Diuretics

High-Ceiling
(Loop Diuretics)

Dr. Amged 1
 High Ceiling Diuretics
Mechanism of Action

 The main site of action is the thick

ascending loop of henle (TALH)
 They inhibit the luminal Na+ /K+ /2Cl-
Symporter
 Additional effects on the PCT and
DCT are also possible

 This class is characterized more by its pharmacological similarities than

by its chemical similarities
 Produce a peak diuresis much greater than observed with the other
commonly used diuretics
 They are characterized by a quick onset and short duration of activit
Dr. Amged 2
 High Ceiling Diuretics
Chemical classes
NH2
NH2

OH
OH
O
2-a mino be nzo ic a c id O

Anthra nilic a c id 3-a m ino be nzo ic a c id

H
Cl N HN
O
O O
OH
S
H2N O
O OH
O
S
Furo se m ide H2N
O O
4-c hlo ro -2-(fura n-2-ylm e thyla m ino )-5-
sulfa m o ylbe nzo ic a c id
Bum e ta nid e
Dr. Amged 3-(butyla m ino )-4-p he no xy-5-sulfa m o ylb e nzo ic a 3c id
 High Ceiling Diuretics
Chemical classes
NH2
O
O
N O
S OH
NH2
O
4-a m ino p yridine -3-sulfo na m ide
phe no xya c e tic a c id

O
NH CH2 OH

N
O O
S Cl
O N H
N
H O Cl
To rse mide
N-iso pro pylc a rbo mo yl-4-(3-
me thylphe nyl)a mino ]pyridine -3-sulfo na m ide
Etha c rynic a c id
[2,3-dic hlo ro -4-(2-m e thyle ne b uta no yl)
p he no xy]a c e tic a c id
Dr. Amged 4
 High Ceiling Diuretics
Furosemide
H  It is a derivative of anthranilic acid or 2-
Cl N
O aminobenzoic acid
O
OH  The chlorine and sulfonamide substitution
S
H2N are essential for activity
O O
 Because it possesses a free COOH gp. It
Furo se m id e
4-c hlo ro -2-(fura n-2-ylm e thyla m ino )-5-
more acidic than thiazide diuretic (pKa 3.9)
sulfa m o ylb e nzo ic a c id

 Has a saluretic effect 8-10 times that of thiazide diuretics, however, it has
shorter duration of action (6-8 hr)
 Furosemide causes an excretion of Na+, Cl-, Ca2+, Mg2+ & HCO3-
 It is effective in treatment of edemas connected with cardiac, hepatic, renal
sites
 Like thiazide, it used in the treatment of hypertension
 Orally effective and used parenterally when a more prompt diuretic effect
is required
Dr. Amged 5
 High Ceiling Diuretics
Bumetanide
H N
Cl N
O O
HN
O O
OH O OH
S S
H2N O H2N
O O OH O O
S
H2N
Furo se m id e O O Pire ta nide
4-c hlo ro -2-(fura n-2-ylme thyla mino )-5- Bume ta nid e
sulfa m o ylb e nzo ic a c id 3-(b utyla m ino )-4-p he no xy-5-sulfa m o ylbe nzo ic a c id 4-p h e n o xy-3-(p yrro lid in -1-yl)-5-su lfa m o ylb e nzo ic a c id

 Structurally related to furosemide

 The N is moved to next position and it is substituted with butyl function. Cl is
replaced with phenoxy, which is also electronegative
 It is 50 times more potent than furosemide with shorter duration of action.
 Replacement of the phenoxy gp at position 4 with C6H5NH- or C6H5S-
gives compounds with favorable activity
 When butyl gp on C5 amine is replaced with furanylmethyl gp, such as in
furosemide, however, the results are not favorable
 Piretanide is bioisostere of Bumetanide.
Dr. Amged 6
 High Ceiling Diuretics
Torsemide
H
Cl N
O NH
O O O
OH N
S S
H2N N N
O O O H H

Furo se m id e To rse m ide

4-c hlo ro -2-(fura n-2-ylm e thyla m ino )-5- N-[(iso p ro p yla m ino )c a rb o nyl]-4-[(3-
sulfa m o ylb e nzo ic a c id m e thylp he nyl)a m ino ]p yrid ine -3-sulfo na m id e

 Obtained by structural modification of furosemide like structure

 Instead of sulfonamide gp found in furosemide & bumetanide, torsemide
contain a sulfonylurea moiety (i.e. Torsemide is a sulfonylurea
derivative)
 Similar to other high ceiling diuretics torsemide promote excretion of of
Na+, Cl-, Ca2+, Mg2+ & water
 Torsemide doesn't act at the PT, in contrast to furosemide and
bumetanide , and therefore doesn’t increase PO42- & HCO3-
Dr. Amged 7
 High Ceiling Diuretics
Ethacrynic acid (phenoxyacetic acid
derivatives)
 Designed to act mechanically similar to the
organomercurials (i.e. via inhibition of O
sulfahydryl-containig enzymes involved in O
solute reabsorption) CH2 OH

 Optimum diuretic activity was obtained when an

Cl
oxyacetic acid gp was positioned para to α, β-
O Cl
unsaturated carbonyl (or other sulfahydryl –
reactive gp) Etha c rynic a c id
 The removal of one of the chlorine atoms [2,3-d ic hlo ro -4-(2-m e thyle ne b uta no yl)
p he no xy]a c e tic a c id
reduces the activity, while the total removal of
both halogens abolishes the activity.

