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Diuretics 237
8.1.3 Bumetanide
Brand Names: Bumex (Roche), Burinex
A diuretic structurally related to furosemide is Bumetanide. This compound also functions as
a high-ceiling diuretic in the ascending limb of the Loop of Henle.
IUPAC Name: 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid
Properties: Bumetanide occurs as a crystalline solid. It is practically insoluble in water, soluble
in acetone and in alcohol, and slightly soluble in methylene chloride. It dissolves in dilute
solutions of alkali hydroxides.
Mechanism of Action: Bumetanide inhibits the sodium-potassium ATPase pump. It appears to
block the active reabsorption of chloride and possibly sodium in the ascending Loop of Henle,
altering electrolyte transfer in the proximal tubule. As a result, excretion of sodium, chloride and
water causes diuresis.
Uses:
➢ Bumetanide is used for relieving edema associated with cardiac insufficiency, for liver
and kidney diseases including nephrotic syndrome, for ascites, and for hypertension.
➢ It is equally used as diuretic after oral and parenteral administration.
➢ It is used in the treatment of autism spectrum disorder.
Dosage Form: The dose of bumetanide is 0.5 to 2 mg/day given as a single dose. It has duration
of action of approximately 4 hours.
Storage: Bumetanide should be stored at room temperature between 20°C and 25°C. Keep this
drug away from light. Dispense the drug in a tight, light-resistant container as defined in the USP
with a child-resistant closure, as required.
8.1.4 Chlorthalidone
Brand Name: Hygroton, Thalitone, Chlorthalid
Chlorthalidone is a thiazide-like diuretic used for the treatment of hypertension and for
management of edema caused by conditions such as heart failure or renal impairment.
Chlorthalidone directly inhibits sodium and chloride reabsorption on the luminal membrane
of the early segment in the distal convoluted tubule (DCT) in the kidney. This leads to an increase
in sodium, chloride, bicarbonate, and potassium secretion resulting in the excretion of water.
238 Text Book of Pharmaceutical Chemistry
Chemistry and Structure: It is a diuretic with monosulfamyl group that differs chemically from
thiazide diuretics in that a double ring system is incorporated in its structure. It is a racemic
mixture of 2-chloro-5(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide, with the following
structural formula:
Nomenclature: 2-chloro-5-(1,3-dihydroxy-1H-isoindol-1-yl)benzene-1-sulfonamide
Properties: It occurs as white to yellowish-white crystalline powder. Its melting point range may
extend from 218°C to 264°C on slow heating. It is practically insoluble in water, in ether and in
chloroform; soluble in methanol; slightly soluble in alcohol.
Uses: Chlorthalidone is used in the management of hypertension either alone or in combination
with other antihypertensive drug. It is indicated as adjunctive therapy in edema associated with
congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. it has also
been found useful in edema due to various forms of renal dysfunction such as nephrotic
syndrome, acute glomerulonephritis, and chronic renal failure.
Dosage Form:
➢ Chlorthalidone Tablets USP 15 mg and 25 mg tablets are for oral administration.
➢ Hypertension dose should be initiated with a single daily dose of 12.5-25 mg/day PO;
may increase to 50 mg/day after a suitable trial; not to exceed 100 mg/day; usual dose
range is 12.5-25 mg/day.
➢ Edema – 50-100 mg/day PO or 100 mg PO every other day; not to exceed 200 mg/day.
➢ Heart Failure – 12.5-25 mg/day PO; not to exceed 100 mg/day.
Storage: Store and dispense in a tight, light-resistant container as defined in the USP. Keep the
medication out of the reach of children. Store at 20°C to 25°C.
Officials:
➢ Chlorthalidone I.P.
➢ Chlorthalidone Tablet, I.P.
8.1.5 Benzthiazide
Brand Name: Exna
Benzthiazide is a member of the class of drug known as 1,2,4-benzothiadiazine-1,1-dioxides.
It is an aromatic heterocyclic compounds containing a 1,2,4-benzothiadiazine ring system with
two S=O bonds at the 1st position. It is a diuretic agent used to treat hypertension and edema.
It has a role as a diuretic and an antihypertensive agent. Benzthiazide have the following
structural formula:
Diuretics 239
Nomenclature: 6-chloro-1,1-dioxo-3-(phenylmethylsulfanylmethyl)-4Hbenzo[e][1,2,4]thiadiazine-
7-sulfonamide.
Benzthiazide supports and promotes water loss from the body which causes diuresis. They
inhibit Na
+
/Cl
–
reabsorption from the distal convoluted tubules in the kidneys. Thiazides also
cause loss of potassium and an increase in serum uric acid.
