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 voltagegated 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-) - 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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