Sulfonylureas

Article Author:
Ryan Costello
Article Editor:
Abhijit Shivkumar
Updated:
9/24/2019 8:18:06 PM
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Sulfonylureas

Indications

This class of medications represents a group of anti-hyperglycemic agents mainly used in the treatment of type 2 diabetes mellitus. Sulfonylureas, commonly divided into first and second generations, can be utilized as adjuvant therapy with metformin in patients not at target hemoglobin A1c after three months on biguanides. If a patient’s hemoglobin A1c initially is greater than 9.0%, providers can consider combination therapy with metformin and a sulfonylurea or other anti-hyperglycemic agent. Additionally, sulfonylurea monotherapy can be considered in patients intolerant to metformin or in those who have a contraindication to this medication. Sulfonylureas can be used in combination with any other class of oral diabetic medications besides meglitinides. Infants with permanent neonatal diabetes also tend to respond well to sulfonylurea treatment. Examples of first-generation sulfonylureas include chlorpropamide, tolazamide, and tolbutamide, while second-generation sulfonylureas include glipizide, gliclazide, and glyburide. Glimepiride occasionally is referred to as a third-generation medication, though it commonly is classified as second-generation. Furthermore, chlorpropamide, glyburide, and glimepiride have a prolonged duration of action when compared to short-acting medications such as gliclazide and tolbutamide. Due to their low cost, wide availability, and effectiveness, sulfonylureas have remained a frequently prescribed medication despite potential hypoglycemic risks.[1][2][3][4][5][6][7][8][1]

Mechanism of Action

Sulfonylureas increase the release of insulin through the stimulation of pancreatic beta cells. By binding to a subunit of potassium ATP-dependent channels are known as the sulfonylurea receptor, this class of medications impedes the cellular release of potassium leading to cell depolarization. As a result, an inflow of calcium into the cell occurs and causes an increase in insulin exocytosis. Sulfonylureas, consequently, are a more potent medication in the earlier stages of type 2 diabetes when a patient has an increased pancreatic beta-cell function. Also, various types of the sulfonylurea subunit exist including SUR1, which is the receptor located on the beta cells of the pancreas as well as the brain, and SUR2, which is present in cardiac, skeletal, and smooth muscles. Individual medications within the sulfonylurea class have a varied affinity for these receptors, which can potentially explain some of the side effects of sulfonylureas, particularly concerning the cardiovascular risks of these insulin secretagogues. Other effects of sulfonylureas include increasing the growth and sensitivity of insulin receptors on other tissues like adipocytes and triggering hepatic gluconeogenesis.[9][3][10][11][6]

Administration

All sulfonylureas are taken orally and bind mainly to albumin after absorption occurs in the intestines. To improve efficacy, medications in this class should be taken about 30 minutes before meals. Low starting doses with an increase in dosage every other week until achieving effective blood glucose control remains the cornerstone of sulfonylurea therapy. Commonly avoided, higher doses of these insulin secretagogues result in an increased risk of hypoglycemia and rarely enhance management of consistently elevated blood sugars.[6]

Adverse Effects

Hypoglycemia remains the most common side effect reported with the administration of sulfonylureas, though it occurs more frequently with long-acting medications. With an annual first episode risk of about 1.8% for a low blood sugar episode, this diagnosis more typically occurs after periods of fasting or exercise. Particularly in the elderly population, hypoglycemia may go unrecognized, and these patients may experience difficulty communicating their symptoms to others. When compared to other sulfonylureas in the second generation, glyburide has been shown to possess a higher hypoglycemic risk. Furthermore, a potential weight gain of around 2.06 kilograms can be expected while taking sulfonylureas. The cardiovascular safety profile of this class of medications has remained uncertain, though sulfonylureas do appear to increase the risk of acute myocardial infarction and stroke with about 1.2 more cardiovascular disease-related events per 1000 person-years when compared to metformin. Utilization of sulfonylureas rarely can cause dermatologic side effects, including photosensitivity and erythroderma. Moreover, chlorpropamide can lead to facial flushing after the consumption of alcohol as well as hyponatremia; both of these effects are unique to this first generation sulfonylurea.[12][13][5][14][6][15]

