Tolbutamide is a first-generation short-acting sulfonylurea. It is indicated for the management of diabetes mellitus type 2 as an adjunct to diet and exercise. Compared to second-generation sulfonylurea, it is more hepatotoxic.

Tolbutamide Uses:

• Diabetes mellitus Type 2:

  • Supplement to diet for the treatment of type 2 diabetes.

Guideline recommendations:

• • For the treatment of type 2 diabetes, later-generation sulfonylureas with fewer hypoglycemia risks  (such as glipizide) are favoured over first-generation sulfonylureas like tolbutamide (ADA 2019).

Tolbutamide Dose in Adults

Tolbutamide Dose in the treatment of Diabetes mellitus Type 2:

P/O:

• Initial: 1-2 g/day as a single dose in the morning or in divided doses throughout the day.
• Maintenance dose: 0.25-3 g/day;
• however, a maintenance dose >2 g/day is seldom required.

Note: Divided doses may improve GI tolerance

Tolbutamide Dose in Childrens

Not recommended for use in children.

Pregnancy Risk Factor C

• Studies on animal reproduction have revealed that unfavourable outcomes are frequent.
• The placenta is crossed by tolbutamide. After maternal use during pregnancy, it can be found in the serum of newborn babies.
• Infants delivered to moms who used a sulfonylurea during labour have been noted to have a severe form of hypoglycemia.  It might last for four to ten days.
• There have been other reported negative outcomes, and these might potentially be connected to the maternal glycemic control.
• Low blood sugar can cause congenital malformations in women with diabetes.
• Preventing adverse outcomes by keeping maternal blood glucose and HbA as close as possible to the target levels before conception and throughout pregnancy is key. However, it should not cause significant hypoglycemia.
• Agents other than tolbutamide should be used for diabetes treatment in pregnant women.
• According to the manufacturer, tolbutamide should be stopped during pregnancy at least two weeks before delivery.

Use of tolbutamide while breastfeeding

• Breast milk contains tolbutamide.
• According to the manufacturer of the drug, low blood glucose could cause severe side effects in breastfeeding infants.
• This should be considered when deciding whether to stop breastfeeding or discontinue using the drug.

Tolbutamide Dose in Kidney Disease:

• The manufacturer's labeling does not include any dosage adjustments.
• It is recommended to use conservative doses for initial and ongoing maintenance.

HemodialysisNot dialyzable (0 to 5%).

Tolbutamide Dose in Liver disease:

• There are no dosage adjustments in the manufacturer's labeling.
• It is recommended to use conservative initial and maintenance doses, and to monitor your blood glucose carefully.

Side effects of Tolbutamide:

• Central Nervous System:

  • Disulfiram-Like Reaction
  • Headache

• Dermatologic:

  • Erythema
  • Pruritus
  • Morbilliform Rash
  • Skin Photosensitivity
  • Maculopapular Rash
  • Urticaria

• Endocrine & Metabolic:

  • Hepatic Porphyria
  • Porphyria Cutanea Tarda
  • Hyponatremia
  • Hypoglycemia
  • SIADH (Syndrome Of Inappropriate Antidiuretic Hormone Secretion)

• Gastrointestinal:

  • Dysgeusia
  • Heartburn
  • Epigastric Fullness
  • Nausea

• Hematologic & Oncologic:

  • Agranulocytosis
  • Thrombocytopenia
  • Hemolytic Anemia
  • Pancytopenia
  • Aplastic Anemia
  • Leukopenia

• Hepatic:

  • Cholestatic Jaundice

• Hypersensitivity:

  • Hypersensitivity Reaction

Contraindications to Tolbutamide:

• Intolerance to tolfonylureas, tolbutamide, or any other ingredient in the formulation
• Type 1 DM Treatment
• Diabetic ketoacidosis

Warnings and precautions

• Cardiovascular mortality

  • Oral hypoglycemic drugs may increase cardiovascular mortality as compared to treatment with diet and insulin, according to product labelling.
  • There are no data to support this relationship. A big prospective research (UKPDS) and several investigations, including those,  do not support the connection.
  • Atherosclerotic heart disease (ASCVD) patients are more likely to receive treatment with additional medications.

• Hypoglycemia

  • All sulfonylurea medications can cause severe hypoglycemia that could lead to death.
  • Hypoglycemia may occur more frequently with exercise or prolonged vigorous activity, with alcoholic consumption, or after using  many glucose-lowering medications.
  • Patients who are older, malnourished, or who have poor renal or hepatic function are more likely to experience it. 

