Chlorpropamide

Chlorpropamide is an Antidiabetic Agent belonging to a group of medicines called first generation sulfonylureas.

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

After oral administration, Chlorpropamide is well absorbed from the gastrointestinal tract and undergoes hepatic metabolism. Its metabolites are chiefly excreted in the urine.

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

Chlorpropamide 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.

Chlorpropamide is an Antidiabetic Agent belonging to a group of medicines called first generation sulfonylurea.

Potassium conductance at the pancreatic cell surface is decreased, and membrane depolarization results from the binding of sulfonylureas, including Chlorpropamide, to ATP-sensitive potassium channels. Depolarization increases intracellular calcium ion concentrations, which triggers the release of insulin, or exocytosis, by stimulating calcium ion inflow through voltage-sensitive calcium channels.

Chlorpropamide 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.

• Chlorpropamide is used to lower and control blood sugar levels in individuals with type 2 diabetes.
• Chlorpropamide has been used off-label in gestational diabetes, polycystic ovary syndrome (PCOS), syndrome of inappropriate antidiuretic hormone (SIADH), and neurogenic diabetes insipidus.

In Treatment of Type 2 diabetes mellitus: Chlorpropamide 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.

Although not approved there have been certain off labelled uses documented for Chlorpropamide which includes gestational diabetes, polycystic ovary syndrome (PCOS), syndrome of inappropriate antidiuretic hormone (SIADH), and neurogenic diabetes insipidus.

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.

Chlorpropamide is indicate treatment of type 2 diabetes mellitus. It helps people with the disease reduce and manage their elevated blood sugar levels. It enhances overall glycemic control in individuals with type 2 diabetes and is usually administered when diet and exercise alone are insufficient to regulate blood glucose.

Orally: Chlorpropamide is available as a tablet that can be taken orally. Chlorpropamide should be taken on an empty stomach, preferably 30 minutes before a meal. 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: 100mg or 250mg

Chlorpropamide is available in the form of Oral Tablets

Dose Adjustment in Adult Patients:

The patient's response should determine the specific dosage.

Diabetes type 2

To enhance absorption, administer thirty minutes before a meal.

Stable diabetic in middle age: PRN may be increased or decreased by 50–125 mg/day at intervals of three to five days after starting at 250 mg/day PO.

Maintenance dosage: One should avoid doses above 750 mg/day. A higher dose of 500 mg/day may be necessary in cases of severe diabetes.

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

Taking Chlorpropamide 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.

Refrain from or limit alcohol consumption as it can interact with the medication and higher the risk of hypoglycemia (low blood sugar).

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

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.

Chlorpropamide may be contraindicated in the following conditions:-

• Type I diabetes
• Diabetes ketoacidosis
• Hypersensitivity, sulfa allergy
• Severe renal impairment

• Macrovascular Outcomes: No Chlorpropamide or any other antidiabetic medication has been shown in any clinical research to reduce macrovascular risk conclusively.
• Hypoglycemia: Hospitalization may be necessary due to the potential for severe hypoglycemia caused by any sulfonylurea medications, including Chlorpropamide. Precise dosing, cautious patient selection, and unambiguous instructions are critical for reducing hypoglycemia episodes. Consuming carbs regularly is essential, especially before missing or erratic meals. Hypoglycemia is more likely to occur in patients with hepatic or renal impairment. Particularly vulnerable groups include those who are elderly, disabled, or on beta-adrenergic blockers. The risk is increased by sustained physical activity, alcohol usage, or several glucose-lowering medications at once. Hypoglycemia patients require careful dosage monitoring, frequent feedings, and maybe hospitalization, as well as the IV infusion of glucose due to the prolonged half-life of Chlorpropamide.
• Patients may lose control of their diabetes treatment if they are stable on any regimen and are stressed from things like fever, trauma, infection, or surgery. Giving insulin and stopping Chlorpropamide at certain times could be essential.
• Patients at high risk for severe hypoglycemia include the elderly, debilitated or malnourished individuals, those with cardiovascular risk factors, and severe liver impairment.

It is unsafe to consume Chlorpropamide with alcohol.

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

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

Refrain from alcohol consumption. Administer 30 minutes before a meal or on an empty stomach since food can slow absorption.

