Oral Antidiabetic Agents - Luzimar Teixeira

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390 Krentz & Bailey recommended in the UK, can be usefully comple- nylureas with respect to the risks of weight gain and mented by self measurement of capillary blood glu- hypoglycaemia. Compared with older sulphocose in selected, empowered patients and in particu- nylureas, glimepiride is relatively expensive and lar clinical scenarios, for example in patients in clinical outcome data are not available, as they are whom iatrogenic hypoglycaemia is a concern. for the agents used in the UKPDS. The clinical relevance of theoretical, but much debated, effects 1. Insulin Secretagogues of glimepiride on ischaemic preconditioning – whereby a brief episode of ischaemia protects the myocardium against the detrimental effects of sub- 1.1 Sulphonylureas sequent and more severe interruption of perfusion – remain uncertain. The issues of the importance of Sulphonylureas have been extensively used for ischaemic preconditioning and the possible influthe treatment of type 2 diabetes for nearly 50 years. ence of different sulphonylureas continue to be de- They lower blood glucose concentrations primarily bated (see section 1.1.5). [14] by stimulating insulin secretion from the β cells of the pancreatic islets. By the 1960s several sulphonylureas were available, including tolbutamide, 1.1.1 Mode of Action acetohexamide, tolazamide and chlorpropamide, ofproducing Sulphonylureas have direct effects on the insulin- fering a range of pharmacokinetic options. Howsulphonylurea islet β cells. The drugs bind to the β-cell ever, doubts about safety were raised in the 1970s. A receptor (SUR)-1, part of a transever, large US multicentre trial of antidiabetic therapy, membrane complex with adenosine 5′-triphosphatethe UGDP (University Group Diabetes Program) [11] sensitive Kir 6.2 potassium channels (KATP chan- reported apparent detrimental cardiovascular effects nels). [14,15] Binding of the sulphonylurea closes these of tolbutamide. The UGDP was heavily criticised KATP channels; this reduces cellular potassium ef- for perceived methodological failings and its find- flux favouring membrane depolarisation. In turn, ings were far from being universally accepted. Sub- depolarisation opens voltage-dependent calcium sequent observational and randomised clinical stud- channels, resulting in an influx of calcium that actiies using sulphonylureas have provided mixed evi- vates calcium-dependent proteins that control the dence, but a review of the available literature release of insulin (figure 2). When sulphonylureas provides little in the way of convincing evidence of interact with SUR1 in the β-cell plasma membrane cardiovascular toxicity. [12] Indeed, some studies they cause prompt release of pre-formed insulin have reported a decreased incidence of cardio- granules adjacent to the plasma membrane – the sovascular events in subjects with lesser degrees of called ‘first phase’ of insulin release. [16] Sulphoglucose intolerance who received sulphony- nylureas also increase the extended (‘second phase’) lureas. [12] The UKPDS investigators did not find any of insulin release that begins approximately 10 minincrease in risk of myocardial infarction among pa- utes later as insulin granules are translocated to the tients treated with sulphonylureas compared with membrane from within the β cell. [17] The protracted patients randomised to insulin as monotherapy. [1] stimulation of the ‘second phase’ of insulin release The Steno-2 Study, [8] has already been mentioned. involves the secretion of newly formed insulin granules. A succession of more potent so-called secondwhile The increased release of insulin continues generation sulphonylureas emerged in the 1970s and there is ongoing drug stimulation, provided 1980s, for example glibenclamide (glyburide), the β cells are fully functional. Sulphonylureas can gliclazide and glipizide. The latest, glimepiride, was cause hypoglycaemia since insulin release is initiat- introduced in the late 1990s. [13] Glimepiride is a ed even when glucose concentrations are below the once-daily drug for which claims have been made normal threshold for glucose-stimulated insulin re- that it might offer advantages over other sulpho- lease (approximately 5 mmol/L). © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 391 Glucose GLUT2 Succinate esters Glucokinase Glucose metabolism ATP SUR1 Kir 6.2 K ATP channel Sulphonylureas Repaglinide Nateglinide Proinsulin biosynthesis Depolarisation PKA Ca 2+ -sensitive proteins Ca 2+ channel GLP-1 Exenatide Adrenergic receptors α 2 -adrenoceptor antagonists Receptors cAMP PDE inhibitors Insulin Exocytosis Insulin Fig. 2. The insulin-releasing effect of sulphonylureas and other agents on the pancreatic islet β cell. Sulphonylureas bind to the sulphonylurea receptor (SUR)-1 located within the plasma membrane. This closes Kir 6.2 potassium channels which reduces potassium efflux, depolarises the cell and opens voltage-dependent calcium influx channels. Raised intracellular calcium brings about insulin release. According to the stimulus-secretion model, metabolism of glucose generates adenosine 5′-triphosphate (ATP) leading to closure of potassium channels, permitting the normal β cell to link insulin secretion closely to glucose concentration. Sulphonylureas may also enhance nutrient-stimulated insulin secretion by other actions on the β cell. Other secretagogues, e.g. repaglinide, nateglinide, also stimulate insulin secretion via the SUR-Kir 6.2 complex. Other agents, e.g. phosphodiesterase (PDE) inhibitors, glucagon-like peptide (GLP)-1 (7–36 amide), act via cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) to promote proinsulin synthesis (reproduced from Krentz and Bailey, [4] with permission from the Royal Society of Medicine Press). GLUT2 = glucose transporter-2. 1.1.2 Pharmacokinetics liver, although metabolites and their routes of elimination The principal distinguishing feature between different vary considerably between compounds. sulphonylureas relates to their pharmacokineproteins Since all sulphonylureas are highly bound to plasma tic characteristics (table III). Duration of action vardrugs they have the potential to interact with other ies from 24 hours for sharing this binding, for example salicylates, chlorpropamide because of differences in (i) rates of sulphonamides and warfarin; displacement from cir- metabolism; (ii) activity of metabolites; and (iii) culating proteins has been implicated in cases of rates of elimination. [18] These properties have im- severe sulphonylurea-induced hypoglycaemia (table portant implications for the risk of hypoglycaemia IV). associated with various sulphonylureas, an issue that 1.1.3 Indications and Contraindications is further complicated by retarded release prepara- Sulphonylureas remain a popular choice as firsttions of some compounds. All sulphonylureas are line oral therapy for patients with type 2 diabetes well absorbed and most reach peak plasma concen- who have not achieved or maintained adequate glytration in 2–4 hours. They are metabolised in the caemic control using nonpharmacological measures. © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
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