Sulfonylureas bind

While producing the same effect as sulfonylureas, nonsulfonylurea secretagogues, also referred to as meglitinides, have a much shorter onset and duration of action. Nonsulfonylurea secretagogues also produce a pharmacologic effect by interacting with ATP-sensitive potassium channels on the (1-cells however, this binding is to a receptor adjacent to those to which sulfonylureas bind. 

Figure 1. Pharmacophore model for the sulfonylurea binding site (amended from Ref. 1).

Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor (Figure 41-2) that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin. 

The structure of mKATp is not known but it is assumed that it incorporates elements of the two known inward rectifier ATP-sensitive K+ channel proteins, Kv6.1 or Kv6.2. All known sarcolemmal KATp channels contain 4 pore-forming channel proteins and 4 sulfonylurea-binding receptor (SUR) proteins. The SUR has the ATP binding site and, as the name implies, binds sulfonylurea compounds like glibenclamide. Sulfonylurea... 

Sulfonylureas such as glyburide and glipizide bind to sulfonylurea receptors located on the surface of beta cells and trigger insuUn releases at nanomolar concentrations (Figure 54). Sulfonylureas bind to ATP-sensitive potassium channels and inhibit potassium efflux through these channels. The inhibition of ATP-sensitive potassinm channels then leads to depolarization of the beta cell. 

Sulfonylureas bind to the SURl subunits and block the ATP-sensitive K channel. The drugs thus resemble physiological secretagogues (e.g., glucose, leucine). 

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Die cytosolic loop between TMs 13 and 14 (KCO I) and TMs 16-17 (KCO II) were identified as critical for KatpCO binding to SURs (Fig. 4d). T1286 and Ml 290 appeared to be particularly important. Close local association of sulfonylurea and KCO binding regions might represent the structural basis for negative allosteric coupling of the sites. 

The answer is b. (Hardman, p 1507. Katzung, pp 723-724J Three proposed mechanisms for sulfonylurea action are (1) the release of insulin from pancreatic cells, (2) reduction of serum glucagon levels, and (.3) increased binding of insulin to tissue receptors. On binding to a specific receptor that is associated with a K channel in cell membranes, sulfo-nylureas inhibit K efflux, which causes influx of Ca followed by release of preformed insulin. 

Repaglinide en nateglinide are not sulfonylurea agents but their mechanism of action is very alike. Repaglinide is the first carbamoylmethyl-benzoic acid derivative that has been registred for the treatment of diabetes mellitus. It closes ATP-dependent potassium channels in the beta cell membrane with consequent depolarization, opening of calcium channels and increased insulin release. It is rapidly absorbed with peak plasma levels after 1 hour. It has a protein binding of over 98%. 

Methotrexate clearance can be decreased by the coadministration of NSAIDs however, this not usually a problem with the low doses of methotrexate used to treat arthritis. Methotrexate can be displaced from plasma protein binding sites by phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other antibiotics. The antifolate effects of methotrexate are additive with those of other folate-inhibitory drugs, such as trimethoprim. 

Sulfasalazine can inhibit the absorption of cardiac glycosides and folic acid. It may displace certain drugs, including warfarin, phenytoin, methotrexate, tolbutamide, chlorpropamide, and oral sulfonylureas, from their protein binding sites. Sulfasalazine can diminish the effectiveness of penicillins and estrogen-containing oral contraceptives. 

Mechanism of Action Afirst-generation sulfonylurea that promotes release of insulin from beta cells of pancreas. Therapeutic Effect Lowers blood glucose concentration. Pharmacokinetics Rapidly absorbed from the gastrointestinal (Gl) tract. Protein binding 60%-90%. Extensively metabolized in liver. Excreted primarily in urine. Removed by hemodialysis. Half-life 30-42 hr. 

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