The adverse reactions related to Chlorpropamide 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 Chlorpropamide are briefly summarized here:

• Miconazole: It has been reported that there may be a significant hypoglycemic reaction when oral miconazole and oral hypoglycemic medications interact. It is unknown if this interaction also occurs with topical, injectable, or vaginal formulations of miconazole.
• Alcohol: Consuming alcohol may cause a disulfiram-like reaction in certain patients. Alcohol use in moderation to excessive levels may raise the risk of hypoglycemia.
• NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): NSAIDs like ibuprofen and aspirin can affect blood sugar levels and increase the risk of hypoglycemia.
• Beta-Blockers: Beta-blockers, often used for heart conditions, may mask the symptoms of hypoglycemia, making it harder to recognize and treat.
• Phenytoin: Phenytoin, an antiepileptic drug, may alter the effectiveness of Chlorpropamide, requiring dosage adjustments.
• Salicylates: High-dose salicylates (aspirin) can potentiate the hypoglycemic effects of Chlorpropamide.
• Sulfonamides: Some sulfonamide antibiotics may affect the metabolism and effectiveness of Chlorpropamide.
• Phenytoin: Phenytoin, an antiepileptic drug, may alter the effectiveness of Chlorpropamide, requiring dosage adjustments.
• Other Antidiabetic Drugs: Concurrent use of multiple antidiabetic medications can increase the risk of hypoglycemia, necessitating close monitoring.

The most common side effects of Chlorpropamide include:

• Headache
• Vomiting
• Dizziness
• Nausea
• Diarrhea
• Loss of appetite
• Hypoglycemia (low blood glucose level)

• Pregnancy

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

Studies on animal reproduction using Chlorpropamide have yet to be carried out.

It is also unknown if it can impair a woman's ability to reproduce or harm a fetus when given to one. A pregnant woman should only get Chlorpropamide if the possible advantages outweigh the potential risks to herself and the unborn child.

Many doctors recommend taking insulin during pregnancy to maintain the blood glucose levels as close to normal as possible since statistics suggest that aberrant blood glucose levels during pregnancy are linked to a higher likelihood of congenital disabilities.

Nonteratogenic Effects:

Neonatal-born women on sulfonylurea medication at delivery have been shown to experience prolonged severe hypoglycemia (four to ten days). This has been reported more often when agents with longer half-lives are used. If a pregnant woman takes Chlorpropamide, she should stop taking medication at least one month before the planned delivery date and start alternative treatments to keep her blood glucose levels as close to normal as feasible.

• Nursing Mothers:

Five milligrams per millilitre were found in a composite sample of two human breast milk samples obtained five hours after a patient consumed 500 milligrams of Chlorpropamide. For comparison, following a single 250 mg dosage, Chlorpropamide's typical peak blood level is 30 mcg/mL. As a result, breastfeeding while using this medicine is not advised for women.

• Pediatric Use

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

• Geriatric Use

Clinical trials have yet to adequately assess the safety and efficacy of Chlorpropamide in patients 65 years of age and older. According to adverse event reports, chronic individuals may be more vulnerable to hypoglycemia and/or hyponatremia when taking Chlorpropamide. Abnormal renal function, medication interactions, and malnutrition are associated with these episodes, while the underlying mechanisms remain unknown.

Dosage adjustment in geriatric patients

Type 2 Diabetes

It is not the drug of choice for the elderly; due to its long half-life (100–125 mg PO qDay initially), there is a higher risk of hypoglycemia and drug interactions. It can also raise or lower PRN by 50–125 mg/day at three to five days intervals.

Dose Adjustment in Kidney Impairment Patient:

CrCl less than 50 mL/minute: Do not use

CrCl more than 50 mL/minute: Closely monitor therapy; cautious dose should be used throughout the beginning and maintenance phases to prevent hypoglycemia.

Dose Adjustment in Hepatic Impairment Patients:

When liver impairment exists, use lower starting and maintenance doses because Chlorpropamide undergoes substantial hepatic metabolism.

Signs and Symptoms

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

Overconsumption of Chlorpropamide 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 Chlorpropamide. However, immediate medical attention is essential. Chlorpropamide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Treating mild hypoglycemia symptoms immediately with oral glucose and changes in medication dosage and/or meal schedules is recommended if there is no loss of consciousness or neurological abnormalities. Close observation should be maintained Until the doctor confirms that the patient has no risk. In rare cases, severe hypoglycemia reactions accompanied by coma, seizures, or other neurological damage can be life-threatening and necessitate rapid hospitalization. Patients suspected or confirmed to be in a hypoglycemia coma should get an immediate intravenous infusion of a concentrated (50%) glucose solution. Subsequently, an ongoing injection of a diluted (10%) glucose solution at a rate sufficient to sustain blood glucose levels over 100 mg/dL should commence. Due to the possibility of recurrent hypoglycemia even after apparent clinical recovery, patients should be closely monitored for at least 24 to 48 hours.

