Diuretics by Dr.MONIKA SINGH

Dr. MONIKA SINGH (Pharmaceutical Chemistry) 07-10-2020
BP501T- Medicinal Chemistry-II UNIT-II 1
DIURETICS
BY
Dr. MONIKA SINGH
Medicinal Chemistry-II (BP-501T)
UNIT-II
1BP-501T Med Chen-II UNIT-II
SyllabusUnit-II 10 Hours
Anti-Anginal: Vasodilators: Amyl Nitrite, Nitroglycerin*, Pentaerythritol tetranitrate,
Isosorbide Dinitrite*, Dipyridamole.
Calcium channel blockers: Verapamil, Bepridil hydrochloride, Diltiazem hydrochloride,
Nifedipine, Amlodipine, Felodipine, Nicardipine, Nimodipine.
Diuretics: Carbonic Anhydrase Inhibitors: Acetazolamide*,
Methazolamide, Dichlorphenamide.
Thiazides: Chlorthiazide*, Hydrochlorothiazide,
Hydroflumethiazide, Cyclothiazide,
Loop Diuretics: Furosemide*, Bumetanide, Ethacrynic acid.
Potassium sparing Diuretics: Spironolactone, Triamterene,
Amiloride.
Osmotic Diuretics: Mannitol.
Anti-hypertensive Agents: Timolol, Captopril, Lisinopril, Enalapril, Benazepril hydrochloride,
Quinapril Hydrochloride, Methyldopate Hydrochloride* Clonidine hydrochloride,
Guanethidine Monosulphate, Guanabenz Acetate, Sodium Nitroprusside, Diazoxide,
Minoxidil, Reserpine, Hydralazine hydrochloride.
BP-501T Med Chen-II UNIT-II
2

• Diuretics are the drugs or agents which promotes
diuresis i.e. increased urine production and
increased rate of urine flow
• The site of action is kidney, specifically different
parts of a nephron
• Diuretic action is achieved by increasing excretion of Na+
ions (natriuretic) which increases excretion of water
• Diuretics reduce extracellular fluid volume (decrease in
edema) by decreasing total body NaCl content.
• Na+ ions are excreted accompanied with other ions,
particularly Cl- ions, also Ca++, Mg++, K+ etc.
BP-501T Med Chen-II UNIT-II 3
THERAPEUTIC USES
• As antihypertensive agent (decreases blood
volume)
• In treatment of edema (by mobilizing
extracellular fluids as NaCl is the major
determinant of extracellular volume)
• Tomaintain urine volume
• In Diabetes insipidus
• Glucoma
• Acute mountain sickness
• Primary hyper Aldosteronism

There are four major sites along the nephron that are responsible
for reabsorption:
Site 1: Proximal Convoluted Tubule (PCT)
Site 2: Ascending Loop of Henle
Site 3: Distal Convoluted Tubule (DCT)
Site 4: Late Distal Tubule and Collecting Duct
5
Renal Cortex
Renal Medulla
6
Classification of Diuretics
1) Site 1 Diuretics : Carbonic Anhydrase Inhibitors
Acetazolamide, Methazolamide,
Dichlorphenamide, Chloraminophenamide.
2) Site 2 Diuretics : Loop Diuretics (High Ceiling)
Furosemide, Bumetanide and Ethacrynic acid
3) Site 3 Diuretics : Thiazides
Chlorthiazide*, Hydrochlorothiazide,
Hydroflumethiazide, Cyclothiazide,
4) Site 4 Diuretics : Potassium Sparing Diuretics
a. Na+ Channel Inhibitors: Triamterene,Amiloride
b. Aldosterone Antagonists: Spironolactone
5) OSMOTIC Diuretics : Mannitol.
6

