Sulfonylureas or sulphonylureas are a class of

organic compounds Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

used in

medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...

and

agriculture Agriculture encompasses crop and livestock production, aquaculture, and forestry for food and non-food products. Agriculture was a key factor in the rise of sedentary human civilization, whereby farming of domesticated species created ...

. The functional group consists of a sulfonyl group (-S(=O)₂) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea, a dehydrogenated derivative of

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

). The side chains R₁ and R₂ distinguish various sulfonylureas. Sulfonylureas are the most widely used herbicide.

Agricultural uses

Many sulfonylureas are also used as herbicides, because they can interfere with plant

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

of certain

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

. As herbicides sulfonylureas function by interfering with biosynthesis of the amino acids valine, isoleucine, and leucine, specifically via acetolactate synthase inhibition. Compounds in this class include amidosulfuron, azimsulfuron, bensulfuron-methyl, chlorimuron-ethyl, chlorsulfuron, ethametsulfuron-methyl, cinosulfuron, ethoxysulfuron, flazasulfuron, flupyrsulfuron-methyl-sodium, imazosulfuron, metsulfuron-methyl, nicosulfuron, oxasulfuron, primisulfuron-methyl, prosulfuron, pyrazosulfuron-ethyl, rimsulfuron, sulfometuron-methyl, sulfosulfuron, thifensulfuron-methyl, triasulfuron, tribenuron-methyl, and triflusulfuron-methyl. These are broad-spectrum herbicides that kill plants weeds or pests by inhibiting the enzyme acetolactate synthase. In the 1960s, more than crop protection chemical was typically applied, while sulfonylureates allow as little as 1% as much material to achieve the same effect.

Medical uses

Treatment of type 2 diabetes

They are widely used as antidiabetic drugs in the management of diabetes mellitus type 2. They act by increasing

secretion Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mec ...

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

from the beta cells in the

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy. Sulfonylureas can be used to treat some types of neonatal diabetes. Historically, people with hyperglycemia and low blood insulin levels were diagnosed with type 1 diabetes by default, but it has been found that patients who receive this diagnosis before 6 months of age are often candidates for receiving sulfonylureas rather than insulin throughout life. A 2011 Cochrane

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

evaluated the effects on treatment of Latent Autoimmune Diabetes in Adults (LADA) and found that Sulfonylureas did not improve metabolic control of

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

at 3 and 12 months, even worsening HbA1c levels in some cases, when compared to insulin. The same review did not find improvement of fasting C-peptide following treatment with sulfonylurea. Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design. While prior sulfonylureas were associated with worse outcomes, newer agents do not appear to increase the risk of death, heart attacks, or strokes. This is further reinforced by a 2020 Cochrane

which did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

, non-fatal

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

or end-stage renal disease when comparing metformin monotherapy to sulfonylureas. This same review also did not find improvement in health-related quality of life. In individuals with impaired-glucose tolerance, a 2019 systematic review only found one suitable trial comparing the effects of Sulphonylurea with metformin in reduction or delay of risk of developing type 2 diabetes, however this trial did not report patient-relevant outcomes. Another

completed in the same year suggested that there is limited evidence if the combined used of Metformin with Sulphonylurea compared to the combination of Metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events, macrovascular and microvascular complications. Combined Metformin and Sulphonylurea therapy did appear to lead to higher risk of

Hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

Interleukin-1 β inhibitors

Sulfonylureas are also used experimentally to inhibit release of interleukin 1 beta from the NALP3 (or NLRP3) inflammasome.

Side effects

Sulfonylureas – as opposed to metformin, the thiazolidinediones, pramlintide and other newer treatments – may induce

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

as a result of excesses in insulin production and release. Hypoglycemia appears to happen more often with sulfonylureas than compared to other treatments. This typically occurs if the dose is too high, and the patient is fasting. Some people attempt to change eating habits to prevent this, however it can be counterproductive. Like

, sulfonylureas can induce weight gain, mainly as a result of their effect to increase insulin levels and thus use of glucose and other metabolic fuels. Other side-effects are: gastrointestinal upset,

