across the indicated membrane or cell. A, antiporter; CH, ion
channel; CA, carbonic anhydrase; BL, basolateral membrane; LM, luminal
membrane.
2. Na+ enter the tubule cell via the luminal Na+ channel, down the e-c gradient
induced by b-l Na+-pump.
3. Lumen negative trans-epithelial potential difference help the secretion of K+
via luminal K+ channel.
4. Type A intercalated cell secrete H+ ion into the tubular lumen.
5. Amiloride block the Na+ channel, decrease K+ loss and produce mild
diuresis.
Amiloride is a pyrazinoylguanidine derivative, and triamterene is a pteridine (Table
256). Both drugs are organic bases and are transported by the organic base
secretory mechanism in proximal tubule
Cirrhotic patients are prone to megaloblastosis because of folic acid deficiency, and
triamterene, a weak folic acid antagonist, may increase the likelihood of this
adverse event. Triamterene also can reduce glucose tolerance and induce
photosensitization and has been associated with interstitial nephritis and renal
stones.
Liddle's syndrome

Liddle's syndrome (pseudoaldosteronism, OMIM 177200) is a hereditary

disease leading to early onset of hypertension. It is associated with
hypokalemic alkalosis, reduced plasma rennin activity and low plasma
aldosterone levels.
ENaC is composed of 3 homologous subunits , and , it is highly selective
for Na+ over K+ and exhibits a relatively low conductance (~5pS) and slow
gating kinetics with prolonged channel openings.
It is regulated in 2 ways:
by altering the gating of the channel that results in increased Na+ transport
without a change in channel surface density
by varying the membrane density or the number of channels located in the
apical membrane
The second way is nonfunctional in liddle syndrome.
This way is based on ubiquitylation a process that usually regulates stability
of target proteins,how does it work?
It is carried out by the sequential activity of E1, E2 and E3 (ubiquitin ligase)
enzymes that have an effect on proteins that are tagged with ubiquitin by the
E3 ligases, in an ATP-dependent way, as showed in the figure below . Most of
these proteins are degraded by the proteasome .

THERAPY

Liddle syndrome patients should be treated with the ENaC antagonist Amiloride and
a low salt diet to stabilize their high blood pressure.
This treatment improve patients prognosis whereas, without treatment,
cardiovascular and renal complications usually occur.
Cystic Fibrosis Exercise - Cell Biology of Disease and Exercisept851.wikidot.com
In a normal ASL lumen, the addition of amiloride, which blocks Na+ transport into
the cell, causes the lumen of the lung to become more positive.[11]. The inhibition
of Na+ causes a decrease in the Cl- absorption into the cell to compensate for this
increase in positive charge in the lumen (outside the cell).[11] This decreases the
TPD with the cell membrane potential becoming less negative in response to the
increase in Na+ ions in the lumen.[11][12]
When amiloride is added to the lumen, there is a rapid increase in the Na+ present
in the lumen due to the inhibition of the Na+ transport back into the cell.[11] This
decreases the TPD as the lumen becomes more positive.[11] Because CFTR is
defective, there is only minimal transport of Cl- via other channels.[11] As a result of
Na+ reabsorption inhibition, there is an increase in the NaCl content of the lumen.
Because water follows solutes, there is an increased ASL volume.[11]

