Unit -3 23 MARCH 20

ANTIDIABETICS- INSULIN AND ORAL HYPOGLYCEMIC AGENTS :

[ chapter 19 kd tripathi]
WHAT TO STUDY :
WHAT IS DIABETES ,ITS TYPES , ROLE OF INSULIN AND
HYPOGLYCEMIC AGENTS ,
MODE OF ACTION, SIDE EFFECTS,PHARMACODYNAMICS AND
PHARMACOKINETICS
INSULIN :[ chapter 19 kd Tripathi]
 Insulin is an anabolic peptide hormone that is produced and secreted
from beta cells located in the islets of Langerhans of the pancreas.
 It has important metabolic functions, which include promoting the
storage of carbohydrates, amino acids, and fat in the liver, skeletal
muscle, and adipose tissues.
 By modulating glucose absorption from the blood, insulin lowers blood
glucose levels. 
 Under basal condition ~1U insulin is secreted per hour by human
pancreas. Much larger quantity is secreted after every meal. Secretion of
insulin from β cells is regulated by chemical, hormonal and neural
mechanisms.
INSULIN THERAPY
INSULIN THERAPY is an important part of treatment for individuals with
insufficient or absent insulin production (e.g., diabetes mellitus, gestational
diabetes). Several insulin analogs (e.g., insulin glargine) are available that are
related to human insulin but have a different molecular structure and differ in
onset, peak, and duration compared to human insulin. It is crucial that patients
receiving insulin therapy undergo in-depth training to prevent potentially life-
threatening conditions such as hypoglycemia as a result of an insulin overdose
or drug interactions.
Drugs used in diabetes treat diabetes mellitus by lowering the glucose level in
the blood. With the exceptions of insulin, exenatide, liraglutide and pramlintide,
all are administered orally and are thus also called oral hypoglycemic agents or
oral antihyperglycemic agents.
A widespread pathological change is thickening of capillary basement
membrane, increase in vessel wall matrix and cellular proliferation resulting in
vascular complications like lumen narrowingelevated blood glucose levels).
The two most common forms are type 1 and type 2 diabetes mellitus.
1. Type 1 is the result of an autoimmune response that triggers the
destruction of insulin-producing β cells in the pancreas and results in an
absolute insulin deficiency. Type 2, which is much more common, has a
strong genetic component as well as a significant association
with obesity and sedentary lifestyles.
2.  Type 2 diabetes is characterized by insulin resistance (insufficient
response of peripheral cells to insulin) and pancreatic β cell dysfunction
(impaired insulin secretion), resulting in relative insulin deficiency. This
form of diabetes usually remains clinically inapparent for many years.
However, abnormal metabolism (prediabetic state or impaired glucose
intolerance), which is associated with chronic hyperglycemia,
causes microvascular and macrovascular changes that eventually result in
cardiovascular, renal, retinal, and neurological complications. In
addition, type 2 diabetic patients often present with other conditions
(e.g. hypertension, dyslipidemia, obesity) that increase the risk of
cardiovascular disease (e.g., myocardial infarction). Renal insufficiency
is primarily responsible for the reduced life expectancy of patients with
DM.
Because of the chronic, progressive nature of type 1 and type 2 diabetes
mellitus, a comprehensive treatment approach is necessary.
The primary treatment goals for type 2 diabetes are the normalization of glucose
metabolism and the management of risk factors (e.g., arterial hypertension).
In theory, weight normalization, physical activity, and a balanced diet should
be sufficient to prevent the manifestation of diabetes in prediabetic patients or
delay the progression of disease in diabetic patients.
Unfortunately, these general measures alone are rarely successful, and treatment
with oral antidiabetic drugs and/or insulin injections is often required for
optimal glycemic control.
In type 1 diabetes, insulin replacement therapy is essential and patients must
learn to coordinate insulin injections and dietary carbohydrates.
Both type 1 and type 2 diabetic patients require regular self-
management training to improve glycemic control, reduce the risk of life-
threatening hypoglycemia or hyperglycemia, and prevent diabetic
Mechanism of action
 Insulin acts on specific receptors located on the cell membrane of practically
every cell, but their density depends on the cell type: liver and fat cells are very
rich. The insulin receptor is a receptor tyrosine kinase (RTK) which is
heterotetrameric glycoprotein consisting of 2 extracellular α and 2
transmembrane β subunits linked together by disulfide bonds. It is oriented
across the cell membrane as a heterodimer (Fig. 19.3). The α subunits carry
insulin binding sites, while the β subunits have tyrosine protein kinase activity.
Binding of insulin to α subunits induces aggregation and internalization of the
receptor along with the bound insulin molecules. This activates tyrosine kinase
activity of the β subunits → pairs of β subunits phosphorylate tyrosine

Side effects
 Hypoglycemia 
 Weight gain 
 Lipodystrophy at the injection site 
 Pain and erythema at injection site
 Hypokalemia
 Allergic reactions (rare)
 Edema (rare
2.ORAL HYPERGLYCEMIC DRUGS

Oral hypoglycemic drugs are used only in the treatment of type 2 diabetes
which is a disorder involving resistance to secreted insulin. Type 1 diabetes
involves a lack of insulin and requires insulin for treatment. There are now four
classes of hypoglycemic drugs:

 Sulfonylureas
 Metformin
 Thiazolidinediones
 Alpha-glucosidase inhibitors.

