Transcript Insulin and drugs us..

Diabetes Mellitus
 The word Diabetes is applied to condition of excessive hunger.
 The other symptoms of Diabetes Mellitus are;
 weigh loss
 Hyperglycemia
 altered metabolism of lipids, carbohydrates, and proteins
 an increased risk of complications from vascular disease.
Clinical Diabetes Mellitus
1-Type 1 Diabetes: - known as insulin-dependant Diabetes Mellitus
(IDDM) is caused by an absolute deficiency of insulin.
 This
results
from
immune-system-mediated
destruction
of
pancreatic β-cells.
 Without insulin, the body's primary source of energy and the
brain's only source of energy, glucose, is unable to enter the
cells. This leads to cells being energy starved as well as
elevated plasma blood glucose levels.
 Administration of exogenous insulin currently is the only
method to effectively resolve this hormone deficiency.
Clinical Diabetes Mellitus
2-Type 2 Diabetes: - known as non-insulin-dependant Diabetes
Mellitus (NDDM).
 Type 2 diabetes is a more complex disease. If one parent has type
2 diabetes, the risk of developing it is 38%, whereas if both
parents are affected then, the risk of developing diabetes before
age 60 is 60%.
 It is characterized by end-organ insulin resistance and/or a relative
deficiency in insulin secretion. Unlike the abrupt loss of β-cell
function characteristic of type 1 diabetes, the pancreatic β cells in
type 2 diabetes undergo progressive deterioration over a fairly
long time.
Clinical Diabetes Mellitus
2-Type 2 Diabetes: - known as non-insulin-dependant Diabetes
Mellitus (NDDM).
 At this point, blood glucose levels likely appear normal and the
patient is asymptomatic.
 For most patients with type 2 diabetes, resolution of their
metabolic disease may occur with appropriate lifestyle changes,
including a well balanced diet and regular exercise.
 For those type 2 patients who are unable to achieve normal blood
glucose levels, several classes of oral agents are available that
target various biochemical processes associated with insulin
secretion and/or insulin receptor sensitivity
Clinical Diabetes Mellitus
3-Gestational Diabetes
 It is classified as any degree of glucose-intolerance that first
occurs during pregnancy, typically during the third trimester.
 The risk factors associated with developing GDM include previous
history of GDM, obesity, glycosuria, or a family history that
includes diabetes.
Structure activity relationship
1. There must be a reasonable bulk group on the urea nitrogen;
methyl and ethyl compound are not active.
2. There is only one (normally para substituent) on the sulfonyl
aromatic ring.
3. Many substituents are active, and the p-(β-arylcarboxamidoethyl)
grouping seen in the second generation compounds is consistent
with a high potency.
4. The spatial relationship between the amide nitrogen of the
substituent and the sulfonamide nitrogen is important.
Mechanism of action
 They stimulate the release of insulin; they interact with receptors
on pancreatic β-cells to block ATP-sensitive potassium channels.
This in turn leads to opening of calcium channels which produce
an influx of calcium resulting in β-cells production of insulin.
 These drugs are effective in patients with type 2 diabetes whose
insulin-secreting capacity is intact but whose ability to produce
adequate insulin in the presence of elevated glucose has been
lost.
 They can cause hypoglycemia, because these drugs can stimulate
insulin secretion even when glucose levels are low.
Members of 1st generation sulfonylureas
Members of 1st generation sulfonylureas
Metabolism
Members of 1st generation sulfonylureas
Metabolism
 Chloropropamide undergoes slow hydroxylation on the propyl
chain to afford 2’ and 3’-hydroxy chloropropamide. Because
these processes are slow, chloropropamide is a long lasting
drug.
Members of 2nd generation sulfonylureas
Members of 2nd generation sulfonylureas
Metabolism
Members of 2nd generation sulfonylureas
Metabolism
Repaglinide
 Repaglinide is a nonsulfonylurea that binds and block the
 ATP-sensitive K+channels, resulting in insulin secretion from βcells in addition to having extrapanereatic effects
 Repaglinide has a rapid onset and short duration of action
compared to other hypoglycemic drugs.
Repaglinide
 It is not associated with the prolonged hyperinsulinemia seen with
the sulfonylureas, and possibly for this reason, it produces fewer
side effects, including weight gain and potentially dangerous
hypoglycemia.
 Repaglinide is at least five fold more potent than glyburide on
intravenous administration and nearly 10-fold more active on oral
administration.
Metformin and phenoformin
Mechanism of Action
 Metformin and the other biguanides are described as insulin
sensitizers; they act in the liver by decreasing excessive, glucose
production, most likely via reduced gluconeogenesis resulting from
an increased sensitivity to insulin.
