Oral Antidiabetic Agent

Oral Antidiabetic Agent

Consist of :
1. Insulin secretagogues
- Sulfonilureas
- Meglitinide
- D-Phenylalanine derivatives : Nateglinide
2.Biguanides
3. Thiazolidinediones
4.-glucosidase inhibitors
Insulin Secretagogues
A. Sulfonilureas
1. Increase insulin release from the pancreas
2. Reduce serum glucagon levels
3. Closure of potassium channels in extrapancreatic
tissues > unknown clinical significance
Ad.1. Increase insulin release from the pancrears
- Sulfonilureas bind to high-afinity sulfonilurea
receptor
- The receptor of sulfonilurea is associated with B cell
- Inhibits the efflux of potassium ions through the
channel  depolarization  opens a voltage-gated
calcium channel  calcium influx  release of
preformed insulin.
Ad.2. Reduce serum glucagon levels
- Mechanism for this suppressive effect on glucagon
levels is unclear.
- Probably it is caused by indirect inhibition due to
enhanced release of both insulin and somatostatin
Classification of sulfonilureas
1. First generation of sulfonilureas
A. Tolbutamide
- Well absorbed
- Rapidly metabolized in the liver
- Its durations of effect is relatively short
- Elimination half-life is 4 – 5 hours
- Administered in divided doses
- The safest sulfonilurea for use in elderly diabetic
- Several drugs : like dicumarol, phenylbutazone,
some sulfonamides can inhibit the metabolism of
tolbutamide
B. Chlorpropamide
- Half life is 32 hours
- Slowly metabolized in the liver
- Approximately 20 – 30% is excreted unchanged in the
urine
- Interact with drugs that depend on hepatic oxidative
catabolism.
- Contra indicated in patients with hepatic or renal
insufficiency
- Dosages in excess of 500 mg daily increase the risk of
jaundice
- Prolonged hypoglycemic reactions are more common
in elderly patients (contraindication)
- Side effects are : hyperemic flush after alcohol
ingestion in genetically predisposed patients,
dilutional hyponatremia, hematologic toxicity
(transient leucopenia, thrombocytopenia)
C. Tolazamide
- More slowly absorbed than other
sulfonilureas
- Half life is about 7 hours
- If more than 500 mg/d is required, the dose
should be divided and given twice daily
2. Second-generation sulfonilureas
A. Glyburide
- Metabolyzed in the liver into products with very low
hypoglycemic activity
- The usual starting dosage is 2,5 mg/d or less
- The average maintenance dosage is 5 – 10 mg/d given as a
single morning dose
- Maintenance dosage higher than 20 mg/d are not
recommended
- A formulation of “micronized” glyburide is available in a
variety of tablet sizes
- Adverse effect : Flushing after ethanol ingestion (rarely)
- Contraindicated in the presence of hepatic impairment
and renal insufficiency
B. Glipizide
- Has the shortest half-life (2 – 4 hours)
- Should be ingested 30 minutes before
breakfast  for maximum effect.
- The absorption is delayed when the drug is
taken with food
- The starting dosage is 5 mg/d, with up to 15
mg/d given as single dose.
- At least 90% of glipizide is metabolyzed in
the liver to inactive products, 10% is excreted
unchanged in the urine.
- Contraindicated in patient with hepatic or
renal dysfunction.
C. Glimepiride
- Approved for once daily use as monotherapy
or in combination with insulin
- Maximal daily dose is 8 mg
- Half-life is 5 hours, long duration of effect
- Metabolyzed in liver
- Reduce blood glucose with the lowest dose of
any sulfonilureas compound.
Secondary Failure of Sulfonilureas
- A progressive decrease in B cell mass
- Reduction in physical activity
- Decline in lean body mass
- Increase in ectopic fat deposition in chronic types 2
diabetes.
B. Meglitinide
- A new class of insulin secretagoues
- Repaglinide
 Has a very fast onset of action ± 1 hours
 Duration of action is 5 – 8 hours
 It is hepatically cleared by CYP3A4
 Half – life is 1 hour
 Indicated for use in controlling post prandial
glucose excursions
 Should be taken just before each meal in doses of
0,25 – 4 mg (maximum, 16 mg/d)
 Repaglinide is approved as monotherapy or in
combination with biguanides
 May be used in type 2 diabetic with sulfur or
sulfonilureas allergy
C. D-PHENILALANINE DERIVATIVE
Nateglinide
- Stimulates very rapid and transient release of
insulin from B cells
- It partially restores initial insulin release in reponse
to IV glucose tolerance test
- Indicated in patient with isolated post prandial
hyperglycemia
- Minimal effect on overnight or fasting glucose level
- It is efficacious when given alone or in combination
with nonsecretagogues oral agent (such as
metformin)
- Dose titration is not required.
- It is ingested just prior to meals
- It is absorbed within 20 minutes after oral
administration
- Time to peak concentration is less than 1
hour
- It is hepatically metabolized by Cyp2cg and
CyP3A4
- Half life is 1.5 hours
- The overall duration of action is less than 4
hours
- Has the advantage of being safe in individual
with very reduced renal function
- Incidence of hypoglycemia is the lowest
D. BIGUANIDES
- Structure of metformin is shown below

