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Hypoglycemic Agents 247
Biosynthesis of Insulin
Insulin is synthesized in large amount in pancreatic β-cells. It is synthesized via transcription
and translation of DNA into mRNA and amino acid chains or polypeptide chains. Thereafter the
protein undergoes structural changes to achieve its final form.
The insulin mRNA is translated as one chain precursor known as preproinsulin.
Subsequently, the removal of its signal peptide during insertion into the endoplasmic reticulum
gives rise to proinsulin.
Proinsulin contains three domains an amino-terminal B chain, a carboxy-terminal A chain
and a connecting peptide called C peptide in the middle. Inside the rough endoplasmic reticulum,
proinsulin is exposed to certain endopeptidases known as prohormones convertases (PR1 and
PR2) and exoprotease carboxypeptidase E. The endopeptidases cleave at position 2 and release a
fragment called C-peptide. Leaving two peptide chains, i.e., A chain and B chain connect with
two disulphide bonds called as mature insulin (Fig. 9.1).
The mature form of insulin and free C peptide are packaged inside the Golgi into secretory
granules waiting for the metabolic signal (such as leucin, arginine, glucose and mannose), and
vagal nerve stimulation to be exocytosed from the cell into the circulation. C peptide is also
secreted into the bloodstream, although its biological action is unknown.
Fig. 9.1: Biosynthesis of Insulin
Officials:
➢ Insulin, I.P.
➢ Insulin Injection, I.P.
➢ Isophane Insulin Injection, I.P.
➢ Protamine Zinc Insulin Injection, I.P.
➢ Insulin Zinc Suspension (Crystalline), I.P.
248 Text Book of Pharmaceutical Chemistry
9.1.2 Metformin
Brand Names: Glucophage, Glumetza, Glucophage XR, Fortamet
Metformin is an antihyperglycemic agent of the biguanide class. It is the first-line medication
for the treatment of type 2 diabetes. This medication is considered as an antihyperglycemic drug
because it lowers blood glucose concentrations in type II diabetes without causing hypoglycemia.
Structure and Chemistry: Metformin (1,1-dimethylbiguanide) is a member of the class of
guanidines that is biguanide carrying two methyl substituents at position 1. It derives from
a biguanide. It is a conjugate base of a metformin (1+).
Nomenclature: 1-[(diaminomethylidene) amino]-N,N-dimethylmethanimidamide
Properties: Metformin occurs as a white, crystalline hygroscopic powder with a bitter taste. It is
freely soluble in water; slightly soluble in ethanol and practically insoluble in acetone, ether or
chloroform.
Dosage: Metformin comes in two dosage forms: tablet and solution. Both forms are taken by
mouth. Metformin oral tablets are available as generic drugs and as brand name drugs – Fortamet
and Glumetza. Dosages of metformin should be given as follows:
Adult dosage forms and strengths for diabetes is 500 mg, 850 mg and 1000 mg.
For adults with Type 2 diabetes mellitus – monotherapy or with sulfonylurea
➢ Immediate Release
Initial dose: 500 mg orally twice a day or 850 mg orally once a day
Dose titration: Increase in 500 mg increments weekly or 850 mg every 2 weeks as
tolerated
Maintenance dose: 2000 mg/day in divided doses
Maximum dose: 2550 mg/day
➢ Extended Release
Initial dose: 500 to 1000 mg orally once a day
Dose titration: Increase in 500 mg increments weekly as tolerated
Maximum dose: 2000 mg/day
Storage: Keep container tightly closed in a dry and well-ventilated place. Recommended storage
temperature is 2°C to 8°C, away from heat, moisture and direct light. Keep from freezing. It is
stable under recommended storage conditions.
Hypoglycemic Agents 249
Officials:
➢ Metformin Tablet, I.P.
➢ Metformin Hydrochloride, I.P.
9.1.3 Glibenclamide
Brand Names: Diabeta, Glynase, Glynase PresTab
Glibenclamide is also known as glyburide. It is a second generation sulfonamide urea
derivative with antihyperglycemic activity. Glyburide is a medication used to treat patients with
diabetes mellitus type 2. It works by increasing the amount of insulin released by the pancreas in
order to lower blood glucose.
