Classification of anti diabetic drugs
Antidiabetic Agents / Oral Hypoglycemic Medications
16.1.1. Introduction
Diabetes mellitus is a group of metabolic diseases
in which an individual has
high blood sugar level because the body either does not produce insulin in
sufficient amount , or the body cells do not respond to the in
sulin formed.
Polyuria (frequent urination), polydipsia (increased
thirst), and polyphagia
(increased hunger) are some typical symptoms caused by high blood sugar.
Diabetes may be of the following two types:
1) Diabetes Mellitus Type 1: It is caused due to the lack of insulin, thus insulin
should be injected to treat this condition.
2) Diabetes Mellitus Type
2: It is caused due to insulin resistance by cells. It is
the most common type of diabetes and can be treated using:
i)
Agents increasing insulin secretion by the pancreas,
ii) Agents increasing the sensitivity of target organs to insulin, and
iii) Agents decreasing the rate at which glucose is absorbed from the GIT.
Anti-diabetic agents are used for treating diabetes mellitus by decreasing
the
blood glucose levels. Some of these drugs are administered orally and termed
oral h ypoglycaemic or oral anti-hyperglycaemic agents ; however, insulin,
exenatide, and pramlinti de are the only
anti-diabetic drugs that are injected.
Different classes of anti-diabetic drugs exist, and they are selected based on the
nature of diabetes, individual’s age and situation, and other factors.
16.1.2. Insulin
Paul Langerhans (a German medical student) in 1869 studied that the pancreas
has two different groups of cells, i.e., the acimer cells that secrete digestive
enzymes, and islets (cells clustered in islands ) that serve a second function.
Banting, Macleod, Bert, and Collip isolated insulin from bovine pancreas and
used it for treating diabetes mellitus.
Insulin is a hormone produced in pancreas and permits the body to utilise sugar
(glucose) from carbohydrates in the food. Insulin restricts the blood sugar level s
from getting too high (hyperglycaemia) or too low (hypoglycaemia).
Insulin
occurs as a white or almost white coloured crystalline powder. It is faintly
soluble in water; soluble in dilute solution of mineral acids and with degradation
in solutions of alkali hydroxide; and almost insoluble in alcohol, chloroform, and
ether.
16.1.2.1. Synthesis
Significant quantity of insulin is synthesised
in the pancreatic beta cells. The
insulin mRNA is translated as a single chain precursor
known as pre-pro
insulin, and removal of its signal peptide during insertion into the endoplasmic
reticulum produces pro-insulin.
Pro-insulin contains three domains, i.e., an amino-terminal B chain, a carboxy
terminal A chain , and a C peptide (connecting peptide in the middle). Pro
insulin, in the endoplasmic reticulum, is exposed to some specific endopeptidases
that excise the C peptide and generates the mature form of insulin. Insulin and
free C peptide are packaged in the Golgi into secretory granules accumulating
collect in the cytoplasm.
Insulin is secrete d from the pancreatic β-cells by exocytosis when these cells
are stimulated. After its release, the insulin diffuses
into islet capillary blood.
C peptide is also secreted into
active.
16.1.2.2. Mechanism of Action
Insulin produces its action throughout specific
cell membranes. Insulin
insulin receptors present on
binds to these receptors with high specificity and
affinity. The resultant insulin-receptor complex enters the cell
insulin.
and releases
The receptors inversely vary with the plasma insulin concentrations. When
insulin concentration is high
, these receptors are down-regulated (number
reduced), whereas in the presence of low insulin concentrations, these receptors
are u p-regulated (numbers increase).
This
leads to reduced and increased
responsiveness to insulin, respectively.
Apart from receptor numbers, reduced affinity of these receptors for insulin may
also contribute to insulin resistance.
Thus in Type II diabetes , reduction in body
weight can restore responsiven ess to endogenous insulin by up-regulation and
increased affinity for insulin by these receptors.
The insulin receptor contains an extracellular α sub-unit (recognition site) and a β
sub-unit, spanning the cell membrane, and containing tyrosine kinase
that
constitutes the second messenger system , which through a complex series of
phosphorylation leads to glucose transporter protein activation and e
ntry of
glucose into the cell.
Internalisation of insulin receptor units inside the cell may help action of insulin
or result in lysosomal degradation of these receptors.
16.1.2.3. Uses
Insulin has the following uses:
1) It is used for controlling diabetes mellitus (uncontrollable by diet alone) or
for treating insulin dependent diabetes mellitus.
2) It is used for regulating carbohydrate metabolism.
3) It is used for treating hyperkalemia.
4) It is used for treating severe ketoacidosis or diabetic coma.
