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Sulfonylureas (UK: sulphonylurea) are a class of
organic compounds In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The s ...
used in medicine and agriculture, for example as
antidiabetic drugs Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are thu ...
widely used in the management of
diabetes mellitus type 2 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
. They act by increasing insulin release from the
beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
s in the
pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...
. A number of sulfonylureas are also used as herbicides, because they can interfere with plant
biosynthesis Biosynthesis is a multi-step, enzyme- catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecule ...
of certain
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
. Sulfonylureas are also used experimentally to inhibit
interleukin 1 beta Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
release from the NALP3 (or NLRP3) inflammasome.


Drugs

* First-generation drugs include
acetohexamide Acetohexamide (trade name Dymelor) is a first-generation sulfonylurea medication used to treat diabetes mellitus type 2, particularly in people whose diabetes cannot be controlled by diet alone. Mechanism of action Acetohexamide bind to an AT ...
,
carbutamide Carbutamide (brand name Glucidoral) is an anti-diabetic drug of the sulfonylurea class, developed by Servier. It is classified as first-generation. It was patented in 1953 and approved for medical use in 1956. See also * Hellmuth Kleinsorge ...
,
chlorpropamide Chlorpropamide is a drug in the sulfonylurea class used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea. Mechanism of action Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, ...
, glycyclamide (tolcyclamide),
metahexamide Metahexamide ( INN) is an anti-diabetic drug from the group of sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of d ...
,
tolazamide Tolazamide is an oral blood glucose lowering drug used for people with Type 2 diabetes. It is part of the sulfonylurea family (ATC A10BB). Synthesis ''para''-Toluenesulfonamide is converted to its carbamate with ethyl chloroformate in the pre ...
and
tolbutamide Tolbutamide is a first-generation potassium channel blocker, sulfonylurea oral hypoglycemic medication. This drug may be used in the management of type 2 diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin b ...
. * Second-generation drugs include
glibenclamide Glibenclamide, also known as glyburide, is an antidiabetic medication used to treat type 2 diabetes. It is recommended that it be taken together with diet and exercise. It may be used with other antidiabetic medication. It is not recommended f ...
(glyburide),
glibornuride Glibornuride ( INN) is an anti-diabetic drug from the group of sulfonylureas. It is manufactured by MEDA Pharma and sold in Switzerland under the brand name Glutril. Synthesis Gliburnide is an endo-endo derivative made from camphor-3-carboxam ...
, gliclazide,
glipizide Glipizide, sold under the brand name Glucotrol among others, is an anti-diabetic medication of the sulfonylurea class used to treat type 2 diabetes. It is used together with a diabetic diet and exercise. It is not indicated for use by itself in ...
,
gliquidone Gliquidone ( INN, sold under the trade name Glurenorm) is an anti-diabetic medication in the sulfonylurea class. It is classified as a second-generation sulfonylurea. It is used in the treatment of diabetes mellitus type 2. It is marketed by the ...
, glisoxepide and
glyclopyramide Glyclopyramide ( INN, marketed under the tradename Deamelin-S) is a sulfonylurea drug used in the treatment of diabetes. It has been marketed in Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East As ...
. * Third-generation drugs include glimepiride, although it is sometimes considered a second-generation agent.


Medical uses

Sulfonylureas are used primarily for the treatment of diabetes mellitus type 2. 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. While historically, people with hyperglycemia and low blood insulin levels were diagnosed with type 1 diabetes by default, it has been found that patients who receive this diagnosis before 6 months of age are often, in fact, candidates for receiving sulfonylureas rather than insulin throughout life. A 2011 Cochrane systematic review evaluated the effects on treatment of Latent Autoimmune Diabetes in Adults (LADA) and found that Sulfonylureas did improve metabolic control of glucose 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 systematic review which did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke 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.


Side effects

Sulfonylureas – as opposed to metformin, the
thiazolidinedione The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in ...
s, pramlintide and other newer treatments – may induce
hypoglycemia Hypoglycemia, also 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 triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
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 insulin, sulfonylureas can induce weight gain, mainly as a result of their effect to increase insulin levels and thus utilization of glucose and other metabolic fuels. Other side-effects are: gastrointestinal upset, headache and
hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...
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 systematic review comparing metformin monotherapy to sulfonylureas did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke or
end-stage renal disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...
. 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 Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
and derivatives,
allopurinol Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth ...
, 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 cholesterol), ...
s. Drugs that worsen
glucose tolerance Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...
, 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 involve ...
s,
isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For lat ...
,
oral contraceptive Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. Female Two types of female oral contraceptive pill, taken once per day, are widely available: * The combin ...
s and other estrogens,
sympathomimetic Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in hea ...
s, and
thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 25 ...
s. 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

All pharmacological 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 In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
sulfonamides (R1—C6H4—SO2NH2) with isocyanates (R2—NCO). image:Chlorpropamide.svg,
Chlorpropamide Chlorpropamide is a drug in the sulfonylurea class used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea. Mechanism of action Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, ...
(1st generation) image:Tolazamide.svg,
Tolazamide Tolazamide is an oral blood glucose lowering drug used for people with Type 2 diabetes. It is part of the sulfonylurea family (ATC A10BB). Synthesis ''para''-Toluenesulfonamide is converted to its carbamate with ethyl chloroformate in the pre ...
(1st generation) image:Gliclazide.svg, Gliclazide (2nd generation) image:Glimepiride.svg, Glimepiride (2nd generation)


Mechanism of action

Sulfonylureas bind to and close ATP-sensitive K+ (KATP) channels on the cell membrane of pancreatic
beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
s, which depolarizes the cell by preventing potassium from exiting. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granules with the cell membrane, and therefore increased secretion of mature insulin. There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by
adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
) and decrease clearance of insulin by the liver. The KATP channel is an octameric complex of the inward-rectifier potassium ion channel Kir6.x and
sulfonylurea receptor In molecular biology, the sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of antidiabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. Mor ...
SUR which associate with a
stoichiometry Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equal ...
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, 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 bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s and discovered that the compound sulfonylurea induced
hypoglycemia Hypoglycemia, also 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 triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
in animals. Research and development ( 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.


Herbicides

A large number of sulfonylureas are used as herbicides. They function by interfering with biosynthesis of the amino acids valine, isoleucine, and leucine, specifically via
acetolactate synthase The acetolactate synthase (ALS) enzyme (also known as acetohydroxy acid or acetohydroxyacid synthase, abbr. AHAS) is a protein found in plants and micro-organisms. ALS catalyzes the first step in the synthesis of the branched-chain amino acids ...
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.Arnold P. Appleby, Franz Müller, Serge Carpy "Weed Control" in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim.


References

{{Oral hypoglycemics Disulfiram-like drugs