2nd unit diuretics

2ND UNIT
DIURETICS
Prepared by
G. Nikitha, M.Pharmacy
Assistant Professor
Department of Pharmaceutical Chemistry
Sree Dattha Institute Of Pharmacy
Hyderabad
1
Subject: Medicinal Chemistry-II
Year: B.Pharmacy 3rd Year
Semister: 1st Semister

CONTENTS
 Introduction.
 General Mechanism of Action
 Classification
 Carbonic anhydrase inhibitors
 Thiazides
 Loop diuretics
 Potassium sparing Diuretics
 Osmotic Diuretics
 SAR.
 Structure , Synthesis.
 Adverse Drug Reactions , Uses.
 References 2

INTRODUCTION
 Diuretics increase the rate of urine flow and sodium excretion and
are used to adjust the volume of body fluids. The normal fluids
filtration in human body is 180 liters about 1.5 liters of urine is
formed in 24 hours.
 Diuretics are concerned with the maintenance of volume as well as
composition of the body fluids. Hence they are indicated in the
treatment of various edematous conditions like chronic heart failure,
nephritic syndrome, hypertension, glaucoma, acute mountain
disease, pregnancy, hepatic disease etc.
3

GENERAL MECHANISM OF ACTION
 The diuretic effect is achieved by direct action on the various
segment of nephron of indirectly by altering the glomerular filtration
content.
4

CLASSIFICATION
Based on Diuretic Potency
a. Highly Potent /High ceiling diuretics
Loop Diuretics: Furosemide, Bumetanide, Torasemide, Ethacrynic
acid.
b. Moderately potent (efficacious) diuretics
i.Thiazide diuretics: Chlorthiazide, Hydrochlorothiazide,
Hydroflumethiazide, Cyclothiazide.
ii. Osmatic diuretics: Mannitol, Urea etc.
c. Mioteldy Potent/ Weak diuretics:
i. Carbonic anhydrase inhibitors: Acetazolamide, Methazolamide,
Dichlorphenamide
ii. Xanthine derivatives: Theophylline, Aminophylline
iii. Potassium sparing diuretics: Spironolactone, Triamterene,
Amiloride 6

Based on Mechanism of action
a. At Proximal Convoluted tubule (PCT)
i. Carbonic anhydrase inhibitors: Acetazolamide, Metazolamide,
Dichlorphenamide
ii. Xanthine derivatives: Theophylline, Aminophylline
b. At the loop of henle (LH)
i. Osmatic diuretics: Mannitol, Urea Glycerine, Isosorbide
ii. Loop diuretics: Furosemide, Bumetanide, Torasemide, Ethacrynic
acid.
7

c. At the Distal Convoluted tubule (DCT)
Thiazide diuretics: Chlorthiazide, Hydrochlorothiazide Indapamide,
Xapamide, Metolazone, Bendroflumethiazide, Hydroflumethiazide,
Cyclothiazide
d. At Collecting tubules (CT) Potassium sparing diuretics
i. Aldosterone antagonist: Spironolactone
ii. Inhibitors of renal epithelial Na+ channels: Triamterene,
Amiloride
8

Based on Chemical structure
i. Organomercurial derivatives:
9
Name R R1 X
Chlormerodrin -NH2 -CH3 -Cl
Mersalyl
Sodium
- CH3 -OH
Meralluride NaOOCCH2CH2CONH- - CH3 -OH

ii. Phenoxyacetic acid:
10
Name R
Ethacrynic acid
Indacrinone

iii. Potassium Sparing Diuretics:
a. Aldosterone antagonist:
Spironolactone
b. Aminopyrazine:
Amiloride
11

iv. Carbonic anhydrase inhibitors:
Acetazolamide
13
Methazolamide
Dichlorphenamide

v. Benzothiadiazines:
a. Thiazide Diuretics:
14
Name R R1
Chlorothiazide -Cl -H
Benzthiazide -Cl
Flumethiazide -CF3 -H

b. Hydrothiazide Diuretics:
15
Name R R1 R2
Hydrochlorothiazide -H -H -Cl
Bendroflumethiazide -H - CH2-C6H5 -CF3
Hydromethiazide -H -H -CF3
Methylchlorthiazide - CH3 - CH2Cl -Cl
Polythiazide - CH3 - CH2SCH3CF3 -Cl
Trichlormethiazide -H - CHCl2 -Cl