16.1.2.4. Insulin Preparations
Some common insulin preparations are given in the table 1:
16.2. ORAL HYPOGLYCAEMIC DRUGS
16.2.1. Introduction
Hypoglycaemic agents are used in the treatment of diabetes mellitus by lowering
the blood glucose levels. With the exceptions of insulin, exenatide, liraglutide
and pramlintide, all the other hypoglycaemic agents are administered orally and
are therefore known as oral hypoglycaemic agents or oral anti-hyperglycaemic
agents.
16.2.2. Classification
Hypoglycaemic agents are classified as follows:
1) Sulphonylureas:
16.2.3. Sulphonylureas
Janbon and colleagues in 1942 accidentally observed that some sulphonamides
initiated hyperglycaemia in the experimental animals. Carbutamide was the first
sulphonylurea that was clinically used
for treating the diabetes.
sulphonylureas are grouped into two generations or groups:
1) First Generation: Tolbutamide
Generally,
2) Second Generation: Glibenclamide, Glimepiride, Glipizide, Gliclazide, and
Gliquidone.
All the sulphonylureas have similar actions, i.e hey decrease blood glucose levels in type 2 diabetes.
16.2.3.1. Mechanism of Action
hey decrease blood glucose
Sulphonylureas stimulate the secretion of insulin from the -cells of pancreas
without entering the cell ( figure 16.2). This occurs when glucose is not present.
Intact pancreatic
-cells are
sulphonylureas.
required for the hypoglycaemic action of
The -cells have sulphonylurea receptors linked to an AT Pase-sensitive K+ ion
channel.
As given in
figure 16.2, inhibition of K + ion efflux causes
depolarisation of -cell membrane and opens the voltage-dependent Ca ++ ion
channels.
The kinases involved in exocytosis of secretory granules are
activated by the
increased influx of Ca++ ions and their intracellular binding to calmodulin. Hence,
more insulin is released with increase in blood glucose level.
The potency order of sulphonylurea in binding to
-cells approximates its
potency for stimulating insulin release and blocking the effect of K
+ ions.
Sulphonylureas also act synergistically with insulin by raising insulin sensitivity
at a post-receptor level.
16.2.3.2. Structure-Activity Relationship
The benzene ring should contain a substituent in the para position. Substituents
like methyl, acetyl, amino, chloro, bromo, trifluoromethyl and thiomethyl
enhance the anti-hyperglycaemic activity.
On substituting the para position of benzene with arylcarboxamidoalkyl group
(second generation sulphonylurea, such as glibenclamide), the anti-hyperglycaemic
is more enhanced. This happens because of a specific distance between the nitrogen
atom of the substituent and the sulphonamide nitrogen atom
.
Size of the group attached to the terminal nitrogen is essential for activity, and
should impart lipophilicity to the compound. N-Methyl and ethyl substituents do
not produce any activity, while
N-propyl and higher homologues are active;
however, their activity is lost when the number of carbons in N-substituent is 12
or more.
16.2.3.3. Study of Individual Drugs
The following oral hypoglycaemic drugs are discussed below:
1) Tolbutamide,
2) Chlorpropamide,
3) Glipizide, and
4) Glimepiride.
6.2.3.4. Tolbutamide
Tolbutamide belongs to the class of sulph onylureas. It decreases the blood sugar
levels by affecting the pancreas to produce insulin and help the body to use
insulin effectively.
Mechanism of Action
Tolbutamide lowers the blood glucose level in individuals having Non-Insulin
Dependent Diabetes Mellitus (NIDDM) by directly stimulating insulin release
from the functioning pancreatic β-cells by a
process that involves a
sulphonylurea receptor (receptor 1) on the beta cell.
Tolbutamide also inhibits the ATP-potassium channels on the β-cell membrane
and efflux of K+ ions. This results in depolarisation, influx of Ca++ ions and their
binding to calmodulin, activation of kinase, and release of insulin-containing
granules by exocytosis.
Uses
1) It is used for controlling blood glucose in previously untreated NIDDM.
2) It is used in the treatment of diabetes which remains uncon trolled even after
proper diet.
3) It is used with metformin to control blood glucose level.
4) It is used as a substitute for other oral hypoglycemic agents.
16.2.3.5. Chlorpropamide
Chlorpropamide is an oral anti-hyperglycaemic agent used for treating NIDDM .
It comes under the sulphonylurea class of insulin secretagogues, which stimulate
the pancreatic β-cells to release insulin
Mechanism of Action
Chlorpropamide binds to ATP-sensitive potassium channels present on the
pancreatic cell surface, thus depolarises the membrane and reduces potassium
conductance.
This depolarisation stimulates the influx of Ca++ ions through voltage-sensitive
calcium channels. As a result, the intracellular concentration
increases, thus inducing the secretion or exocytosis of insulin
Uses
1) It is taken with a proper diet and exercise program for controlling high blood
sugar in type 2 diabetic patients.