These drugs are approved for use only in patients with type 2 diabetes and are
used in patients who have not responded to diet, weight reduction, and exercise.
They are not approved for the treatment of women who are pregnant with
diabetes.

1.SULFONYLUREAS – Sulfonylureas are the most widely used drugs for the
treatment of type 2 diabetes and appear to function by stimulating insulin
secretion. The net effect is increased responsiveness of ß-cells (insulin secreting
cells located in the pancreas) to both glucose and non-glucose secretagogues,
resulting in more insulin being released at all blood glucose concentrations.
Sulfonylureas may also have extra-pancreatic effects, one of which is to
increase tissue sensitivity to insulin, but the clinical importance of these effects
is minimal.

Pharmacokinetics – Sulfonylureas differ mainly in their potency & their

duration of action. Glipizide, glyburide (glibenclamide), and glimepiride are so-
called second-generation sulfonylureas. They have a potency that allows them
to be given in much lower doses.

Those drugs with longer half-lives (particularly chlorpropamide, glyburide, and

glimepiride) can be given once daily. This benefit may be counterbalanced by a
substantially increased risk of hypoglycemia.

Side effects – Sulfonylureas are usually well tolerated. Hypoglycemia is the

most common side effect and is more common with long-acting sulfonylureas.
Patients recently discharged from hospital are at the highest risk for
hypoglycemia.

Patients should be cautioned about those settings in which hypoglycemia is

most likely to occur. They are:

 After exercise or a missed meal.

 When the drug dose is too high.
 With the use of longer-acting drugs (glyburide, chlorpropamide).
 In patients who are undernourished or abuse alcohol.
 In patients with impaired renal or cardiac function or inter-current
gastrointestinal disease.
  With concurrent therapy with salicylates, sulfonamides, fibric acid
derivatives (such as gemfibrozil), and warfarin.
 After being in the hospital.

Other, infrequent side effects that can occur with all sulfonylureas include
nausea, skin reactions, and abnormal liver function tests. Weight gain can also
occur unless the diabetic diet and exercise program are followed.
Chlorpropamide has two unique effects: it can cause an unpleasant flushing
reaction after alcohol ingestion and it can cause hyponatremia (low blood
sodium), primarily by increasing the action of antidiuretic hormone.

Clinical use – Sulfonylureas usually lower blood glucose concentrations by

about 20 percent. They are most likely to be effective in patients whose weight
is normal or slightly increased. In contrast, insulin should be used in patients
who are underweight, are losing weight, or are ketotic despite adequate caloric
intake.

The choice of sulfonylurea is primarily dependent upon cost and availability,

because their efficacy is similar. However, given the relatively high incidence
of hypoglycemia in patients taking glyburide or chlorpropamide, shorter acting
drugs should probably be used in elderly patients

Repaglinide – Repaglinide is a short-acting glucose-lowering drug recently

approved by the Food and Drug Administration for therapy of type 2 diabetes
alone or in combination with metformin. It is structurally different than
sulfonylureas, but acts similarly by increasing insulin secretion.

The clinical efficacy of repaglinide is similar to that of the sulfonylureas. The

recommended starting dose is 0.5 mg before each meal for patients who have
not previously taken oral hypoglycemic drugs. The maximum dose is 4 mg
before each meal; the dose should be skipped if the meal is missed.
Hypoglycemia is the most common adverse effect.

Natiglinide – Natiglinide (Starlix) is a very short-acting glucose lowering drug

whose mode of action is similar to the sulfonylureas and is nearing approval by
the FDA. A potential advantage of this drug is that it seems to have it’s effect
on the first phase of insulin release rather than the late phase of insulin release.
The first phase of insulin release is brisk, of short duration and occurs within
minutes of ingesting food. It is this first phase of insulin release that is abnormal
in early diabetes & can often be found in patients with impaired glucose
tolerance prior to the onset of diabetes. The usual dose is 120 mg before meals.

2.METFORMIN – Metformin has been used in Europe for over thirty years, and
has been available in the United States since March 1995. It is effective only in
the presence of insulin but, in contrast to sulfonylureas, it does not directly
stimulate insulin secretion. Its major effect is to increase insulin action.