C. Thiazides like diuretics:
1. Benzhydrazides
Indapamide
16

2. Tetrahydro Quinazolines:
17
Name R R1
Quinethazone - C2H5 -H
Metalazone - CH3

3. Pthalimide Derivative:
Chlorthalidone
vi. High celling (Loop) Diuretics:
Furosemide
18

vii. Miscellaneous
a. Xanthene Derivatives:
20
Name R R1 R2
Caffeine - CH3 - CH3 - CH3
Theophylline - CH3 - CH3 -H
Theobromine -H - CH3 - CH3

b. Osmotic Diuretics
Mannitol
21
Urea
Isosorbide

CARBONIC ANHYDRASE
INHIBITORS
22

 Carbonic anhydrase is an enzyme found in various segments of
nephron, especially in the cells of proximal convoluted tubule. Its
function to catalyse the reversible reaction involved in the formation
of carbonic acid from H2O and Co2 and enhances the rate of reaction
to many folds. The carbonic acid dissociates to form H+ and HCO3
ions.
 The carbonic anhydrase inhibitors inhibit this reaction leading to
urinary excretion of Na+, K+, Ca+, and HCO3 ions. These are
heterocyclic derivatives.
23

 This class of diuretics inhibit carbonic anhydrase enzyme in the
membrane and cytoplasm of the epithelial cells. The primary site of
action is proximal tubules. These agents interfere with the
reabsorption of HCO3
−.
 HCO3
− is reabsorbed in the proximal tubule and requires the activity
of carbonic anhydrase. Intracellularly carbonic anhydrase converts
H2O and CO2 to carbonic acid (H2CO3). H2CO3 dissociates into H+
and HCO3
–. The HCO3
–is transported across the basolateral
membrane. H+ is secreted into the tubular lumen in exchange for
Na+. The H+ combines with a filtered HCO3
– (using CA) to form
H2CO3, which immediately dissociates into H2O and CO2 that, is
reabsorbed. Therefore, filtered bicarbonate is reabsorbed for every
H+ secreted. Carbonic anhydrase inhibitors, by blocking the enzyme,
prevent the reabsorption of HCO3
–.
 Accumulation of HCO3
– in the tubular lumen subsequently inhibits
Na+ —H+ exchange and Na+ reabsorption. The increase in sodium
concentration in the tubular fluid may be compensated partially by
increased NaCl reabsorption in later segments of the tubule. Thus,
the diuretic effect of the carbonic anhydrase inhibitors is mild. 25

SAR:
These are heterocyclic sulphonamide and derivatives of m-
disulfamoyl benzene. Both these groups are essential. Hence the
SAR of carbonic anhydrase inhibitors would be studied under two
headings.
Heterocyclic Sulphonamide:
 The diuretic potency and carbonic inhibitory activity is entirely due
to the sulphamoyl group present at C-5.
 The nitrogen atom of the sulphamoyl group should remain
unsubstituted as the mono and di- substituted compound were
pharmacologically inactive.
 The sulphamoyl group must be attached to an aromatic moiety.
 Substitution of methyl group at 3rd position yielded methazolomide
which exhibits carbonic anhydrase inhibitory activity. 26

Derivatives of m-disulpamoyl benzene:
 Similar to the heterocyclic sulphonamide the essential resistant for
diuretic activity of m-disulphamoyl benzene derivatives is the
presence of a sulphamoyl moiety in the unsubstituted form. These
derivatives also possess an additional sulphamoyl group at C-3
which produced compounds with increased uretic activity.
 The basic structure disulphamoylbenzene is devoid any activity
however substituted derivatives exhibit appreciable diuretic activity.
27

 The replacement of additional sulphamoyl group present at C-3 with
other electron withdrawing groups yield potent diuretic compound.
 Substitution of halogen groups like Cl, CF3, Br, and NO2 at C-4 has
maximum activity.
 When an additional Chlorine atom is substituted at C-5 the analogue
termed dichlorphenamide induces relatively less uretic effect.
 When amino group substituted at C-6 position the resulting
compound induce increase excretion of Na+ and Cl- ion but less
inhibitory activity towards the enzyme.
28

Methazolamide
Structure:
IUPAC: N-(3-methyl-5-sulfamoyl-4,5-dihydro-1,3,4-thiadiazol -2-
ylidene)acetamide
Properties:
White or yellow crystalline powder, slight odor, soluble in water,
alcohol, acetone, dimethyl formamide. 29
Molecular formula: C5H8N4O3S2