K-Sparing Diuretics: Aldosterone Antagonists

Effects of aldosterone on late distal tubule and collecting duct and diuretic
mechanism of aldosterone antagonists. A.Cortisol also has affinity for the
mineralocorticoid receptor (MR), but is inactivated in the cell by 11--hydroxysteroid
dehydrogenase (HSD) type II. B. Serum and glucorticoid-regulated kinase (SGK)-1 is
upregulated after ~30 minutes by aldosterone. SGK-1 phosphorylates and
inactivates Nedd4-2 a ubiquitin-protein ligase that acts on ENaC, leading to its
degradation. Phosphorylated Nedd4-2 no longer interacts with the PY motif of ENaC.
As a result, the protein is not ubiquitinated and remains in the membrane, the end
result of which is increased Na+ entry into the cell. 1. Activation of membranebound Na+ channels. 2. Na+ channel (ENaC) removal from the membrane is
inhibited. 3. De novo synthesis of Na+ channels. 4. Activation of membrane-bound
Na+,K+- ATPase. 5. Redistribution of Na+,K+-ATPase from cytosol to membrane. 6.
De novo synthesis of Na+,K+-ATPase. 7. Changes in permeability of tight junctions.
8. Increased mitochondrial production of ATP. AIP, aldosterone-induced proteins;
ALDO, aldosterone; MR, mineralocorticoid receptor; CH, ion channel; BL, basolateral
membrane; LM, luminal membrane.
Legend:
1. Ion transport pathways across the luminal and basolateral membranes of
collecting tubule and collecting duct cells. Inward diffusion of Na+ via the
epithelial sodium channel (ENaC) leaves a lumen-negative potential, which
drives reabsorption of Cl and efflux of K+. (R, aldosterone receptor.)
2. Aldosterone enters the epithelial cell and binds to MR.

3. The MR-A complex translocates to nucleus, binds to DNA and regulates

aldosterone induced proteins (AIPs).
4. AIPs activate silent Na+ channel and Na+ pumps, with net effect of Na+
absorption.
5. Spironolactone inhibits the binding of aldosterone to MR and blocks synthesis
of AIPs.
Pharmacological Actions
Reduces sodium absorption by 2 % and potassium is conserved. Interfere with
steroid biosynthesis.
Pharmacokinetics
Well absorbed (65%), t 1.6 hr, active metabolite canrenone with t 16.5 hr. Onset
of action is very slow (days).
Side Effects
Hyperkalemia, mild acidosis, Steroid like effects (gynaecomastia, impotency,
hirsutism, irregular menses), CNS effects (confusion, drowsiness, lethargy).
Mechanism of action and effects
Drugs in this class produce a diuresis while preventing urinary K + loss. All
potassium-sparing diuretics act at the late distal convoluted tubule and cortical
collecting duct. Spironolactone, its active metabolite canrenone, and eplerenone are
the only diuretics that do not act at the luminal membrane of the tubular cells. They
compete with aldosterone for the cytoplasmic MR in the distal convoluted tubular
cells and block transcriptional upregulation of the ENaC, the basolateral Na + /K +
-ATPase pump and AIPs. They therefore antagonise the effects of aldosterone on Na
+ reabsorption and K + excretion ( Fig. 14.2 , site 5). Spironolactone and eplerenone
only work in the presence of aldosterone so their effect is enhanced in
hyperaldosteronism.
Amiloride and triamterene have a different mechanism of action: they directly block
the epithelial Na + channel (ENaC) at the luminal surface of the renal tubule ( Fig.
14.2 ). Their action is independent of the presence of aldosterone.
The maximum natriuresis achieved by potassium-sparing diuretics is small (usually
less than 23% of filtered Na + ) unless there is marked secondary
hyperaldosteronism, when spironolactone and eplerenone are much more effective.
With potassium-sparing diuretics the Na + and water loss is accompanied by
preservation of plasma K + , because the reduced Na + reabsorption limits ATPdependent Na + exchange with K + at the basolateral membrane ( Fig. 14.2 , site
5). When used together with thiazide or loop diuretics, potassium-sparing diuretics
reduce or eliminate the excess urinary K + loss.
Pharmacokinetics
All potassium-sparing diuretics are given orally. Spironolactone is metabolised in the
wall of the gut and the liver to canrenone, which has a much longer half-life and is

