1. Insuline and Anti diabetics

Prepared by: Mirza Anwar Baig
M.Pharm (Pharmacology)
Anjuman I Islam's Kalsekar Technical Campus,
School of Pharmacy.
New Panvel,Navi Mumbai

 Synthesis, MOA & role of insulin.
 Diagnosis and symptoms of insulin related
disorders.
 Classification & MOA at receptor level, side
effects of antidiabetics.
 Pharmacotherapeutics of diabetic disorders.
COMPILED BY: PROF.ANWAR BAIG
(AIKTC,SOP) 2

Outline:
Insulin
Chemistry
Secretion
Degradation
Receptors
Effects on its targets
Insuline delivary system
Complication of insuline therapy
Diabetes & antidiabetics
Types
Benefits of tight blood glucose control
Oral hypoglycemic drugs
Combination therapy
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 It is hormone & protein. It contains 51 amino
acids arranged in two chains (A and B).
 Secreted by Beta cells of islets of Langerhans.
Granules within the B cells store the insulin in the
form of crystals consisting of two atoms of zinc
and six molecules of insulin. The entire human
pancreas contains up to 8 mg of insulin,
Proinsulin, a long single/ chain protein molecule,
is processed within the Golgi apparatus and
packaged into granules, where it is hydrolyzed
into insulin and a residual connecting segment
called C/ peptide by removal of four amino acids.
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 The liver and kidney are the two main
organs that remove insulin from the
circulation.
 The half/ life of circulating insulin is 3–5
minutes.
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Ø Portable Pen Injectors
Ø Continuous Subcutaneous Insulin Infusion
Devices (Csii, Insulin Pumps)
Ø Inhaled Insulin
COMPLICATIONS OF INSULIN THERAPY
 Hypoglycemia
 Insulin Allergy
 Immune Insulin Resistance
 Lipodystrophy at Injection Sites
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Diabetes mellitus (DM) is a group of
diseases characterized by chronic
hyperglycemia resulting from defects in
insulin production, insulin action, or both.
It involves the disturbances of carbohydrate,
fat and protein metabolism.
The effects of diabetes mellitus include
long–term damage, dysfunction and failure
of various organs.
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 Diabetes mellitus affects approximately
5 to 8% of the population. A large
number of individuals are
asymptomatic and do not know they
have the disease.
 Prevalence of Diabetes in variousPrevalence of Diabetes in various
regions of world WHOregions of world WHO
Report(Geneva)1997Report(Geneva)1997
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 Random value : 200mg/dl or more DM
 Fasting value: Below 100mg/dl Normal value
100-125 mg/dl IFG
126 mg/dl or more DM
Ø Oral glucose tolerance test:
less than 140 mg/dl Normal value
140-199 mg/dl IGT
200mg/dl or more DM
(AIKTC,SOP)

Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Gestational Diabetes
Other types:
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 Was previously called insulin-dependent diabetes mellitus
(IDDM) or juvenile-onset diabetes.
 Type 1 diabetes develops when the body’s immune system
destroys pancreatic beta cells, the only cells in the body
that make the hormone insulin that regulates blood glucose.
 This form of diabetes usually strikes children and young
adults, although disease onset can occur at any age.
 Type 1 diabetes may account for 5% to 10% of all
diagnosed cases of diabetes.
 Risk factors for type 1 diabetes may include autoimmune,
genetic, and environmental factors.
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 Was previously called non-insulin-dependent diabetes
mellitus (NIDDM) or adult-onset diabetes.
 Type 2 diabetes may account for about 90% to 95%
of all diagnosed cases of diabetes.
 It usually begins as insulin resistance, a disorder in
which the cells do not use insulin properly. As the
need for insulin rises, the pancreas gradually loses its
ability to produce insulin.
 Type 2 diabetes is associated with older age, obesity,
family history of diabetes, history of gestational
diabetes, impaired glucose metabolism, physical
inactivity.
 Type 2 diabetes is increasingly being diagnosed in
children and adolescents.
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Cells of pancreas Glands of pancreas
(AIKTC,SOP) 20