Pharmacokinetics:
Oral route of administration metabolized in liver by cytochrome
enzyme, under goes the urine elimination.
Adverse Drug Reactions:
 decreased appetite, nausea, vomiting, constipation, diarrhea,
 changes in taste,
 drowsiness, dizziness, fatigue, weakness, nervousness, tremor,
headache, confusion,
 increased sensitivity of the skin to sunlight,
 worsening gout,
 loss of blood sugar control (if you are diabetic),
 ringing in your ears (tinnitus) or hearing problems,
 changes in vision,
 tingling feeling in the extremities,
 General feeling of being unwell (malaise), and increased urination. 30

Therapeutic Uses:
 It is a carbonic anhydrase inhibitor.
 It will block the protein in the body called carbonic anhydrase.
 Blocking these protein can help to reduce amount of fluid inside the
eye.
 It is used to lower pressure inside the eye.
 It is also used as diuretic in people with congestive heart failure to
reduce edema.
Dose:
 25 mg to 50 mg bid
31

Dichlorphenamide
Structure:
IUPAC: 5,6-dichlorobenzene-1,3-disulfonamide
Properties:
White or nearly white crystalline powder, slightly characteristic odor,
insoluble in water, soluble in alkaline solution, sodium hydroxide,
alcohol, sodium carbonate, slightly soluble in ether.
32
Molecular formula: C6H6Cl2N2O4S2

Pharmacokinetics:
Oral route of administration metabolized in liver by cytochrome
enzyme, under goes the urine elimination.
 Numbness/tingling,
 change in the sense of taste,
 Nausea, diarrhea, vomiting, loss of appetite
 weight loss, muscle spasms/twitching, tiredness,
 Dizziness or drowsiness, confusion, convulsion
 Abdominal Pain, stomach pain, diarrhea
 Chest pain, cough, dry mouth,
 Head ache, fever, weakness, Irregular breathing
 Joint pain, muscle pain 33

Therapeutic Uses:
It reduces the action of protein, Used to treat glaucoma occasional
paralysis (loss of movement) caused by high or low levels of K+ in
blood.
Dose:
Initiate dosing at 50 mg by mouth once or twice daily.
34

Acetazolamide
Structure:
IUPAC: N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Properties:
White crystalline powder, odorless, soluble in dilute alkali hydroxide
solution, slightly soluble in water and alcohol, insoluble in
chloroform, diethyl ether, carbon tetrachloride.
35
Molecular formula: C4H6N4O3S2

Pharmacokinetics:
Acetazolamide in oral administration exhibits bioavailability of
almost 100%. It has a biological half-life of about 6-9 hours and is
excreted unchanged in urine.
 Dizziness, lightheadedness, or increased urination may occur,
especially during the first few days as your body adjusts to
the medication.
 Blurred vision, dry mouth,
 drowsiness, loss of appetite,
 nausea, vomiting, diarrhea, or changes in taste
 Fever, skin rashes, impairment of renal function, depression of bone
marrow functioning
40

Therapeutic Uses:
 Acetazolamide is used to prevent and reduce the symptoms of
altitude sickness. This medication can decrease headache,
tiredness, nausea, dizziness, and shortness of breath that can occur
when you climb quickly to high altitudes.
 It is also used in the treatment of Glaucoma, Metabolic alkalosis,
epileptic seizures, edema
41

Dose:
 Usual Dose for Edema
Initial dose: 250 to 375 mg orally/IV once a day
 Usual Dose for Acute Mountain Sickness
500 to 1000 mg orally per day in divided doses
 Usual Dose for Glaucoma
-Immediate-release (IR) tablets: 250 to 1000 mg orally per day;
amounts over 250 mg should be administered in divided doses
-Extended-release (ER) capsules: 500 mg orally 2 times a day
Usual Dose for Seizure Prophylaxis
 Initial dose: 8 to 30 mg/kg orally/IV in divided doses
42

 Thiazides diuretics are group of moderately efficacious diuretics,
which enjoy vast clinical applications. All the Thiazides diuretics are
inhibitors of Na+ Cl– symporter and their major site of action is the
early segment of the distal convoluted tubule (DCT).
 Thiazide diuretic differs among themselves only in their duration of
action and potency, with the thiazide like diuretic exhibiting longer
duration of action.
44