Enzym e ---SH O
O Enzym e ---SH
O
O
CH2 OH CH2 OH

Cl Cl
O Cl OH Cl
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Potassium-sparing Diuretics

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Potassium-Sparing Diuretics

1. Aldosterone Antagonist
(Spironolactone)
2. Na+ Channel Inhibitors
(Triamterene & Amiloride)

R, Aldosterone receptor

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 Mineralocorticoid Receptor Antagonist
Spironolactone
 The adrenal cortex secretes a potent antidiuretic hormone called aldosterone
which promotes salt and water retention and potassium & hydrogen ion
excretion
 Aldosterone has 3000 times activity than cortisone to cause reabsorption of Na+
and Cl- and increased K+ excretion.
 A substance that antagonizes the effects of aldosterone could be a good diuretic
drug.
 Spironolactone is such an antagonist.`

O
HO O
OH
HO OHC OH
H O H

H3C H3C

H H
H H
O O

Aldosterone Aldosterone
(Aldehyde form) (Hemiacetal form)
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 Mineralocorticoid Receptor Antagonist
Spironolactone
 Spironolactone is a competitive antagonist to the mineralocorticoids such as
aldosterone.
 The mineralocorticoids receptor is an intracellular protein that can bind
aldosterone
 Spironolactone bind to the receptor and competitively inhibits aldosterone
binding to the receptor
 Thus, aldosterone is prevented from binding to the receptor and reabsorption of
Na+ and Cl- with the accompanying water is prevented.
 The most important site of these receptors is in the late distal tubule and
collecting system.
O O
OH
HO OHC H

O
H3C

H O
H
O
O S
Aldosterone Dr. Amged 12
(Aldehyde form) Spironolactone
 Mineralocorticoid Receptor Antagonist
Spironolactone
 After oral administration, about 70% of the dose of spironolactone is absorbed.
 The drug is significantly metabolized during its first passage through the liver.
 The major metabolite is canrenone, which can easily be converted to
canrenoate anion.
 Canrenone is an antagonist to aldosterone. The canrenoic acid anion is not
active per se, but acts as aldosterone antagonist because of its conversion to
canrenone, which exists in the lactone form.

O O O
OH
O O OH

O S O O
Spironolactone Canrenone Canrenoic acid anion

Dr. Amged 13
 Mineralocorticoid Receptor Antagonist
Spironolactone
 Both canrenone and potassium canrenoate are used as diuretics
 The most serious side effect of Spironolactone is hyperkalemia because it has a
potassium-sparing effect
 Potassium levels should be monitored during the use of this drug
 Spironolactone can be administered in a fixed dose combination with
hydrochlorothiazide

O O O
OH
O O OH

O S O O
Spironolactone Canrenone Canrenoic acid anion

Dr. Amged 14
 Potassium-sparing Diuretics
Pteridines - Triamterene
 Structure modification of certain pteridine derivatives led to development of
triamterene
 Triamterene works by directly blocking the Epithelial Sodium Channel
(ENaC) in the distal tubule.
 It blocks re-absorption of Na+ and blocks excretion of K+ by a mechanism
different from that of aldosterone antagonists.
 The net result is increased NaCl excretion in the urine and almost no K +
execration.
 Most serious side effect is hyperkalemia. K+ level should regularly be shacked
and potassium supplements should be controlled.

8 1 H2N N N NH2
N N 2
7 N
N
N3 NH2
6 N
4
5 Triamterene
Pteridine 6-
Dr. Amged p he nylp te ridine - 15
2,4,7-tria m ine
 Potassium-sparing Diuretics
Aminopyrazines-Amiloride
 Amiloride , is an aminopyrazine structurally related to triamterene as an open
chain analoge.
 Amiloride, is a gauanidinum group containg pyrazine derivatives
 Similar to triamterene, it interferes with the process of cationic exchange in DCT by
blocking luminal sodium channels
 It blocks the reabsorption of Na+ and the secretion of K+
 It has no effect on the action of aldosterone
 Oral amiloride is about 50% absorbed with the duration of action of 10-12 hr.
 The most serious side effect is hperkalemia
 Amiloride can be administered in a fixed dose combination with
hydrochlorothiazide
H2N N N NH2
O HN

N
N
Cl N
N NH2
H
NH2
H2N N NH2
Triamterene
Amiloride
6-
3,5-d ia m ino - N-c a rba m im ido yl-6- Dr. Amged p he nylp te ridine - 16
c hlo ro p yra zine -2-c a rb o xa m id e 2,4,7-tria m ine
Osmotic diuretics

Dr. Amged 17
 Osmotic diuretics
 Osmotic diuretics are low-molecular-weight compounds that are not
extensively metabolized and are passively filtered through Bowman’s
Capsules into the renal tubules.
 Once in the renal tubules they have limited reabsorption.
 They form a hypertonic solution and cause water to pass from the body into
the tubules, producing a diuretic effect.
 Polyols such as mannitol, sorbitol and isosorbed provide this effect.
 Mannitol and sorbitol are used intravenously in solutions of 5-50%.
 Isosorbide is basically a bicyclic form of sorbitol (upon double dehydration)
used orally to cause a reduction in intraocular pressure

CH2OH
CH2OH
H OH OH
HO H H
HO H O
HO H
H OH
H OH O
H OH OH
H OH H
CH2OH
CH2OH
Dr. Amged
Sorbitol Isosorbide 18
Mannitol
Miscellaneous Diuretics

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 Miscellaneous Diuretics
 Theophylline, xanthine derivative that promote a weak diuresis by
stimulation of cardiac function (increases the glomelular filtrate) and by
direct action on the nephron

O
H

N
N

O N N

Theophylline

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 Classification of Diuretics
The following classes of diuretics are therapeutically used:

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