Tolbutamide

Tolbutamide is an Anti-diabetic Agent belonging to the pharmacological class of first-generation sulfonylureas.

Tolbutamide is approved for treating type 2 diabetes mellitus in adults and works by stimulating the pancreas to release more insulin, helping to reduce blood sugar levels in those individuals with type 2 diabetes.

Tolbutamine is rapidly absorbed by the mouth, reaching peak plasma levels in three to five hours. Its main distribution sites are the liver and the plasma, where it regulates insulin release. The medication is primarily metabolized in the liver and excreted in urine and faeces.

Tolbutamide's most common side effects include low blood glucose levels (hypoglycemia), headache, nausea, and dizziness.

Tolbutamide is available in the form of oral Tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Brazil, South Africa, Germany and Australia.

Tolbutamide is an Anti-diabetic Agent belonging to the pharmacological class of first-generation sulfonylureas.

By directly stimulating the acute release of insulin from functional beta cells of the pancreatic islet tissue, sulfonylureas lower blood glucose in individuals with non-insulin-dependent diabetic diabetes mellitus (NIDDM). This method is unclear and requires a sulfonylurea receptor (receptor 1) on the beta cell. A comparable action to that of glucose is produced by sulfonylureas, which block potassium efflux and ATP-potassium channels on the beta cell membrane. This leads to calcium influx and depolarization, calcium-calmodulin binding, kinase activation, and the release of insulin-containing granules through exocytosis.

Tolbutamide is available in oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

• Type 2 Diabetes: The primary treatment for type 2 diabetes is Tolbutamide. It works by encouraging the pancreas to release more insulin. It lowers blood sugar levels.
• Adjunct to Diet and Exercise: It should be used when dietary and exercise modifications alone cannot regulate blood sugar levels.
• Glycemic Control: By helping to maintain glycemic control, Tolbutamide lowers the risk of complications connected to diabetes, including kidney problems, nerve damage, and cardiovascular problems.

In Treatment of Type 2 diabetes mellitus

Tolbutamide helps increase the amount of insulin your body produces (in the pancreas). It works by boosting the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of developing any significant consequences of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

When a patient has type 2 diabetes, which is not dependent on insulin and whose hyperglycemia cannot be managed with diet alone, it is indicated as an adjunct to reduce blood glucose levels.

Orally: Tolbutamide is available as a tablet that can be taken orally. Tolbutamide should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 500 mg

Tolbutamide is available in the form of Oral Tablets

Dose Adjustment in Adult Patients:

Type 2 Diabetes

250 mg–2 g PO per day or every 8–12 hours; not to exceed 3 g daily; maintenance doses more than 2 g daily are infrequently necessary.

Separate dosages could reduce adverse effects on the gastrointestinal tract.

Tolbutamide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

Taking Tolbutamide before or with meals is advised, as it enhances insulin release when glucose levels rise after eating. And also to eat meals at regular intervals and avoid skipping meals to help stabilize blood sugar levels.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation, causing hypoglycemia (low blood sugar).

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages, as they can lead to blood sugar spikes.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Tolbutamide may be contraindicated in the following conditions:-

• Hypersensitivity or allergy to the medication is reported.
• Diabetic ketoacidosis, either in a coma or not. Insulin should be used to treat the disease.
• Diabetes type I is a single treatment.

When a patient's caloric intake is reduced or their stress level is elevated due to an infection, fever, trauma, or surgery, they may need to stop their therapy for hypoglycemia.

When using oral hypoglycemic medications instead of diet alone or with insulin, the risk of cardiovascular death rises.

Individuals lacking in glucose-6-phosphate dehydrogenase may be more susceptible to hemolytic anaemia brought on by sulfonylureas.

It is unsafe to consume Tolbutamide with alcohol.

There is no sufficient scientific evidence regarding the use and safety of Tolbutamide in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.

Increase intake of fibre-rich foods and minimize the carbohydrate or sugary intake.

The adverse reactions related to Tolbutamide can be categorized as

• Common Adverse Effects: Hypoglycemia (low blood sugar), nausea, weight gain, digestive issues (e.g., diarrhoea, abdominal discomfort)
• Less Common Adverse Effects: Skin reactions (e.g., photosensitivity, rashes), Mental/mood changes (e.g., anxiety, depression), and visual disturbances.
• Rare Adverse Effects: Allergic reactions (e.g., rash, itching, swelling), Liver problems (rare, but may affect liver function), blood disorders (e.g., low blood cell levels)

The clinically relevant drug interactions of Tolbutamide are briefly summarized here:

• Potentiating Hypoglycemia: There is a higher risk of hypoglycemia (low blood sugar) when certain medications, such as insulin, other sulfonylureas, and other anti-diabetic treatments, are taken together.
• Alcohol: When alcohol and Tolbutamide are used together, there may be a disulfiram-like reaction that results in flushing of the face, nausea, and vomiting.
• Cimetidine: Cimetidine is an ulcer and heartburn drug that might raise blood levels of Tolbutamide, which may cause hypoglycemia.
• Some Antibiotics: Certain antibiotics, such as sulfa medications, may alter tolbutamide metabolism and raise the possibility of hypoglycemia.
• Warfarin: Warfarin is an anticoagulant, and Tolbutamide may interact with it to change its anticoagulant properties.
• Phenytoin: Phenytoin is an antiepileptic medication that may change how well tolbutamide works, necessitating dosage changes.
• Beta-Blockers: Some beta-blockers may mask hypoglycemia's symptoms, making it more challenging to diagnose and manage.
• Miconazole: There have been reports of a possible severe hypoglycemia-causing interaction between oral miconazole and oral hypoglycemic medications.

