Glibenclamide

1. Drug Name

• Generic Name: Glibenclamide (also Glyburide)

• Brand Names: Diabeta, Glynase, Micronase, Gliben, and others.

2. Drug Classification

• Class: Antidiabetic Agent

• Subclass: Sulfonylurea

3. Mechanism of Action

Glibenclamide is an oral hypoglycemic agent that belongs to the sulfonylurea class. It works primarily by stimulating insulin secretion from the pancreatic β-cells. The drug binds to the sulfonylurea receptor (SUR1) on the ATP-sensitive potassium channels (K_ATP) on β-cells of the pancreas. This binding inhibits the efflux of potassium ions, leading to membrane depolarization. This depolarization opens voltage-gated calcium channels, resulting in an influx of calcium ions, which triggers insulin release from the pancreas.

In addition to its effects on insulin release, glibenclamide may also increase the sensitivity of peripheral tissues to insulin and may reduce hepatic glucose production, though the primary mechanism is through increased insulin secretion.

4. Pharmacokinetics

• Absorption: Glibenclamide is rapidly absorbed from the gastrointestinal tract following oral administration. The bioavailability is approximately 100%. It has a peak plasma concentration within 2–4 hours of administration.

• Distribution: The drug is extensively bound to plasma proteins (approximately 95–99%). It is widely distributed in the body, including in the liver and pancreas, where its action is most relevant.

• Metabolism: Glibenclamide is primarily metabolized in the liver by CYP2C9 enzymes to inactive metabolites. Its metabolism is relatively predictable, and dose adjustments may not be necessary in individuals with normal liver function.

• Excretion: The half-life of glibenclamide is approximately 10 hours. The drug and its metabolites are excreted primarily via urine, with a smaller amount excreted in the feces.

• Special Considerations:

  • Renal Impairment: Glibenclamide should be used cautiously in patients with renal impairment, as accumulation of the drug or its metabolites may occur.

  • Hepatic Impairment: Dosage adjustments may be needed in hepatic impairment due to reduced clearance.

5. Indications

• Primary Indication:

  • Type 2 Diabetes Mellitus: Glibenclamide is used as an adjunct to diet and exercise to lower blood glucose levels in patients with type 2 diabetes. It is effective in patients who are unable to control blood sugar with lifestyle changes alone.

• Off-label Uses:

  • Occasionally used in combination therapy with other antidiabetic agents, such as metformin, to control blood sugar levels more effectively.

6. Dosage and Administration

• Adult Dosing:

  • Initial Dose: The usual starting dose is 2.5–5 mg orally once daily with breakfast.

  • Maintenance Dose: The dose can be gradually increased, based on clinical response, typically in increments of 2.5 mg per day. The typical maintenance dose ranges from 5 to 15 mg per day.

  • Maximum Dose: The maximum daily dose is 20 mg.

• Pediatric Dosing: Not typically recommended in children due to a lack of sufficient data.

• Renal or Hepatic Impairment: Start at lower doses and adjust based on blood glucose response and renal function.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to sulfonylureas or glibenclamide.

  • Type 1 diabetes mellitus (where insulin is typically required for survival).

  • Diabetic ketoacidosis (DKA).

• Relative Contraindications:

  • Severe renal or hepatic dysfunction (adjustments required).

  • Pregnancy (use only if clearly needed, as glibenclamide may cross the placenta).

  • Lactation (use with caution, as it may be excreted in breast milk).

8. Warnings and Precautions

• Hypoglycemia: The most common and serious risk with glibenclamide is hypoglycemia, especially in elderly patients, those with renal or hepatic dysfunction, or those who miss meals or exercise excessively. Monitoring blood glucose levels is essential.

• Cardiovascular Risk: Use cautiously in patients with a history of cardiovascular disease, as hypoglycemia could exacerbate such conditions.

• Weight Gain: Sulfonylureas like glibenclamide can cause weight gain due to increased insulin secretion.

• Pregnancy: Category C in pregnancy. Animal studies have shown adverse effects, and there is insufficient evidence of safety in human pregnancy. Use only if the benefit outweighs the risk.

• Lactation: Glibenclamide is excreted in breast milk, and its use in lactating women is not recommended unless absolutely necessary.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Hypoglycemia (low blood sugar).

  • Weight gain.

• Less Common but Clinically Significant Side Effects:

  • Nausea, vomiting, and dyspepsia.

