Sulphonylureas glibenclamide

Fluconazole is a triazole antifungal that may be administered in recurrent vaginal candidiasis. Fluconazole interacts with sulphonylureas such as glibenclamide, resulting in increased plasma concentrations of the sulphonylurea. 

Glibenclamide is an oral antidiabetic agent (sulphonylurea). It acts by increasing insulin secretion and is therefore indicated in type 2 diabetes (non-insulin dependent) where there is pancreatic activity. 

Landgraf R, Bilo HJ, Muller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 1999 55(3) 165-71. 

Renal and hepatic disease. A biguanide should not be used in patients with either condition as the risk of lactic acidosis is too great. Sulphonylureas are potentiated in these diseases and a drug with a short t) (i.e. not glibenclamide) should be used in low dose. 

Sulphonylureas appear to induce their insulin secretory effect mainly from the extracellular site of the cytoplasmic membrane. Thus Heilman et al. (1984) have shown that, except for glibenclamide, sulphonylureas do not enter B-cells or only to a small extent (tolbutamide, carbutamide, chlorpropamide and glibizide). 

An important location of the sulphonylurea receptor is the ATP-sensitive K+ channel. Here, in contrast to ATP action, the binding site for sulphonylureas is not on the intracellular side but on the extracellular side of this channel (Niki et al., 1990). Niki et al. (1989, 1990) have provided evidence that ADP also binds to and competitively displaces glibenclamide from high-affinity HIT-cell sulphonylurea-binding sites. They also showed that ADP inhibited 86Rb+ efflux, elicited a rapid and sustained increase in [Ca2+]j and caused insulin secretion. Since ADP is unable to cross the cytoplasmic membrane, they concluded that ADP and sulphonylureas have common binding sites on the outer cell surface. 

Ca2+ Fluxes. As can be expected, sulphonylureas increase net Ca2+ uptake along voltage-dependent Ca2+ channels (Henquin, 1980b Ammon et al., 1986) and, as far as the chemical structure is concerned, only those sulphonylureas that produce insulin release enhance uptake of Ca2+ (Heilman, 1981). Uptake of Ca2+ is associated with increased [Ca2+]j (Abrahamson et al., 1985). In HIT cells, membrane depolarization effected by the addition of glibenclamide or tolbutamide increased intracellular Ca2+ by activating voltage-dependent Ca2+ channels (Nelson et al., 1987). 

Absorption of both first- and second-generation sulphonylureas is rapid and complete except for gliclazide and tolazamide, which are absorbed more slowly. The maximal plasma concentrations are usually reached within 2-4 h. The kinetics of absorption depend on the formulation and crystalline structure of the drug. Absorption of chlorpropamide may also depend on pH and therefore on food intake, which appears not to be true for the other sulphonylureas (Sartor et al., 1980). The absorption of glibenclamide, although rapid and almost complete, can be improved by an appropriate formulation (Haupt et al., 1984) which leads to a reduction in the daily dosage required. 

In acute poisoning the stomach should be emptied by aspiration and lavage. Activated charcoal probably adsorbs sulphonylureas and so may be of benefit in acute poisoning (Neuvonen et al., 1983 Neuvonen and Karkkainen, 1983 Kannisto and Neuvonen, 1984). Glibenclamide is cytotoxic in vitro (Popiela and Moore, 1991). 

The sulphonylureas, particularly chlorpropamide, may infrequently induce a syndrome of inappropriate secretion of antidiuretic hormone (augmenting hypothalamic-pituitary release of this hormone) characterized by water retention, hyponatraemia, low serum osmolality and high urine osmolality, and central nervous system signs. Water retention and dilutional hyponatraemia have occurred after administration of chlorpropamide and tolbutamide to NIDDM patients, especially those with congestive heart failure or hepatic cirrhosis. Glipizide, acetohexamide (Moses et al., 1973), tolazamide, glibenclamide are mildly diuretic. 

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