Sulfonylurea (UK: Sulphonylurea) derivatives are a class of
antidiabetic drugsthat are used in the management of diabetes mellitustype 2 ("adult-onset"). They act by increasing insulinrelease from the beta cells in the pancreas.
Drugs in this class
All sulfonylureas contain a central "S"-phenylsulfonylurea structure with p-substitution on the phenyl ring and various groups terminating the urea N' end group.
Mechanism of action
Sulfonylureas bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic
beta cells. This inhibits a tonic, hyperpolarizing efflux of potassium, thus causing the electric potential over the membrane to become more positive. This depolarizationopens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulingranulae with the cell membrane, and therefore increased secretion of (pro)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) and decrease clearance of insulin by the liver.
The KATP channel in turn is a complex of the
inward-rectifier potassium ion channelKir6.2 and sulfonylurea receptorSUR1 which associate with a stoichiometryof Kir6.24/SUR14.
Various sulfonylureas have different pharmacokinetics. The choice depends on the propensity of the patient to develop
hypoglycemia- long-acting sulfonylureas with active metabolites can induce hypoglycemia. They can, however, help achieve glycemic control when tolerated by the patient. The shorter-acting agents may not control blood sugar levels adequately.
Due to varying half-life, some drugs have to be taken twice (e.g. tolbutamide) or three times a day rather than once (e.g. glimepiride). The short-acting agents may have to be taken about 30 minutes before the meal, to ascertain maximum efficacy when the food leads to increased blood glucose levels.
Some sulfonylureas are metabolised by liver metabolic enzymes (
cytochrome P450) and inducers of this enzyme system (such as the antibiotic rifampicin) can therefore increase the clearance of sulfonylureas. In addition, because some sulfonylureas are bound to plasma proteins, use of drugs that also bind to plasma proteins can release the sulfonylureas from their binding places, leading to increased clearance.
Sulfonylureas are used almost exclusively in
diabetes mellitustype 2. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy.
Although for many years sulfonylureas were the first drugs to be used in new cases of diabetes, in the 1990s it was discovered that obese patients might benefit more from
In about 10% of patients, sulfonylureas alone are ineffective in controlling blood glucose levels. Addition of metformin or a
thiazolidinedionemay be necessary, or (ultimately) insulin. Triple therapy of sulfonylureas, a biguanide (metformin) and a thiazolidinedione is generally discouraged, but some doctors prefer this combination over resorting to insulin.
More recently, a pharmaceutical startup, Remedy Pharmaceuticals, Inc. has begun developing intravenous glyburidecite web |url= http://www.carrotcapital.com/news_080705.html |title= Breakthrough Discovery Offers Hope to Stroke Victims |accessdate= 2008-01-06 |publisher= Carrot Capital ] as a treatment for acute stroke, traumatic brain injury and spinal cord injury based on the identification of a non-selective ATP-gated cation channel which is upregulated in neurovascular tissue during these conditions and closed by sulfonylurea agents.cite journal | author = Kunte H, Schmidt S, Eliasziw M, del Zoppo GJ, Simard JM, Masuhr F, Weih M, Dirnagl U | title = Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke | journal = Stroke | volume = 38 | issue = 9 | pages = 2526–30 | year = 2007 | pmid = 17673715 | doi = 10.1161/STROKEAHA.107.482216 ] cite journal | author = Simard JM, Woo SK, Bhatta S, Gerzanich V | title = Drugs acting on SUR1 to treat CNS ischemia and trauma | journal = Curr Opin Pharmacol | volume = 8| issue = | pages = 42| year = 2007 | pmid = 18032110 | doi = 10.1016/j.coph.2007.10.004 ]
Some diabetes experts feel that sulfonylureas accelerate the loss of beta cells from the pancreas, and should be avoided.fact|date=May 2008
ide-effects and cautions
Sulfonylureas, as opposed to
metformin, the thiazolidinediones, exenatide, symlinand other newer treatment agents induce hypoglycemiaas a result of intermittent excesses in insulin production and release. Thus use of these agents, as with extra insulin from ouside the body, typically prevents achieving good glucose control; people usually keep their blood glucose elevated above optimal in order to reduce the frequency and severity of hypoglycemia. Hypoglycemia is treated with increasing sugar in take by mouth or injection, or (in the case of hypoglycemic coma) with parenteral(injected into the skin or muscle) glucagonand intravenous dextrose.
insulin, sulfonylureas can induce weight gain, mainly as a result of edemaand reduction of the osmotic diuresiscaused by hyperglycemia. Other side-effects are: abdominal upset, headacheand hypersensitivityreactions.