CLASSIFICATION OF DIURETICS
Type Example Site of Action Mechanism of Action
Carbonic anhydrase
inhibitors
Acetazolamide
Methazolamide,
Dichlorphenamide
Proximal convoluted
tubule
(Site-I)
Inhibition of carbonic
anhydrase enzyme
Loop diuretics Furosemide
Bumetanide
Ethacrynic acid
Loop of Henle
(Site-II)
Blocks Na+/K+/Cl-
Cotransport/
symporter
Thiazide and thiazide
like diuretics
Chlorthiazide*,
Hydrochlorthiazid,
Hydroflumethiazide,
Cyclothiazide
Distal convoluted
tubule
(Site-III)
Blocks Na+/Cl-
symporter
Potassiumsparring
diuretics Collecting tubule
(Site-IV)
Blocks renal
epithelial Na+
channel
Na+ channel blockers Triamterene
Amiloride
Blocks the action of
aldosteroneAldosterone
antagonist
Spironolactone
Osmotic diuretics Mannitol
Isosorbide
Proximal convoluted
tubule;
Loop of Henle
7

SITE OF ACTION OF VARIOUS DIURETICS
Impermeable
to ions
Impermeable
to WATER
9BP-501T Med Chen-II UNIT-II
SITE OF ACTION OF VARIOUS DIURETICS 10BP-501T Med Chen-II UNIT-II

CARBONIC ANHYDRASE INHIBITORS
• Weak type of diuretics
• Act by inhibiting carbonic anhydrase enzyme
• Examples: Acetazolamide, Methazolamide,
Dichlorphenamide
• Catalyzes the following reaction
• Located in proximal convoluted tubule; both in the cytoplasm
of tubular cells and on luminal membrane
• Plays a key role in NaHCO3 reabsorption
Fig. Action of Carbonic Anhydrase Enzyme
sodium–proton exchanger

• Basolateral Na+ pump maintain a lesser
concentration of Na+ inside the tubular cells
which activated Na+/H+ exchanger present on
luminal membrane
• H+, transported into lumen in exchange of Na+,
bind with HCO3
- to form H2CO3 which in presence
of luminal CA breaks down into H2O and CO2
• CO2 diffuses into tubular cells where it binds with
H2O and then breaks into HCO3
- via cytoplasmic
CA enzyme
• This creates electrochemical gradient of HCO3
-
across basolateral membrane which is used by
Na+/HCO3
- cotransport present on basolateral
membrane resulting in reabsorption of NaHCO3
followed by water reabsorption isotonically
MOA of carbonic anhydrase
inhibitors (ACETAZOLAMIDE)
• Inhibition of both luminal and cytoplasmic
carbonic anhydrase enzyme results in
blockage of NaHCO3 reabsorption in PCT
And thereby increase excretion of water
Besides Na+ and HCO -, CA inhibitors also
increase excretion of Cl- and K+ ; but have no
effect on Ca++ and Mg++ reabsorption
• It shows self limiting diuretic action

EXTRARENAL ACTIONS OF CA INHIBITORS
-
• Ciliary processes of eye:
– CA mediates formation of HCO3 in aqueous humour
– CA inhibitors decrease rate of formation of
aqueous humour and decrease IOP
• CNS
– Lowering of
pH resulting in
sedation and
elevation of
seizure
threshold
THERAPEUTIC USES
 Because of self limiting action, production of
acidosis and hypokalemia, it is not used as
diuretic
 Edema (oedema) (in combination with other
distal diuretics)
 Used in glaucoma
 To alkalinize urine (during UTI and to promote
excretion of acidic drugs)
 Altitude sickness (for symptomatic relief as well
as prophylaxis; due to reduced CSF formation as
well lowering of brain and CSF pH)
 Epilepsy
 Totreat metabolic alkalosis
16

