Antidiabetics agents

by Frehiwot Beyene
 Introduction
 Diabetes is a disease that leads to high blood glucose levels
due to defects in either insulin secretion or insulin action.
 Diabetes is a medical disorder that causes the body to
produce an excessive amount of urine

 Diabetes is a heterogeneous group of disorders

characterized by abnormalities in carbohydrate, protein, and
lipid metabolism; and is usually refers to diabetes mellitus.

 It is the third leading cause of death by disease, the second

leading cause of blindness, and the second leading cause of
renal failure.
 Introduction….
 Diabetes mellitus (DM) is characterized by
 Hyperglycemia (elevated blood glucose level)
 Hyperlipidemia
 Hyperaminoacidemia
 It is also frequently associated with the development of
 Micro- & macrovascular diseases(e.g. neuropathy & atherosclerosis)
 Chronic hyperglycemia and other metabolic disturbances of
DM lead to
 Long-term tissue and organ damage
 As well as dysfunction involving the eyes, kidneys, and nervous
and vascular systems
 It is a leading cause of death, disability, and blindness
Introduction….
 Diabetes is a condition where the body no longer produces
insulin (-cells dysfunction) or uses insulin efficiently.

 There are 4 pancreatic cells (islets of langerhans) which is

responsible for the secretions different cells.
 Insulin-in the beta (β) cells,
 Glucagon-in the alpha (α) cells,
 Somatostatin-in the delta (δ) cells, and
 Pancreatic polypeptide-in the PP or F cell.
MANAGEMENT OF DIABETES

 Diet is the cornerstone of the management of diabetes,

regardless of the severity of the symptoms or the type of
diabetes.

 Exercise is also an important component in managing diabetes,

particularly in obese individuals with NIDDM who may have a
component of insulin resistance as a consequence of obesity.

 Treatment regimens that have proved effective (oral

hypoglycemic drugs).
 The clinical diabetes mellitus invariably occurs in two forms,
associated with different causes and methods of therapy.

A. Type 1 Diabetes (10% of cases)

The insulin-dependent diabetes mellitus (IDDM), normally takes

place when the β-cells of the prevailing pancreatic islets of
Langerhans are destroyed, perhaps by an autoimmune mechanism
as a consequence of which the ‘insulin production’ in vivo is
overwhelmingly insufficient.
 Develops suddenly, usually before age 15.
 Caused by inadequate production of insulin because T cell-
mediated autoimmune response destroys beta cells.
 Controlled by insulin injections.
B. Type 2 Diabetes (90% of cases)

The noninsulin-dependent diabetes mellitus (NIDDM), i.e., type 2

diabetes, is most abundantly linked with obesity in its adult patients
largely.

 The etiology of the condition bears a strong genetic hereditary; and,

hence, insulin therapy may not prove to be quite effective.

 Usually occurs after age 40 and in obese individuals, but genetics, aging,
and peripheral insulin resistance also.

 Controlled by dietary changes and regular exercise.

Primary structure of proinsulin, depicting cleavage sites to produce insulin.
Structure Activity Relationships of Insulin (SAR)
(1) Proinsulin (86 aa) is the immediate precursor to insulin in
the single-chain peptide.
(2) Proinsulin folds to adopt the ‘correct orientation of the
prevailing ‘disulphide bonds’ plus other relevant
conformational constraints.
(3) Proinsulin in reality, has a precursor of its own,
preproinsulin (110 aa)–a peptide, that essentially comprises
of hundreds of ‘additional residues’.
(4) At an emerging critical situation the insulin gets generated
from proinsulin due to the ensuing cleavage of proinsulin at
the two points.
 SAR of insulin…..

 This eventually produces insulin, that comprises of a 21-residue A

chain and strategically linked with two disulphide bonds ultimately to a
30-residue B chain.

 The active insulin is composed of a 21-amino acid A chain and a 30-

amino acid B chain that are linked by two disulfide bonds. Separately,
each chain is biologically inactive.

structure of insulin
 SAR of insulin…..

 loss of hormonal activity is observed upon the removal of aa units

from chain A

 Activity is reduced to 10 - 20% by replacement of A1 (Aone) glycine

with L-Ala but fully active up on replacing by D- Ala.

 Several aa residues of B are not essential. Up to the first 6 and the last
3 can be removed.

 Breakage of disulphide linkage results in loss of activity.

 Being protein insulin cannot be given orally as it is digested by

proteases and other enzymes.

