B.Pharm 5th semester

BP501T. Medicinal Chemistry-II

Unit-V

Antidiabetic agents

Local Anaesthetics

Compiled by: Dr Manoj Kumar Mahapatra

Associate Professor

KMIPS, Rourkela

ANTIDIABETIC AGENTS

Agents which are used in the treatment of diabetes are called as antidiabetic agents. They

used to lower the blood sugar level in patients suffering from hyperglycaemia. These are also

called as anti-hyperglycaemic agents.

Diabetes mellitus: It is a chronic metabolic disorder which is characterized by

hyperglycaemia (increased blood sugar level). The common symptoms are polydipsia (excess

thirst), polyphagia (excess hunger), and polyurea (excess urination). The classification of

diabetes has been presented in Table-1.

Table-1: Classification of diabetes mellitus

Type-1 (IDDM) Type-2 (NIDDM)

Insulin dependent diabetes mellitus Non-insulin dependent diabetes mellitus

Juvenile onset diabetes mellitus Adult onset diabetes mellitus

Occurs in children Occurs in adults

Pancreatic β-cells are destroyed Less insulin secretion or insulin resistance

No insulin secretion (cells don’t respond to insulin)

Treatment: insulin injection Treatment: oral hypoglycaemic agents

Insulin: It is a peptidic hormone secreted by β-cells of pancreas. It was discovered by Banting

& Best in 1921. It regulates metabolism of carbohydrate, lipids and proteins. It decreases

blood sugar level by decreasing gluconeogenesis, increasing glucose uptake and increasing

glycogen synthesis.

Insulin structure: Its full structure was elucidated by Sanger in 1956. It is a polypeptide

hormone with a molecular weight of 6000 Da. Inside body, the inactive pro-insulin is

converted into active insulin which is composed of 2 chains (A & B). A chain has 21 amino

acid residues, whereas B chain has 30 amino acid residues and both the chains are attached to

each other by 2 disulphide (-S-S-) bonds. The structure of insulin has been depicted in

Figure-1.

Sources of insulin: Bovine, Porcine, Recombinant human insulin

Figure-1: Structure of insulin

Insulin preparations: Various insulin preparations has been classified and presented in Table-

2, according to their onset of action.

Table-2: Classification of various insulin preparations

Short acting Intermediate acting Long acting

Regular Isophane (NPH) Protamine zinc

Lispro Lente Ultra Lente

Insulin zinc Biphasic insulin aspart Insulin glargine

Insulin aspart Insulin detemir

Insulin degludec

Regular insulin: Also called as neutral or soluble insulin. Rapid acting with 0.5-1 hr duration

of action.

Lispro insulin: Rapid acting with 6-8 hr duration of action. In the carboxyl terminal of B-

chain, lysine and proline residues are reversed. It is a recombinant human insulin.

Insulin Zinc: It is a suspension of insulin and zinc chloride, having 6-8 hr duration of action.

Insulin aspart: Synthetic form of human insulin where a single amino acid, proline (B-28) is

replaced by aspartic acid. It has 3-5 hr duration of action.

Isophane insulin: Also called as Neutral Protamine Hagedorn (NPH) insulin. It is

intermediate acting with 18-24 hr duration of action. It is composed of zinc, protamine, and

regular insulin.

Lente insulin: It is intermediate acting with 18-24 hr duration of action. It is composed of

acetate buffer, zinc, and regular insulin.

Biphasic insulin aspart: It is intermediate acting with 24 hr duration of action. It is

composed of 30% soluble insulin aspart and 70% protamine bound insulin aspart.

Protamine zinc insulin: It is composed of insulin, zinc chloride, and protamine. It has

duration of action upto 36 hrs.

Ultra lente insulin: It contains 65% of lente insulin, having duration of action upto 36 hrs.

Insulin glargine: It is obtained by addition of two arginine residues in B-chain carboxy

terminal and by replacement of asparagine with glycine in A-21 position of human insulin. It

has duration of action upto 24 hrs.

Insulin detemir: It is obtained by addition of a fatty acid (myristic acid) to lysine residue in

B-29 position of human insulin. It has duration of action upto 24 hrs.

Insulin degludec: It is obtained by addition of hexadecanedioic acid to lysine residue in B-29

position of human insulin. It has duration of action upto 24 hrs.

Oral hypoglycaemic agents

Sulfonyl ureas: These are the first class of oral hypoglycaemic agents used for treatment of

diabetes. They are also called as insulin secretagogues.