probably responsible for most of the diuretic effect. The onset of action of
spironolactone or eplerenone is slow, starting after 1 day and becoming maximal by
34 days, largely a consequence of their transcriptional mechanism of action.
Triamterene is extensively metabolised in the liver, and tubular secretion of the
sulphate ester metabolite is responsible for the diuretic action. Amiloride is secreted
unchanged into the proximal renal tubule. The onset of action of both drugs is rapid.
Unwanted effects
Hyperkalaemia. This is more common in the presence of pre-existing renal
disease, in the elderly and during combination treatment with angiotensinconverting enzyme (ACE) inhibitors or angiotensin II receptor antagonists ( Ch. 6 ).
Retention of Mg 2+ also occurs, in contrast to the loss of Mg 2+ with the thiazides
and loop diuretics.
Hyponatraemia. This is more common with thiazide/amiloride combinations.
Spironolactone has an anti-androgenic effect, a consequence of its ability to bind
to androgen receptors and prevent their interaction with dihydrotestosterone. This
causes gynaecomastia and impotence in males, and menstrual irregularities in
women. The anti-androgenic effect is sometimes used in women to treat hirsutism
(such as in polycystic ovary syndrome; Ch. 43 ), male-pattern hair loss and acne.
Eplerenone has greater aldosterone receptor selectivity and does not have antiandrogenic actions.
Gastrointestinal disturbances.

Osmotic Diuretics
Osmotic diuretics are used to increase water excretion in preference to sodium
excretion. This effect can be useful when avid Na+ retention limits the response to
conventional agents. It can be used to maintain urine volume and to prevent anuria
that might otherwise result from presentation of large pigment loads to the kidney
(eg, from hemolysis or rhabdomyolysis). Some oliguric patients do not respond to
osmotic diuretics. Therefore, a test dose of mannitol (12.5 g intravenously) should
be given before starting a continuous infusion. Mannitol should not be continued
unless there is an increase in urine flow rate to more than 50 mL/h during the 3
hours after the test dose. Mannitol (12.525 g intravenously) can be repeated every
12 hours to maintain urine flow rate greater than 100 mL/h. Prolonged use of
mannitol is not advised.
Reduction of Intracranial and Intraocular Pressure
Osmotic diuretics alter Starling forces so that water leaves cells and reduces
intracellular volume. This effect is used to reduce intracranial pressure in neurologic
conditions and to reduce intraocular pressure before ophthalmologic procedures. A
dose of 12 g/kg mannitol is administered intravenously. Intracranial pressure, which
must be monitored, should fall in 6090 minutes.
Mechanism of action

Mannitol is filtered at the glomerulus but not reabsorbed from the renal tubule. It
exerts osmotic activity within the proximal renal tubule and particularly in the
descending limb of the loop of Henle, and limits passive tubular reabsorption of
water. Water loss produced by mannitol is accompanied by a variable natriuresis (up
to 25% of filtered Na + ). Unlike other diuretics, the osmotic action of mannitol
produces an initial expansion of plasma and extracellular fluid volume, which limits
its clinical uses.
Mannitol does not readily cross the bloodbrain barrier. It is used to treat some
forms of acute brain injury, when the main mechanism of action may be through
haemodilution and reduced blood viscosity which may limit ischaemic damage,
rather than a dehydrating action on cerebral tissues.
Pharmacokinetics
Mannitol is given by intravenous infusion and is excreted unchanged at the
glomerulus. It has a half-life of 2h, which is substantially increased in renal
impairment.
Unwanted effects
Expansion of plasma volume can precipitate heart failure.
Urinary K + loss can lead to hypokalaemia (see loop diuretics ).
>>>In the renal tubule
1. OD inhibit renin release and increase RBF.
2. Act mainly in LOP by osmotic effect and by reducing medullary hypertonicity
3. Increase RBF remove NaCl and urea from renal medulla reduce medulla
tonicity reduce extraction of water from DTL limit concentration of NaCl
in tubular fluid entering ATL reduce passive reabsorption of NaCl in the
ATL.
4. Mannitol acts as counterforce to normal reabsorption of water and rate of
urine flow (mainly water) is enhanced (not used to remove oedema, but to
maintain patency of tubules).
Osmotic diuretics are agents that are freely filtered at the glomerulus, undergo
limited reabsorption by the renal tubule, and are relatively inert pharmacologically.
Osmotic diuretics are administered in doses large enough to increase significantly
the osmolality of plasma and tubular fluid. Table 253 lists four osmotic diuretics
glycerin (OSMOGLYN), isosorbide, mannitol (osmitrol, others), and urea (currently
not available in the U.S.).
Mechanism and Site of Action
For many years it was thought that osmotic diuretics act primarily in the proximal
tubule as nonreabsorbable solutes that limit the osmosis of water into the interstitial
space and thereby reduce luminal Na+ concentration to the point that net Na+
reabsorption ceases. Although early micropuncture studies supported this concept,
subsequent studies suggested that this mechanism, while operative, may be of only