2) It can also be used as an adjunct to other diabetes drugs.
6.2.3.6. Glipizide
Glipizide is an oral medium-to-long acting anti-diabetic drug belonging to the
class of sulphonylurea. It is an oral hypoglycaemic agent that undergoes rapid
absorption and complete metabolism.
Mechanism of Action
Glipizide
Glipizide binds to ATP-sensitive potassium channels presen t on the pancreatic
cell surface, thus depolarises the membrane and reduces potassium conductance.
This depolarisation stimulates the influx of Ca ++ ions through voltage-sensitive
calcium channels. As a result, the intracellular concentration of Ca
++ ions
increases, thus inducing the secretion or exocytosis of insulin.
Uses
It is use d as an adjunct to diet for controlling hyperglycaemia and its related
symptoms in patients having NIDDM (earlier NIDDM was known as maturity
onset diabetes).
16.2.3.7. Glimepiride
Glimepiride is the first III generation sulphonyl urea. It is a highly potent
sulphonylurea having a long duration of action.
Mechanism of Action
Glimepiride decreases blood glucose levels by stimulating insulin release from
the functioning pancreatic β-cells, and by increasing the sensitivity of peripheral
tissues to insulin. Glimepiride binds to ATP-sensitive potassium channels present
on the pancreatic cell surface, thus depolarises the membrane and reduces
potassium conductance.
This depolarisation stimulates the influx of Ca ++ ions through voltage-sensitive
calcium channels. As a result, the intracellular concentration of Ca
increases, thus inducing the secretion or exocytosis of insulin.
Uses
++ ions
It is used with insulin for treating the non-insulin-dependent (type 2) diabetes
mellitus.
6.2.4. Biguanides
The generic formula of biguanides is:
Two commonly used biguanides are phenformin and metformin. They decrease
the blood glucose level in diabetic patien ts by potentiating the hyperglycaemic
action of insulin. They also increase the utilisation of glucose by muscles and
decrease the deflation of insulin.
16.2.4.1. Mechanism of Action
Biguanides act by:
1) Directly stimulating glycolysis in tissues,
2) Reducing hepatic and renal gluconeogenesis,
3) Delaying glucose absorption from the GIT by increasing the conversion of
glucose to lactate by enterocytes, and
4) Reducing the plasma levels of glucagon.
16.2.4.2. Study of Individual Drug
- Metformin
Metformin is a biguanid e antihypertensive agent. It improves glycaemic control
by decreasing hepatic glucose production and glucose absorption, and also by
increasing insulin-mediated glucose uptake.
Mechanism of Action
Metformin reduces the blood glucose levels by decre asing hepatic glucose
production (gluconeogenesis), decreasing the intestinal absorption of glucose,
and increasing insulin sensitivity by increasing the glucose uptake and utilisation
by the peripheral tissues.
Uses
1) It is used as an adjunct to diet and e xercise in NIDDM patients older than 18
years.
2) It can also be used for managing metabolic and reproductive abnormalities
related to polycystic ovary syndrome.
3) It can also be used with a sulphonylurea or insulin to improve glycaemic
control in adults.
16.2.5. Thiazolidinediones
Thiazolidinediones (TZDs or glitazones ) act by reducing the insulin resistance,
which is a common problem in many individuals having type 2 diabetes.
Thiazolidinediones allow insulin to effectively improve the blood glucose levels
by decreasing the body’s resistance to it. They also reduce the blood pressure and
improve lipid metabolism by increasing the levels of HDL (or good) cholesterol.
16.2.5.1. Mechanism of Action
Thiazolidinediones are selective agonists for nuclea r Peroxisome Proliferator
Activated Receptor- (PPAR) that enhances the transcription of several insulin
responsive genes. Thiazolidinediones reverse insulin resistance by stimulating
GLUT4 expression and translocation, and also improve the entry of glucose into
muscles and fat. They also suppress h epatic gluconeogenesis. The insulin
sensitizing action of
thiazolidinediones is due to the a
ctivation of genes
regulating fatty acid metabolism and lipogenesis in adipose tissue.
16.2.5.2. Uses
Thiazolidinediones are used in individuals having type 2 diabetes mellitus. They
decrease blood glucose levels and HbA 1c without increasing the circulating
insulin. Some patients with low baseline insulin levels
are non-responders.
Generally, they are used to supplement sulph onylureas/metformin in case of
insulin resistance. Thiazolidinediones are also used as monotherapy along with
diet and exercise in mild cases. They are also used
to supplement insulin in
advanced cases.
16.2.5.3. Study of Individual Drugs
The following thiazolidinediones are discussed below:
1) Pioglitazone, and
2) Rosiglitazone.
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