How metformin increases insulin action is not known but it is known to affect
many tissues. One important effect appears to be suppression of glucose output
from the liver.

Clinical use – Metformin is most often used in patients with type 2 diabetes who
are obese, because it promotes modest weight reduction or at least weight
stabilization. This is in contrast to the increased appetite and weight gain often
induced by insulin and sulfonylureas.

Metformin typically lowers fasting blood glucose concentrations by

approximately 20 percent, a response similar to that achieved with a
sulfonylurea.

Metformin given in combination with a sulfonylurea lowers blood glucose

concentrations more than either drug alone.

In addition to causing modest weight loss, metformin has two other advantages
as compared with sulfonylureas. They are:

 It is less likely to cause hypoglycemia.

 It has prominent lipid-lowering activity, producing a significant reduction
in serum triglyceride and free fatty acid concentrations, a small reduction
in serum low-density lipoprotein (LDL) cholesterol concentration, and an
 elevation in serum high-density lipoprotein (HDL) cholesterol
concentration.

There are, however, two disadvantages to metformin: the risk for lactic acidosis
described below and its prominent gastrointestinal side effects.

Pharmacokinetics – Metformin should be taken with meals and should be

started at a low dose to avoid intestinal side effects. The dose can be increased
slowly as necessary to a maximum of 2550 mg/day (850 mg TID).

Side effects – The most common side effects of metformin are gastrointestinal,
including a metallic taste in the mouth, mild anorexia, nausea, abdominal
discomfort, and diarrhea. These symptoms are usually mild, transient, and
reversible after dose reduction or discontinuation of the drug.

A rare problem is lactic acidosis, which may be fatal in as many as one-half of

cases. The risk is much less than with another biguanide, phenformin, which
was withdrawn from use in the United States in the 1970s because of this
complication. Serious lactic acid accumulation usually occurs only in the
presence of a predisposing conditions including:

 Renal insufficiency.
 Current liver disease or alcohol abuse.
 Heart failure.
 Past history of lactic acidosis.
 Severe infection with decreased tissue perfusion.
 Hypoxic states
 Serious acute illness
 Hemodynamic instability
 Age 80 years or more

Drug interactions – A potential drug interaction exists between metformin and

cimetidine (Tagamet) resulting in an increase in metformin blood levels. This
interaction could increase the risk of hypoglycemia in patients taking metformin
plus a sulfonylurea or insulin, and could increase the risk of lactic acidosis in
those with impaired renal function. These risks could increase now that
cimetidine is available over-the-counter. Other H2-blockers are less likely to
cause this problem.

The manufacturer also recommends discontinuing metformin for 48 hours after

any radiologic procedure involving the administration of iodinated contrast
material into the blood. The rationale for this recommendation is to avoid the
potential for high plasma metformin concentrations if the patient develops
contrast-induced acute renal failure

3.THIAZOLIDINEDIONES – The thiazolidinediones such as Avandia

(Rosiglitazone) and Actos (Pioglitazone) reverse insulin resistance by acting on
muscle, fat and to a lesser extent liver to increase glucose utilization and
diminish glucose production.

The mechanism by which the thiazolidinediones increase insulin action is not

well understood but they may be acting by redistributing fat from the visceral
compartment to the subcutaneous compartment. We know that visceral fat is
associated with insulin resistance.

Efficacy – In one large study of 284 patients with type 2 diabetes treated with
Rezulin, the fall in mean fasting blood glucose concentration was significant but
not dramatic over 12 weeks; patients treated with placebo had a fall in blood
glucose concentration of only 4 mg/dL. The HbA1c value in the troglitazone
group fell from 8.6 to 8.1 percent.

Thiazolidinediones are also effective when given in combination with

metformin, although they are not currently approved for this purpose.

Safety – There have been reports of severe liver injury in small numbers of
patients receiving Rezulin and this product has now been removed from the
market. Most cases of liver damage occured early in treatment with the drug and
were reversible when it was stopped but there have been some deaths. The
newer agents such as Actos and Avandia have a much lower incidence of this
side effect.
4.ALPHA-GLUCOSIDASE INHIBITORS – The alpha-glucosidase inhibitors
include acarbose (Precose) & Miglitol (Glycet) and are available in the United
States. They inhibit the upper gastrointestinal enzymes that converts dietary
starch and other complex carbohydrates into simple sugars which can be
absorbed. The result is to slow the absorption of glucose after meals.

As in patients with type 2 diabetes, patients with type 1 diabetes have a

reduction in the amplitude of glucose excursion and HbA1c and a possible
reduction in nocturnal hypoglycemia with alpha-glucosidase inhibitors.

The main side effects of alpha-glucosidase inhibitors are flatulence and

diarrhea. These symptoms are usually mild and do not necessitate cessation of
therapy.