Oral Anti Diabetic Drugs

Sulfonylureas

Ist Generation

• Tolbutamide
• Acetohexamide
• Chlorpropamide

2nd Generation

• Glibenclamide (glyburide)
• Glipizide
• Glimepiride

Meglitinide

• Repaglinide

D-Phenyl alanine Derivative

• Nateglinide

Biguanide

• Metformin

Alpha Glucosidase Inhibitor

• Acarbose

Thiazolidinedione Derivatives

• Rosiglitazone
• Pioglitazone
• Troglitazone

Dipeptidyl Peptidase 4 Inhibitors

• Sitagliptin
• Pramlintide
• Exenatide              

Sulfonyl Ureas

Chemically derivatives of sulfonamides. Divided into two main groups:

1st generation	2nd generation
Older drugs	Newer drugs
Less potent	100 times potent

Mechanism of action

Also known as insulin secretogoug.

1. Mainly act by causing increased secretion of insulin from beta cells of pancreas by binding receptors on surface of beta cells.
2. Also cause increased sensitivity of tissues to insulin
3. Also cause decrease in release of glucagon.
4. Cause decrease in gluconeogenesis
5. Increase in number of insulin receptors

Ineffective in type I diabetes mellitus, requiring up to 30% of beta cells to be intact for action.

Cause a decrease in conductance of ATP sensitive potassium channels à decreased conductance leads to increase in positivity inside cells à leading to depolarization resulting in à increased entry of calcium through calcium channels à increased release of insulin from beta cells.

Pharmacokinetics

• Well absorbed after oral administration.
• Extensively bound to plasma proteins, maximum is for Glibenclamide, while Chlorpropamide has the least.
• Half life varies. 1^st generation drugs have short half life (4-7 hours) and short duration of action. Chlorpropamide has long half life of 36 hours (longest in 1^st generation). Acetohexamide has active metabolite having same half life (4-7 hours)
• Second generation compounds have shorter half life of 1.5-5 hours, but have longer duration of action than 1^st generation compounds, which may be due to active metabolites formed. Since more potent, usually given once daily.
• Most drugs are metabolized in liver and excreted in urine. Chlorpropamide is 20% excreted unchanged in urine. Glipizide and Tolbutamide are mainly excreted through bile and less through urine.

Adverse Effects (4%)

1. Hypoglycemia

More with drugs with longer half life including Chlorpropamide and Glibenclamide, in renal insufficiency, especially in elderly. Treatment is same:

• Glucose by mouth
• I/V

2. Cholestatic jaundice

Since metabolized in liver, hepatotoxicity might occur.

3. Agranulocytosis

Blood dyscrasias

4. Anaemia (hemolytic and aplastic)

Alcohol intolerance

In presence of alcohol, there are more chances of hypoglycemia

1. Allergic reactions

Drugs Interaction Of Sulphonylureas

1. Alcohol

• Hypoglycemia
• Chlorpropamide can cause disulfiram like reaction with alcohol

2. Enzyme inducers
3. Enzyme inhibitors à hypoglycemia
4. Chlorpropamide potentiates the effects of ADH on collecting tubules, also used in treatment of diabetes insipidus.

Interacting drugs	Type of interaction	Result
Thiazides	Antagonism	Diminished effect of sulphonylureas
Rifampicin	Enhanced metabolism of sulphonylureas	Diminished effect of sulphonylureas
Aspirin Sulfonamides	Displacement of sulphonylureas from plasma proteins	Enhanced effect of suophonylureas
Chloramphenicol Dicoumarol	Decreased metabolism of sulphonylureas	Enhanced effect of suophonylureas

Preparations and dosage of Sulphonylureas

Tolbutamide:

Initial dose is 500 mg while 3000 mg is max. effective dose.

Acetohexamide:

250 -1500 mg

Tolazamide and Chlorpropamide:

Initially 100-250 mg while 750 to 1000 mg is maximal.

Glyburide:

Initial daily dose 2.5 -5 mg. maximum range is 20 mg

Glipzide: Initially 5 mg. Max is 40 mg in divided doses

Gliclazide: Initially 40 – 80 mg and max is 320 mg

Meglitinide

• Repaglinide
• Nateglinide

Have same mechanism of action and effects as sulfonyl ureas, but differ from others in:

1. Rapid onset of action
2. Short duration
3. Are metabolized in liver, excreted in bile, thus can be given in renal insufficiency
4. Cause less incidence of hypoglycemia as compared with sulfonyl ureas (shorter duration of action).

Nateglinide may cause severe hypoglycemia.

Sulfonyl ureas are not given in obese patients as cause increased apetite, these drugs cause less increase in weight thus can be given

Dose

Ranges between 0.5-4 mg twice or thrice daily depending upon severity.

Biguanides

Chemically are guanidine derivative. Most of these are withdrawn due to adverse effects including lactic acidosis. Only one drug, Metformin is used.

