Sulfonylurea 732108 223048124 2008-07-02T10:03:40Z DOI bot 6652755 Citation maintenance. Removed redundant parameters. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. [[Image:Chlorpropamide.svg|thumb|[[Chlorpropamide]]]] [[Image:Tolbutamide.svg|thumb|[[Tolbutamide]]]] [[Image:Tolazamide.svg|thumb|[[Tolazamide]]]] [[Image:Gliclazide.svg|thumb|[[Gliclazide]]]] '''Sulfonylurea''' (UK: Sulphonylurea) derivatives are a class of [[antidiabetic drugs]] that are used in the management of [[diabetes mellitus]] [[Diabetes mellitus type 2|type 2]] ("adult-onset"). They act by increasing [[insulin]] release from the [[beta cell]]s in the [[pancreas]]. ==Drugs in this class== First generation: * [[Acetohexamide]] * [[Chlorpropamide]] * [[Tolbutamide]] * [[Tolazamide]] Second generation: * [[Glipizide]] * [[Gliclazide]] * [[Glibenclamide]] (glyburide) * [[Gliquidone]] Third generation: * [[Glimepiride]] ==Chemistry== All sulfonylureas contain a central sulfonylurea structure with p-substitution on the phenyl ring and various groups terminating the urea N' end group. [[Image:Sulfonyl_urea.jpg]] ==Pharmacology== ===Mechanism of action=== Sulfonylureas bind to an [[adenosine triphosphate|ATP]]-dependent [[potassium|K]]<sup>+</sup> (K<sub>ATP</sub>) channel on the cell membrane of pancreatic [[beta cell]]s. This inhibits a tonic, hyperpolarizing efflux of potassium, thus causing the electric potential over the membrane to become more positive. This [[depolarization]] opens voltage-gated [[calcium|Ca]]<sup>2+</sup> channels. The rise in intracellular calcium leads to increased fusion of [[insulin]] granulae 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 acid]]s by [[adipose tissue]]) and decrease clearance of insulin by the liver. The K<sub>ATP</sub> channel in turn is a complex of the [[inward-rectifier potassium ion channel]] K<sub>ir</sub>6.2 and [[sulfonylurea receptor]] SUR1 which associate with a [[stoichiometry]] of K<sub>ir</sub>6.2<sub>4</sub>/SUR1<sub>4</sub>. ===Pharmacokinetics=== 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. ==Uses== Sulfonylureas are used almost exclusively in [[diabetes mellitus]] type 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 [[obesity|obese]] patients might benefit more from [[metformin]]. In about 10% of patients, sulfonylureas alone are ineffective in controlling blood glucose levels. Addition of metformin or a [[thiazolidinedione]] may 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 glyburide<ref name="carrotcapital">{{cite web |url= http://www.carrotcapital.com/news_080705.html |title= Breakthrough Discovery Offers Hope to Stroke Victims |accessdate= 2008-01-06 |publisher= Carrot Capital }}</ref> 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.<ref name="pmid17673715">{{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 }}</ref><ref name="pmid18032110">{{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 }}</ref> Some diabetes experts feel that sulfonylureas accelerate the loss of beta cells from the pancreas, and should be avoided.{{fact|date=May 2008}} ==Side-effects and cautions== Sulfonylureas, as opposed to [[metformin]], the [[thiazolidinedione]]s, [[exenatide]], [[symlin]] and other newer treatment agents induce [[hypoglycemia]] as 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 [[Hypoglycemia#Reversing_acute_hypoglycemia|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) [[glucagon]] and [[intravenous]] [[dextrose]]. Like [[insulin]], sulfonylureas can induce weight gain, mainly as a result of [[edema]] and reduction of the [[osmotic diuresis]] caused by [[hyperglycemia]]. Other side-effects are: abdominal upset, [[headache]] and [[hypersensitivity]] reactions. Sulfonylureas are potentially [[teratogenic]] and 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. ==History== Sulfonylureas were discovered by the chemist Marcel Janbon and co-workers,<ref name="Janbon_1942">{{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 = }}</ref> who were studying [[Sulfonamide (medicine)|sulfonamide]] [[antibiotic]]s and discovered that the compound sulfonylurea induced [[hypoglycemia]] in animals.<ref name="pmid12468446">{{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 }}</ref> ==See also== * [[diabetes mellitus]] * [[metformin]] * [[thiazolidinedione]]s ==References== {{Reflist}} {{Oral_hypoglycemics}} [[Category:Sulfonylureas]] [[fr:Sulfonylurée]]