Mechanism of action- They bind to the sulfonyl urea receptors present in pancreatic β-cells. It

leads to closure of ATP-sensitive K+ channels and depolarises the β-cell membrane. Then it

opens voltage gated Ca+2 channels and stimulates β-cells to secrete more insulin.

1st generation- Chlorpropamide, Tolbutamide, Acetohexamide

2nd generation- Glibenclamide, Glipizide, Glyburide

3rd generation- Glimepiride

Chlorpropamide- 1-(p-chlorophenyl)-sulfonyl-3-propyl urea

More resistant to metabolism than tolbutamide. So, it has longer duration of action. Used as

oral hypoglycaemic agent for treatment of type-2 diabetes.

Tolbutamide- 1-(p-tolyl)-sulfonyl-3-butyl urea

It is the least potent and short acting sulfonyl urea. It is safely used for treatment of type-2

diabetes in elderly patients and those prone to hypoglycemia.

Synthesis:

O C2H5

O O O O

H3C S NH2 + C H3C S N
2H

H
5

Cl O
O O

p-tolyl sulphonamide Ethyl chloroformate
CH3-CH2-CH2-CH2-NH2

CH3

O

O NH

H3C S NH

O

Tolbutamide

Glipizide- 1-cyclohexyl-3-[p-[2-[5-methyl pyrazin-2-yl]carboxamido]ethyl]phenyl]-sulfonyl

urea

It has quick onset of action. Used as oral hypoglycaemic agent for treatment of type-2

diabetes.

Glimepiride- 1-[p-[2-[3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-carboxamido]-ethyl]-phenyl]

sulfonyl-3-(p-methyl cyclohexyl) urea

It’s a long acting potent sulfonylurea. Used as oral hypoglycaemic agent for treatment of

type-2 diabetes.

Biguanides: Phenformin, Metformin, Butformin

Mechanism of action- They reduce hepatic gluconeogenesis, decrease intestinal absorption of

glucose, increase glucose uptake and utilization to decrease the blood sugar level. As they

improve the insulin resistance, they are also known as insulin sensitizers.

Metformin- N,N-dimethyl biguanide

Used for treatment of type-2 diabetes in obese patients. Also used for treatment of polycystic

ovarian syndrome.

Thiazolidinediones: Pioglitazone, Rosiglitazone

Mechanism of action- They binds to and stimulates Peroxisome Proliferator Activated

Receptor-γ (PPAR-γ), due to which they are also known as PPAR- γ agonists. They increase

the expression of GLUT-1 & GLUT-4 receptors on cell surface to increase glucose uptake.

They reduce insulin resistance and hepatic gluconeogenesis. They decrease the post-prandial

glucose level and also HbA1c level.

Pioglitazone- 5-[4-[2-[5-ethyl pyridin-2-yl]ethoxy]benzyl]thiazolidin-2,4-dione

Used as oral hypoglycaemic agent for treatment of type-2 diabetes.

Rosiglitazone- 5-[4-[2-[N-methyl-pyridin-2-yl]amino]ethoxy]benzyl]thiazolidin-2,4-dione

Used as oral hypoglycaemic agent for treatment of type-2 diabetes.

Meglitinides: Repaglinide, Nateglinide

Mechanism of action- Same as that of sulfonylureas. They bind to the sulfonyl urea receptors

present in pancreatic β-cells. It leads to closure of ATP-sensitive K+ channels and depolarises

the β-cell membrane. Then it opens voltage gated Ca+2 channels and stimulates β-cells to

secrete more insulin. These agents are also known as insulin secretagogues.

Repaglinide- 2-ethoxy-4-[2-[3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamino]-2-oxo-ethyl]

benzoic acid

It induces fast onset and short-lasting insulin secretion. Administered before each meal to

control post-prandial hyperglycaemia.

Used as oral hypoglycaemic agent for treatment of type-2 diabetes.

Nateglinide- N-[{4-(propan-2-yl)cyclohexyl}carbonyl]-D-phenylalanine

It’s a phenylalanine derivative. Causes faster onset and short-lasting insulin secretion than

repaglinide. Used as oral hypoglycaemic agent for treatment of type-2 diabetes.

Glucosidase inhibitors: Acarbose, Voglibose

Mechanism of action- They delays the absorption and metabolism of carbohydrates by

inhibiting α-glucosidase enzyme found in the brush border epithelium of small intestine. α-

glucosidase helps in hydrolysing polysaccharides and oligosaccharides into monosaccharides

and helps in their absorption. Flatulence and loose motion are the common side effects of this

class of drugs. These drugs produce anti-hyperglycaemic effect but do not produce

hypoglycaemia.