Contraindications

Cross-reactivity of sulfonamides has been a topic of debate in patients with a sulfa allergy. One model suggests careful monitoring if prescribing sulfonylureas in a sulfa-allergic patient with alternative therapy as a consideration. However, clinicians may do well to avoid this class of medication in sulfa-allergic patients who experienced prior severe allergic reactions. For patients with gestational diabetes, glyburide can be considered for use in pregnancy, as fetal adverse effect profiles have been shown to be similar to that of insulin. Despite these findings, fetuses could potentially experience hypoglycemia as some of this medication could enter fetal circulation in theory. Additionally, the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults lists glyburide as a medication that should generally be avoided in geriatric patients.[16][17][18]

Monitoring

In patients who have a diagnosis of renal failure, the effects of sulfonylureas may become more prolonged; therefore, clinicians should check the creatinine level regularly. Genetic mutations that encode for potassium ATP-dependent channels, as well as the failure of pancreatic beta cells, can also influence the effectiveness of sulfonylureas and prescribers should consider this factor in patients whose glycemic control is not improved while taking these medications. Due to the potential side effect of weight gain, regular weights should be obtained at clinical visits. Also, a hemoglobin A1c should be regularly monitored up to four times a year, depending on glycemic control with a goal of less than 7.0%. Monotherapy with sulfonylureas has been shown to decrease hemoglobin A1c values by approximately 1.5%.[19][6][20]

Toxicity

With the vast majority of exposures classified as unintentional, sulfonylurea overdoses involved children 6 years or younger in approximately half of all single-substance incidents. Toxicity due to sulfonylureas commonly includes an episode of hypoglycemia, which may present up to 12 hours after the inciting event and last for multiple days. Possible risk factors for unintentional toxicities in diabetic patients on chronic sulfonylurea therapy consist of advanced age, poor nutrition, beta-blocker or insulin use, and the use of long-acting sulfonylureas such as glyburide, glimepiride, and chlorpropamide. A hypoglycemic patient can initially appear asymptomatic but may later develop tachycardia, drowsiness, agitation, and confusion. These symptoms can lead to seizures, coma, hypotension, and even death if the blood sugar continues to decrease or if it goes untreated. The initial management of low blood glucose secondary to sulfonylurea administration consists of intravenous dextrose or oral glucose tablets with a likely transition to a continuous intravenous infusion of a rapidly metabolized sugar. Activated charcoal can also be an option with substantial ingestions that may accompany suicide attempts. Recurrent hypoglycemia can ensue through the utilization of intravenous dextrose via the release of insulin after the administration of dextrose leads to hyperglycemia. Consequently, hourly blood glucose monitoring should be performed in suspected sulfonylurea toxicity cases and should be considered more frequently in patients with active symptoms of hypoglycemia. In patients who remain hypoglycemic despite treatment with supplemental intravenous carbohydrates, octreotide has been effective in the prevention of additional insulin secretion and the resulting hypoglycemia potentiated by dextrose. This somatostatin analog has essentially replaced the use of diazoxide and glucagon in the treatment of sulfonylurea-induced hypoglycemia. In a patient without symptoms, an observation period of at least 8 hours with hourly blood sugar monitoring should ensue before considering discharge from a healthcare facility. If timely treatment gets initiated, favorable outcomes from sulfonylurea overdoses typically result.[21][7]

Enhancing Healthcare Team Outcomes

The management of type 2 diabetes is with an interprofessional team that includes a diabetic educator, a primary care provider, and possibly an endocrinologist. Sulfonylureas are typically an option for management of hyperglycemia after a trial of biguanide therapy or if a patient is intolerant to metformin. Hypoglycemia is a known side effect of this class of medications, and patients' blood sugars should have regular monitoring if they are on a regimen involving a sulfonylurea. Patients taking sulfonylureas also should have their renal function and body weight monitored regularly. [Level V]

Pharmacists need to have involvement with sulfonylurea therapy, verifying dosing, checking for drug interactions, counseling patients, and also providing education on blood glucose monitoring, specifically how to use a home glucose meter. Nursing is also another valuable patient training resource and can monitor for treatment effectiveness, observe for sulfonylurea adverse events, and serving as a bridge to the treating clinician with other members of the healthcare team. Sulfonylurea therapy can be a useful adjunct in diabetes management, but to implement these medications successfully require a collaborative interprofessional effort, to maximize therapeutic effect while minimizing potential adverse events. [Level V]


References

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