In some cases, gastric lavage (stomach pumping) may be performed to remove the remaining Chlorpropamide from the stomach. Activated charcoal may also help absorb any remaining drug in the stomach and prevent further absorption into the bloodstream.

Pharmacodynamics

Chlorpropamide is a type 2 diabetes mellitus patient's second-generation sulfonylurea antidiabetic drug used with nutritional therapy to control high blood glucose. It exhibits twice the potency of its analogue, glipizide among second-generation agents. Enhancing peripheral tissue sensitivity to insulin and inducing the pancreas to produce insulin are the main mechanisms of action. As a result, there is an increase in the uptake and use of glucose. Interestingly, Chlorpropamide only works when blood sugar levels are high since its effects depend on glucose levels. Moreover, Chlorpropamide may impact the liver's other metabolic functions, including gluconeogenesis and glycogenolysis, which enhance the liver's overall ability to lower blood glucose levels efficiently.

Pharmacokinetics:

Absorption

The gastrointestinal system absorbs Chlorpropamide quickly; it reaches peak plasma concentrations in 2-4 hours and starts to work in an hour. The total effect becomes noticeable three to six hours after oral ingestion.

Half-Life: 25-48 hr

Duration: 24 hr

Initial effect: Diabetes mellitus: 1 hr and Diabetes insipidus: 1 day

Maximum impact: Diabetes mellitus: 3-6 hr; Diabetes insipidus: 4-5 d

Distribution

Chlorpropamide is distributed throughout the body, with a preference for blood plasma and the liver, where it exerts its therapeutic effects.

Protein Bound: 60-90%

Vd: 0.13-0.23 L/kg

Metabolism

The liver likely converts up to 80% of the dosage into p-chlorobenzene sulfonamide (CBSA), 3-hydroxyl Chlorpropamide (3-OH CPA), 2-hydroxyl Chlorpropamide (2-OH CPA), and p-chlorobenzene sulfonylurea (CBSU). CBSA may also be created through the breakdown in the urine. The potential hypoglycemic consequences of chlorpropamide metabolites are unknown.

Metabolism: It is moderately to extensively metabolized in the liver

Metabolites: Hydroxychlorpropamide, chlorobenzene-sulfonylurea (inactive)

Excretion

Approximately 80-90% of a single oral dose of Chlorpropamide is eliminated in the urine as the unchanged drug and its metabolites within 96 hours.

Excretion: Mainly in urine (80-90%)

• T Powell, Leonard Howells; Diabetes Mellitus Treated with Chlorpropamide and Chlorpropamide: A Four-year Clinical Study. Diabetes Apr 1 1966; 15 (4): 269–275. https://doi.org/10.2337/diab.15.4.269
• Cushard WG Jr, Beauchamp CJ, Martin ND. Oral therapy of diabetes insipidus with Chlorpropamide. Calif Med. 1971 Aug;115(2):1-5. PMID: 5563815; PMCID: PMC1517999.
• Seviour PW, Teal TK, Richmond W, Elkeles RS. Chlorpropamide lowers serum and lipoprotein cholesterol in insulin-dependent diabetes. Diabet Med. 1986 Mar;3(2):152-4. Doi: 10.1111/j.1464-5491.1986.tb00727.x. PMID: 2951157.
• Elkeles RS, Heding LG, Paisey RB. The long-term effects of Chlorpropamide on insulin, C-peptide, and proinsulin secretion. Diabetes Care. 1982 Jul-Aug;5(4):427-9. doi: 10.2337/diacare.5.4.427. PMID: 6759080.
• Uhrig JD, Hurley RM. Chlorpropamide in pregnancy and transient neonatal diabetes insipidus. Can Med Assoc J. 1983 Feb 15;128(4):368, 370-1. PMID: 6821792; PMCID: PMC1875019.

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https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/011641Orig1s065.pdf

https://www.medicinenet.com/chlorpropamide/article.htm

https://www.sciencedirect.com/topics/medicine-and-dentistry/chlorpropamide