diabetes mellitus the word diabetes is applied to condition of excessive hunger. the other...
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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 Mellitus2-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
R
O
S
O
NH
NH
R-
O
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
Tolbutamide (Orinase)
H3C
O
S
O
NH
NH
C4H9
O
Cl
O
S
O
NH
NH
C3H7
O
Chloropropamide (Diabinese)
H3C
O
S
O
NH
NH
N
O
Acetohexamide (Dymelor)
H3C
O
S
O
NH
NH
N
O
Tolazamide (Tolinase)
Members of 1st generation sulfonylureas
Metabolism
H3C
O
S
O
NH
NH
R
O
H3C
O
S
O
NH
NH
N
O
HOOC
O
S
O
NH
NH
R
O
HOH2C
O
S
O
NH
NH
R
O
Active
Inactive4-Hydroxy tolazamide(Active)
OH
Tolbutamide or tolazamide
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.
Ar NH
NH
CH2CH2CH2
O
Ar NH
NH
CH2CHCH3
O OH
OH
Chloropropamide
Members of 2nd generation sulfonylureas
O
S
O
NH
NH
OHN
O
Glyburide or glibenclamide (Diabeta)
Cl
OCH3
O
S
O
NH
NH
OHN
O
N
N
H3C
Glipizide (Glucotrol)
O
S
O
NH
NH
OHN
O
Glimepiride (Amaryl)
H3C
C2H5
O
CH3
Members of 2nd generation sulfonylureas
Metabolism
R
O
S
O
NH
NH
O
R
O
S
O
NH
NH
O
R
O
S
O
NH
NH
O
(H2C)2
O
S
O
NH
NH
ONH
H3C
O
Glyburide or Glibizide
OH
Trans-4'-metabolite Cis-3'-metabolite
OH
+
Members of 2nd generation sulfonylureas
Metabolism O
S
O
NH
NH
OHN
NH3C
H3CH2C O
CH3
O
O
S
O
NH
NH
O
CH2OH
O
S
O
NH
NH
O
COOH
R
R
Active
Inactive
Repaglinide
O CH3HN
N
OCOOH
CH3
H3C
Repaglinide
Repaglinide is a nonsulfonylurea that binds and block the
ATP-sensitive K+channels, resulting in insulin secretion from β-cells in
addition to having extrapanereatic effects
Repaglinide has a rapid onset and short duration of action compared to
other hypoglycemic drugs.
Repaglinide
O CH3HN
N
OCOOH
CH3
H3C
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
NH
NH
NH2
NH NH
H3CN N
HNH2
NH NH
CH3
Phenoformin Metformin (Glucophage)
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
NH
NH
NH2
NH NH
H3CN N
HNH2
NH NH
CH3
Phenoformin Metformin (Glucophage)
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 to be an antihyperglycemic rather
than a hypoglycemic agent.
4- Thiazolidinediones (Glitazones)
SNH
O
OO
H3C
Ciglitazone
SNH
O
OO
N
CH3
N
Rosiglitazone (Avandia)
4- Thiazolidinediones (Glitazones)
SNH
O
OO
O
CH3
HO
H3C
CH3
CH3
Troglitazone (Rezuli)
SNH
O
OON
H3C
Pioglitazone (Actos)
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, and glycogenolysis
(liver).
The PPAR-γ expression is highest in adipose tissue.
4- Thiazolidinediones (Glitazones)Metabolism
SNH
O
OO
O
CH3
HO
H3C
CH3
CH3
Troglitazone (Rezuli)
R
O
CH3
HO3SO
H3C
CH3
CH3
R
O
CH2OH
HO3SO
H3C
CH3
CH3
R
O
CH3
Glucuronide-O
H3C
CH3
CH3
SNH
O
OO
O
CH3
O
H3C
CH3
CH3
HO
4- Thiazolidinediones (Glitazones)Metabolism
SNH
O
OON
H3C
Pioglitazone (Actos)
ON
H3C
ON
H3C
RR
OH O
ON
H3C
R
ON
HOOC
RON
HOOC
R
OH
Taurine conjugate
Glucuronide conjugate
Sulfate conjugate
4- Thiazolidinediones (Glitazones)Metabolism
SNH
O
OO
N
CH3
N
Rosiglitazone (Avandia)
ON
CH3
NO
N
H
NR R
OH
ON
H
NR
OH
Sulfate conjugate Sulfate conjugateGlucuronide conjugate
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 demonstrated the expected benefits for muraglitazar, and
it is intended as a monotherapy or 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
O
N
CH3
O
N
COOH
O
O OCH3
Muraglitazar
OS
H3C
OO
O
O
COOH
Tesaglitazar
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 hydrol ysis 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 from protonating the glycosidic
oxygen bonds of the substrate.
Acarbose (Precose)
O
O
O
H3C
OOH
HO
HN
HO
CH2OH
OHO
HOOH
OH
CH2OH
OH
OH
HOHO
Acarbose (Precose)
Carvosine
Acarbose competitvely inhibits glucoamylase and sucrase but has weak
effects on pancreatic α-amylase.
Voglibose
OH
OHHO
HO HN
OH
OH
HO
Voglibose (Basan)
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.
Cl
Cl
N
N
CH3
Cl
O
NH
N
Rimonabant (Acomplia)
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 decreased consumption of fats
and sugar, resulting in weight loses
Cl
Cl
N
N
CH3
Cl
O
NH
N
Rimonabant (Acomplia)
