Sulfonylurea/ja: Difference between revisions

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===Side effects===

Sulfonylureas – as opposed to [[metformin]], the [[thiazolidinedione]]s, [[pramlintide]] and other newer treatments – may induce [[hypoglycemia]] 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 use of glucose and other metabolic fuels. Other side-effects are: gastrointestinal upset, [[headache]] 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 [[Latent autoimmune diabetes in adults|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 (organisation)|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 [[Chronic kidney disease|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.

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=== Interactions ===

Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include [[acetylsalicylic acid]] and derivatives, [[allopurinol]], [[sulfonamide (medicine)|sulfonamide]]s, and [[fibrate]]s. Drugs that worsen [[glucose tolerance]], contravening the effects of antidiabetics, include [[corticosteroid]]s, [[isoniazid]], [[oral contraceptive]]s and other [[estrogen]]s, [[sympathomimetic]]s, and [[thyroid hormone]]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.

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== Structure ==

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

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===Classification===

* 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.

[[File:Glucose Insulin Release Pancreas.svg|thumb|Diagram of glucose reduction and insulin release in the pancreas]]

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Sulfonylureas bind to and close [[ATP-sensitive potassium channel|ATP-sensitive K⁺]] (K_ATP) channels on the cell membrane of pancreatic [[beta cell]]s, which depolarizes the cell by preventing potassium from exiting. This [[depolarization]] opens voltage-gated [[calcium|Ca]]²⁺ channels. The rise in intracellular calcium leads to increased fusion of [[insulin]] granules with the cell membrane, and therefore increased [[Insulin#Synthesis|secretion]] of mature insulin.

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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.

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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]] of 4:4.

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Furthermore, it has been shown that sulfonylureas interact with the nucleotide exchange factor [[RAPGEF4|Epac2]]. Mice lacking this factor exhibited a decreased glucose-lowering effect upon sulfonylurea treatment.

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Sulfonylureas were discovered in 1942, by the chemist Marcel Janbon and co-workers, who were studying [[Sulfonamide (medicine)|sulfonamide]] [[antibiotic]]s and discovered that the compound sulfonylurea induced [[hypoglycemia]] in animals.

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[[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|Tolbutamide § History]]''.

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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.