Properties: It occurs as fine, white, crystalline powder with characteristic odor and bitter taste.
Its melting point is 231°C to 232°C. It is practically insoluble in water; soluble in alkaline
solution; freely soluble in dimethyl formamide; slightly soluble in acetone; and practically
insoluble in ether and chloroform.
Uses:
➢ It is used in hypertension (high blood pressure). It is generally used to treat oedema (fluid
overload) associated with heart, liver, kidney or lung disease.
➢ It lowers blood pressure and fluid retention in edema by removing the extra water and
certain electrolytes from the body.
Dosage Form:
➢ Dose for Edema:
Initial dose: 25 to 100 mg orally twice a day after meals.
Maintenance dose: 50 to 150 mg/day orally in 2 to 3 divided doses.
➢ Dose for Hypertension: 5 to 50 mg orally twice a day after meals.
Storage and Stability: It should be store in dry and dark place at room temperature between
15°C to 25°C). It is stable in both light and air. When heated to decomposition, it emits very toxic
fumes of sulfoxides, nitroxides, and hydrogen chloride.
8.1.6 Metolazone
Brand Names: Zaroxolyn, Mykrox
Metolazone is a medication used as a “water pill” (diuretic) that increases the amount of
urine, which causes the body to get rid of excess water. This drug is used to treat high blood
pressure. Lowering high blood pressure help to prevent strokes, heart attacks and kidney
problems.
240 Text Book of Pharmaceutical Chemistry
Metolazone is a quinazoline derivative. It is an analog of 1,2,4-benzothiadizine-1,1-dioxide
(benzothiadiazine). In terms of chemistry, metolazone is not a substituted benzothiadiazine.
Therefore, it is not technically a thiazide. Since metolazone (as well as other drugs
like indapamide) have similar physiological properties to a thiazide diuretic, but does not have the
chemical properties of a thiazide, lacking the benzothiadiazine molecular structure and called as a
“thiazide-like diuretic”. Therefore, metolazone and similar drugs are often categorized with
thiazide diuretics despite not being thiazides themselves.
Chemistry and Structure: The chemical name of Metolazone is 7-chloro-1,2,3,4-tetrahydro-2-
methyl-3-(2-methyl phenyl)- 4-oxo-6-quinazolinesulfonamide with a molecular weight of 365.83.
The structural formula is:
Properties: Metolazone occurs as odorless, tasteless, crystalline solid with melting point 256°C.
It is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic
solvents.
Uses:
➢ It reduces the swelling/fluid retention (edema) which can result from conditions such
as congestive heart failure or kidney disease. This can help to improve symptoms such as
trouble breathing.
➢ It is also used to treat high blood pressure (hypertension).
➢ Metolazone is also used in combination with other medicines to treat high blood pressure
(hypertension).
➢ It is a thiazide diuretic (water pill). It reduces the amount of water in the body by
increasing the flow of urine, which helps to lower blood pressure.
Dosage Form of Metolazone:
➢ Hypertension: 2.5-5 mg PO once daily; may be increased to 20 mg once daily.
➢ Edema: 2.5-10 mg PO once daily initially; may be gradually increased to 20 mg once
daily.
Storage: Store at room temperature (77°F or 25°C) away from light and moisture. Dispense in a
tight, light-resistant container as defined in the USP using a child-resistant closure.
Diuretics 241
8.1.7 Xipamide
Brand Names: Aquaphor, Aquaphoril
Xipamide is a sulfonamide diuretics agent. It acts on the kidneys to reduce sodium
reabsorption in the distal convoluted tubule. It lowers blood pressure and fluid retention in edema
by removing the extra water and certain electrolytes from the body. Over time, it also works by
relaxing blood vessels and improving blood flow.
IUPAC Name: 4-Chloro-N-(2,6-dimethylphenyl)-2-hydroxy-5-sulphamoylbenzamide
Properties: Xipamide is off-white solid compound. It is poorly soluble in water and highly
soluble in polar organic solvents. It is lipophilic in nature. In the physiological pH range,
Xipamide forms an anion (phenolate anion, p = 4.79, which has an octanol/water partition
coefficient of ~1).
Mechanism of Action: Xipamide acts on the kidneys to reduce sodium reabsorption in the
distal convoluted tubule. This increases the osmolarity in the lumen, causing less water to be
reabsorbed by the collecting ducts. This leads to increased urinary output. In addition, this agent
has a weak inhibitory effect on carbonic anhydrase (CA).