 Thiazides inhibit a Na+—Cl– symport in the luminal membrane of
the epithelial cells in the distal convoluted tubule. Thus, thiazides
inhibit NaCl reabsorption in the distal convoluted tubule, and may
have a small effect on the NaCl reabsorption in the proximal tubule.
 Thiazides enhance Ca++ reabsorption in the distal convoluted tubule
by inhibiting Na+ entry and thus enhancing the activity of Na+ —
Ca++ exchanger in the basolateral membrane of epithelial cells.
46

SAR:
These compounds are weakly acidic;
1. H atom at N-2 is the most acidic due to the electron-withdrawing
effects of the neighboring sulfone group.
2. Sulfonamide group at C-7 provides an additional point of acidity in
molecule but is less acidic than N-2 proton. A free sulfamoyl group
at position 7 is essential for diuretic activity.
3. These acidic protons make possible the formation of a water-soluble
sodium salt that can be used for I.V. dosing.
4. An electron-withdrawing group is essential at position 6.
47

5. The diuretic activity is enhanced by substitution at position 3.
6. Replacement of 6-Cl by 6-CF3 does not change potency but alters
duration of action.
7. Replacement of 6-Cl by electron-donating groups (e.g. CH3) reduces
diuretic activity.
8. Saturation of thiadiazine ring to give 3, 4-dihydro derivative and
replacement replace or removal of sulfonamide group at position C-
7 yields compounds with little or no diuretic activity.
48

Hydrochlorothiazide
Structure:
IUPAC:6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzo
thiadiazine -7-sulfonamide
Properties:
White, or practically white crystalline powder, practically odorless,
slightly bitter taste, soluble in ethanol , acetone, dilute ammonia;
freely soluble in sodium hydroxide solution, n-
butylamine, dimethylformamide; sparingly soluble in alcohol;
insoluble in ether, chloroform, dilute mineral acids.
49
Molecular formula: C7H8ClN3O4S2

Pharmacokinetics:
 Oral route of administration.
 Hydrochlorothiazide is not metabolized, but eliminated in the urine
as unchanged hydrochlorothiazide.
 blood pressure that’s lower than normal (especially when standing
up after sitting or lying down)
 dizziness, headache, weakness
 erectile dysfunction (trouble getting or keeping an erection)
 tingling in your hands, legs, and feet
50

Therapeutic Uses:
 This medication is used to treat high blood pressure. Lowering high
blood pressure helps prevent strokes, heart attacks,
and kidney problems.
 This medication also reduces extra fluid in the body (edema) caused
by conditions such as heart failure, liver disease, or kidney disease.
This can lessen symptoms such as shortness of breath or swelling in
your ankles or feet.
Dose:
 For oedema- 25-200 mg in 1 or 2 divided doses, orally.
 For hypertension- 12-25 mg in 1 or 2 divided doses, orally.
51

Hydroflumethiazide
Structure:
IUPAC:6-(trifluoromethyl)-1,1-dioxo-4H-1,2,4 benzothiadiazine -7-
sulfonamide
Properties:
White to cream colored, finely divided, crystalline powder, odorless,
Soluble in dilute alkali but unstable in alkaline solutions, freely
soluble in acetone, insoluble in acids.
52
Molecular formula: C8H8F3N3O4S2

Pharmacokinetics:
 Oral route of administration, metabolized in liver, undergoes urinary
excretion.
 Low blood sodium or potassium levels
 an imbalance of sodium and potassium in the blood
 high blood sugar, low blood pressure
 sun sensitive skin
 Nausea, vomiting
 Diarrhea, stomach cramps, loss of appetite
 sexual problems
 dizziness, and fatigue
53

Therapeutic Uses:
 It is used in the treatment of Hypertension, oedema.
Dose:
54

Cyclothiazide
Structure:
IUPAC: 3-{bicyclohept-5-en-2-yl}-6-chloro-1,1-dioxo-3,4-dihydro-
2H-1,2,4-benzothiadiazine-7-sulfonamide
Properties:
White to nearly white powder, odorless, freely soluble in acetone,
ethyl acetate, methanol, insoluble in water, chloroform, water.
55

Pharmacokinetics:
Oral route of administration, metabolized in liver, undergoes urinary
excretion.
 Dizziness, dehydration,
 Salt imbalance, Anorexia, Gastric irritation, Nausea, Vomiting
 Cramping, Diarrhea, Jaundice, Vertigo
 Headache, Fever, Respiratory distress
Therapeutic Uses:
 Cyclothiazide is used in the treatment of:
 Edema, Hypertension, Nephrotic Syndrome, Heart Failure
Dose:
 For hypertension- 12-25 mg in 1 or 2 divided doses, orally. 56