secondary importance and that the major site of action of osmotic diuretics is the
loop of Henle.
By extracting water from intracellular compartments, osmotic diuretics expand
extracellular fluid volume, decrease blood viscosity, and inhibit renin release. These
effects increase RBF, and the increase in renal medullary blood flow removes NaCl
and urea from the renal medulla, thus reducing medullary tonicity. Under some
circumstances, prostaglandins may contribute to the renal vasodilation and
medullary washout induced by osmotic diuretics. A reduction in medullary tonicity
causes a decrease in the extraction of water from the DTL, which in turn limits the
concentration of NaCl in the tubular fluid entering the ATL. This latter effect
diminishes the passive reabsorption of NaCl in the ATL. In addition, the marked
ability of osmotic diuretics to inhibit Mg2+ reabsorption, a cation that is reabsorbed
mainly in the thick ascending limb, suggests that osmotic diuretics also interfere
with transport processes in the thick ascending limb. The mechanism of this effect
is unknown.
In summary, osmotic diuretics act both in proximal tubule and loop of Henle, with
the latter being the primary site of action. Also, osmotic diuretics probably act by an
osmotic effect in the tubules and by reducing medullary tonicity.
Effects on Urinary Excretion
Osmotic diuretics increase urinary excretion of nearly all electrolytes, including Na+,
K+, Ca2+, Mg2+, Cl, HCO3, and phosphate.
Effects on Renal Hemodynamics
Osmotic diuretics increase RBF by a variety of mechanisms. Osmotic diuretics dilate
the afferent arteriole, which increases PGC, and dilute the plasma, which decreases
GC. These effects would increase GFR were it not for the fact that osmotic
diuretics also increase PT. In general, superficial SNGFR is increased, but total GFR is
little changed.
Absorption and Elimination
Pharmacokinetic data on the osmotic diuretics are listed in Table 253. Glycerin and
isosorbide can be given orally, whereas mannitol and urea must be administered
intravenously.
Toxicity, Adverse Effects, Contraindications, and Drug Interactions
Osmotic diuretics are distributed in the extracellular fluid and contribute to the
extracellular osmolality. Thus, water is extracted from intracellular compartments,
and the extracellular fluid volume becomes expanded. In patients with heart failure
or pulmonary congestion, this may cause frank pulmonary edema. Extraction of
water also causes hyponatremia, which may explain the common adverse effects,
including headache, nausea, and vomiting. On the other hand, loss of water in
excess of electrolytes can cause hypernatremia and dehydration. Osmotic diuretics
are contraindicated in patients who are anuric owing to severe renal disease. Urea
may cause thrombosis or pain if extravasation occurs, and it should not be

administered to patients with impaired liver function because of the risk of elevation
of blood ammonia levels. Both mannitol and urea are contraindicated in patients
with active cranial bleeding. Glycerin is metabolized and can cause hyperglycemia.
Therapeutic Uses
One use for mannitol is in the treatment of dialysis disequilibrium syndrome. Too
rapid a removal of solutes from the extracellular fluid by hemodialysis results in a
reduction in the osmolality of extracellular fluid. Consequently, water moves from
the extracellular compartment into the intracellular compartment, causing
hypotension and CNS symptoms (headache, nausea, muscle cramps, restlessness,
CNS depression, and convulsions). Osmotic diuretics increase the osmolality of the
extracellular fluid compartment and thereby shift water back into the extracellular
compartment.
By increasing the osmotic pressure of plasma, osmotic diuretics extract water from
the eye and brain. All osmotic diuretics are used to control intraocular pressure
during acute attacks of glaucoma and for short-term reductions in intraocular
pressure both preoperatively and postoperatively in patients who require ocular
surgery. Also, mannitol and urea are used to reduce cerebral edema and brain mass
before and after neurosurgery.
Clinical Indications & Dosage
Increase of Urine Volume
Osmotic diuretics are used to increase water excretion in preference to sodium
excretion
Mannitol (12.525 g intravenously) can be repeated every 12 hours to maintain
urine flow rate greater than 100 mL/h. Prolonged use of mannitol is not advised.
Reduction of Intracranial and Intraocular Pressure
Osmotic diuretics alter Starling forces so that water leaves cells and reduces
intracellular volume. This effect is used to reduce intracranial pressure in neurologic
conditions and to reduce intraocular pressure before ophthalmologic procedures. A
dose of 12 g/kg mannitol is administered intravenously. Intracranial pressure, which
must be monitored, should fall in 6090 minutes.