Uses: It is used in Hypertension (high blood pressure) and for the treatment of oedema associated
with heart, liver, kidney, lung disease or hepatic oedema caused by Cirrhosis, Ascites and
Lymphoedema.
Dosage:
➢ Oedema: Adult: Initially, 40 smg daily in the morning, reduced to 20 mg daily according
to response. Max: 80 mg daily.
➢ Hypertension: Adult: 20 mg daily as a single dose in the morning.
Storage: Xipamide should be stored at room temperature (25°C) away from light and moisture in
an airtight container. Brief storage between (15°C to 30°C) is permitted.
8.1.8 Spironolactone
Brand Names: Aldactone, CaroSpir
Spironolactone belongs to a class of drugs called aldosterone antagonists or potassium-
sparing diuretics that prevents the body from absorbing too much salt and keeps the potassium
levels from getting too low.
242 Text Book of Pharmaceutical Chemistry
Chemistry and Structure: Spironolactone, also known as 7α-acetylthiospirolactone, is a
steroidal 17α-spirolactone, or more simply a spirolactone. It is a derivative of progesterone. It is a
steroid lactone, an oxaspiro compound, a thioester and a 3-oxo-Delta(4) steroid. Structure of
Spironolactone is 17α-pregn-4-ene-21,17-carbolactone substituted by an oxo group at position 3
and an alpha-acetylsulfanyl group at position 7. The structural formula of spironolactone is:
IUPAC Name: 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylicacidγ-lactone.
7α-Acetylthio- 3-oxo-17α-pregn-4-ene-21,17β-carbolactone.
Properties: It occurs as light cream-colored to light tan, crystalline powder, mild mercaptan-like
odor with melting point 134-135°C. It is practically insoluble in water; soluble in most organic
solvents like alcohol and ethyl acetate; slightly soluble in methanol and freely soluble in benzene
and in chloroform.
Uses: It is used to treat high blood pressure (hypertension), heart failure or hypokalemia and fluid
retention (edema) in people with congestive heart failure, cirrhosis of the liver, or a kidney
disorder called nephrotic syndrome. It is also used to treat excessive hair growth (hirsutism) in
women with polycystic ovary disease.
Dosage Forms and Strengths: Spironolactone is available in the form of tablets (25 mg, 50 mg,
100 mg; brand name Aldactone) and suspensions (25 mg/5 mL; brand name CaroSpir) for use by
mouth.
1. Edema
For oral dosage form (suspension):
Adults: Starting dose is 7 5 mg (15 ml) per day, taken in either single or divided doses.
For oral dosage form (tablets):
Adults: Starting dose is 100 mg per day, taken in either single or divided doses.
2. Congestive Heart Failure
For oral dosage form (suspension):
Adults: Starting dose is 20 mg (4 ml) per day.
For oral dosage form (tablets):
Adults: Starting dose is 25 mg once a day.
Diuretics 243
3. For high blood pressure
For oral dosage form (suspension):
Adults: Starting dose is 20 mg (4 ml) to 75 mg (15 ml) per day, taken in either single or
divided doses.
For oral dosage form (tablets):
Adults: Initial dose is 25 to 100 mg per day, taken in either single or divided doses.
Storage: Store the drug in a closed container at room temperature, away from heat, moisture and
direct light. Spironolactone tablets should be stored in tight, light-resistant containers at a
temperature less than 40°C, preferably between 15-30°C. Oral suspensions of spironolactone
syrup have been reported to be stable for one month at 2°C to 8°C. When heated to
decomposition, it emits toxic fumes of sulfoxides.
Officials:
➢ Spironolactone, I.P.
➢ Spironolactone Tablet, I.P.
8.2 EXERCISE
A. Long Answer Type Questions
1. Write chemical name, structure and medicinal uses of:
(a) Metolazone
(b) Xipamide
2. What are diuretics? Classify them and give the structure, properties and uses of
Furosemide.
3. Write structure and medicinal uses of bumetanide and chlorthalidone.
4. Write a note on carbonic anhydrase inhibitors.
B. Short Answer Type Questions
1. Define diuretics.
2. What are high ceiling loop diuretics? Give two examples.
3. Give two examples of potassium sparing diuretics.
4. What are osmotic diuretics?
5. Write the medicinal uses of Chlorthiazide.
6. Give the chemical name of Furosemide.
7. Write the uses of:
(a) Benzthiazide
(b) Mannitol
244 Text Book of Pharmaceutical Chemistry
8. Outline the therapeutic uses of Acetazolamide.
9. What are thiazide diuretics? Write the name of any two thiazide diuretics.
10. Write the uses of potassium-sparing diuretics.
11. Write the chemistry and structure of Spironolactone.
C. Fill in the Blanks
1. Brand Name of Furosemide is ______________.
2. Example of carbonic anhydrase inhibitors ______________.
3. Aldactone is the brand name of ______________.
4. Site of action of high ceiling loop diuretics is ______________.
5. Diuretics are also called as ______________.
6. ______________ drugs increase the excretion of water and salt from the body as urine.