Chlorthiazide
Structure:
IUPAC:6-chloro-1,1-dioxo-4H-1,2,4-benzothiadiazine-7-sulfonamide
Properties:
White crystalline powder, odorless, soluble in water, freely soluble in
Dimethylformamide, dimethyl sulfoxide, slightly soluble in
methanol, pyridine, insoluble in ether, benzene, and chloroform. 57

Pharmacokinetics:
 Chlorothiazide is not metabolized but is eliminated rapidly by the
kidney.
 After oral doses, 10 to 15 percent of the dose is excreted unchanged
in the urine.
 Chlorothiazide crosses the placental but not the blood-brain barrier
and is excreted in breast milk.
 Dizziness, lightheadedness, headache, blurred vision, loss of
appetite,
 stomach upset, diarrhea, or constipation
59

Therapeutic Uses:
 This medication is used to treat high blood pressure.
Lowering high blood pressure helps prevent strokes, heart
attacks, and kidney problems. Chlorothiazide is a "water pill"
(diuretic) that causes you to make more urine. This helps your
body get rid of extra salt and water.
 This medication is also used to decrease swelling (edema)
caused by conditions such as cancer, congestive heart
failure, liver disease, and kidney disease. This effect can help
your kidneys work better and lessen symptoms such as trouble
breathing and swelling in your ankles, feet, hands, or belly.
Dose:
 For oedema- 500-1000 mg orally.
60

 Loop Diuretics are more potent and efficacious diuretics. In normal
doses, loop diuretics are capable of inducing up to 20-30% of
natriuresis and increasing the dose, up to 30-40% natriuresis can be
achieved. Such an excretion is not exhibited by any other diuretics
like thaizides or potassium sparing diuretics.
 Loop diuretics are more efficacious because their site of action is
thick ascending limb of loop of henel which accounts for the
reabsorption of 30-40% NaCl.
62

 Loop diuretics inhibit reabsorption of NaCl and KCl by inhibiting
the Na+ —K+ —2Cl– symport in the luminal membrane of the thick
ascending limb (TAL) of loop of Henle.
 As TAL is responsible for the reabsorption of 35% of filtered
sodium, and loop diuretics are highly efficacious and are thus called
high ceiling diuretics.
 The Na+ —K+ —2Cl– symport and sodium pump together generate a
positive lumen potential that drives the reabsorption of Ca++ and
Mg++, inhibitors of the Na+ -K+ -2Cl– symport also inhibit
reabsorption of Ca++ and Mg++.
 Loop diuretics also have direct effects on vasculature including
increase in renal blood flow, and increase in systemic venous
capacitance.
64

SAR:
 They are either 5-sulphamoyl-2-amino benzoic acid or 5-sulhamoyl-3-
amino benzoic acid derivatives.
 The carbonyl group C-1 provides optimal diuretic activity.
 The substitution of activating group (X) in the position 4 by Cl, alkoxy,
aniline, benzyl or benzoyl group at 4th position increases the diuretic
activity.
 The presence of sulphamoyl group in the 5th position is essential for
activity.
 The two series of 5-sulphamoyl benzoic acid differ in the nature of the
functional group that substituted in 2nd and 3rd position.
 The presence of furfuryl, phenyl, and thienyl methyl group at 2nd amino
group of 5-sulphomoyl.
 2-amino benzoic acid gives maximum diuretic activity.
 The wide range of alkyl group can be substituted at 3rd amino group of
5-sulfamoyl-3-amino benzoic acid without modifying the optimal
diuretic activity.
 A molecule with a week acidic group to direct the drug to the kidney
and alkylating moiety to react with sulphydryl groups and lipophilic
groups seemed to provide the best combination of a diuretic in the class.
65

Ethacrynic acid
Structure:
 IUPAC:2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic
acid
Properties:
White crystalline powder, odorless, soluble in alcohol, ether,
chloroform, very slightly soluble in water
66
Molecular formula: C13H12Cl2O4

Pharmacokinetics:
 On set of action upon oral administration is after 2-3 hours and
within minutes on i.v route of administration. About 38% of the oral
dose is biotransformed while the remaining fraction undergoes renal
excretion in an unchanged form.
 It may cause frequent urination, muscle cramps
 Loss of hearing, liver damage
 On oral administration it may cause diarrhea, dry mouth, nausea,
vomiting muscle pain, uneven heart beat.
 Loss of appetite, stomach pain, difficulty swallowing
 Weakness, headache, confusion
67