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 A form of glucose intolerance that is diagnosed in
some women during pregnancy.
 It is also more common among obese women and
women with a family history of diabetes.
 During pregnancy, gestational diabetes requires
treatment to normalize maternal blood glucose
levels to avoid complications in the infant.
 After pregnancy, 5% to 10% of women with
gestational diabetes are found to have type 2
diabetes.
 Women who have had gestational diabetes have a
20% to 50% chance of developing diabetes in the
next 5- 10 years.
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 Other specific types of diabetes result
from specific genetic conditions,
surgery, drugs, malnutrition, infections,
and other illnesses.
 Such types of diabetes may account for
1% to 5% of all diagnosed cases of
diabetes.
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 Research studies have found that lifestyle changes
can prevent or delay the onset of type 2 diabetes
among high/ risk adults.
 These studies included people with IGT and other
high/ risk characteristics for developing diabetes.
 Lifestyle interventions included diet and
moderate/ intensity physical activity (such as
walking for 21/2 hours each week).
 In the Diabetes Prevention Program, a large
prevention study of people at high risk for diabetes,
the development of diabetes was reduced 58% over
3 years.
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 In the Diabetes Prevention Program, people treated with
the drug metformin reduced their risk of developing
diabetes by 31% over 3 years.
 Treatment with metformin was most effective among
younger, heavier people (those 25 to 40 years of age
who were 50 to 80 pounds overweight) and less effective
among older people and people who were not as
overweight.
 Similarly, treatment of people with IGT with the drug
acarbose reduced the risk of developing diabetes by 25%
over 3 years.
 Other medication studies are ongoing. In addition to
preventing progression from IGT to diabetes, both
lifestyle changes and medication have also been shown
to increase the probability of reverting from IGT to
normal glucose tolerance.
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Management of
Diabetes
Mellitus
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 The major components of the treatment of
diabetes are:
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Dietary treatment should aim at:
Ensuring weight control
Providing nutritional requirements
Allowing good glycaemic control with blood
glucose levels as close to normal as possible
Correcting any associated blood lipid
abnormalities
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 Physical activity promotes weight reduction
and improves insulin sensitivity, thus
lowering blood glucose levels.
 Together with dietary treatment, a
programme of regular physical activity and
exercise should be considered for each
person.
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 There are currently four classes of oral
anti/ diabetic agents:
i. Biguanides
ii. Insulin Secretagogues – Sulphonylureas
iii. Insulin Secretagogues – Meglitinide
iv. α/ glucosidase inhibitors
v. Thiazolidinediones (TZDs)
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1. Biguanides:
 Metformin, it increases glucose uptake and utilization by target
tissues. It requires the presence of insulin to be effective but does
not promote insulin secretion. The risk of hypoglycemia is greatly
reduced.
 Mechanism: Metformin reduces plasma glucose levels by inhibiting
hepatic gluconeogenesis. It also slows the intestinal absorption of
sugars. It also reduces hyperlipidemia (↓LDL and VLDL cholesterol
and ↑ HDL). Lipid lower requires 4-6 weeks of treatment.
Metformin also decreases appetite. It is the only oral hypoglycemic
shown to reduce cardiovascular mortality. It can be used in
combination with other oral agents and insulin.
 Adverse effects: Hypoglycemia occurs only when combined with
other agents. Rarely severe lactic acidosis is associated with
metformin use particularly in diabetics with CHF. Drug interactions
with cimetidine, furosemide, nifedipine have been identified.

These agents promote the release of insulin from β-cells;
tolbutamide, glyburide, glipizide and glimepiride.
 Mechanism:
◦ These agents require functioning β-cells, they stimulate release
by blocking ATP-sensitive K+ channels resulting in
depolarization with Ca2+ influx which promotes insulin secretion.
◦ They also reduce glucagon secretion and increase the binding of
insulin to target tissues.
◦ They may also increase the number of insulin receptors
 Pharmacokinetics: These agents bind to plasma proteins, are
metabolized in the liver and excreted by the liver or kidney.
Tolbutamide has the shortest duration of action (6-12 hrs) the
other agents are effective for ~24 hrs.

Adverse Effects: These agents tend to
cause weight gain, hyperinsulinemia and
hypopglycemia. Hepatic or renal
insufficiency causes accumulation of
these agents promoting the risk of
hypoglycemia.
Elderly patients appear particularly
susceptible to the toxicities of these
agents.
 Tolbutamide is asociated with a 2.5X ↑ in
cardiovascular mortality.
Onset and Duration
 Short acting: Tolbutamide (Orinase)
 Intermediate acting: Tolazamide
(Tolinase), Glipizide (Glucotrol), Glyburide
(Diabeta)
 Long acting: Chloropropamide,
Glimerpiride

These agents (repaglinide (Prandin) and nateglinide (Starlix)) act as
secretogogues.
 MECHANISM:
MOA is like sulfonylureas however their onset and duration of
action are much shorter. They are particularly effective at
mimicking the prandial and post-prandial release of insulin. When
used in combination with other oral agents they produce better
control than any monotherapy.
 PHARMACOKINETICS: These agents reach effective plasma levels
when taken 10-30 minutes before meals. These agents are
metabolized to inactive products by CYP3A4 and excreted in bile.
 ADVERSE EFFECTS: Less hypoglycemia than sulfonylureas; drugs
that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin, etc.)
prolong their duration of effect. Drugs that promote CYP3A4
(barbiturates, carbamazepine and rifampin) decrease their
effectiveness. The combination of gemfibrozil and repaglinide has
been reported to cause severe hypoglycemia.