- Mechanism of action
 Direct stimulation of glycolysis in tissues with
increased glucose removal from blood
 Reduced hepatic and renal gluconeogenesis
 Slowing of glucose absorption from the gastrointestinal
tract, with increased glucose to lactate conversion by
enterocytes
 Reduction of Plasma glucagon levels
Metabolisme and Excretion of metformin
- Half – life is 1,5 – 3 hours
- It is not bound to Plasma protein
- It is not metabolized
- Metformin is excreted by the kidneys as the
active compound
- May impair the hepatic metabolism of lactic
acid
- May increase the risk of lactic acidosis in patient
with renal insufficiency
Clinical Use of metformin
- Indication :
a. Patient with hyperglycemia due to ineffective
insulin action like insulin resistence syndrome
b. Use in combination with insulin secretagones in
type 2 diabetes with inadequate oral monotherapy
- Effective in preventing new onset of type 2
diabetics in midde aged.
 Obese individual with impaired glucose tolerance
- Dosage is from 500 mg to a maximum 0f 2.25 g
daily
 A common schedule would be to begin with
a single 500 mg tablet given with breakfast for
several days
 If this is tolerated without GI discomfort and
hyperglycemia persist → 500 mg tablet may be
added with evening meal.
- Dosage should always be divided
- Adverse effect : Gastrointestinal discomfort
Contraindication :
- Renal disease
- Alcoholism
- Hepatic disease
- Condition Predisposing to tissue anoxia
(Chronic cardiopulmonary disfunction)
E. THIAZOLIDINEDIONES
- Decrease insulin resistance
- Major site of Tzd action is adipose tissue
- Regulates adiposity apoptosis and differentiation
- Two Tzd are : Pioglitazone and Rosiglitazone
- Mechanism of action involves gene regulation
- Tzds are ligands of peroxisome proliferator – activated
receptor gamma (PPAR-γ)
- Long term therapy is associated with a drop of Tryglyceride
level and a slight rise in HDL and LDL levels
- Adverse effect is :
 Fluid retention
 mild anemia
 peripheral edema (combination with insulin / insulin
secretagogues)
 Hepatotoxic
F. ALPHA GLUCOSIDASE INHIBITORS
- Competitive inhibitors of the intestinal - glucosidases
- Reduce postprandial digestion and absorption of starch and
disaccharides → lowering postmeal glycemic excursions as
much as 45 - 60 mg / dll
- Consist of Acarbose and Miglitol
- Therapy should be initiated with the lowest dose ; slowly titrated
upward
- Adverse effect : flatulence (because undigested carbohydrate will
be fermented into short chain fattyacids releosing gas),
diarrhea, abdominal pain
- Contraindication :
 Inflammatory bowel disease
 Any intestinal condition that could be worsened by gas and
distention
 Patient with renal impairment
 Patient with hepatic disease
- Dosage of AGI : 25 – 100 mg before meals
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