• Metabolic acidosis because of loss of HCO3
- ions
• Hypokalemia i.e Potassium depletion
• Drowsiness
• Tinnitus
• Abdominal discomfort
• Bone marrow depression
• Renal lesions, allergic reactions
• Renal stones
Contraindications
• Liver cirrhosis
– May precipitate hepatic coma by interfering with urinary elimination
of NH3 due to alkaline urine
• COPD
– Increased risk of acidosis
17
Adverse Effects
DOSE
• Adult dose for Glaucoma
– Open angle glaucoma: tab or inj. 250 mg 1 to 4 times a day
– Closed angle glaucoma: 250 to 500 mg PO/IV followed by 125-
250 mg PO q 4 hrs
• For altitude sickness: 125 to 250 mg orally q 6-12 hrs
• For seizure prophylaxis: 8 to 30 mg/Kg/day in 1 to 4 divided
doses
Drug – Drug Interactions
• Acetazolamide + Aspirin -Inhibit each others renal tubular secretion
resulting increased plasma levels; also CAIs displace salicylates from plasma
to CNS resulting to neurotoxicity
• Acetazolamide + Carbamazepine - Increased levels of carbamazepine,
due to inhibition of CYP3A4 by acetazolamide
• Acetazolamide + ephedrine- Increase tubular reabsorption of ephedrine

7
Structural ActivityRelationship
S
1) SAR involving simple heterocyclic sulfonamides
Acetazolamide is the most important compound of this group.
N N
H2NO2S NH C CH3
O
Acetazolamide
S
H2NO2S N C CH3
O
a) The sulfamoyl group is essential for activity.
b) The sulfamoyl nitrogen atom must be unsubstituted.
c) Substitution of a methyl group on one of the ring nitrogen
retains CA inhibitory activity, eg. methazolamide.
CH3
N N
Methazolamide
d) The moiety to which the sulfamoyl group is attached must
possess aromatic character.
19
N-(sulphamoyl-1,3,4-thiadiazol-2-yl)acetamide
a) The parent 1,3-disulfamoylbenzene is inactive, but substituted
analogues have diuretic activity
b) Maximum diuretic activity is observed when the position 4 is
substituted with, Cl-, Br-, CF3 or NO2
c) An unsubstituted sulfamoyl moiety at position 3 is essential for
activity
d) Replacement of the sulfamoyl moiety at position 1 with an
electrophilic group (eg., carboxylic group) results in decreased
CA inhibitory activity
8
2) SAR studies involving meta-disulfamoylbenzenes
H2NO2S SO2NH2
1
2
3
4
5
6
H2NO2S SO2NH2
Cl
Cl
Dichlorphenamide
1,3-Disulfamoylbenzene
(inactive)
20

LOOP DIURETICS
• Also called high ceiling diuretics
• High efficacy diuretics
• Site of action is thick ascending limb of loop of Henle,
specifically Na+/K+/2Cl- Co-transpoart system
• Ex: Furosemide, Bumetanide, Ethacrynic acid
5-sulfamoylbenzoic acid derivatives
21
Ethacrynic acid
4-chloro N-furfuryl-5-sulphamoyl anthranilic acid
phenoxyacetic acid derivatives
MOA OF FUROSEMIDE
(LOOP DIURETICS)
FUROSEMIDE
22

 Na+/K+/2Cl- Cotransport present on luminal
membrane of (Thick ascending Loop) TAL
is responsible for reabsorption of NaCl and
KCl.
 By inhibiting this cotransport, furosemide inhibits
the reabsorption of Na+, K+ and Cl- thereby
resulting in diuretic action.
 TAL is responsible for reabsorption of 35% of Na+;
hence inhibition at this site helps in achieving
highly efficacious diuretic action.
 Besides, it also inhibits reabsorption of Ca++ and
Mg++
THERAPEUTIC USES
 Edema (Drug of choice for edema in nephrotic
syndrome)
 Acute pulmonary edema
 Cerebral edema
 Hypertension
 Hypercalcaemia
Adverse Effects
• Hypokalemia
• Hyperuricaemia
• Hypotension
• Hypomagnesaemia,
hypocalcemia
• Nausea, vomiting,
diarrhoea
• Ototoxicity
• Hypersensitivity reactions
• Alkalosis