• Allergy to sulfonamide ("sulfa")

  • Many drugs with sulfonamide chemical groups have wide contraindications for patients who have previously experienced an allergic reaction to sulfonamides, according to FDA-approved product labelling.
  • It is possible for members of a class to interact with one another (e.g., two antibiotics sulfonamides).
  • Crossreactivity issues have previously been brought up for all substances of the sulfonamide structural class (SO NH).
  • A fuller understanding of allergic pathways shows that it may not be possible for non-antibiotic or antibiotic sulfonamides to cross-react with each other.
  • Due to the formation of antibodies, non-antibiotic sulfonamides are unlikely to result in anaphylaxis (or mechanisms of cross-reaction).
  • Less is known about type IV T-cell reactions, such as maculopapular skin rash. Based on what is known at the moment,  it is difficult to rule out this possibility.
  • In situations where there are severe reactions (Stevens Johnson syndrome/TEN), some clinicians choose to avoid these classes.

• Bariatric surgery

  • Absorption altered:

    • Use immediate-release formulations to reduce potential negative effects from bypassing  the stomach or proximal bowel following surgery.
    • Following a gastric bypass or sleeve gastrectomy, ER formulations can change the release and absorption patterns  (but they do not affect the gastric band).

  • Hypoglycemia

    • Use an anti-hypoglycemic agent if possible.
    • Gastric band hypoglycemia, sleeve-gastrectomy, or gastric bypass may be possible.
    • These techniques may lead to a partial or complete recovery of insulin secretion and sensitivity. The gastric bypass,  followed by the sleeves, and then the band, is the most successful operation.
    • In the days after gastric bypass and Sleeve gastrectomy, first-phase insulin secretion  as well as hepatic insulin sensitivity considerably increased.
    • The healing effects of these treatments may not be recognised right away, often 3 to 12 months later.

  • Weight loss

    • Consider alternative therapies after gastric bypass, gastric banding, or sleeve-gastrectomy.
    • It is possible to gain weight.

  • Deficiency of Glucose-6phosphate dehydrogenase(G6PD) 

    • Patients with G6PD deficits may be more susceptible to hemolytic anaemia brought on by sulfonylureas.  Nevertheless, cases that have not yet been officially diagnosed as G6PD have been reported to patients during post-marketing surveillance.

    • Patients with G6PD deficiency should exercise caution and search for alternatives to sulfonylureas.

• Stress-related disorders:

  • If the patient experiences stressors like fever, trauma, illness, or surgery, they may need to stop getting therapy and start taking  insulin.

Tolbutamide: Drug Interaction

Monitoring parameters:

• Blood glucose
• Hemoglobin A (at least twice a year in patients with stable glycemic control and who are reaching their treatment objectives; every three months in patients who are not meeting their goals or require medication adjustment).
• Hypoglycemia symptoms and signs

How to administer Tolbutamide?

P/O:

•  The full dosage can be given in the morning.
• GI tolerance may be enhanced by divided dosages.

Mechanism of action of Tolbutamide:

• Induces insulin to be released from the pancreatic beta cells.
• The liver produces less glucose
• Peripheral target sites increase insulin sensitivity
• Glucagon suppression could potentially be beneficial.

The onset of action:

• 1 hour

Duration:

• Oral: 6-24 hours

Absorption:

• Oral: Rapid

Protein binding:

• ~95% (concentration-dependent)

Metabolism:

• Age does not appear to have an impact on the hepatic through CYP2C9 to hydroxymethyltolbutamide (mildly active) and carboxytolbutamide  (inactive) metabolism.
• Age does not appear to have an impact on the hepatic through CYP2C9 to hydroxymethyltolbutamide (mildly active) and carboxytolbutamide  (inactive) metabolism.

Half-life elimination:

• 4.5-6.5 hours (range: 4-25 hours)

Time to peak serum concentration:

• 3-4 hours

Excretion:

• Urine (75% to 85% primarily as metabolites)
• feces

International Brands of Tolbutamide:

• Aglycid
• Arcosal
• Artosin
• Asto
• Butamide
• Diaben
• Diabeton Metilato
• Diabetose
• Diatol
• Dirastan
• Dolipol
• Mellitos D
• Neobezeta
• Orabet
• Rastinon
• Tobumide
• Tolbutamid R.A.N.
• Tolmide
• Tolsiran
• Tolumide
• Tydadex

Tolbutamide Brand Names in Pakistan:

No Brands Available in Pakistan.