ORAL HYPOGLYCEMIC DRUGS

ORAL HYPOGLYCEMIC DRUGS

• Drugs may be classified into 2 groups based on MOA.

I) INSULIN SECRETAGOGUES:

• Secretes insulin. Hence, insulin secretagogues.
• Effective only if, 30% more of β-cells in pancreas.
• Drugs include sulfonylureas & meglitinides.
• Limitation – Causes hypoglycemia.

MOA:

• These drugs acting by insulin release.
• Drugs inhibit ATP sensitive K+ channels à Depolarization of β-cells à Insulin release.

A. Sulfonylureas

• Classified into 1^st generation & 2^nd generation.

 1^st generation:

• Chlorpropamide.
• Tolbutamide
• Tolazamide
• Acetohexamide

2^nd generation:

• Glibenclamide
• Glipizide
• Gliclazide
• Glimepiride

Important points on individual drugs: 

• 2^nd gen. drugs are more potent than 1^st gen. agents.
• Shortest acting sulfonylurea – Tolbutamide.
• Longest acting sulfonylurea – Chlorpropamide.
• All drugs can cause hypoglycemia (maximum with Chlorpropamide) & weight gain.
• Chlorpropamide – Cause dilutional hyponatremia (ADH like action), cholestatic jaundice & disulfiram-like-reaction (alcohol intolerance).
• Gliclazide – Additional anti-platelet action.
• Glimepiride exerts beneficial effects with ischemic pre-conditioning.  
  • Due to lower potency & shorter duration of action.
• Safety – Tolbutamide & glipizide (relatively safe in elderly patients & renal disease).
• Insulinotropic potency – Maximum – Glyburide (Glibenclamide); Least – Tolbutamide.

Glyburide –

• Half-life – 1-2 hours; Effect persists beyond 24 hrs.
• Persistent effect due to,
• Production of active metabolite.
• Binding to membrane receptor.
• Gets sequestered within β-cells of pancreas  – Distinguishing property of sulfonylurea.
• Among sulfonylureas, glimepiride decreases blood glucose at lowest dose.

B. Meglitinides:

• Similar mechanism releasing insulin.
• Drugs included – Nateglinide & repaglinide.
• Uses – For treatment of postprandial hyperglycemia (due to rapid onset & short duration of action).

Disadvantages – 

• Result in hypoglycemic episodes.
• Result in weight gain.

II. DRUGS ACTING BY OTHER MECHANISMS:

1. Biguanides:

• Metformin (main drug) & phenformin – Preferred for obese patients
• Are weight neutral.
• Improves hypertriglyceridemia in obese patients.

MOA:

• Decreases blood glucose by activating AMPK (Adenosine Mono Phosphate-activated protein kinase).

2 mode of action –

• Decreasing glucose production – By inhibiting gluconeogenesis & glycogenolysis.
• Increasing glucose utilization – By stimulation of glycolysis & tissue glucose uptake.
• Also inhibits intestinal glucose absorption.
• Reduced hepatic glucose production – By antagonizing glucagon’s ability to generate cAMP in Hepatocytes.

Drug actions:

Phenformin –

• Lactic acidosis – More likely in presence of hepatic & renal impairment or alcohol ingestion.

Metformin –

• Useful for polycystic ovarian disease (PCOD).  
• Only oral agent demonstrating reduce macrovascular events in type-2 DM.
• First-line therapy for type 2 diabetes & cause maximum reduction in HbA1C levels.

Disadvantages: 

• Megaloblastic anemia (due to vitamin B12 deficiency)
• Interferes with calcium-dependent vitamin B12 absorption-intrinsic factor complex in terminal ileum.
• Prevented by increased dietary calcium intake.

2. Thiazolidinediones:

• Drugs – Troglitazone, pioglitazone & rosiglitazone.

MOA: 

• Acts as agonists of nuclear receptor (peroxisome proliferator-activated receptor gamma (PPAR7).
• Regulates genes transcription involved in glucose & lipid metabolism.

Important genes regulated by PPARI are:

• Adiponectin
• Fatty acid transport protein.
• Insulin receptor substrate.
• GLUT-4

Uses: 

• Drugs are used to reverse insulin resistance in type II DM.

Disadvantages –

• Cause weight gain & edema.
• New onset or worsening of macular edema
• Increase in fracture risk in women
• Anemia
• Plasma volume expansion – Be avoided in CHF patients. (NYHA class III & IV).

Troglitazone – 

• Hepatotoxicity (More incidence).

Rosiglitazone – 

• Increases total & LDL cholesterol as well as HDL-cholesterol.

Pioglitazone – 

• Increases HDL cholesterol. Total & LDL-cholesterol remains unaffected.
• Increased risk of bladder cancer on long-term use.

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