CONTRA INDICATIONS
• Severe hyponatremia
• Severe dehydration
• Anuria
• Hypersensitivity to sulfonamides
DOSE
• For edema
– 20 to 80 mg PO OD (per os i.e by mouth, once a Day)
• For hypertension
– 20-80 mg PO q 12hr
• Acute pulmonary edema
– 0.5-1 mg/Kg IV over 1-2 minutes
25
DRUG-DRUG INTERACTION
• Furosemide + Aminoglycoside antibiotics
(amikacin, gentamycin, streptomycin) – Synergistic
pharmacological effects results in ototoxicity and nephrotoxicity
• Furosemide + NSAIDS
– Diminished action of furosemide
• Furosemide + Probenecid
- Inhibit tubular secretion of furosemide decreasing their action
- Diminish uricosuric action of probenecid
• Furosemide + Lithium
– Increased plasma levels of Lithium dueto enhanced
reabsorption
• Furosemide + cardiac glycosides
– Enhances digitalis toxicity

SAR of Loop diuretics (Sulfonamide Derivatives)
These agents are 5-Sulfamoylbenzoic acid derivatives,
examples are Furosemide, bumetanide etc.
H2NO2S COOH
Cl
CH2
NH
O
Furosemide
Bumetanide
H2NO2S COOH
O
HN
(CH2)3 CH3
1
27
2
3
4
5
6
1
2
3
4
5
6
There are two series of 5-sulfamoylbenzoic acid derivatives, that
differ in the nature of the functional groups that can be substituted
at 2 and 3 positions.
a) 5-sulfamoyl-2-aminobenzoic acid: Furosemide
b) 5-Sulfamoyl-3-aminobenzoic acid: Bumetanide
28
Structural ActivityRelationship
 The substituents at the 1 position must be acidic. The carboxylic
group provides optimal diuretic activity, but other groups such as
tetrazole impart good activity.
 A sulfamoyl group at the position 5 is essential for optimal diuretic
activity.
 The ‘activating’ group at the 4 position can be Cl- or CF3- as in
thiazide diuretics. Better activity was observed when these groups
have been replaced by phenoxy, alkoxy, aniline and benzyl moieties.
 The substitutions possible on the 2-amino group in 5-sulfamoyl-2-
aminobenzoic acid derivatives is limited in the order:
furfuryl > benzyl > thienyl methyl only.
 In case of 5-sulfamoyl-3-aminobenzoic acid the
3-amino group can be widely substituted without much
change in the activity.


Activating group (Cl- or CH3-) occupy either the 3 position or the 2 and 3
positions.
An Acryloyl moiety which reacts with sulfhydryl containing receptor
present in renal tissues should be at the para to the oxyacetic acid group.
Reduction or epoxidation of the carbon-carbon double bond in the
acryloyl moiety yielded compounds with little or nodiuretic activity.
SAR of Loop diuretics (Non-sulphonamide)
Ethacrynic acid is a phenoxyacetic acid derivative which is the
only important member of this class of drugs.
Cl
2OCH COOHC2H C CH3
O
Cl
2
1
3
4
C
CH2
Ethacrynic acid
Structure Activity Relationship



29
2,3-dichloro -4-(2-ethyl acryloyl)phenoxyacetic acid
THIAZIDE AND THIAZIDE LIKE DIURETICS
• These are diuretics of medium efficacy
• Site of action is distal convoluted tubule;
specifically Na+/Cl- symporter
• E.g.: Chlorthiazide*, Hydrochlorothiazide,
Hydroflumethiazide, Cyclothiazide
• Na+/Cl- cotransport, presenton luminal membraneof
DCT, is responsible for Na+ reabsorption at this
site (about 5%)
• Thiazides compete for Cl- binding site of this cotransport
and by blocking this, it inhibits Na+ reabsorption
• Simultaneously, it also inhibit reabsorption of Cl-, K+
and Mg++
• It increases the reabsorption of Ca++
MOA
30

