Usage
- Tolbutamide is an oral antidiabetic medication prescribed for the management of type 2 diabetes mellitus in adults. It is specifically indicated when hyperglycemia cannot be controlled by diet and exercise alone. It is not indicated for type 1 diabetes mellitus or diabetic ketoacidosis.
- Pharmacological Classification: Sulfonylurea, Antidiabetic Agent
- Mechanism of Action: Tolbutamide primarily stimulates the release of insulin from the beta cells of the pancreas. It may also increase peripheral tissue sensitivity to insulin and decrease hepatic glucose production.
Alternate Names
- While Tolbutamide is the generic name, a previously available brand name was Orinase. However, Orinase is discontinued in many countries. Note that availability of medications and brand names may vary regionally.
How It Works
- Pharmacodynamics: Tolbutamide’s primary effect is to lower blood glucose levels by promoting insulin release from the pancreatic beta cells. It binds to specific receptors on these cells, closing ATP-sensitive potassium channels, leading to depolarization and calcium influx. This triggers insulin secretion. Additional mechanisms may include increased peripheral insulin sensitivity and reduced hepatic glucose output.
- Pharmacokinetics:
- Absorption: Tolbutamide is well-absorbed from the gastrointestinal tract.
- Metabolism: Primarily metabolized in the liver to an inactive metabolite (carboxytolbutamide) by CYP2C9 enzymes.
- Elimination: Excreted mainly in the urine, with a small amount in feces. The elimination half-life is approximately 4-6 hours, but can be prolonged in patients with renal or hepatic impairment.
- Mode of Action: Binds to sulfonylurea receptors (SUR1) on pancreatic beta cells, ultimately leading to insulin secretion.
- Elimination Pathways: Primarily hepatic metabolism via CYP2C9 followed by renal excretion of the inactive metabolite.
Dosage
Standard Dosage
Adults:
- Initial: 1-2 g orally per day, as a single dose or divided doses.
- Maintenance: 0.25 - 2 g orally per day. Adjust based on blood glucose response.
- Maximum: Do not exceed 3 g per day.
Children:
- Not established. Tolbutamide is generally not recommended for use in children.
Special Cases:
- Elderly Patients – Start with a lower dose (e.g., 250 mg 1-3 times/day) and titrate cautiously to avoid hypoglycemia. The maximum dose in the elderly is also 3g/day.
- Patients with Renal Impairment – Use with caution. Reduce dosage based on the degree of impairment. Contraindicated in severe renal impairment.
- Patients with Hepatic Dysfunction – Use with caution. Reduce dosage based on the degree of impairment.
- Patients with Comorbid Conditions – Monitor closely, especially in patients with cardiovascular disease.
Clinical Use Cases
Tolbutamide does not have specific dosage recommendations for settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Insulin is typically preferred in these acute care settings.
Dosage Adjustments
- Adjust dosage based on patient response, renal function, and hepatic function. Titrate gradually to minimize the risk of hypoglycemia.
Side Effects
Common Side Effects
- Hypoglycemia
- Nausea
- Heartburn
- Epigastric fullness
- Headache
Rare but Serious Side Effects
- Jaundice (cholestatic)
- Blood dyscrasias (leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia)
- Hepatic dysfunction
- Disulfiram-like reaction with alcohol
- Hypoglycemia
Long-Term Effects
- Potential for secondary failure (loss of glycemic control over time).
Adverse Drug Reactions (ADR)
- Severe hypoglycemia, hepatic failure, blood dyscrasias.
Contraindications
- Hypersensitivity to tolbutamide or sulfonylureas.
- Type 1 diabetes.
- Diabetic ketoacidosis.
- Severe renal or hepatic impairment.
- Porphyria.
Drug Interactions
- Many drugs can interact with tolbutamide, including:
- NSAIDs (aspirin, ibuprofen)
- Sulfonamides (sulfamethoxazole)
- Anticoagulants (warfarin)
- Beta-blockers
- Alcohol (disulfiram-like reaction)
- Antifungals (miconazole, fluconazole)
- MAOIs
Consult a comprehensive drug interaction resource before co-prescribing.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (US FDA). Not recommended during pregnancy, particularly the first trimester. Insulin is typically preferred for managing diabetes during pregnancy. If used near term, discontinue at least two weeks before expected delivery to minimize the risk of neonatal hypoglycemia.