Chemistry and Structure: Glyburide is an N-sulfonylurea that is acetohexamide in which the
acetyl group is replaced by a 2-(5-chloro-2-methoxybenzamido) ethyl group. It has hypoglycemic
effect by reducing blood glucose by increasing insulin secretion from pancreatic beta cells. The
structural formula is shown below:
Nomenclature: Chemical name is: N-[2-[4-[[(Cyclohexylamino)carbonyl]isamino]alkylsulfonyl]
phenyl]ethyl]-2- methoxyl group-5-chlorobenzamide
OR
5-chloro-N-[2-[4-(cyclohexyl carbamoyl sulfamoyl) phenyl]ethyl]-2-methoxybenzamide
Properties: It appears as white almost white crystalline powder with melting point 169°C to
170°C. It is insoluble in water and slightly soluble in ethanol, acetone and chloroform.
Dosage Forms: Glyburide comes in different types of tablets which provide different amounts of
the medication. Dosage forms and strengths are 1.25 mg, 2.5 mg and 5 mg.
Dosing considerations for type 2 diabetes mellitus:
➢ Initial dose: 2.5-5 mg orally once/day.
➢ Maintenance dose: 1.25-20 mg orally once/day or every 12 hours. Not to exceed 20
mg/day.
Uses:
➢ Hypoglycemic agents with stronger effect than toluene sulfonylurea used for the
treatment of mild, non-insulin-dependent diabetes.
➢ It is used to lower the blood sugar level in patients with type 2 diabetes mellitus that is
not controlled by diet and exercise alone.
➢ It is used along with diet and exercise to improve blood sugar control in adults with type
2 diabetes.
250 Text Book of Pharmaceutical Chemistry
Officials:
➢ Glibenclamide, I.P.
➢ Glibenclamide Tablet, I.P.
9.1.4 Glimepiride
Brand Name: Amaryl
Glimepiride lowers blood sugar by causing the pancreas to produce insulin (a natural
substance that is needed to break down sugar in the body) and helping the body use insulin
efficiently. It is an oral diabetes medication that is used together with diet and exercise to improve
blood sugar control in adults with type 2 diabetes mellitus. Glimepiride is not for treating type 1
diabetes.
Structure and Chemistry: Glimepiride is a sulfonamide, a N-acylurea and a N-sulfonylurea. It
has a role as a hypoglycemic agent and an insulin secretagogue. The structural formula is shown
below:
Nomenclature: Chemical structure of Glimepiride IUPAC name: 4-ethyl-3- methyl-N-[2-[4-[(4
methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide
Properties: Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless
powder formulated into tablets of 1 mg, 2 mg and 4 mg strengths for oral administration.
Glimepiride is practically insoluble in water.
Uses:
➢ Glimepiride is used with a proper diet and exercise program to control high blood
sugar in people with type 2 diabetes.
➢ It may be used alone, or in combination with other diabetes medications, insulin or
another oral medicine such as metformin.
Dosage Forms: Glimepiride is only available in oral form (tablet). A doctor may prescribe it in
one of the following dosages – 1 mg, 2 mg, 3 mg, 4 mg, 6 mg and 8 mg.
For type 2 diabetes:
➢ Initial dose: 1 to 2 mg orally once a day.
➢ Maintenance dose: Increase in 1 mg or 2 mg. Increments no more frequently than every
1 to 2 weeks based on glycemic response.
➢ Maximum dose: 8 mg per day.
Storage: Store the medicine in a closed container at room temperature, away from heat, moisture,
and direct light. Keep from freezing.
Hypoglycemic Agents 251
Pioglitazone
Brand Names: Actos, Actoplus Met, Glidipion, Glubrava
Pioglitazone is a drug of class thiazolidenediones that is 1,3-thiazolidine-2,4-dione substituted
by a benzyl group at position 5 which in turn is substituted by a 2-(5-ethylpyridin-2-yl)ethoxy
group at position 4 of the phenyl ring. The structural formula of pioglitazone is as shown below:
Nomenclature: 5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione;
hydrochloride
Uses:
➢ Pioglitazone is an antidiabetic medication used to treat type 2 diabetes.
➢ It may be used with metformin, a sulfonylurea, or insulin.
➢ Its use is recommended together with exercise and diet.
➢ It is not recommended in type 1 diabetes.