MOA OF HYDROCHLORTHIAZIDE
These agents are 1,2,4-
benzothiadiazine-1,1-
dioxide derivatives and
are known as thiazides
and hydrothiazides
(lacking double bond at
position 3-4).
Thiazide Diuretics
H2NO2S
R R1
O O1
NH
S 2
3
4
N
5
6
7
8
Name R R1
Chlorthiazide -Cl -H
Cyclothiazide -Cl
or
32
Hydrothiazide Diuretics
H2NO2S
R R1
O
NH
S 2
1 O
3
H 4
N
5
6
7
8
Name R R1
Hydrochlorothiazide -Cl -H
Hydroflumethiazide -CF3 -H
IUPAC name of Chlorthiazide:
6-chloro-2H-1,2,4-benzothiadiazine-7-sulphonamide-1,1,-dioxide

THERAPEUTIC USES
 To treat edema associated with heart
(congestive heart failure), liver (cirrhosis), and renal
(nephrotic syndrome, chronic renal failure, and acute
glomerulonephritis) disease
 As antihypertensive agents(mainly used
diuretics)
 Osteoporosis Adverse Effects
• Hypotension
• Hypokalemia
• Metabolic alkalosis
• Hypernatremia ( Na+ ion in blood)
• Hypochloremia
• Hypomagnesaemia
• Hypercalcemia
• Hyperuricaemia
CONTRA INDICATIONS
• Sulfonamides hypersensitivity
33
DOSE
• For hypertension
– 12.5-50 mg PO OD (per os i.e by mouth, once a Day)
• For edema
– 25-100 mg PO OD or BD (before dinner)
• For osteoporosis
– 25 mg PO OD

Structure Activity Relationship
a) Substitutions at position 2 with small alkyl groups such as methyl (-CH3) does
not change the activity.
b) Substituents at position 3 determine the potency and duration of action of the
thiazide diuretics.
c) Loss of the carbon-carbondouble bond between the 3
and 4 positions of the thiazide nucleus increases the potency approximately
3 to 10 folds.
d) Direct substitution at 4, 5 or 8 positions with an alkyl group
usually diminishes diuretic activity.
e) Substitution at the 6 position with an ‘activating’ group is essential for diuretic
activity. The best substituents include Cl-, Br-, CF3- and NO2 groups. For example
replacement of 6-Cl- by 6- CF3 does not change potency, whereas replacement
with CH3 reduces diuretic activity.
f) The sulfonamide group at the position 7 is essential for diuretic activity. Removal
of this group yields compounds with little or no diuretic activity.
H2NO2S
R R1
O
S
1
NH
2
O
3
4
N
5
6
7
8
35
• Thiazides + NSAIDS/Bile acid sequestrants
– Reduced activity of thiazides due to reduced
absorption
• Thiazides + antiarrythmic drugs (Quinidine)
– Increased risk of polymorphic ventricular tachycardia
due to hypokalaemia induced by thiazides
• Thiazides + Probenecid
secretion of furosemide decreasing– Inhibit tubular
their action
– Diminish uricosuric action of probenecid

POTASSIUM SPARRING DIURETICS
• These are the diuretics that have are able to
conserve K+ while inducing mild natriuresis
• Includes:
1. Aldosterone antagonists
– E.g.: Spironolactone
2. Renal epithelial Na+ channel inhibitors
– E.g.: Triamterene, Amiloride
• Steroid, chemically related to
mineralocorticoid aldosterone
• Acts as antagonist of aldosterone
N
N
NH2
NH2H N2 N N
Triamterene
NH
1
N
O
C NH C NH2
2
3N
4
5
Cl
6
NH2
must be
unsubstitutedAmiloride
H2N
must be
unsubstituted
Triamterene is an aminopteridine derivative and
has a structural resemblance to folic acid whereas
Amiloride is a pyrazinoguanidine derivative
essential for activity

 Spironolactone is the only available aldosterone
antagonist. A metabolite of spironolactone, “canrenone”,
is also active.
 Spironolactone is steroidal derivative, structurally
related to progesterone
O
H3C
CH3
O
O
S C CH3
O
Spironolactone
O
H C3
CH3
O
O
Canrenone
(a major active metabolite)
ACTION OF ALDOSTERONE