Carbonic Anhydrase Inhibitors Acetazolamide

Mechanism of action
Acetazolamide interferes with the small proportion of Na + that is actively
reabsorbed in the proximal tubule in exchange for H + ( Fig. 14.2 , site 2 in MPT4e).
This process is dependent on carbonic anhydrase, which is inhibited by
acetazolamide. Acetazolamide increases HCO 3 , Na + and K + secretion, causing
alkaline urine. H + retention produces mild acidosis in the blood, but the fall in

plasma HCO 3 concentration stimulates carbonic anhydrase activity, which

rapidly leads to tolerance to the diuretic action of acetazolamide. In consequence,
acetazolamide does not have a clinically useful diuretic action. Its clinical use is
restricted to treatment of altitude sickness ( Ch. 13 ) and glaucoma ( Ch. 50 ).
Other Actions
Carbonic anhydrase is present in a number of extrarenal tissues, including the eye,
gastric mucosa, pancreas, central nervous system (CNS), and erythrocytes.
Carbonic anhydrase in the ciliary processes of the eye mediates formation of large
amounts of HCO3 in aqueous humor. Inhibition of carbonic anhydrase decreases
the rate of formation of aqueous humor and consequently reduces intraocular
pressure. Acetazolamide frequently causes paresthesias and somnolence,
suggesting an action of carbonic anhydrase inhibitors in the CNS. The efficacy of
acetazolamide in epilepsy is due in part to the production of metabolic acidosis;
however, direct actions of acetazolamide in the CNS also contribute to its
anticonvulsant action. Owing to interference with carbonic anhydrase activity in
erythrocytes, carbonic anhydrase inhibitors increase CO2 levels in peripheral tissues
and decrease CO2 levels in expired gas. Large doses of carbonic anhydrase
inhibitors reduce gastric acid secretion, but this has no therapeutic application.
Acetazolamide causes vasodilation by opening vascular Ca2+-activated K+
channels; however, the clinical significance of this effect is unclear.

Therapeutic Uses
Autonomic drugs are used extensively for diagnostic and surgical purposes and for
the treatment of glaucoma, uveitis, and strabismus.
Glaucoma
In the U.S., glaucoma is the second leading cause of blindness in African-Americans,
the third leading cause in Caucasians, and the leading cause in Hispanic Americans
(Congdon et al., 2004).
Elevated IOP is a risk factor for glaucoma. Several randomized, controlled trials
have determined that reducing IOP can delay glaucomatous nerve or field damage
The Ocular Hypertension Treatment Study found that prophylactic medical reduction
of IOP reduced the risk of progression to glaucoma from ~10-5% (Kass et al., 2002).
Current pharmacotherapies are targeted at decreasing the production of aqueous
humor at the ciliary body and increasing outflow through the trabecular meshwork
and uveoscleral pathways.
The goal is to prevent progressive glaucomatous optic-nerve damage with minimum
risk and side effects from either topical or systemic therapy. With these general
principles in mind, a stepped medical approach may begin with a topical
prostaglandin (PG) analog. Due to their once-daily dosing, low incidence of systemic
side effects, and potent IOP-lowering effect, PG analogs have largely replaced
adrenergicreceptor antagonists as first-line medical therapy for glaucoma. The PG