Dosage Forms: Oral tablet (15 mg, 30 mg and 45 mg)
➢ Usual adult dose for Type 2 diabetes: Pioglitazone is available in oral form (tablet).
A doctor may prescribe it in one of the following dosages: 15 mg, 30 mg and 45 mg.
Starting dose of Pioglitazone is 15 mg or 30 mg orally once a day.
➢ Maintenance dose: 15 mg to 45 mg orally once a day based on glycemic response as
determined by HbA1c.
9.1.5 Repaglinide
Brand Names: Enyglid, Gluconorm, Prandin
Repaglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-
dependent diabetes mellitus (NIDDM). It belongs to the class known as meglitinides. It is
a benzoic acid derivative that stimulates insulin secretion from the pancreas and is used in the
therapy of type 2 diabetes. The structural formula is as shown below:
252 Text Book of Pharmaceutical Chemistry
IUPAC Name: 2-ethoxy-4-[2-[[(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxo
ethyl]benzoic acid.
Properties: Repaglinide is a white to off-white powder with molecular formula C
27
H
36
N
2
O
4
. It is
odorless with melting point is 126°C to 128°C. It is an insulin secretagogue, meaning it binds to
receptors on pancreatic beta cells and stimulates insulin release.
Uses:
➢ It is used alone or with other medications to control high blood sugar along with a proper
diet and exercise.
➢ It is used in people with type 2 diabetes.
➢ It is used for controlling high blood sugar helps prevent kidney damage, blindness, nerve
problems, loss of limbs, and sexual function problems.
Dosage and Administration: Tablet: 0.5 mg, 1.0 mg and 2.0 mg. Repaglinide (trade name:
NovoNorm) should be taken before main meals.
Storage: Store at room temperature between (15°C to 25°C) away from light and moisture.
9.1.6 Gliflozins
Gliflozins is sodium-glucose co-transporter 2 inhibitor is the newly developed class of oral
hypoglycaemic agents used for the treatment of the type 2 diabetes mellitus. It has been approved
for use as a treatment for diabetes since 2013. They are taken once a day with or without food.
They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called
SGLT-2 inhibitors.
Uses:
➢ The gliflozins are used to treat type 2 diabetes mellitus but are most often used as second-
or third-line agents instead of first-line.
➢ They are often used in combination therapy, e.g., the dual therapy metformin plus
gliflozin and the triple therapy metformin, sulfonylurea and gliflozin.
9.1.7 Gliptins
Gliptins is accepted as a standard therapy for treatment of diabetes mellitus. It acts by
inhibition of the enzyme dipeptidyl peptidase 4 (DPP4), gliptins prolong the GLP1-dependent
insulin secretion in the pancreatic β-cells, and thus support physiological blood glucose control.
Hypoglycemic Agents 253
Uses:
➢ Gliptin is used in the treatment of hyperglycaemia in type 2 diabetes.
➢ Gliptins prolong insulin secretion from pancreatic β-cells via stabilization of GLP1/GIP.
➢ It shows beneficial effects on blood glucose and HbA1c without a relevant risk for
hypoglycaemia or gain of body weight.