ACTION OF SPIRONOLACTONE
MOA OF SPIRONOLACTONE
• Aldosterone penetrates the late distal tubule
(DT) and collecting duct (CD) cells
• Bind to intracellular mineralocorticoid
receptor (MR)
• Induces formation of aldosterone induced
proteins (AIP)
• AIPS promote Na+ reabsorption by a number of
mechanism and K+ secretion
• Spironolactone binds to MR and inhibits formation
of AIPs
• As a result it increases Na+ and decreases K+
excretion

THERAPEUTIC USES
 In combination with other diuretics to
counteract K+ loss
 Edema
 Hypertension
 Congestive heart failure
 Primary Hyperaldosteronism
Adverse Effects
• Hyperkalemia
• Metabolic acidosis in cirrhotic patients
• Diarrhoea, gastritis
• Gynaecomastia
• Erectile dysfunction
• Menstrual irregularities
• Drowsiness, mental confusion
CONTRA INDICATIONS
• In case of severe
hyperkalemia
• Peptic ulcer (may aggravate)
DOSE
• For edema
– 25-200 mg/day orally
• Hypertension
– 50-100 mg/day orally
• Congestive heart failure
– 25 mg orally OD
• Primary Hyperaldosteronism
– 400 mg/day orally
• Spironolactone + Salicylates
– Inhibit tubular secretion of spironolactone thus
reducing its action
• Spironolactone + Cardiac glycosides
– Increase plasma levels of cardiac glycosides by
altering its elimination
44

OSMOTIC DIURETIC
• MANNITOL is a osmotic diuretic
• Its major site of action is loop of henle
• Chemically it is sugar alcohol
• It is a nonelectrolyte of low molecular weight
• Pharmacologically inert
MOA OF MANNITOL
• Mannitol is freely filtered at glomerulus, undergo
limited reabsorption
• Being a hypertonic solute, it increase intraluminal
osmotic pressure
• This OP extract from the tubular cells and also
prevents water reabsorption
• Thereby increasing the urine volume
• Though primary action is to increase urinary volume,
mannitol also results in enhanced excretion of all
ions
THERAPEUTIC USES
 Totreat increased intracranial or intraocular pressure
 Drug of choice for cerebral edema
 In acute renal failure
46

Adverse effects
• Pulmonary edema
• Headache
• Nausea
• Vomiting
• Dehydration
CONTRA INDICATIONS
• Active intracranial bleeding
• Pulmonary edema
• CHF
• Anuria
• Mannitol + aminoglycosides
– Increased risk of nephrotoxicity
DOSE
• For Cerebral edema - 1.5-2 g/kg IV infused over 30-60
minutes
• For increased IOP - 1.5-2 g/kg IV infused over 30-60 minutes
47
Acetazolamide SYNTHESIS
CHLORTHIAZIDE Synthesis
3-chlor aniline
Chlorosulphonic acid
Ammonia
Formic acid or
Ammonium
Thiocyanate
Hydrazine
Phosgene

Furosemide synthesis

REFERENCES
• Wilson and Gisvold’s Organic Medicinal and Pharmaceutical
Chemistry by Block J.H. and Beale J.M., Lippincott Williams and
Wilkins.
• Foye’s Principles of Medicinal Chemistry by Lemke T.L., Williams
D.A., Roche V.F. and Zito S.W., Lippincott Williams and Wilkins.
• Medicinal and Pharmaceutical Chemistry by Singh H. and Kapoor
V.K., Vallabh Prakashan, Delhi.
• Burger’s Medicinal Chemistry and Drug Discovery by Abraham D.J., Vol
I to IV. John Wiley and Sons Inc., New York.
• TRIPATHI, K.D., (2014). Essentials of Medical Pharmacology. 7th
Edition. New Delhi, India: Jaypee Brothers Medical Publishers Pvt.
Ltd.
• BRUNTON, L.L., PARKER, K.L., BLUMENTHAL, D.K., BUXTON, I.L.O,
(2006). Goodman and Gilman’s Manual of Pharmacology and
Therapeutics. 11th Edition. USA: The McGraw- Hill Companies, Inc.
51
THANK YOU

Diuretics by Dr.MONIKA SINGH

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