Therapeutic Uses:
 Ethacrynic acid is used to treat edema (fluid retention; excess fluid
held in body tissues) in adults and children caused by medical
problems such as cancer, heart, kidney, or liver disease.
 Ethacrynic acid is in a class of medications called diuretics ('water
pills').
Dose:
 Oral: 50 to 200 mg orally per day in 1 to 2 divided doses.
 50 mg (or 0.5 to 1 mg/kg) IV once; occasionally, a second dose at a
new injection site may be required.
68

Bumetanide
Structure:
IUPAC: 3-butylamino-4-phenoxy-5-sulfamoylbenzoic acid
Properties:
White crystalline powder, insoluble in water, soluble in acetone,
alcohol, dilute solutions of alkali hydroxide, slightly soluble in
methylene chloride. 69
Molecular formula: C17H20N2O5S

Pharmacokinetics:
 Oral route of administration, some fraction of administered in gets
metabolized in the liver while the reaming fraction undergoes
urinary excretion in an unchanged form.
 Muscle pain, weakness, tiredness,
 convulsions, dizziness, drowsiness,
 skin rashes, vomiting, irregular heartbeat,
 Stomach pain, dry mouth, loss of appetite, memory problems,
 low blood pressure, headache, nausea
70

Therapeutic Uses:
 Bumetanide is used to treat edema (fluid retention; excess fluid held
in body tissues) caused by various medical problems, including
heart, kidney, and liver disease.
 Bumetanide is in a class of medications called diuretics ('water
pills').
 It works by causing the kidneys to get rid of unneeded water and salt
from the body into the urine.
Dose:
The usual total daily dosage of Bumetanide tablets is 0.5 mg to 2 mg
and in most patients is given as a single dose.
71

Furosemide
Structure:
IUPAC: 4-chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoic
acid
Properties:
White to off-white crystalline powder, odorless , practically tasteless,
slightly soluble in water, chloroform, ether, soluble
in acetone, methanol, DMF, aqueous solutions above pH 8.0, less
soluble in ethanol, freely soluble in alkali hydroxide. 72
Molecular formula: C12H11ClN2O5S

Pharmacokinetics:
 Oral, i.v route of administration, the metabolism of furosemide
occurs mainly in the kidneys and the liver, to a smaller extent. The
kidneys are responsible for about 85% of total furosemide total
clearance, where about 40% involves biotransformation. Two major
metabolites of furosemide are furosemide glucuronide, which is
pharmacologically active, and saluamine (CSA) or 4-chloro-5-
sulfamoylanthranilic acid. Excreted unchanged in urine.
 increased urination, thirst, muscle cramps, itching or rash,
 weakness, dizziness,, spinning sensation,
 Diarrhea, stomach pain and constipation.
 dehydration, dark urine, clay-colored stools,
 nausea, vomiting, fever, jaundice (yellowing of skin or eyes),
 electrolyte abnormalities, Loss of appetite and rapid weight loss.
 Cardiac arrest can occur following i.v administration.
75

Therapeutic Uses:
 Furosemide is used in the treatment of hypertension,
hypercalcaemia, acute renal failure.
 Furosemide is used to treat edema (fluid retention; excess fluid held
in body tissues) caused by various medical problems, including
heart, kidney, and liver disease.
Dose:
 Edema
The usual initial dose of Furosemide is 20 to 80 mg given as a single
dose.
 Hypertension
The usual initial dose of Furosemide for hypertension is 80 mg, usually
divided into 40 mg twice a day.
76

POTASSIUM SPARING DIURETICS
77

 Potassium sparing Diuretics are a class of weak diuretics whose site
of actions are the distal and collecting tubules where they inhibit the
reabsorption of Na+ ions.
 Due to this, the stimulation secretion of monovalent ions i.e K+ and
H+ are also inhibited.
 As these diuretics conserve K+ ions, they are used along with other
diuretics which have significant uretic effect.
 Such a combination is beneficial in maintaining the potassium
homeostasis in the body.
78

 Aldosterone Antagonists
Mechanism of action:
 Aldosterone, by binding to its receptor in the cytoplasm of
epithelial cells in collecting tubule and duct, increases
expression and function of Na+ channel and sodium pump,
and thus enhances sodium reabsorption (see “Na+ channel
inhibitors” above).
 Spironolactone competitively inhibits binding of aldosterone to
its receptor and abolishes its biological effects.
79