Mechanism of action

Although does not cause release of insulin, but for action of oral antidiabetic should be so. Mainly act by:

1. Suppress hepatic gluconeogenesis, preventing hepatic outflow of glucose as liver is mostly responsible, especially during night time.
2. Stimulate glycolysis leading to breakdown of glucose
3. Inhibit absorption of glucose from intestine

• Require some endogenous insulin secretion
• Do not cause hypoglycemia
• Reduce hyperlipidemia
• Loss of appetite

Pharmacokinetics

• After oral administration, less rapidly absorbed.
• Not metabolized.
• PPB is very insignificant.
• Mainly excreted in urine, mostly unchanged.
• Metformin t ½ 1.5 – 3 hrs
• Duration of action 8-12 hrs

Uses

1. Mainly used in treatment of type II diabetes mellitus, in combination with sulfonyl ureas and insulin. Can also be used alone.
2. Also used in polycystic ovarian syndrome (drug causes decrease in insulin, resistance leading to ovulation in these women)

Adverse effects

1. Mainly GIT effects:
   • GIT upset
   • Diarrhea
   • Abdominal discomfort
   • Sometimes so severe that patient may leave drug
   • Lactic acidosis –more common in patients of renal insufficiency, in alcoholics.

   Contraindications

1. Renal disease –as cause lactic acidosis
2. Pregnancy
3. Lactation
4. Severe infections

Cause increases in HDL and decrease in LDL, beneficial for patients of cardiac diseases. Effects are over after 4-6 weeks of treatment.

Dose: start at low dose of 0.5 g, can be increased to 0.85 g tid or 1 g thrice or twice daily.

Metformin does not cause hypoglycemia, as there is no release of insulin.

Alpha Glucoside Inhibitor

Acarbose

Mechanism of action

1. Inhibit alpha-glucosidase in intestinal brush border
2. Inhibit hydrolysis of oligosaccharides to glucose
3. Also inhibits pancreatic alpha-amylase, responsible for converting starch into oligosaccharides.

Ultimately causes decrease in conversion into glucose.

Pharmacokinetics

• Not absorbed from intestine when given orally, only a small amount is absorbed, excreted unchanged in urine.
• Most of drug is broken down by bacteria in intestines.
• Duration of action 3-4 hrs

Dose:25-100mg bid or tid

Adverse effects

1. Does not cause hypoglycemia when given alone
2. GIT –as not absorbed, may cause:
   • GIT upsets
   • Flatulence
   • Diarrhea
   • Abdominal cramps

Contraindications

Mainly in patients suffering from GIT disease, may lead to ulceration or intestinal obstruction.

Drug interactions

Also inhibit or decrease absorption of metformine so not given in combination.

Thiazolidinediones or Glitazones

Rosiglitazone, Troglitazone withdrawn due to adverse effects. Only Pioglitazone is available.

Mechanism of action

Also known as insulin sensitizers as increase sensitivity of tissues to insulin.

1. Mainly act by binding peroxisome proliferator activated receptor-g (PPAR-g), which is a nuclear receptor mainly concerned with regulation of glucose of lipids.
2. bind receptors leading to increase utilization of glucose
3. • Increased HDL levels, decrease in breakdown of fats
   • Expansion of S/C fat

   Thus, increased insulin sensitivity to tissues.

Pharmacokinetics

• Well absorbed after oral administration.
• Have extensive PPB.
• Mainly metabolized in liver
• Pioglitazone also has active metabolites, which are excreted in urine.
• Some parent drug is also excreted in bile, so drug can be given in renal insufficiency.
• Duration of action 12-24 hrs

Used for polycystic ovarian syndrome

Adverse effects

1. All drugs are hepatotoxic, Troglitazone has been withdrawn due to hepatotoxic effects. Thus all patients should have regular LFTs.
2. Rosiglitazone causes increase in LDL levels so drug is withdrawn from market (cardiovascular disease)
3. Retention of sodium and water
4. Increase in subcutaneous fat (increase in weight), used carefully in cardiovascular diseases.

Dose: Pioglitazone: 15-30mg o.d

Dipeptidyl Peptidase Inhibitors

Pramlintide & Exenatide

GLIP stands for glucagon like peptide. Pfzmlintide and Exenatide act through GLIIP enzyme.

Mechanism of action

Normally when patient takes glucose by mouth, increase in release of insulin occurs. Release is more when taken orally than I/V. this effect is said to be due to GLIP.

In diabetics, decrease in release of insulin in response to glucose occurs.

These drugs cause increase in activity of GLIP, so improve insulin release in response to glucose.

• Slow gastric emptying
• Decrease food intake
• Increase glucose suppression of glucagon secretion
• Promote beta cell regeneration
• Decrease apoptosis
• Reduce weight gain, postprandial hyperglycemia & loss of beta cells

Drawbacks

1. Main drawback is that since they are peptides, they cannot be given orally. They are usually given parentally.
2. Have short duration of action

So not in practice, only long acting drugs may have some benefits.

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Diabetes Mellitus and Insulin