 They
also
improve
glucose
utilization
by
restoring
tissue
sensitivity to insulin
 They appear to have their main action in the liver mitochondria via
activation of adenosine 5'-monophosphate-activated protein kinase
(AMPK)
Metformin and phenoformin
Mechanism of Action
 Metformin can lower free fatty acid concentrations by 10 to 30%.
 The therapeutic effect of metformin requires the presence of
insulin, and metformin does not stimulate the release of insulin or
other factors, such as glucagon.
 The drug does not induce hypoglycemia at any reasonable dose.
For
that
reason,
metformine
is
usually
said
antihyperglycemic rather than a hypoglycemic agent.
to
be
an
4- Thiazolidinediones (Glitazones)
4- Thiazolidinediones (Glitazones)
4- Thiazolidinediones (Glitazones)
 Like
bignanides,
thiazolidinediones
are
insulin
sensitizers;
however, they have a different mechanism of action from that of
the biguanides.
 The thiazolidincdiones stimulate peroxisome proliferator-activated
receptor (PPAR)-γ stimulation, leading to the transcription of
insulin-sensitive genes and, subsequently, a wide variety of
actions including increases in:
 glucose uptake (adipose, muscle, liver)
 lipogenesis (adipose, liver)
 fatly acid uptake and preadipocyte differentiation (adipose),
and glycolysis and glucose oxidation (muscle)
 In
addition
to
decreases
in
gluconeogenesis,
glycogenolysis (liver).
 The PPAR-γ expression is highest in adipose tissue.
and
4- Thiazolidinediones (Glitazones)
Metabolism
4- Thiazolidinediones (Glitazones)
Metabolism
4- Thiazolidinediones (Glitazones)
Metabolism
5- Dual PPARα and PPARγ
Coactivators
 Because of weight gain can occur as an undesirable effect,a
drug that activated both PPARα and PPARγ may be less prone to this
side effect because of promotion of fatty acid oxidation.
 Activation of PPARα also is reported to reduce plasma triglyceride
levels and to increase high-density lipoprotein levels; these are
very desirable actions for the populations prone to type 2 diabetes.
5- Dual PPARα and PPARγ
Coactivators
Muraglitazar and Tesaglitazar
 Clinical
trials
muraglitazar,
demonstrated
and
it
is
the
intended
expected
as
a
benefits
monotherapy
or
for
in
combination with metformin.
 Some concerns from the trials, however, is an increase, compared
to placebo, in serious cardiovascular events, including death,
myocardial infarction and congestive heart failure.
5- Dual PPARα and PPARγ
Coactivators
Muraglitazar and Tesaglitazar
6-α-glucosidase inhibitors
 To be absorbed from the gastrointestinal tract into the blood
stream, the complex carbohydrates we ingest as a part of our diet
must first be hydrolyzed to monosaccharides by α-glucosidase
enzyme.
 The rationale for the α-glucosidase inhibitors is that by preventing
the hydrolysis of carbohydrate their absorption could be reduced.
 The oligosaccharidases responsible for final hydrolysis of these
materials are all located in the brush border of the small intestine
and consist of two classes:
 1-The β-galaclosidases hydrolyze β-disaccharides, such as lactose,
 2- α-glucosidases act on α-disaccharides, such as maltose,
isomaltose, and sucrose
6-α-glucosidase inhibitors
Structure activity relationship
 Active α-glucosidase inhibitors have a common pharmacophore,
comprising a substituted cyclohexane ring and 4.6-dideoxy-4-
amine-D-glucose unit known as carvosine.
 The secondary amino group of this structure prevents an essential
carboxyl
group
of
the
α-glucosidase
glycosidic oxygen bonds of the substrate.
from
protonating
the
Acarbose (Precose)
 Acarbose competitvely inhibits glucoamylase and sucrase but has
weak effects on pancreatic α-amylase.
Voglibose
 It slows the release of monosacharides from polymeric materials,
and thereby lowers the glucose level.
Rimonabant
 Obesity is a major factor leading to type-2 diabetes. As such,
effective treatment of obesity may prevent or slow the onset of
diabetes.
 Researchers hypothesized that if cannabinoids stimulate appetite
in a receptor-specific fashion, then blocking, central cannabinoid
receptors might lead to decreased appetite.

Rimonabant
 Rimonabant was found to be a selective and potent antagonist of
CB1 endocannabinoid receptor.
 Rimonabant was found to be a selective and potent antagonist of
the
receptor
and
its
administration
led
to
the
consumption of fats and sugar, resulting in weight loses
decreased