Spironolactone
Structure:
IUPAC: 7- acetylsulfanyl-17-hydroxy-3-oxopregn-4-ene-21-
carboxylic acid γ-lactone
Properties:
Light cream-colored to light tan, crystalline powder, Mild mercaptan-
like odor, Soluble in ethyl acetate and ethanol; slightly soluble
in methanol.
80
Molecular formula: C24H32O4S

Pharmacokinetics:
 Oral route of administration, metabolized in liver, it gets
metabolically transformed to canrenone which is active.
 The drug undergoes urinary excretion and some fraction is also
found in bile.
 Drowsiness, dizziness, lightheadedness, confusion
 Stomach upset, diarrhea, nausea, vomiting, or headache may occur.
 To minimize lightheadedness, get up slowly when rising from a
seated or lying position.
 Abdominal upset, menstrual irregularities.
81

Therapeutic Uses:
 Spironolactone is used to treat high blood pressure and heart failure.
Lowering high blood pressure helps prevent strokes, heart attacks,
and kidney problems. It is also used to treat swelling (edema) caused
by certain conditions (such as heart failure, liver disease) by
removing excess fluid and improving symptoms such as breathing
problems.
 This medication is also used to treat low potassium levels and
conditions in which the body is making too much of a natural
chemical (aldosterone).
82

Dose:
 Usual Dose for Edema:
25 to 200 mg orally per day in single or divided doses
 Usual Dose for Hypertension:
Initial dose: 50 to 100 mg orally per day in single or divided doses
 Usual Dose for Congestive Heart Failure:
Initial dose: 25 mg orally once a day assuming serum potassium is less
than or equal to 5 mEq/L and serum creatinine is less than or equal
to 2.5 mg/dL
83

 Na+ Channel Inhibitors
 Amiloride and triamterene inhibit the sodium channel in theluminal
membrane of collecting tubule and collecting duct.
 This sodium channel is critical for Na+ entry into cells down the
electrochemical gradient created by sodium pump in the basolateral
membrane, which pumps Na+ into interstitium.
 This selective transepithelial transportof Na+ establishes a luminal
negative transepithelial potential which in turn drives secretionof K+
into the tubule fluid.
 The luminal negative potential also facilitates H+ secretion via the
proton pump in the intercalated epithelial cells in collecting tubule
and collecting duct.
 Inhibition of the sodium channel thus not only inhibits Na+
reabsorption but also inhibitssecretion of K+ and H+, resulting in
conservation of K+ and H+.
84

Amiloride
Structure:
IUPAC: 3,5-diamino-N-carbamimidoyl-6-chloropyrazine-2-
carboxamide
Properties:
Pale yellow to greenish-yellow powder, slightly soluble in water,
ethanol. 85
Molecular formula: C6H8ClN7O

Pharmacokinetics:
 Amiloride is partly absorbed by GIT. It has an oral bioavailability of
about 15-25% and it undergoes metabolism and is excreted
unchanged in urine.
 Headache, dizziness, nausea, vomiting,
 loss of appetite, stomach/abdominal pain, gas, or diarrhea
 Skin rashes, emesis, hyperkalaemic.
86

Therapeutic Uses:
 Amiloride is used with other "water pills"/diuretics (such
as furosemide, thiazide diuretics like hydrochlorothiazide) to
treat high blood pressure (hypertension), heart failure, or extra fluid
in the body (edema), Ascites.
 Amiloride also helps to treat or prevent low blood potassium levels
caused by the other diuretics. Lowering high blood pressure helps
prevent strokes, heart attacks, and kidney problems.
 Amiloride is called a "water pill" (diuretic) and causes your body to
get rid of extra salt and water while also preventing the kidneys from
getting rid of too much potassium.
87

Dose:
 Usual Adult Dose for Ascites
Initial dose: 5 mg orally once a day.
Maintenance dose: 5-10 mg once a day.
 Usual Adult Dose for Congestive Heart Failure
 Usual Adult Dose for Edema
 Usual Adult Dose for Hypertension
88

