2. What is the Purpose of
Antidiabetic & Hypoglycemic
Agents?
• Treat Diabetes
• Lower Blood Sugar
3. Diabetes Mellitus :
a group of diseases characterized by high levels of blood glucose resulting from
defects in insulin production, insulin action, or both
• 20.8 million in US ( 7% of population)
• estimated 14.6 million diagnosed (only 2/3)
• Consists of 3 types:
1) Type 1 diabetes
2) Type 2 diabetes
3) Gestational diabetes
Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage
4. Diabetes Mellitus
• Type 1 Diabetes
- cells that produce insulin are
destroyed
- results in insulin dependence
- commonly detected before 30
• Type 2 Diabetes
- blood glucose levels rise due to
1) Lack of insulin
production
2) Insufficient insulin
action (resistant cells)
- commonly detected after 40
- effects > 90%
- eventually leads to β-cell failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US develop
gestational diabetes
6. Macrovascular Microvascular
Stroke
Heart disease and
hypertension
2-4 X increased risk
Foot problems
Diabetic eye disease
(retinopathy and cataracts)
Renal disease
Peripheral Neuropathy
Peripheral
vascular disease
Diabetes: Complications
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
Complications
Erectile Dysfunction
7.
8. Diabetes Mellitus
2. Hyperglycemia leads to
• a. Polyuria (hyperglycemia acts as osmotic diuretic)
• b. Polydipsia (thirst from dehydration from polyuria)
• c. Polyphagia (hunger and eats more since cell cannot
utilize glucose)
• d. Weight loss (body breaking down fat and protein to
restore energy source
• e. Malaise and fatigue (from decrease in energy)
• f. Blurred vision (swelling of lenses from osmotic effects)
12. Insulin affects many organs:
• It stimulates skeletal muscle fibers.
• It stimulates liver cells.
• It acts on fat cells
• It inhibits production of certain
enzyme.
In each case, insulin triggers
these effects by binding to the
insulin receptor.
glucose
uptake
glycogen
synthesis
protein
synthesis
amino acids
uptake
enzyme
production
glycogen
breaking
fat
synthesis
13. Glucagon Action on Cells:
Dominates in Fasting State Metabolism
Figure 21-14: Endocrine response to hypoglycemia
17. Sulfonylureas : stimulate β cells to produce more
insulin
• 1st generation
– (1)Orinase (tolbutamide)
– (3)Tolinase (tolazamide)
– (6)Diabinese (chlorpropamide)
2nd generation
– (75)Glucotrol (glipizide)
– (150)Glucotrol XL (ex. rel. glipizide)
– (150)Micronase, Diabeta (glyburide)
– (250)Glynase (micronized glyburide)
3rd generation
– (350)Amaryl (glimepiride)
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)
was used in treatment of typhoid fever in 1940’s hypoglycemia
Currently > 12,000
Rel.
Potency
bind
to
protein
may become dislodged delayed activity
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity
18. Mechanism of Action
• Sulfonylureas interact with receptors on
pancreatic b-cells to block ATP-sensitive
potassium channels
• This, in turn, leads to opening of calcium
channels
• Which leads to the production of insulin
19. Biguanides : improves insulin’s ability to move glucose
into cells (esp. muscle)
• Metformin
- Glucophage®, Fortamet®,
Riomet®
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with
diabetes (UKPDS 1998).
- Metformin was first described in the scientific literature in 1957 (Unger et al).
- It was first marketed in France in 1979 but did not receive FDA approval for Type
2 diabetes until 1994.
N
N
N
N
N
R
R R
R
R
R
R
N N
N
N
N
H
H
H
H H
+ HCl
- mechanism improves insulin sensitivity by increasing peripheral glucose
uptake and utilization.
- Zhou et al (2001) showed that metformin stimulates the hepatic enzyme
AMP-activated protein kinase
Metformin is a widely used monotherapy, and also used in combination with
the sulfonylureas in treatment of type 2 diabetes
20. Thiazolidinediones (TZD’s) :make cells more
sensitive to insulin (esp. fatty cells)
• Pioglitazone
- Actos®, Avandia®
- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ).
- PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue,
cardiac and skeletal muscle, liver and placenta
PPAR - γ
- upon activation of this nuclear receptor by a ligand such as a TZD,
PPARγ–ligand complex binds to a specific region of DNA and thereby
regulates the transcription of many genes involved in glucose and fatty
acid metabolism.
S
NH
O
O
O
N
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
- Marketed in USA in August of 1999
21.
22. Αlpha – glycosidase inhibitors :
Block enzymes that help digest starches slowing the rise in
B.G.L.
• AGI’s
- Precose ® (acarbose),
- Glyset ® (miglitol)
N
O
O
O
O
O
H
H H
H H
1-(2-Hydroxy-ethyl)-2-hydroxymethyl-
piperidine-3,4,5-triol
