1. Insuline and Anti diabetics

Diabetes and antidiabetics

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

2. 
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
.
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2

3. 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

3
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4. 
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
.
4
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5. 5
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6. 
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
.
6
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7. 7
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8. 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
8
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9. 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
.
9
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11. 11
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12. 12
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13. 13
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14. 
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 various
Prevalence of Diabetes in various
regions of world WHO
regions of world WHO
Report(Geneva)1997
Report(Geneva)1997
14
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16. 16

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
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17. Type
1
Diabetes

Mellitus

Type
2
Diabetes

Mellitus
Gestational

Diabetes
Other

types
:
17
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18. 
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.
18
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19. 
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.
19
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20. Cells

of

pancreas
Glands

of

pancreas
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21. 21
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22. 22
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23. 
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
.
23
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24. 
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
.
24
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25. 
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
2
1/2

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
.
25
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26. 
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
.
26
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27. Management

of

Diabetes

Mellitus
27
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28. 
The

major

components

of

the

treatment

of

diabetes

are
:
28
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29. 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
29
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30. 
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
.
30
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31. 
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
)
31
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33. 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.

34. 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 Ca
2+
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.

35. 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
2.5
X

↑

in

cardiovascular

mortality
.
Onset

and

Duration

Short

acting
:
Tolbutamide
(
Orinase
)

Intermediate

acting
:
Tolazamide

(
Tolinase
),
Glipizide
(
Glucotrol
),
Glyburide

(
Diabeta
)

Long

acting
:
Chloropropamide
,
Glimerpiride

36. 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
.

37. 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
.

38. 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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40. 
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
(
GLP
1)
and

gastric

inhibitory

peptide
.

Both

GLP
/
1
and

GIP

are

rapidly

inactivated

by

the

enzyme
dipeptidyl

peptidase
4 (
DPP
4).

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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41. COMPILED

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42. 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
.
42
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43. Combination

oral

agents

is

indicated

in
:

Newly

diagnosed

symptomatic

patients

with

HbA
1
c

=
10

Patients

who

are

not

reaching

targets

after

3
months

on

monotherapy
43
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44. 
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
.
44
COMPILED

BY
:
PROF
.
ANWAR

BAIG

(
AIKTC
,
SOP
)

45. Diabetes

Management

Algorithm

45
COMPILED

BY
:
PROF
.
ANWAR

BAIG

(
AIKTC
,
SOP
)

46. 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
.
46
COMPILED

BY
:
PROF
.
ANWAR

BAIG

(
AIKTC
,
SOP
)

47. 
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
47
COMPILED

BY
:
PROF
.
ANWAR

BAIG

(
AIKTC
,
SOP
)

48. Thank

You
48
COMPILED

BY
:
PROF
.
ANWAR

BAIG

(
AIKTC
,
SOP
)