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394 Krentz & Bailey caemia is more likely with longer-acting sulpho- patients receiving insulin therapy is orders of magninylureas such as glibenclamide, with tolbutamide tude higher. However, this does not detract from the holding the lowest place in the hierarchy of risk (see importance of sulphonylurea-induced hypoglyalso section 1.1.6). Individuals with irregular eating caemia. Minor recurrent hypoglycaemia should habits (see section 1.2.3) or excessive alcohol con- prompt a reassessment of the choice of agent and sumption are at higher risk of sulphonylurea-in- consideration of an alternative secretagogue, for exduced hypoglycaemia. As mentioned in section ample a rapid-acting insulin releaser (see section 1.1.3, hypoglycaemia is also more likely to occur in 1.2). The treatment schedule, the possibility of drug patients with satisfactory glycaemic control, as indi- interactions (table IV) and relevant features of the cated by an HbA1c concentration within, or just patient’s lifestyle, such as diet, meal patterns and above, the non-diabetic reference range. These pa- alcohol use, should be reviewed. Severe episodes of tients should always be questioned directly about sulphonylurea-induced hypoglycaemia mandate imrecent symptoms of hypoglycaemia, although their mediate admission to hospital: treatment with a connonspecific nature can raise problems of over-diag- tinuous intravenous infusion of dextrose may be nosis; self-monitoring of capillary blood glucose required for several days. There is a tendency for concentrations during suggestive episodes should hypoglycaemia to recur shortly after initial resuscihelp to clarify this issue, although uncertainties may tation with intravenous dextrose; the patient should not be completely dispelled. If there is continuing not be prematurely discharged after emergency doubt, a temporary reduction in dose is usually treatment. Where accumulation of chlorpropamide indicated. Estimates of the incidence of mild hypo- is suspected, renal elimination may be enhanced by glycaemia, that is, not requiring assistance from forced alkaline diuresis. The vasodilator diazoxide another individual, are often based on symptoms and the somatostatin analogue octreotide [24] have which have not necessarily been confirmed by conbeen used successfully to reversibly inhibit insulin temporaneous self-measurement of capillary blood secretion in severe sulphonylurea-induced hypoglyglucose. In the UKPDS, for example, about 20% of caemia, thereby reducing intravenous dextrose resulphonylurea-treated patients reported one or more quirements. These drugs should be regarded as poepisodes suggestive of hypoglycaemia annually; tentially useful adjuncts to intravenous glucose in other studies have suggested similar rates. [23] The some patients; octreotide avoids the adverse haemotiming of hypoglycaemia tends to reflect the dynamic effects of diazoxide, an obsolete antihyperpharmacokinetics of the sulphonylurea. Thus, glitensive agent that may pose a hazard in the elderly benclamide has a propensity to cause inter-prandial patient with compromised cardiovascular reflexes. hypoglycaemia whereas chlorpropamide tends to induce hypoglycaemia in the pre-breakfast period. Other adverse events of sulphonylureas include More severe hypoglycaemia (i.e. requiring assis- uncommon sensitivity reactions – usually cutaneous tance) occurred in about 1% of sulphonylurea-treatrare. – that are usually transient; erythema multiforme is ed patients annually in the UKPDS. In general, Fever, jaundice and blood dyscrasias are very lower rates (approximately 0.2–2.5 episodes per rare; some sulphonylureas can reportedly precipitate 1000 patient-years) have been reported from adheyday, acute porphyria in predisposed individuals. In its verse event reporting to regulatory authorities or chlorpropamide was notorious for causing from physician-completed questionnaires. The morquantities unpleasant facial flushing after consuming small tality risk from severe sulphonylurea-induced hyporeported. of alcohol; photosensitivity has also been glycaemia has been calculated to be 0.014–0.033 per Chlorpropamide could also increase renal 1000 patient-years. [23] Predictably, longer-acting sensitivity to antidiuretic hormone, occasionally high-potency agents, such as glibenclamide, appear causing water retention with hyponatraemia. In con- to carry the greater mortality risk. For comparison, trast, glibenclamide is credited with a mild diuretic the occurrence of severe hypoglycaemia induced in action. Weight gain is regarded as a class effect of © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Oral Antidiabetic Agents 395 sulphonylurea therapy, typically amounting to held to be equivalent to 80mg of unmodified glicla- 1–4kg and stabilising after about 6 months. This zide. In a recent 6-month comparative multicentre weight gain, which is always unwelcome, is thought study, gliclazide MR was associated with approxito reflect the anabolic effects of increased plasma mately 50% reduction in episodes of minor hypoglyinsulin concentrations; some studies have suggested caemia compared with glimepiride, at similar levels that reduced loss of calories as glucose in the urine of glycaemic control; no episodes of severe hypomay account for the majority of the weight glycaemia were observed with either agent in this gain. [19,21] study. [26] The saga of the questionable cardiovascular safety of the sulphonylureas was given a nudge by the 1.2 Rapid-Acting Prandial Insulin Releasers discovery that cardiac muscle and vascular smooth Under experimental conditions the first phase of muscle express isoforms of the SUR2A and SUR2B. glucose-stimulated insulin secretion is diminished Sulphonylureas that contain a benzamido group (gliearly in the natural history of type 2 diabetes. The benclamide, glipizide, glimepiride) can bind to prompt physiological rise in plasma insulin in res- SUR2A and SUR2B, [15] whereas those without (e.g. ponse to meals is attenuated and its peak delayed. tolbutamide, chlorpropamide and gliclazide) show An initial surge of insulin release appears to be very little interaction with the cardiac and vascular particularly important for effective postprandial SUR receptors. The effects of the KATP channel suppression of hepatic glucose production; failure to opener nicorandil (an anti-anginal drug with cardisuppress endogenous glucose production exaceroprotective properties) are blocked by sulphobates postprandial hyperglycaemia. Because postnylureas that have a benzamido group. [15] The clinprandial hyperglycaemia contributes to elevated ical implications of these observations remain to be HbA1c levels it is a logical therapeutic target. Rapiddetermined. Although very high concentrations of acting prandial insulin releasers are available that sulphonylureas can cause contraction of cardiac and stimulate rapid, but short-lived, insulin secrevascular muscle, this is regarded as being unlikely to tion. [27,28] These agents are taken orally immediately be clinically significant effect at therapeutic drug before a meal. Derivatives of meglitinide, such as concentrations. Nonetheless, on the basis of adverse repaglinide and the phenylalanine derivative nategclinical experiences in high-risk patients, some high linide, are promoted as ‘prandial glucose regulaprofile authorities continue to advocate that sulphotors’; in fact, fasting hyperglycaemia is also imnylurea use be kept to a minimum in patients with proved to a lesser extent, particularly with repagliovert coronary artery disease. [25] nide. Clinical experience with these agents remains limited in most countries; these drugs are appreci- 1.1.6 New Formulations of Sulphonylureas ably more expensive than most sulphonylureas, the Alterations to the formulation of some sulpholatter also having the reassurance of outcome data nylureas have been undertaken to modify the durafrom the UKPDS. tion of action. [4] For example, a micronised formulation of glibenclamide is available in the US that 1.2.1 Mode of Action increases the rate of gastrointestinal absorption, Benzamido prandial insulin releasers bind to the thereby enabling an earlier onset of action. A longer- SUR1 in the plasma membrane of the β cell at a site acting (‘extended release’) formulation of glipizide distinct from the sulphonylurea binding site (figure has also been introduced. A new (‘modified release’ 2). Since the KATP channel is closed when either the [MR]) formulation of gliclazide was launched in benzamido binding site or the sulphonylurea bindsome countries in 2002. This formulation has been ing site on the SUR1 is bound with its respective designed to produce an initially rapid, followed by agonist, there is no advantage in giving a prandial steady release of the drug to enable once-daily dos- insulin releaser in addition to a sulphonylurea. Howage. For the MR formulation of gliclazide, 30mg is ever, drugs are also in development that promote β- © 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)
Page 1 and 2: Drugs 2005; 65 (3): 385-411 REVIEW
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Page 7 and 8: Oral Antidiabetic Agents 391 Glucos
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