Sulphonylureas actions

According to modern pathophysiological understanding of Type-II diabetes and the mechanism of sulphonylurea action, combined insulin-sulphonylurea therapy appears to be an interesting alternative for treating NIDDM patients with secondary failure to sulphonylureas. Several recent clinical trials confirmed favourable results (Stenman et al., 1988). Holman et al. (1987) studied the metabolic profiles of 24 Type-II diabetics who were treated... 

II.f.2.2. Sulphonylureas. These drugs stimulate pancreatic /3-cell insulin secretion, reduce serum glucagon levels, potentiate insulin action on target tissues, and improve /3-cell function. The sulphonylureas differ in their potency, extent of hepatic metabolism, hypoglycaemic activity of their metabolites, renal excretion, peak and duration of action, side effects and costs. 

SULPHONYLUREAS CLOZAPINE May cause t blood sugar and loss of control of blood sugar Clozapine can cause resistance to the action of insulin Watch/monitor for diabetes mellitus in subjects on long-term clozapine treatment... 

U-56324 (28), a nicotinic acid derivative, has hypoglycaemic activity in the 18-h fasted normal rat [173] and stimulates in vitro insulin secretion [174]. Study of the in vitro activity in membrane patches from cultured mouse pancreatic jff-cells revealed that it acts directly on ATP-sensitive potassium channels and probably has the same mechanism of action as sulphonylureas [174]. 

In islets, A-4166 causes a steep rise in insulin release followed by a slow sustained rise to twice the basal level. The insulinotropic effect is not glucose-dependent and takes place in the absence of glucose [191, 192]. The in vivo pharmacodynamic profile (rapid and short-term action) appears to result from a rapid plasma appearance and disappearance of the compound rather than an intrinsic feature of the mechanism [191]. A-4166 may be useful as therapy for NIDDM patients with secondary failure to sulphonylureas [190]. 

Antidiabetics azapropazone and phenylbutazone inhibit the metabolism of sulphonylurea hypoglycaemics, increasing their intensity and duration of action. 

Sulphonylureas block the ATP-sensitive potassium channels on the P-islet cell plasma membrane. This results in the release of stored insulin in response to glucose. They do not increase insulin formation. Sulphonylureas appear to enhance insulin action on liver, muscle and adipose tissue by increasing insulin receptor number and by enhancing the postreceptor complex enzyme reactions mediated by insulin. The principal result is decreased hepatic... 

Repaglinide is a very short-acting oral hypogly-caemic agent whose action, like the sulphonylureas, is mediated through blockade of ATP-dependent potassium channels. It affects only postprandial insulin profiles, and should in theory reduce risk of hypoglycaemia. 

Metformin (t) 5 h) is taken with or after meals. Its chief use is in the obese patient with Type 2 diabetes either alone or in combination with a sulphonylurea. It has a mild anorexic effect which helps to reduce weight in the obese. The action of metformin is terminated by excretion by the kidney and it should not be used in the presence of renal impairment. 

The action of sulphonylureas is intensified by heavy sulphonamide dosage and some sulphonamides increase free tolbutamide concentrations, probably by competing for plasma protein binding sites. These examples suffice to show that the possibility of interactions of practical clinical importance is a real one. 

Sulphonylureas have been used for the treatment of Type-II diabetes for more than 30 years. Two actions are thought to be responsible for their ability to lower glucose concentration in blood (1) their action on B-cells which causes insulin secretion (2) the so-called extrapancreatic effects which have been mainly demonstrated in in vitro experiments. 

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. 

It thus seems clear that the initiating mechanism by which sulphonylureas promote insulin secretion is depolarization and subsequent uptake of Ca2+ which is similar to the mode of action of glucose. However, and here is the difference, sulphonylureas cannot replace the metabolism of glucose in B-cells. In contrast, their action on Ca2+ uptake, but not K+ efflux, depends on the concentration of glucose in other words, it depends on the metabolism of glucose which seems to modulate the action of sulphonylureas on the B-cell. 

The interrelationships between sulphonylureas and modulating systems of the B-cell can be seen from two aspects. First, do modulating systems interfere with the initiating action of sulphonylureas Second, do sulphonylureas affect the modulating systems As discussed in chapter 6, section 4, there are at least three modulating systems, i.e. glucose metabolism, the adenylate cyclase system and the PLC system. 

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