oral antidiabetic agent

7/28/2019 Oral Antidiabetic Agent

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Oral Antidiabetic Agent


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Oral Antidiabetic Agent

Consist of :

1. Insulin secretagogues

- Sulfonilureas- Meglitinide

- D-Phenylalanine derivatives : Nateglinide

2. Biguanides

3. Thiazolidinediones

4.-glucosidase inhibitors


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Insulin SecretagoguesA. Sulfonilureas

1. Increase insulin release from the pancreas

2. Reduce serum glucagon levels3. Closure of potassium channels in extrapancreatic

tissues > unknown clinical significance


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Ad.1. Increase insulin release from the pancrears

- Sulfonilureas bind to high-afinity sulfonilureareceptor

- The receptor of sulfonilurea is associated with B cell

- Inhibits the eff lux of potassium ions through the

channel depolarization opens a voltage-gated calcium channel calcium influx release ofpreformed insulin.

Ad.2. Reduce serum glucagon levels

- Mechanism for this suppressive effect on glucagonlevels is unclear.

- Probably it is caused by indirect inhibition due toenhanced release of both insulin and somatostatin


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Classification of sulfonilureas1. 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 elderlydiabetic

- Several drugs : like dicumarol, phenylbutazone,some sulfonamides can inhibit the metabolism

of tolbutamide


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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 renalinsufficiency- 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 alcoholingestion in genetically predisposed patients,

dilutional hyponatremia, hematologictoxicity (transient leucopenia,thrombocytopenia)


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C. Tolazamide- More slowly absorbed than othersulfonilureas

- Half life is about 7 hours

- If more than 500 mg/d is required, the doseshould be divided and given twice daily


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2. Second-generation sulfonilureas

A. Glyburide- Metabolyzed in the liver into products with very lowhypoglycemic 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


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B. Glipizide

- Has the shortest half-life (2 4 hours)- Should be ingested 30 minutes beforebreakfast for maximum effect.

- The absorption is delayed when the drug is

taken with food- The starting dosage is 5 mg/d, with up to 15mg/d given as single dose.

- At least 90% of glipizide is metabolyzed in the

liver to inactive products, 10% is excretedunchanged in the urine.

- Contraindicated in patient with hepatic orrenal dysfunction.


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C. Glimepiride

- Approved for once daily use as monotherapy orin 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 ofany sulfonilureas compound.


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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 2diabetes.


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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


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C. D-PHENILALANINE DERIVATIVE

Nateglinide- Stimulates very rapid and transient release ofinsulin 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 incombination with nonsecretagogues oral agent(such as metformin)

- Dose titration is not required.


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- It is ingested just prior to meals

- It is absorbed within 20 minutes after oraladministration

- Time to peak concentration is less than 1 hour

- It is hepatically metabolized by Cyp2cg andCyP3A4

- 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


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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 gastrointestinaltract, with increased glucose to lactate conversion byenterocytes

Reduction of Plasma glucagon levels


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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 patientwith renal insufficiency


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Clinical Use of metformin- Indication :

a. Patient with hyperglycemia due toineffective insulin action like insulinresistence syndrome

b. Use in combination with insulin secretagones intype 2 diabetes with inadequate oral

monotherapy

- Effective in preventing new onset of type 2diabetics in midde aged.

Obese individual with impaired glucose tolerance


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- Dosage is from 500 mg to a maximum 0f 2.25 gdaily

A common schedule would be to begin with asingle 500 mg tablet given with breakfast for

several days

If this is tolerated without GI discomfort andhyperglycemia persist 500 mg tablet may be

added with evening meal.

- Dosage should always be divided

- Adverse effect : Gastrointestinal discomfort


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Contraindication :- Renal disease

- Alcoholism- Hepatic disease

- Condition Predisposing to tissue anoxia

(Chronic cardiopulmonary disfunction)


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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 activatedreceptor 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


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F. ALPHA GLUCOSIDASE INHIBITORS- Competitive inhibitors of the intestinal - glucosidases- Reduce postprandial digestion and absorption of starch and

disaccharides lowering postmeal glycemic excursions as muchas 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 willbe fermented into short chain fattyacids releosinggas), diarrhea, abdominal pain- Contraindication :

Inflammatory bowel disease

Any intestinal condition that could be worsened by gas anddistention Patient with renal impairment Patient with hepatic disease

- Dosage of AGI : 25 100 mg before meals


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oral antidiabetic agent

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