Sulfonylureas are potentially
teratogenicand cannot be used in pregnancy or in patients who may become pregnant. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. As other anti-diabetic drugs cannot be used either under these circumstances, insulin therapy is typically recommended during pregnancy and in hepatic and renal failure, although some of the newer agents offer potentially better options.
Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. They have decreased side effects but are more expensive.
Sulfonylureas were discovered by the chemist Marcel Janbon and co-workers,cite journal | author = Janbon M, Chaptal J, Vedel A, Schaap J | title = Accidents hypoglycémiques graves par un sulfamidothiodiazol (le VK 57 ou 2254 RP) | journal = Montpellier Med. | volume = 441 | issue = | pages = 21–22 | year = 1942 | pmid = | doi = | issn = | url = ] who were studying sulfonamide
antibiotics and discovered that the compound sulfonylurea induced hypoglycemiain animals.cite journal | author = Patlak M | title = New weapons to combat an ancient disease: treating diabetes | journal = FASEB J. | volume = 16 | issue = 14 | pages = 1853 | year = 2002 | pmid = 12468446 | doi = | issn = | url = http://www.fasebj.org/cgi/content/full/16/14/1853e ]
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sulfonylurea — [sul΄fə nil yo͞o rē′ə] n. any of a group of oral drugs, as tolbutamide, that stimulate the pancreas to secrete more insulin, used to treat diabetes * * * sul·fo·nyl·u·re·a (sŭl fə nĭl yo͝o rēʹə) n. Any of a group of hypoglycemic drugs, such as… … Universalium
sulfonylurea — [sul΄fə nil yo͞o rē′ə] n. any of a group of oral drugs, as tolbutamide, that stimulate the pancreas to secrete more insulin, used to treat diabetes … English World dictionary
sulfonylurea — noun Etymology: New Latin, from International Scientific Vocabulary sulfonyl + New Latin urea Date: 1956 any of several hypoglycemic compounds related to the sulfonamides and used in the oral treatment of diabetes … New Collegiate Dictionary
sulfonylurea — noun Any of a class of antidiabetic drugs that act by increasing insulin release from the beta cells in the pancreas … Wiktionary
Sulfonylurea — A class of oral hypoglycemic agents (pills and capsules taken to lower the level of blood glucose) by people with type 2 diabetes. The sulfonylureas increase the secretion of insulin by the pancreas. There are two generations of sulfonylureas.… … Medical dictionary
sulfonylurea — n. (Medicine) any of several compounds which stimulate the pancreatic islet cells to produce insulin (used as a treatment for some forms of diabetes) … English contemporary dictionary
sulfonylurea — sul·fo·nyl·urea … English syllables
sulfonylurea — noun antidiabetic consisting of any of several drugs that reduce the level of glucose in the blood; used to treat diabetes mellitus • Hypernyms: ↑antidiabetic, ↑antidiabetic drug • Hyponyms: ↑tolazamide, ↑Tolinase, ↑tolbutamide, ↑Orinase * * * … Useful english dictionary
Sulfonylurea receptor — protein Name=ATP binding cassette, sub family C (CFTR/MRP), member 8 caption= width= HGNCid=59 Symbol=ABCC8 AltSymbols=SUR1, HRINS EntrezGene=6833 OMIM=600509 RefSeq=NM 000352 UniProt=Q09428 PDB= ECnumber= Chromosome=11 Arm=p Band=15.1… … Wikipedia
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