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

and hypersensitivity reactions. The safety of sulfonylurea therapy in pregnancy is unestablished. Prolonged hypoglycemia (4 to 10 days) has been reported in children borne to mothers taking sulfonylureas at the time of delivery. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. Since other antidiabetic drugs cannot be used either under these circumstances, insulin therapy is typically recommended during pregnancy and in liver and kidney failure, although some of the newer agents offer potentially better options. A 2011 Cochrane review found evidence that treatment of LADA using sulfonylureas lead to earlier insulin dependence in approximately 30% of cases. A 2014 Cochrane review found tentative evidence that people treated with sulfonylureas have fewer non-fatal cardiovascular events than those treated with metformin (RR 0.7) but a higher risk of severe hypoglycemia (RR 5.6). There was not enough data available to determine the risk of mortality or of cardiovascular mortality. An earlier review by the same group found a statistically significant increase in the risk of cardiovascular death for first generation sulfonylureas relative to placebo (RR 2.6) but there was not enough data to determine the relative risk of first generation sulfonylureas relative to insulin (RR 1.4). Likewise it was not possible to determine the relative mortality risk of second generation sulfonylureas relative to metformin (RR 1.0), insulin (RR 1.0), or placebo. The FDA requires sulfonylureas to carry a label warning regarding increased risk of cardiovascular death. A 2020 Cochrane

comparing metformin monotherapy to sulfonylureas did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal

, non-fatal

or end-stage renal disease. Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. Similarly, ACCORD (Action to Control Cardiovascular Risk in Diabetes) and the VADT (Veterans Affairs Diabetes Trial) studies showed no reduction in heart attack or death in patients assigned to tight glucose control with various drugs.

Interactions

Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include acetylsalicylic acid and derivatives, allopurinol, sulfonamides, and

fibrate In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high choles ...

s. Drugs that worsen glucose tolerance, contravening the effects of antidiabetics, include

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...

s, isoniazid, oral contraceptives and other

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

s, sympathomimetics, and thyroid hormones. Sulfonylureas tend to interact with a wide variety of other drugs, but these interactions, as well as their clinical significance, vary from substance to substance.

Structure

Sulfonylureas contain a central ''S''-arylsulfonylurea structure with a ''p''-substituent on the phenyl ring (R¹) and various groups terminating the urea ''N'' end group (R²). Chemically, this functionality can be easily installed by reacting aryl

sulfonamides In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the Chemical structure, structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this gro ...

(R¹—C₆H₄—SO₂NH₂) with isocyanates (R²—NCO). image:Chlorpropamide.svg, Chlorpropamide (1st generation) image:Tolazamide.svg, Tolazamide (1st generation) image:Gliclazide.svg, Gliclazide (2nd generation) image:Glimepiride.svg, Glimepiride (2nd generation)

Classification

Sulfonylureas are divided into 3 classes on basis of therapeutic efficiency of their antidiabetic action: * First-generation drugs: They include acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolcyclamide), metahexamide, tolazamide and tolbutamide. * Second-generation drugs: They include glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide and glyclopyramide. * Third-generation drugs: They include glimepiride, although it is sometimes considered a second-generation drug.

Mechanism of action

Sulfonylureas bind to and close ATP-sensitive K⁺ (K_ATP) channels on the cell membrane of pancreatic beta cells, which depolarizes the cell by preventing potassium from exiting. This

depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

opens voltage-gated Ca²⁺ channels. The rise in intracellular calcium leads to increased fusion of

granules with the cell membrane, and therefore increased

of mature insulin. There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, that they decrease lipolysis (breakdown and release of

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

s by adipose tissue) and decrease clearance of insulin by the liver. The K_ATP channel is an octameric complex of the inward-rectifier potassium ion channel K_ir6.x and sulfonylurea receptor SUR which associate with a

stoichiometry Stoichiometry () is the relationships between the masses of reactants and Product (chemistry), products before, during, and following chemical reactions. Stoichiometry is based on the law of conservation of mass; the total mass of reactants must ...

of 4:4. Furthermore, it has been shown that sulfonylureas interact with the nucleotide exchange factor Epac2. Mice lacking this factor exhibited a decreased glucose-lowering effect upon sulfonylurea treatment.

History

Sulfonylureas were discovered in 1942, by the chemist Marcel Janbon and co-workers in France, who were studying sulfonamide

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

s and discovered that the compound sulfonylurea induced

in animals.

Research and development Research and development (R&D or R+D), known in some countries as OKB, experiment and design, is the set of innovative activities undertaken by corporations or governments in developing new services or products. R&D constitutes the first stage ...

( translational research and commercial application development) for sulfonylureas as pharmaceuticals (as diagnostic and therapeutic agents in prediabetes and diabetes) happened in the 1950s and 1960s, as explored at '' Tolbutamide § History''. Research and development (translational research and commercial application development) for sulfonylureas as herbicides happened in the 1970s and 1980s, as explored for example in a volume of the Sloan Technology Series focusing on the sociotechnological aspects of agriculture (Canine 1995); the DuPont Experimental Station led this development.

References

{{Oral hypoglycemics Disulfiram-like drugs