Triamterene
Structure:
IUPAC: 6-phenylpteridine-2,4,7-triamine
Properties:
Yellow crystalline powder, odorless, slightly soluble
in water, ethanol, chloroform, soluble in formic acid,
dilute ammonia, dilute aqueous sodium hydroxide, and dimethyl
formamide, sparingly soluble in methoxyethanol, methanol, very
slightly soluble in acetic acid, dilute mineral acids
, benzene, chloroform, ether, and dilute alkali hydroxides, alcohol 89
Molecular formula: C12H11N7

Pharmacokinetics:
 Oral route of administration, undergoes hepatic metabolism to yield
an active metabolite, undergoes urinary elimination.
 congestive heart failure, low blood pressure
 headache, light sensitivity
 rash, yellowing of eyes and skin (jaundice), severe allergic
reaction (anaphylaxis)
 diarrhea, nausea, vomiting, gastrointestinal upset, dry mouth
 uric acid in the blood, kidney damage, kidney stones,
kidney inflammation, acute kidney failure
 low platelets in the blood
 folic acid antagonism, high blood potassium level,
megaloblastic anemia
 liver enzyme abnormalities 90

Therapeutic Uses:
 This drug is used to treat high blood pressure. Lowering high blood
pressure helps prevent strokes, heart attacks, and kidney problems.
 This medication is a combination of two "water pills" (diuretics):
triamterene and hydrochlorothiazide. This combination is used by
people who have developed or are at risk for having low
potassium levels on hydrochlorothiazide.
 It causes you to make more urine, which helps your body get rid of
extra salt and water.
 This medication also reduces extra fluid in the body (edema) caused
by conditions such as heart failure, liver disease, or kidney disease.
This can lessen symptoms such as shortness of breath or swelling in
your ankles or feet.
91

Dose:
 Edema
 Adults
100-300 mg/day orally each day or divided every 12 hours
 Geriatric
 Hypertension
 Adults
 Geriatric
92

 Osmotic diuretics exert their diuretic effect indirectly by altering the
contents of the tubular lumen.
 These agents are pharmacologically inert, enhance the osmolatility
of plasma and tubular fluids and are filtered freely by the Bowman’s
capsule.
 In addition, these are not metabolized and are reabsorbed partially or
completely by the various segment of the nephron which ultimately
reduces the tubular water reabsorption.
94

 Osmotic diuretics are substances to which the tubule epithelial cell
membrane has limited permeability.
 When administered (often in a large dosage), osmotic diuretics
significantly increase the osmolarity of plasma and tubular fluid.
 The osmotic force thus generated prevents water reabsorption, and
also extracts water from the intracellular compartment, expands
extracellular fluid volume and increases renal blood flow resulting in
reduced medulla tonicity.
 The primary sites of action for osmotic diuretics are the Loop of
Henle and the proximal tubule where the membrane is most
permeable to water.
95

Mannitol
Structure:
IUPAC: Hexane-1,2,3,4,5,6-hexol
Properties:
White crystalline powder or freely flowing granules, odorless, sweet
taste, soluble in pyridine, aniline, alkalies, water, insoluble in ether. 96
Molecular formula: C6H14O6

Pharmacokinetics:
 Oral, i.v route of administration. The preferred route of administered
is i.v as its absorption via the oral route is poor. Upon administration
Mannitol, is not metabolized but undergoes glomerular filteration
(without being effectively reabsorbed), with an hour of its
administration. It is rapidly excreted in the urine.
 headache, nausea, vomiting, dry mouth, thirst, dizziness,
 diarrhea, dehydration,
 blurred vision, runny nose,
 arm pain, chills, hives, chest pain
 low blood pressure (hypotension), irregular heart beat
 Electrolyte imbalance and irritation/pain/swelling at the injection
site.
 Thrombophlebitis (inflammation of the walls veins). This may
subsequently leads to local tissue death.
97

Therapeutic Uses:
 Used to treat edema formation due heart failure, kidney failure.
 Used in the treatment of high blood pressure, liver cirrhosis.
Dose:
 The usual adult dosage ranges from 50 to 200 g in a 24-hour period
98

Reference books
 Text book of Medicinal chemistry volume-1-3rd edition by
V.Alagarasamy.
 Text book of Medicinal chemistry volume-2-3rd edition by
V.Alagarasamy.
 Medicinal chemistry by Rama Rao Nadendla.
 Faye’s Principles of Medicinal Chemistry- 7th edition by Thoms
L.Lemke, Victoria F.Roche, S. Willam Zito.
 Medicinal Chemistry- 4th edition by Ashutosh Kar
 Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K
Kapoor.
99

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