Acarbose- It is a complex oligosaccharide which is isolated from cultures of actinoplanes (a

bacteria). It is composed of acarviosin moiety and a maltose moiety.

Used for treatment of type-2 diabetes.

Voglibose- 5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cylcohexan-1,2,3,4-

tetraol It is obtained from validamycin-A (metabolic product of Streptomyces hygroscopius).

It is a valiolamine derivative.

Used for treatment of type-2 diabetes.

References:

1. Wilson & Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry.

2. Text book of Medicinal Chemistry- S. N. Pandeya

3. William Foye’s Principles of Medicinal Chemistry.

LOCAL ANAESTHETICS

These are agents which upon topical application or local injection cause reversible loss of

pain sensation in a restricted area of the body. They act by blocking both sensory and motor

nerve conduction to produce temporary loss of sensation without loss of consciousness.

Mechanism of action- These drugs reversibly prevent the generation and propagation of

impulses in all excitable membranes including nerve fibre by stabilising the membrane. Local

anaesthetics block the nerve conduction by decreasing the entry of Na+ during action

potential. They interact with a receptor situated within the voltage sensitive Na+ channel and

raise the threshold of Na+ channel opening. Therefore, Na+ can’t enter into the cell in

response to an impulse which prevents depolarisation. Thus, action potential is not generated.

This action affecting the depolarisation which leads to failure of conduction of impulse

without affecting the resting membrane potential (RMP) is known as membrane stabilising

effect.

Uses- These are used for i) temporary relief of localised pain

ii) itching due to minor burns, insect bites & allergy

iii) minor surgery and in dentistry

Methods or sites of administration:

1. Surface anaesthesia- Applied directly to the mucosal surfaces of nose, mouth,

bronchial tree, oesophagus & genito-urinary tract

2. Infiltration anaesthesia- It is injected under the skin in the area of operation

3. Nerve block anaesthesia- It is injected around the nerve trunks or plexuses. Used for

peripheral anaesthesia.

4. Spinal anaesthesia- It is injected into the sub-arachnoid space so that the local

anaesthetic mixes with the spinal fluid. Lower abdomen and hind limbs are paralysed.

Used for operation in lower limbs, pelvis, abdomen, prostatectomy, fracture setting,

obstetric procedures, caesarean surgery etc.

5. Epidural anaesthesia- It is injected into a narrow spinal dural space containing

semiliquid fat where the nerve roots pass.

Ideal characteristics of Local anaesthetics:

1. Non-irritating to the tissue.

2. Doesn’t cause damage to the nerve structure.

3. Rapid onset & short duration of action.

4. Low systemic toxicity.

5. Must be effective whether injected or topically applied.

CLASSIFICATION

1. Benzoic acid esters- Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine,

Piperocaine

2. p-Aminobenzoic acid esters- Benzocaine, Butamben, Procaine, Butacaine,

Propoxycaine, Tetracaine, Benoxinate

3. Amide/Anilide derivatives- Lignocaine/Lidocaine/Xylocaine, Mepivacaine,

Prilocaine, Etidocaine

4. Miscellaneous agents-

Amidine derivative- Phenacaine

Carbamate derivative- Diperodon

Quinoline derivative- Dibucaine

Cocaine- 2-methoxy carbonyl-tropan-3-yl-benzoate

It is a natural alkaloid, isolated from the leaves of Erythroxylon coca. It is the first drug to be

used as local anaesthetic.

Used as anaesthesia for eye, ear, nose & throat.

Hexylcaine- 1-cyclohexyl amino-propan-2-yl-benzoate

Used as surface anaesthesia.

Meprylcaine- 2-methyl-2-(propylamino) propyl benzoate

O

H
N

O CH3

H3C CH3

Used for dental anaesthesia.

Cyclomethycaine- 3-(2-methyl-1-piperidinyl) propyl-p-(cyclohexyloxy) benzoate

Used as topical anaesthesia.

Piperocaine- 3-(2-methyl-1-piperidinyl) propyl benzoate

Used as ocular anaesthesia.

Benzocaine- Ethyl-p-aminobenzoate

O

O CH3

H2N

Used to reduce pain due to sunburn, teeth pain, piles, vaginal/rectal irritation.

Synthesis-

Butamben- Butyl-p-aminobenzoate

O

O CH3

H2N

Used as surface anaesthesia for relief of pain and itching associated with anorectal disorders.

Procaine- Also called as novocaine.