analogs consist of latanoprost (xalatan), travoprost (travatan, travatan z), and

bimatoprost (lumigan, latisse).
The receptor antagonists now are the next most common topical medical
treatment. There are two classes of topical blockers. The nonselective ones bind
to both 1 and 2 receptors and include timolol maleate, levobunolol,metipranolol,
and carteolol. There is one 1-selective antagonist, betaxolol, available for
ophthalmic use, but it is less efficacious than the nonselective blockers because
the receptors of the eye are largely of the 2 subtype.
When there are medical contraindications to the use of PG analogs or receptor
antagonists, other agents, such as a 2 adrenergic receptor agonist or topical
carbonic anhydrase inhibitor (CAI), may be used as first-line therapy. The 2
adrenergic agonists improve the pharmacological profile of the nonselective
sympathomimetic agent epinephrine and its derivative, dipivefrin (propine, others).
Epinephrine stimulates both and adrenergic receptors. The drug appears to
decrease IOP by enhancing both conventional (via a 2 receptor mechanism) and
uveoscleral outflow (perhaps via PG production) from the eye.
Therapeutic Uses
Although acetazolamide is used for treatment of edema, the efficacy of carbonic
anhydrase inhibitors as single agents is low, and carbonic anhydrase inhibitors are
not employed widely in this regard. The combination of acetazolamide with diuretics
that block Na+ reabsorption at more distal sites in the nephron causes a marked
natriuretic response in patients with low basal fractional excretion of Na+ (<0.2%)
who are resistant to diuretic monotherapy (Knauf and Mutschler, 1997). Even so,
the long-term usefulness of carbonic anhydrase inhibitors often is compromised by
the development of metabolic acidosis.
The major indication for carbonic anhydrase inhibitors is open-angle glaucoma. Two
products developed specifically for this use are dorzolamide (trusopt, others) and
brinzolamide (azopt), which are available only as ophthalmic drops. Carbonic
anhydrase inhibitors also may be employed for secondary glaucoma and
preoperatively in acute angle-closure glaucoma to lower intraocular pressure before
surgery (Chapter 64). Acetazolamide also is used for the treatment of epilepsy
(Chapter 21). The rapid development of tolerance, however, may limit the
usefulness of carbonic anhydrase inhibitors for epilepsy.
Acetazolamide can provide symptomatic relief in patients with high-altitude illness
or mountain sickness; however, it is more appropriate to give acetazolamide as a
prophylactic measure. Acetazolamide also is useful in patients with familial periodic
paralysis. The mechanism for the beneficial effects of acetazolamide in altitude
sickness and familial periodic paralysis is not clear, but it may be related to the
induction of a metabolic acidosis. Other off-label clinical uses include the treatment
of dural ectasia in individuals with Marfan syndrome, of sleep apnea, and of
idiopathic intracranial hypertension. Finally, carbonic anhydrase inhibitors can be
useful for correcting a metabolic alkalosis, especially one caused by diuretic-induced
increases in H+ excretion.

Acetazolamide (ass-ett-az-zole-am-mide)
Topically active agents, which reduce intraocular pressure without producing renal
or systemic effects, are available (dorzolamide, brinzolamide).
Glaucoma
The reduction of aqueous humor formation by carbonic anhydrase inhibitors
decreases the intraocular pressure. This effect is valuable in the management of
glaucoma, making it the most common indication for use of carbonic anhydrase
inhibitors. Topically active agents, which reduce intraocular pressure without
producing renal or systemic effects, are available (dorzolamide, brinzolamide).
Urinary Alkalinization
Uric acid and cystine are relatively insoluble and may form stones in acidic urine.
Therefore, in cystinuria, a disorder of cystine reabsorption, solubility of cystine can
be enhanced by increasing urinary pH from 7.0 to 7.5 with carbonic anhydrase
inhibitors. In the case of uric acid, pH needs to be raised only to 6.0 or 6.5. In the
absence of HCO3 administration, these effects of acetazolamide last only 23
days, so prolonged therapy requires oral HCO3. Excessive urinary alkalinization
can lead to stone formation from calcium salts (see below), so urine pH should be
followed during treatment with acetazolamide.
Metabolic Alkalosis
Metabolic alkalosis is generally treated by correction of abnormalities in total body
K+, intravascular volume, or mineralocorticoid levels. However, when the alkalosis
is due to excessive use of diuretics in patients with severe heart failure,
replacement of intravascular volume may be contraindicated. In these cases,
acetazolamide can be useful in correcting the alkalosis as well as producing a small
additional diuresis for correction of volume overload. Acetazolamide can also be
used to rapidly correct the metabolic alkalosis that may appear following the
correction of respiratory acidosis.
Acute Mountain Sickness
Weakness, dizziness, insomnia, headache, and nausea can occur in mountain
travelers who rapidly ascend above 3000 m. The symptoms are usually mild and
last for a few days. In more serious cases, rapidly progressing pulmonary or cerebral
edema can be life-threatening. By decreasing cerebrospinal fluid formation and by
decreasing the pH of the cerebrospinal fluid and brain, acetazolamide can increase
ventilation and diminish symptoms of mountain sickness. This mild metabolic
central and cerebrospinal fluid (CSF) acidosis is also useful in the treatment of sleep
apnea.
Other Uses
Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of
epilepsy and in some forms of hypokalemic periodic paralysis. They are also useful
in treating patients with CSF leakage (usually caused by tumor or head trauma, but