  • Abdominal pain.

  • Headache.

  • Dizziness.

• Rare/Serious Adverse Reactions:

  • Severe hypoglycemia (potentially leading to coma or death).

  • Allergic reactions (e.g., rash, pruritus, and rare cases of anaphylaxis).

  • Hepatotoxicity (rare).

  • Blood dyscrasias such as thrombocytopenia, leukopenia, and aplastic anemia.

10. Drug Interactions

• Major Drug Interactions:

  • Anticoagulants (e.g., warfarin): Concomitant use may increase the risk of bleeding and potentiate the effects of warfarin.

  • Beta-blockers: Beta-blockers can mask the symptoms of hypoglycemia and may enhance the effects of glibenclamide.

  • Corticosteroids: Corticosteroids may raise blood glucose levels and may reduce the effectiveness of glibenclamide.

  • Alcohol: Alcohol can exacerbate the hypoglycemic effects of glibenclamide, especially if consumed on an empty stomach.

  • Other Antidiabetic Agents: When combined with other antidiabetic drugs (e.g., metformin), the risk of hypoglycemia increases.

11. Clinical Pharmacology

• Pharmacodynamics: Glibenclamide's action is primarily through increased insulin secretion by inhibiting K_ATP channels, thus enhancing the body's ability to process glucose. It is effective at lowering fasting plasma glucose levels and postprandial glucose spikes.

• Additional Pharmacological Effects: Although it predominantly increases insulin release, glibenclamide may also enhance peripheral insulin sensitivity.

12. Special Populations

• Pregnancy: Category C. The use of glibenclamide during pregnancy is not recommended unless necessary. Insulin is typically preferred during pregnancy due to better control of blood glucose levels.

• Lactation: Glibenclamide is excreted in breast milk. Its use during lactation should be avoided, as the potential risks to the infant are not fully understood.

• Elderly: The elderly population is more prone to hypoglycemia due to age-related changes in renal and hepatic function, thus lower starting doses may be necessary.

• Renal or Hepatic Impairment: Use cautiously in patients with renal or hepatic dysfunction. Consider alternative therapies if renal or hepatic dysfunction is severe.

13. Therapeutic Uses

• Type 2 Diabetes Mellitus: Glibenclamide is used for controlling blood sugar levels in type 2 diabetes, especially when diet and exercise alone are insufficient.

• Combination Therapy: It can be used in combination with other oral hypoglycemic agents or insulin for better blood sugar control in patients who require multiple medications.

14. Monitoring and Follow-Up

• Blood Glucose Levels: Regular monitoring of blood glucose is necessary, especially during dose adjustments or when initiating therapy.

• Renal and Hepatic Function: Periodic assessment of renal and liver function is recommended, particularly in elderly patients and those with preexisting liver or kidney disease.

• Hemoglobin A1c: Regular measurement of A1c helps assess the overall effectiveness of therapy.

• Hypoglycemia: Patients should be educated on recognizing signs of hypoglycemia (e.g., dizziness, sweating, confusion) and should be advised to carry glucose tablets.

15. Overdose Management

• Symptoms of Overdose: The primary risk of overdose is severe hypoglycemia. Symptoms include sweating, tremors, confusion, dizziness, and in extreme cases, loss of consciousness or seizures.

• Treatment Protocols:

  • Mild Overdose: Oral glucose or other carbohydrates may be sufficient to reverse mild hypoglycemia.

  • Severe Overdose: If severe hypoglycemia occurs, intravenous dextrose (glucose) should be administered. Glucagon may also be used if intravenous access is not available.

  • Supportive Care: Hospitalization may be required for monitoring in more severe cases.

16. Patient Counseling Information

• Key Points to Discuss:

  • Instruct patients to take glibenclamide exactly as prescribed, preferably with breakfast to minimize the risk of hypoglycemia.

  • Advise patients to monitor blood glucose levels regularly, especially during exercise, illness, or periods of dietary changes.

  • Educate patients about recognizing and treating hypoglycemia, including the need to carry fast-acting carbohydrates (e.g., glucose tablets).

• Important Lifestyle Recommendations:

  • Emphasize the importance of maintaining a balanced diet and regular exercise to optimize blood sugar control.

  • Patients should avoid alcohol, or if consumed, it should be taken with food to prevent hypoglycemia.