The most common side effects of Tolbutamide include:

• Hypoglycemia
• Nausea
• Weight gain
• Digestive issues
• Allergic reactions
• Skin reactions
• Liver problems
• Blood disorders
• Visual disturbances
• Mental/mood changes.

• Pregnancy

Effects of Teratogenicity: Pregnancy Category C: Use caution if the benefits outweigh the risks.

Tolbutamide has been demonstrated to be teratogenic in rats at doses 25–100 times higher than those recommended for humans. High doses of Tolbutamide administered to pregnant rats have been shown in certain studies to cause ophthalmic and bone abnormalities and increase offspring mortality. Subsequent research on rabbits and other species has not shown any teratogenic effects. There isn't enough reliable research on expectant mothers. It is not advised to treat pregnant diabetic patients with Tolbutamide.

The potential risks associated with tolbutamide use in women who are or may become pregnant while taking the medication should also be carefully considered.

Insulin is often recommended during pregnancy to maintain the blood glucose levels as close to normal as possible. New research indicates that aberrant blood glucose levels during pregnancy are associated to a higher incidence of congenital disabilities.

Non-Teratogenic Effects

There have been cases of neonates born to mothers on sulfonylurea medication at delivery experiencing prolonged severe hypoglycemia (four to ten days). With the use of agents with extended half-lives, this has been documented increasingly frequently. Two weeks or more before the anticipated delivery date, tolbutamide use should end if it is used during pregnancy.

• Nursing Mothers

Tolbutamide excretion in human milk is unknown, but several sulfonylurea medications are known to pass via the breast milk system. Considering the significance of the drug to the mother, a choice should be taken, either stopping the medication or stopping breastfeeding, because there is a chance that nursing babies will experience hypoglycemia. Consider insulin therapy if the drug is stopped and diet alone is not sufficient to regulate blood glucose.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

• Geriatrics

In geriatric populations (older individuals), the safety and efficacy of Tolbutamide, a sulfonylurea drug used to treat type 2 diabetes, have not been thoroughly investigated. Because of changes in metabolism associated with ageing, older people are more vulnerable to the risk of hypoglycemia (low blood sugar) when using this medication. As such, cautious dosing and close monitoring are necessary.

Dosage adjustment in geriatric patients

250 mg PO per day or every 8 to 12 hours; maximum dose of 3 g/day; seldom needed for maintenance if the amount exceeds two g/day

Divided dosages could reduce adverse effects on the gastrointestinal tract.

Dose Adjustment in Kidney Impairment Patient:

There are no specific dosage adjustments provided.

Dose Adjustment in Hepatic Impairment Patients:

Maybe less of a dose is needed (monitor)

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Tolbutamide.

Overconsumption of Tolbutamide may lead to hypoglycemia (low blood sugar) symptoms, including excessive sweating, dizziness, confusion, palpitations, shaking, and, in severe cases, loss of consciousness, seizures, and coma.

Management

There is no specific antidote or treatment for excessive intake of Tolbutamide. However, immediate medical attention is essential. Tolbutamide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Mild episodes of hypoglycemia can be treated with oral glucose, whereas severe hypoglycemia with seizure, coma, or neurological impairment can be treated with glucagon or intravenous (IV) glucose. In Severe hypoglycemic reactions, hospitalization may be necessary to monitor and treat the individual until their blood sugar levels are stable.

Management typically involves supportive measures such as providing IV fluids and maintaining airway and ventilation, which may be required for symptomatic treatment. The patient will also be continued to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

Pharmacodynamics

Patients with diabetes mellitus type 2 can lower their blood glucose levels using Tolbutamide, a first-generation sulfonylurea anti-diabetic medication, in conjunction with diet. Glipizide, a comparable second-generation agent, has half the potency of Tolbutamide. Tolbutamide decreases blood sugar by promoting insulin secretion from the pancreas and facilitating the body's effective use of insulin. This medication cannot function if the pancreas is unable to make insulin.

Pharmacokinetics

Absorption

Tolbutamide is rapidly absorbed after oral intake. Detectable in the bloodstream within 30-60 minutes after a single oral dose, it reaches peak concentrations in 3-5 hours. Absorption remains consistent with or without food, but high pH levels can enhance it.

Half-Life: 4.5-6.5 hr

Duration: 6-24 hr

Onset: 1hr

Max Effect: 5-8 hr

Time to peak, serum: 3-4 hr

Distribution

Tolbutamide is distributed all over the body but is remarkably like the liver and blood plasma. Its distribution allows it to stimulate the release of insulin, which helps manage diabetes.

Protein Bound: 80-99%

Vd: 0.15 L/kg

Metabolism

The primary method by which it is broken down in the liver is by oxidizing the p-methyl group, which results in the carboxyl metabolite 1-butyl-3-p-carboxyphenylsulfonylurea. It has the potential to be converted into hydroxytolbutamide during metabolism. Because it lacks a p-amino group, Tolbutamide is not acetylated like antibacterial sulfonamides.

Metabolites: carboxytolbutamide, hydroxymethyl tolbutamide (inactive); metabolites by hepatic P450 enzyme CYP2C9

Excretion

Urine and faeces are where unchanged drugs and metabolites are removed. In 24 hours, 75–85% of a single oral dosage is eliminated through the urine, primarily as 1-butyl-3-p-carboxyphenylsulfonylurea.

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