Oral Hypoglycemic Drugs

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 1st generation & 2nd generation.
  • 1st generation:
    • Chlorpropamide.
    • Tolbutamide
    • Tolazamide
    • Acetohexamide
  • 2nd generation:
    • Glibenclamide
    • Glipizide
    • Gliclazide
    • Glimepiride

Important points on individual drugs: 

  • 2nd gen. drugs are more potent than 1st 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).
  • GliclazideAdditional 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.

Exam Important

ORAL HYPOGLYCEMIC DRUGS

  • Insulin secretagogues – Drugs include sulfonylureas & meglitinides.
  • 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.
  • Tolbutamide & glipizide are relatively safe in elderly patients & renal disease.
  • Insulinotropic potency – Maximum – Glyburide (Glibenclamide); Least – Tolbutamide.
  • Glyburide 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.
  • Meglitinides drugs included – Nateglinide & repaglinide.
    • Uses – For treatment of postprandial hyperglycemia (due to rapid onset & short duration of action).
    • Disadvantages – Result in hypoglycemic episodes & weight gain.
  • Biguanides-
    • Decreases blood glucose by activating AMPK (Adenosine Mono Phosphate-activated protein kinase).
  • 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.
  • 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
3. Thiazolidinediones:
  • Thiazolidinediones used to reverse insulin resistance in type II DM.
  • Drugs – Troglitazone, pioglitazone & rosiglitazone.
  • MOA: Acts as agonists of nuclear receptor (peroxisome proliferator-activated receptor gamma (PPAR7).
  • 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. 
    • Increased risk of bladder cancer on long-term use.

 

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