 A chain (21 amino acid residues) are essential

 Insulin consists of 2 peptide chains:
 Acidic A chain of 21 aa residues
 Basic B chain of 30 aa residues
 It has 3 disulphide bridges b/n aa residues
 A7 – B7
 A20 – B19
 A6 – A11
 In addition to the disulphide linkage the two chains
are held together by
 Hydrophobic bonds
 Hydrogen bonds
 Salt linkage
 Species variation
 Same structural framework but variable aa
substitution
 Porcine insulin is the closest to human insulin
 Differences of insulin from different spps
Species A8 A10 B28 B29 B30
Human Thr Ile Pro Lys Thr
Lispro Thr Ile Lys Pro Thr
Porcine Thr Ile Pro Lys Ala
Bovine Ala Val Pro Lys Ala
A. Rapid onset and ultrashort-acting preparations

1. Insulin Injection (Crystalline Zinc Insulin, Regular Insulin):It is purified

insulin crystallized as a zinc salt. It is administered subcutaneously and
lowers the blood sugar within minutes.
2. Lispro (Humalog), Aspart (Novolog): preparations are classified as
ultrashort acting forms with onset more rapid than regular insulin
and a shorter duration. Lispro is a human insulin analogue of rDNA
origin synthesized from a special nonpathogenic strain of E. coli,
genetically altered by the addition of the gene for insulin lispro; Pro
(B28), Lys(B29).
3. Semilente insulin: It is a suspension of amorphous insulin, which is also
administered subcutaneously.
 B. Intermediate –acting insulin preparations

1. Insulin Zinc Suspension (Lente insulin): It is a mixture of

30% of semilente insulin and 70% ultralente insulin. It is

administered subcutaneously.

2. Isophane insulin suspenssion(NPH): It is a suspension of

crystalline zinc insulin with the positively charged peptide
mixture called protamine.

Its duration of action is intermediate between crystalline zinc

insulin and protamine zinc insulin.
C. Prolonged-acting insulin preparations

1. Extended Insulin Zinc Suspension (Ultralente): a suspension of zinc

insulin forming large particles which dissolve slowly, delaying onset and
prolonging duration of action.

2.Insulin glargine (Lantus): Precipitation at the injection site extends the

duration of action of this preparation.

3. Detemir insulin(Levemir): has a fatty acid complexed with insulin

resulting in slow dissolution.
Chemistry of Oral Hypoglycemic agents

 Some milder forms of diabetes mellitus that do not respond to diet

management or weight loss and exercise can be treated with oral
hypoglycemic agents.

 The success of oral hypoglycemic drug therapy is usually based on a

restoration of normal blood glucose levels and the absence of

glycosuria.
 Oral hypoglycemic drugs used for the treatment of Type II
DM can be classified based on their chemical structures as

1. Sulfonylureas (secretogogues)

2. Biguanides (sensitizers)

3.Alpha glucosidase inhibitors (enzyme inhibitors)

4.Thiazolidinediones (sensitizers)

5. Meglitinides (secretogogues)
 1. Sulfonylureas
 Sulfonylurea's are the most widely prescribed drugs in the
treatment of type II diabetes mellitus.
 The sulfonylurea hypoglycemic agents are basically sulphonamide
structural analogues but they do not essentially possess any
‘antibacterial activity’ whatsoever.

O O
H H Sulphonamide
R1 S N C N R2
1 2 3
O

General chemical structure

Structure Activity Relationships (SAR)
 These are urea derivatives having an arylsulfonyl
moiety in the 1 position and an aliphatic function
at the 3-position.
 The benzene ring should contain one substituent,
preferably at the para position.
 The substituents that seem to enhance
hypoglycemic activity are methyl, amino, acetyl,
chloro, bromo, methylthio, and trifluoromethyl
groups
SAR…
 The aliphatic moiety, R2, essentially confers lipophilic
characteristic properties to the newer drug molecule.
 Optimal therapeutic activity often results when R2
comprises of 3 to 6 carbon atoms, as in
acetohexamide, chlorpropamide and tolbutamide.
 Aryl functional moieties at R2 invariably give rise to
toxic compounds.
 The R1 moiety strategically positioned on the
‘aromatic ring’ is primarily responsible for the
duration of action of the compound.
MOA:-The primary mechanism of action of the sulfonylurea is direct
stimulation of insulin release from the pancreatic β-cells
(secretogogues).

 At higher doses, these drugs also decrease hepatic glucose production

 The second-generation sulfonylurea may possess additional

extrapancreatic effects that increase insulin sensitivity

 The sulfonylureas are ineffective for the management of type I and

severe type II diabetes mellitus,

 since the number of viable β-cells in these forms of diabetes is small.

 All are hypoglycemic.

 Severely obese diabetics often respond poorly to the

sulfonylureas, possibly because of the insulin resistance that
often accompanies obesity.