Ø This enzyme hydrolyses
oligosaccharides to
monosaccharides which are then
absorbed.
Ø Acarbose also inhibits
pancreatic amylase.
Ø Use with other agents may
result in hypoglycemia. Sucrase
is also inhibited by these drugs.

Eg: Acarbose and miglitol are two agents of this class
used for type 2 diabetes.
Mechanism of action: These agents are oligosaccharide
derivatives taken at the beginning of a meal delay
carbohydrate digestion by competitively inhibiting α-
glucosidase, a membrane bound enzyme of the
intestinal brush border.
Pharmacokinetics: Acarbose is poorly absorbed
remaining in the intestinal lumen. Migitol is
absorbed and excreted by the kidney. Both agents
exert their effect in the intestinal lumen.
Adverse Effects: (flatulence, diarrhea, cramping).
Metformin bioavailability is severely decreased when
used concomitantly. These agents should not be used
in diabetics with intestinal pathology.

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 Incretins are a group of metabolic hormones that
stimulate a decrease in blood glucose levels.
 Incretins do so by causing
v an increase in the amount of insulin released from pancreatic
beta cells of the islets of Langerhans after eating, before blood
glucose levels become elevated.
v Slow the rate of absorption of nutrients into the blood stream by
reducing gastric emptying and may directly reduce food intake.
v Inhibit glucagon release from the alpha cells of the islets of
Langerhans.
The two main candidate molecules that fulfill criteria for an
incretin are the intestinal peptides glucagon/ like peptide 1
(GLP1) and gastric inhibitory peptide.
Both GLP/ 1 and GIP are rapidly inactivated by the enzyme
dipeptidyl peptidase4 (DPP4).
 A new class of oral hypoglycemics called dipeptidyl peptidase/ 4
inhibitors work by inhibiting the action of this enzyme, thereby
prolonging incretin effect in vivo.
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As first line therapy:
 Obese type 2 patients, consider use of metformin,
acarbose or TZD.
 Non/ obese type 2 patients, consider the use of
metformin or insulin secretagogues.
 Metformin is the drug of choice in overweight/obese
patients. TZDs and acarbose are acceptable alternatives
in those who are intolerant to metformin.
 If monotherapy fails, a combination of TZDs, acarbose
and metformin is recommended. If targets are still not
achieved, insulin secretagogues may be added.
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Combination oral agents is indicated in:
 Newly diagnosed symptomatic patients with
HbA1c =10
 Patients who are not reaching targets after
3 months on monotherapy
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 If targets have not been reached after optimal dose of
combination therapy for 3 months, consider adding
intermediate/ acting/long/ acting insulin.
 Combination of insulin+ oral anti/ diabetic agents has been
shown to improve glycaemic control in those not achieving
target despite maximal combination oral anti/ diabetic agents.
 Combining insulin and the following oral anti/ diabetic agents
has been shown to be effective in people with type 2 diabetes:
◦ Biguanide (metformin)
◦ Insulin secretagogues (sulphonylureas)
◦ Insulin sensitizers (TZDs)
◦ α/ glucosidase inhibitor (acarbose)
 Insulin dose can be increased until target FPG is achieved.
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Diabetes
Management
Algorithm
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Short- term use:
 Surgery, stress
 Pregnancy
 Breast/ feeding
 Insulin may be used as initial therapy in type 2 diabetes
 In marked hyperglycaemia
 Severe metabolic decompensation
Long- term use:
 If targets have not been reached after optimal dose of
combination therapy , consider change to multi/ dose
insulin therapy. When initiating this,insulin
secretagogues should be stopped and insulin sensitisers
e.g. Metformin or TZDs, can be continued.
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 Patients should be educated to practice self/
care. This allows the patient to assume
responsibility and control of his / her own
diabetes management. Self/ care should
include:
◦ Blood glucose monitoring
◦ Body weight monitoring
◦ Foot/ care
◦ Personal hygiene
◦ Healthy lifestyle/diet or physical activity
◦ Identify targets for control
◦ Stopping smoking
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Thank You
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1. Insuline and Anti diabetics

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