7. Mannitol is the drug of class ______________ diuretic.
8. Bumetanide is the drug of class ______________.
Answers:
1. Lasix
2. Acetazolamide
3. Spironolactone
4. Thick ascending loop of henle
5. Water pills
6. Diuretics
7. Osmotic
8. Loop diuretics
Chapter
9
HYPOGLYCAEMIC AGENTS
STRUCTURE
9.1 Introduction
9.2 Exercise
OBJECTIVES
Hypoglycemic Agents: Insulin and its Preparations, Metformin, Glibenclamide, Glimepiride,
Pioglitazone, Repaglinide, Gliflozins, Gliptins.
9.1 INTRODUCTION
Diabetes Mellitus
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycaemia (elevated
blood glucose level). The condition arises due to abnormal metabolism of carbohydrate, fats and
proteins. Inadequate pancreatic insulin secretion, insulin action, or both cause hyperglycemia. The
chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction, and failure
of various organs, especially, the eyes, kidneys, nerves, heart, and blood vessels.
Diabetes mellitus are classified into four categories: type 1 (insulin-dependent diabetes), type
2 (non-insulin-dependent diabetes), type 3 and type 4 (gestational diabetes mellitus).
Type 1 Diabetes
Type 1 diabetes is formerly called as (Insulin-dependent diabetes mellitus (IDDM) or
(Juvenile-onset diabetes) as it develops generally in youth. Insulin is essential to treat this type of
diabetes as patients have little or no endogenous insulin.
Type 2 Diabetes
In type 2 diabetes (formerly called non-insulin-dependent diabetes) or (adult-onset diabetes),
the pancreas often continues to produce insulin. It is treated by dietary modification or by use of
oral hypoglycemic agents, and in certain cases, by insulin.
Type 3 Diabetes Mellitus
The type 3 diabetes refers to multiple other specific causes of elevated blood glucose:
pancreatectomy, pancreatitis, non-pancreatic diseases, drug therapy, etc.
246 Text Book of Pharmaceutical Chemistry
Type 4 Diabetes Mellitus
Type 4 Diabetes, also called as gestational diabetes mellitus (GDM), is defined as any
abnormality in glucose levels noted for the first time during pregnancy.
Classification of Hypoglycaemic Agents
Hypoglycaemic agents may be classified into the following groups:
1. Hormones: Insulin and its preparation.
2. Oral hypoglycaemic agents or synthetic hypoglycemic agents:
(a) Sulphonylureas –
(i) First Generation, e.g., Chlorpropamide, Tolbutamide, Acetohexamide
(ii) Second Generation, e.g., Glibenclamide, Glipizide, Glimepiride
(b) Biguanides – Phenformin, Metformin.
(c) Meglitinides – Repaglinide, Nateglinide
(d) Thiazolidinediones – Rosiglitazone, Pioglitazone
(e) Alpha glucosidase inhibitors – Acarbose, Miglitol
(f) Dipeptidyl peptidase (DPP4) – Sitagliptin
(g) Glucagon like peptide (GLP-1) analogoue – Exenatide
9.1.1 Insulin and its Preparations
Insulin is an endogenous hormone produced by beta cells of Islets of Langerhans of pancreas.
It is a protein hormone that is used as a medication to treat high blood glucose includes diabetes
mellitus type 1, diabetes mellitus type 2, and gestational diabetes.
Insulin is a polypeptide containing 51 amino acids arranged in two chains namely, A and B,
having 21 and 30 amino acids respectively. These two chains are connected by two disulphide
bridges (~S~S-bonds of cysteine).
Chemistry
Insulin is a small protein contains 51 amino acids arranged in two chains (A and B) linked by
disulfide bridges. There are 21 amino acids in chain A and 30 amino acids in chain B. Two chains
are interlinked by a disulfide bridge. There is an additional disulfide bridge between the 6th and
11th amino acid residues of the chain A. Disulfide bonds are essential for the receptor binding
activity of insulin, when any one of these bonds is lost, the receptor binding activity decrease
below 0.02%. It is protein in nature.