 These agents tend to cause weight gain, hyperinsulinemia and

hypopglycemia

 Sulfonylurea's are now divided into two sub-groups, namely:

 1st generation and
 2nd generation
 a. 1st generation

 The first-generation sulfonylureas are not frequently

used in the modern management of diabetes
mellitus because of their

 relatively low specificity of action

 delay in time of onset

 occasional long duration of action, and

 a variety of side effects

 have more adverse drug interactions than the second-

generation sulfonylureas
 R SO2NHCONHR'

R R'
n-Butyl
Tolbutamide CH3

Chlorpropamide n- Propyl
Cl

Tolazamide CH3 N

Acetohexamide CH3CO

Gliclazide CH3 N

 Tolbutamide (Orinase) is the least potent of all of all oral hypoglycemic agents.
 Chlorpropamide (Dibenese) more potent and has prolonged duration of action
since it is only slightly metabilized
b. 2nd generation
 The second-generation sulfonylureas display
 A higher specificity and affinity for the sulfonylurea receptor

 More predictable pharmacokinetics in terms of time of onset

and duration of action

 Fewer side effects.

 higher potency

 The second-generation sulfonylureas display higher potency

cause of large groups at p- position
 R SO2NHCONH

Cl

R= CONHCH2CH2 Glibenclamide

OCH3

N CONHCH2CH2
Glipizide
R=
H3C
N

H3C CH3
O Gliquidone
R=
N CH2CH2
H3CO

Glyburide (glibenclamide) the most potent

 Glimepiride typically is classified as a second
generation sulfonylureas and it has a similar
extended binding group like glipizide;

Glimepiride

H 3C
H
N H
N H N
N
O S
H3C
O O O CH3
O
2) Biguanides
no longer produced

H
R N NH2
N
R'
NH NH

R R'

H PhCH2CH2
Phenformin

Metformin CH3 CH3

Buformin H n-Butyl
 Biguanides increase insulin sensitivity in liver and muscle,
inhibit glucose synthesis and release by the liver, and
enhance the ability of tissues to take up glucose.

 Unlike the sulfonylureas, these are not hypoglycemic agents

but rather act as antihyperglycemics
 Metformin is approved for the treatment of patients with
NIDDM that are refractory to dietary management alone

 Does not cause hypoglycemia when used as monotherapy

3) alpha-glucosidase inhibitors
 Work by preventing the digestion of carbohydrates
 Startch, table sugar
 They act by competitively inhibiting α-glucosidases, a
group of enzymes in the intestinal brush border epithelial cells
that includes glycoamylase, sucrase, maltase, and dextranase.
 Reduces rate of digestion of carbohydrates!

 The prolongation of the intestinal absorption of carbohydrates

results keeping postprandial hyperglycemia under control.

 Alone does not cause hypoglycemia

i. Acarbose (Glucobay, Precose, Prandase)

 is a complex oligosaccharide

 it delays CHO metabolism by inhibiting -D-Glucosidase

 Does not cause hypoglycemia when used as monotherapy

ii.Voglibose
 Voglibose is newest , less side effects and Economical

 is orally active inhibitor of -D-Glucosidase

 much more potent and with fewer side effects than Acarbose

iii. Miglitol (Glyset)

 It also lowers blood-glucose level

 Cause hypoglycemia when used as monotherapy

 Acarbose

OH

OH OH
HOH2C H HO N
N
OH

HO OH
HO OH
OH
OH
Voglibose Miglitol
 4) Thiazolidinediones
 Thiazolidinediones (sometimes termed glitazones) are a
novel class of drugs that were initially identified for their
insulin-sensitizing properties.

 They all act to decrease insulin resistance and enhance

insulin action in target tissues.
 Troglitazone was taken off the market in 1999 because of
its hepatic toxicity.
 Rosiglitazone and pioglitazone are now available for clinical
use and are extremely potent in reducing insulin resistance
 The patient who would benefit the most from a

thiazolidinedione is

 a type II diabetic with a substantial amount of

insulin resistance

 They do not cause hypoglycemia (similar to metformin and

acarbose ) when used as monotherapy

 5. Meglitinides
 Repaglinide (Prandin) and Nateglinide (Starlix) are novel
oral blood glucose-lowering agents that are distinct from
all other antidiabetic agents in their chemical structure,
mechanism of binding to target channels in beta-cells, and
mode of elimination.
 Combination therapy with repaglinide/ Nateglinide and
metformin resulted in synergistic improvement in glycemic
control than monotherapy
 They stimulate insulin secretion in a different way from
the sulfonylureas.