9.2 EXERCISE
A. Long Answer Type Questions
1. What are parenteral hypoglycemic agents? Give a detail account on insulin.
2. What are oral hypoglycemic agents? Classify them with examples.
3. Give the structure, properties and medicinal uses of Phenformin and Metformin.
4. Discus the structure, properties and uses of Tolbutamide and Chlorpropamide.
5. Discus in detail preparation and uses of Insulin.
6. Explain biguanides used as hypoglycemic agents with examples.
7. Write a note on types of diabetes.
B. Short Answer Type Questions
1. Define the term diabetes.
2. What are sulfonyl urea derivative? Give one example.
3. Write a short note on Oral hypoglycemic agents.
4. Give structure and uses of Metformin.
5. Write the properties of Tolbutamide.
6. Explain type 1 diabetes.
7. What is gestational diabetes?
8. Give the properties and uses of Chlorpropamide.
9. Write a short note on Insulin.
254 Text Book of Pharmaceutical Chemistry
C. Fill in the Blanks
1. Brand name of Metformin is ____________.
2. Example of biguanide derivative is ____________.
3. A chain of insulin contains ____________ amino acids
4. B chain of insulin contains ____________ amino acids.
5. Brand name of Glimepiride is ____________.
6. Insulin is secreted by ____________.
7. Metformin belongs to the group of ____________.
8. Chlorpropamide is an example of ____________.
9. Pioglitazone is a drug of class ____________
10. Repaglinide belongs to the class known as ____________.
Answers:
1. Glucophage
2. Phenformin, metformin.
3. 21
4. 30
5. Amaryl
6. Β-cells of islet of langerhans
7. Biguanides
8. Sulfonyl ureas
9. Thiazolidenediones
10. meglitinides
Chapter
10
ANALGESIC AND
ANTI-INFLAMMATORY AGENTS
STRUCTURE
10.1 Introduction
10.2 Non-steroidal Anti-inflammatory Agents (NSAIDS)
10.3 Exercise
OBJECTIVES
Analgesic and Anti-inflammatory Agents: Morphine Analogues, Narcotic Antagonists;
Nonsteroidal Anti-inflammatory Agents (NSAIDs) – Aspirin*, Diclofenac, Ibuprofen*,
Piroxicam, Celecoxib, Mefenamic Acid, Paracetamol*, Aceclofenac
10.1 INTRODUCTION
Pain is an unpleasant sensation and emotional experience that sensory neurons transmit to the
brain. It enables the body to respond and prevent further tissue damage. The five most common
types of pain are: acute pain, chronic pain, neuropathic pain, nociceptive pain, radicular pain
(a type of pain that radiates from your back and hip into your legs through the spine).
Analgesics are the medical term for painkillers, which are any drugs that reduce pain
selectively without blocking nerve impulse conduction.
Classification:
Analgesics may be classified into two groups:
➢ Opioid Analgesics – Narcotics/Morphine like analgesics
➢ Non-opioid Analgesics – NSAIDs/Non-narcotic/Aspirin like analgesics
Opioids (narcotics) analgesics are a class of pain-relieving medications that function by
interacting with opioid receptors in the cells. They are prescribed by doctors to treat chronic or
severe pain. Opioids can be made from the poppy plant, e.g., morphine or synthesized in a
laboratory, e.g., Fentanyl.
256 Text Book of Pharmaceutical Chemistry
10.1.1 Morphine
Morphine is an opiate drug that is derived naturally from the poppy plant (Papaver
somniferum). It was first isolated between 1803 and 1805 by German pharmacist Friedrich
Sertürner. It can be taken orally or injected. It is used officially as morphine hydrochloride and
morphine sulphate.
Chemistry: Three-dimensional structure of morphine has five rings. Of these, three lie
approximately in the same plane. Morphine has a methyl group attached to a nitrogen atom. If this
methyl group is replaced by a propenyl group, an antagonist of morphine called nalorphine is
formed.
Morphine structure have been used to create synthetic drugs such as the morphinan family
(levorphanol, dextromethorphan and others) and other groups that have many members with
morphine-like qualities. Modification of morphine structure give rise to non-narcotic drugs with
other uses such as emetics, stimulants, anti-tussives, anticholinergics, muscle relaxants, local
anaesthetics, general anaesthetics, and others. Morphine-derived agonist-antagonist drugs have
also been developed.
All opioid analgesics have some similarities in their structure. These are: an aromatic ring and a
quaternary carbon atom linked to a tertiary amine group by two other carbon atoms.
Properties: Morphine occurs as white, crystalline alkaloid, small rhombic prisms or needles from
dilute alcohol as the monohydrate, odorless, bitter in taste with melting point 255°C.
Morphine and its hydrated form, C
17
H
19
NO
3
.H
2
O, are not vey soluble in water or lipids.
Commercially available forms of morphine are the morphine salts such as hydrochloride and
sulfate that are around 300 times more water soluble that the parent molecule.
Uses:
➢ Morphine is primarily used to treat both acute and chronic severe pain. Its duration of
analgesia is about three to seven hours.
➢ It is used for pain due to myocardial infarction and for labour pains.
➢ It is used in the treatment of acute pulmonary oedema.
➢ It is effective in relieving cancer pain.
➢ It reduces intestinal motility and used in the treatment of diarrhoea.
➢ It is also used for suppression of cough and relief of anxiety.