often idiopathic). By reducing the rate of CSF formation and intracranial pressure,
carbonic anhydrase inhibitors can significantly slow the rate of CSF leakage. Finally,
they also increase urinary phosphate excretion during severe hyperphosphatemia.
>>>>>
POAG: In general, prostaglandin analogues are the firstline of medical therapy.
These drugs reduce intraocular pressure by reducing outflow resistance resulting in
increased aqueous humor flow through the uveoscleral pathway.43 These drugs are
administered once nightly and have few, if any, systemic adverse effects. However,
they can cause local adverse effects such as conjunctival hyperemia, elongation
and darkening of eyelashes, loss of orbital fat (so-called prostaglandin-associated
periorbitopathy), induced iris darkening, and periocular skin pigmentation. Other
classesof topical medications are less effective in lowering intraocular pressure than
prostaglandin analogues.44They are used as second-line agents or when there is a
contraindication or intolerance to the use of prostaglandin analogues (Table 2).
Prostaglandin analogues and carbonic anhydrase inhibitors lower intraocular
pressure during both the day and night. Other drugs such as the -adrenergic
blockers and -adrenergic agonists are effective only during the day and not at
night.45Someof these agents, such as -adrenergic blockers, mayhave significant
systemic adverse effects and are contraindicated in patients with history of chronic
pulmonary obstructive disease, asthma, or bradycardia. To decrease systemic
absorption of topical medications, it is advisable for patients to use gentle punctual
occlusion or eyelid closure for 2 minutes after drug instillation.
CAG: The first-line treatment of angle closure is laser peripheral iridotomy a
procedure in which a full thickness hole is created in the iris (Figure 6) to eliminate
pupillary block. If pressure remains high after iridotomy, long-term medical
treatment(including topical -blockers, 2agonists, carbonic anhydrase inhibitors,
and prostaglandin analogues) can be instituted, similar to the management of open
angle glaucoma.
Acute Primary Angle Closure
Acute primary angle closure is an ocular emergency and requires immediate
management to avoid blindness. Patients usually present with a painful red eye
associated with blurring of vision, headache, and nausea and vomiting. The cornea
is usually hazy due to the very high intraocular pressure, and the pupil is frequently
mid dilated and poorly reactive to light .The aims of the treatment are to achieve
rapid pressure control with topical and systemic medications to limit optic nerve
damage. This is followed by iridotomy to alleviate pupillary block. Iridotomy
successfully aborts the attack in 42%to 72% of cases, and many patients recover
without optic disc or visual field damage if the pressure is promptly and adequately
controlled.63 Laser iridoplasty (contraction of the peripheral iris) can be performed
if conventional medical treatment is not tolerated or does not abort the attack. If
iridotomy is unsuccessful or difficult to perform because of a cloudy cornea, surgical
iridectomy is indicated. Prophylactic iridotomy should be carried out for the fellow
eye, which is at high risk of acute angle closure

