Oral Antidiabetic Agent

Consist of :
1. Insulin secretagogues
- Sulfonilureas,
- Meglitinide
- D-Phenylalanine devtatives : 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 sulfonelurea
receptor
- The receptor of sulfenilurea 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 gulcagon
levels in 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 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 exreted 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 (contraindicated)
- Side effects are : hyperemic flush after alcohol ingestion
in genetically predisposed patients, dilutional
hyponatremia, hematologic toxicity (transient
leucopania, 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
- Adverses effect : Flushing after ethanol ingestion (rarely)
- Contraindicated in the presence of hepatic impairment
and renal insufficienaj
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 any
sulfonilureas compound.
Secondary Failure of Sulfonilureas
- A progresive decrease in B cell mass
- Reduction in physical activity
- Decline in lean body mass
- Increase in ectopic fat deposition in chroniz types
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 biguanedes
May be used in type 2 diabetic with sulfur or
sulfonolureas allergy
C. D-PHENILALANINE DERIVATIVE
Natiglinide
- Stimulates very rapid and transient release of
insulin from B cells
- It partially restores initial insulin release in reponse
to IV glucose tolerance test
- Indocated in patient with isolated post prandial
hyperglycemia
- Minimal effect or fasting glucose level
- It is efficaciores when given a lone 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 glucosed 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 metabolisme of lactic acid
- May increase the risk of lactic acidosis in patient
with renal insufficiency
Clinical Use of metformin
- Indication : Patient with hyperglycemia due to
ineffective insulin action like insulin resistence
syndrome
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 07 2,25 gr
daily
A cuman 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
Kontraindication :
- Renal disease
- Alcoholism
- Hepatic disease
- Condition Predisposing to tissue anoxia
(Chronic cardiopulmonary disfunction)
E. THIAZOLIDINEDIONES
- Decrease insulin resistance
- Major site of T2d action is adipose tissue
- Regulates adiposity apoptosis and differentiation
- Two T2d ate : Pioglitazone and Rosiglitazone
- Mechanism of action involves gene regulation
- t2ds are legends of peroxisome proliferators activated
receptor gamma (PPAR-Y)
- Long term therapy is associated with a drop of Tryglyceride
level and a slight rise in HDL and LDL valves
- 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 initeated with the lowest dose ; slowly titrated
upward
- adverse effect : flatulence, diarrhea, abdominal pain
(because undigested carbohydrate will be
fermented into short chain fattyacids releosing gas)
- Contraindication :
inflammatory bowel disease
Any intestinal condition that could be worsened by gas and
distention
Pasien with renal impairment
Dosage of AGI : 25 100 mg before meals