- Breastfeeding: Tolbutamide is excreted in breast milk. Breastfeeding is generally not recommended while taking this medication. Consider the risks and benefits, and if tolbutamide is essential, closely monitor the infant for signs of hypoglycemia.
Drug Profile Summary
- Mechanism of Action: Stimulates insulin release from pancreatic beta cells; may enhance peripheral insulin sensitivity and reduce hepatic glucose output.
- Side Effects: Hypoglycemia, nausea, heartburn, headache, rash, jaundice, blood dyscrasias.
- Contraindications: Type 1 diabetes, diabetic ketoacidosis, severe renal/hepatic impairment, hypersensitivity to sulfonylureas.
- Drug Interactions: Numerous; consult drug interaction resources.
- Pregnancy & Breastfeeding: Generally avoided.
- Dosage: Adults: 1-2 g/day initially; 0.25-2g/day maintenance, max 3g/day. Adjust based on patient response.
- Monitoring Parameters: Blood glucose, HbA1c, liver function tests (periodically).
Popular Combinations
- Tolbutamide is not typically used in combination with other oral hypoglycemic agents. However, it may have been used in combination with metformin in the past. It is essential to consult up-to-date clinical guidelines as treatment recommendations evolve.
Precautions
- General Precautions: Renal and hepatic function monitoring, blood glucose monitoring. Careful selection of patients is critical, especially in the elderly.
- Specific Populations: Avoid or use with extreme caution in patients with hepatic or renal dysfunction. In older adults, start with a lower dose and titrate cautiously. Avoid in pregnancy and breastfeeding.
- Lifestyle Considerations: Dietary adherence and regular exercise are essential components of diabetes management.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tolbutamide?
A: The initial dose is 1-2 g daily, adjusted based on blood glucose response. Maintenance dose is 0.25 - 2 g daily, not to exceed 3 g daily. Elderly patients should start with a lower dose.
Q2: What are the common side effects of Tolbutamide?
A: Common side effects include hypoglycemia, gastrointestinal upset (nausea, heartburn, and epigastric fullness), headache, and skin reactions.
Q3: Is Tolbutamide safe to use during pregnancy?
A: Tolbutamide is generally not recommended during pregnancy, especially in the first trimester. Insulin is usually preferred.
Q4: Can Tolbutamide be used in patients with type 1 diabetes?
A: No, Tolbutamide is contraindicated in patients with type 1 diabetes. It is only indicated for type 2 diabetes.
Q5: How does Tolbutamide interact with alcohol?
A: Alcohol can potentiate the hypoglycemic effects of Tolbutamide and may also cause a disulfiram-like reaction (flushing, headache, nausea, vomiting).
Q6: What are the signs of Tolbutamide overdose?
A: Overdose primarily manifests as hypoglycemia (weakness, dizziness, confusion, sweating, tachycardia).
Q7: What should be done if a patient experiences hypoglycemia while taking Tolbutamide?
A: If conscious, administer oral glucose (e.g., glucose tablets, juice). If unconscious, intravenous glucose or glucagon may be necessary.
Q8: What are the contraindications to using Tolbutamide?
A: Contraindications include hypersensitivity to tolbutamide or sulfonylureas, type 1 diabetes, diabetic ketoacidosis, severe renal or hepatic impairment, and porphyria.
Q9: Can Tolbutamide be used with other oral antidiabetic medications?
A: Tolbutamide is not generally combined with other sulfonylureas. While historic practices may have involved combinations like metformin and tolbutamide, current guidelines should be consulted.
Q10: How does renal impairment affect Tolbutamide dosage?
A: Reduce the dosage in patients with renal impairment, as the drug and/or its metabolites may accumulate. Contraindicated in severe renal disease.