True/false answers
1. True. Hypokalaemia can also affect brain and skeletal muscle function.
2. False. Much of the filtered K + is reabsorbed in the proximal tubule and loop of
Henle, and its loss into the urine occurs mainly in the collecting ducts.
3. False. The basolateral Na + /K + -ATPase pump is present throughout the renal
tubule.
4. True. Impermeability to water and the NKCC2 transporter that co-transports Na
+ , K + and Cl ions from the lumen into the tubular cell in the thick ascending
limb together generate the hyperosmotic interstitium important in concentrating
urine in the collecting duct.
5. True. Osmotic diuretics are retained within the tubule where their osmotic activity
reduces passive reabsorption of water in the proximal tubule and descending limb
of the loop of Henle.
6. True. By extracting water from intracellular compartments and expanding
extracellular and intravascular fluid volumes, osmotic diuretics can precipitate
pulmonary oedema.
7. True. Acetazolamide reduces the formation of aqueous humour.
8. False. Some thiazide diuretics such as chlortalidone can produce a diuresis for 48
72h, while most loop diuretics are relatively short-lived.
9. False. Thiazide diuretics act from within the renal tubular lumen on the thiazidesensitive Na + /Cl co-transporter (NCC) on the luminal (apical) membrane.
10. False. The thiazide diuretics do not increase urinary Ca 2+ excretion, unlike the
loop diuretics.
11. True. Thiazide diuretics may exacerbate diabetes mellitus, probably through
hypokalaemia reducing insulin release from pancreatic -cells.
12. False. Amiloride blocks the epithelial Na + channel (ENaC) directly, whereas
spironolactone competes with aldosterone at mineralocorticoid receptors, thus
reducing the transcriptional expression of ENaC. The reduced Na + reabsorption
produced by both drugs in the collecting duct reduces the loss of K + into the urine.
13. True. ACE inhibitors, by reducing angiotensin-induced aldosterone secretion, will
reduce K + excretion and hence increase plasma K + concentration, particularly
when combined with potassium-sparing diuretics.
14. False. Thiazides and loop diuretics increase Na + concentrations in the tubular
fluid reaching the collecting duct; the excessive loss of K + that results can be
reduced by combining the thiazide or loop diuretic with a potassium-sparing
diuretic.
15. True. NSAIDs inhibit prostaglandin synthesis in the kidney and this reduces renal
blood flow, leading to reduced natriuretic responses to thiazide and loop diuretics.

1. Answer C is correct. Triamterene is a potassium-sparing diuretic that directly

blocks a selective Na + channel (ENaC) on the luminal membrane of tubule cells in
the collecting duct. Answer A is the mechanism of action of aldosterone
(mineralocorticoid) receptor antagonists such as spironolactone. Answers B, D and E
are the mechanisms of action of loop diuretics, thiazides and carbonic anhydrase
inhibitors respectively.
2. Answer A is correct.
A. Correct . Loop diuretics are widely used in the control of oedema in heart failure
for the elimination of excessive salt and water load. The direct venodilator activity
of furosemide reduces central blood volume.
B. Incorrect. A thiazide diuretic can be added to a loop diuretic to act sequentially at
different sites in the nephron, thus producing a marked diuresis and natriuresis.
C. Incorrect. Delivery of greater concentrations of Na + to the collecting ducts
increases the exchange for K + at that site, thus increasing K + loss.
D. Incorrect. By inhibiting the Na + /K + /2Cl co-transporter (NKCC2), the
medullary interstitial hypertonicity falls and this reduces the reabsorption of water
in the collecting ducts (in the presence of antidiuretic hormone).
E. Incorrect. Loop diuretics alone can cause ototoxicity (especially at high doses or
in renal impairment) and also when taken with other ototoxic drugs such as
aminoglycosides.
Extended-matching-item answers
Case 1. Answer A . The combination of a potassium-sparing diuretic (amiloride) and
an ACE inhibitor (lisinopril) may have raised the plasma K + concentration and this
may have been the cause of the profound bradycardia.
Case 2. Answer E . Thiazide-like diuretics can worsen insulin resistance, resulting in
an increased plasma glucose concentration.
Case 3. Answer B . The loop diuretic may cause hypokalaemia. This enhances the
toxicity of digoxin, resulting in arrhythmias.