2-(diethylamino) ethyl-p-amino benzoate

Used as infiltration, nerve block and spinal anaesthesia. It is a vassodilator. So, adrenaline is

added to it to retard the absorption and prolong its duration of action.

Synthesis-

Butacaine- 3-(dibutylamino) propyl-p-amino benzoate

Used as topical anaesthesia.

Propoxycaine- 2-(diethylamino)ethyl-2’-propoxy-4’-amino benzoate

Used as dental anaesthesia.

Tetracaine- 2-(dimethylamino)ethyl-p-(butylamino) benzoate

Used as topical and spinal anaesthesia.

Benoxinate- Also called as oxybuprocaine.

2-(diethylamino)ethyl-3’-butoxy-4’-amino benzoate

Used in ophthalmology.

Lignocaine- Also called as Lidocaine or Xylocaine.

2-(diethylamino)-N-2,6-(dimethyl phenyl) acetamide

Used as infiltration, nerve block and surface anaesthesia. Also used for dental anaesthesia.

Mepivacaine- 1-methyl-N-(2,6-dimethyl phenyl)piperidin-2-carboxamide

Used as epidural and nerve block anesthesia. Also used in dental procedures.

Prilocaine- N-(2-methyl phenyl)-2-propylamino propenamide

Used for infiltration, nerve block anaesthesia. A mixture of prilocaine and lignocaine

(eutectic mixture) is used as topical dosage form.

Etidocaine- N-(2,6-dimethyl phenyl)-2-(ethyl propyl amino)-butanamide

Used along with adrenaline for infiltration, epidural and nerve block anaesthesia.

Phenacaine- Also known as holocaine.

N,N’-bis(p-ethoxyphenyl)ethan imidamide

Used in ophthalmology.

Diperodon- 3-(1-piperidinyl)-1,2-propandiol-bis-(phenyl carbamate)

Used as topical anaesthetic.

Dibucaine- Also known as Cinchocaine. It is the most potent, most toxic, longest acting local

anaesthetic.

N-(2-diethyl amino ethyl)-2-butoxy-quinolin-4-carboxamide

Synthesis-

O O

(CH CO NaOH
O 3 )2O

O
Intramol. Rearrangement

N N
H

Isatin
CH3

O

O
COOH

COOH

NH
N O
H

O CH3

COOH COCl

(C2H5)2N-CH2-CH2-NH2
PCl5

N OH N Cl

H H
O N C2H5 O N C2H5

N

C2H5 C2H5
C4H9ONa

N Cl N OC4H9

Dibucaine

Dibucaine is used as surface anaesthetic on less delicate mucous membrane like anal canal.

Can be used parenterally for spinal anaesthesia only.

SAR OF LOCAL ANAESTHETICS

1. Ester derivatives-

i) Presence of electron withdrawing group at 2nd position of aryl moiety provides rapid onset

of action. Eg- Chloroprocaine has more rapid onset of action because it is 4 times faster

hydrolysed than procaine.

ii) Presence of non-polar groups on aromatic N atom imparts greater lipid solubility and good

absorption. Eg- Tetracaine

O CH3

N
O CH3

C4H9

N
H

Tetracaine

iii) Aryl group- It is attached directly to the carbonyl moiety.

 Conjugation of aromatic moiety with carbonyl group enhances local anaesthetic

activity.

 Substituents like amino, alkoxy, alkyl amino groups increase the electron density on

carbonyl oxygen and enhances the activity.

 Presence of alkyl group in between aryl and carbonyl results in inactive compounds.

iv) Bridge X- X may be C, O, N, or S

Anaesthetic potency: S > O > C > N

Amides (X=N) are resistant to metabolic hydrolysis.

v) Amino alkyl group- Tertiary amines have longer duration of action, but they are more

irritating than primary amines. Alkyl groups also influence the lipid solubility.

2. Amide derivatives-

These are essentially anilide derivatives having the general structure:

Aryl group- Phenyl group is attached to the sp2 ‘C’ atom through nitrogen bridge.

Substitution of phenyl group with a methyl in 2 or 6 position enhances the activity. It

provides steric hindrance to hydrolysis and also increases the coefficient of distribution.

The amide bond is more stable to hydrolysis than esters.

Substituent X- X may be C (eg- isogramine), O (eg- lidocaine), N (eg- phenacaine)

Amino alkyl group- It is the hydrophilic part which helps in salt formation.

1° and 2° amines are more irritating than 3° amines.

References:

1. Wilson & Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry.

2. Text book of Medicinal Chemistry- S. N. Pandeya

3. William Foye’s Principles of Medicinal Chemistry.