Glimepiride for Diabetes mellitus

Glimepiride

Pharmacodynamics  Pharmacokinetics  Clinical Trials  Dosage  Contraindications  Special Precautions  Drug Interactions  Adverse Effects

Diabetes Mellitus is a chronic disorder characterised,by hyperglycaemia and disturbances in the carbohydrate, fat and protein metabolism, secondary to the absolute or relative deficiency of insulin secretion and/or action. It is in this context that one has to individualise the treatment in every patient with type 2 diabetes mellitus. Other factors that affect decision making include body habitus, symptoms, complications, weight loss and presence of other diseases. Diet and exercise are the mainstay of the therapy in the management of type 2 diabetes mellitus. Pharmacotherapy plays a major role when diet and exercise alone do not achieve satisfactory metabolic control. The choice of a hypoglycaemic agent is determined by the presence of  insulin deficiency or that of insulin re sistance (in the liver or the periphery), in a particular patient. Individuals with in sulin deficiency or very severe insulin resistance respond only to insulin therapy, whereas those with partial or rela tive insulin deficiency with or without insulin resistance respond to oral drugs viz. sulfonylureas, metiglinides or to insulin sensitising agents like metformin or thiazolinediones. The sulfonylureas are oral hypoglycae mic agents of which two distinct gen erations of drugs have been introduced. 

Pharmacodynamics                                                    

Glimepiride is a second generation sulfonylurea that  is noted for its ability to obviate certain side effects which are peculiar to the first generation of sulfonylurea compounds. These in clude the absence of hyponatremia, potentiation of hypoglycaemia due to non-ionic binding, single dose therapy and compliance. Glimepiride has a pancreatic as well as an extrapancreatic effect. Pancreatic effects may be acute or chronic. An acute response occurs when glimepiride binds to the specific sulfonylurea receptor and brings about closure of the K+ ion channels of the beta cells of the pancreas, facilitating the influx of the Ca2+ ions into the cells. The rise of the cytosolic calcium is responsi ble for the secretion of insulin. The chronic effect on insulin secretion depends on the degree of nutrient induced rise in plasma glucose. The extrapancreatic effects include direct stimulation of peripheral glucose disposal; stimulation of glycogenesis and lipogenesis and increased activity of glyco gen synthetase. The pharmacodynamic profile of glimepiride resembles that of glibenclamide but it is more potent in re ducing blood sugar by a less pronounced effect on insulin secretion, and release of glucagon. It maintains a physiological response to acute physical exercise with respect to insulin secretion and thus has a lower risk of hypoglycaemia following exercise when compared to glibebclamide. It also inhibits platelet aggre gation thus preventing macrovascular complications. This effect is more pro nounced than gliclazide.

Pharmacokinetics                                                Back to Top

  The pharmacokinetic studies of glimepiride have shown that it is com pletely absorbed and its absolute bioavailability is 100% after oral administration. The maximum absorption takes place within one hour of oral administra tion and peak drug levels are reached at 2-3 hours. Its absorption is decreased if it is taken along with or after meals. It is gradually released in the circulation be cause it is tissue (protein) bound. Its half life is 9 hours. 

Clinical Trials

Placebo controlled trials conducted in patients with NIDDM treated with glimepiride showed that plasma glucose levels are reduced significantly but the stimulated insulin secretion is not as high as seen with other sulfonylureas. The most effective reduction in the blood glu cose values is seen in patients with the highest HbAIC values to start with. An other beneficial effect noted in these studies was that the insulin stimulation and release occurs at the time of peak of the postprandial blood glucose levels. Comparative studies between glimepiride and other sulfonylureas show that the blood glucose lowering response to glimepiride is more prompt and safe. There is more reduction in the fasting blood sugars with glimepiride (-51.5 mg% ) than with,glipizide (-32 mg% ) and the incidence of hypoglycaemia has been found to be comparable at these levels {3% in case of glimepiride and 2.8% in glipizide). Short term studies show that Glimepiride has a more pronounced ef fect on the peripheral glucose utilization, it releases lesser amounts of insulin on exercise and maintains the physiological response (reduced insulin secretion) to exercise when compared with glibenclamide.

Dosage                                                                    Back to Top

Total Dose: In principle, the dosage is governed by the desired blood sugar level. The dosage of Glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. The initial and the maintenance doses are set based on the results of regular checks of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy. Initial dose and dose titration The usual initial dose is 1 mg once daily. If necessary, the daily dose can be increased. Any increase can be based on regular blood sugar monitoring, and should be gradual. i.e., at intervals of two to 6 weeks, stepwise, as follows: 1 mg- 2 mg -3 mg -4 mg -6 mg. Dose range in patients with well controlled diabetes. The usual dose range in patients with well controlled diabetes is 1 to 4 mg daily.

Distribution of dosage: Timing and distribution of dosage are decided by the physician, in consideration of the patient's current life style. Normally, a single daily dose is sufficient. This should be taken immediately before a substantial breakfast or -if none is taken -immediately before the first main meal. It is very important not to skip meals after taking Glimepiride.

Secondary dosage adjustment: As the control of diabetes improves, sensitivity to insulin increases; therefore, Glimepiride requirements may fall as treatment proceeds. To avoid hypoglycaemia, a timely dose reduction or cessation of therapy must be considered. A dose adjustment must also be considered whenever the patient's weight or life-style changes, or other factors arise which cause an increased susceptibility to hypo -or hyperglycaemia.

Duration of treatment: Treatment normally a long-term therapy. Changeover from other oral antidiabetics to Glimepiride There is no exact dosage relationship between Glimepiride and other oral blood -sugar -lowering agents. When substituting Gliimepiride for other such agents, the initial daily dose is 1 mg; this applies even in changeovers from the maximum dose of another oral blood -sugar -lowering agent.

Contraindications                                                    Back to Top

 Glimepiride is not suitable for the treatment of insulin-dependent (type I) diabetes mellitus (e.g. for the treatment of diabetics with a history of ketoacidosis), or of diabetic precoma or coma. Glimepiride must not be used in patients hypersensitive to Glimepiride, other sulfonylureas, other sulfonamides, or any of the excipients (risk of hypersensitivity reactions). No experience has been gained concerning use of Glimepiride in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairement of renal or hepatic function, a changeover to insulin is indicated.

Use in pregnancy and Lactation: To avoid risk of harm to the child, Glimepiride must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician, and should changeover to insulin. Ingestion of Glimepiride with the breast milk may harm the child. Therefore, Glimepiride must not be taken by breast-feeding women. Either a changeover to insulin or a complete discontinuation of breast-feeding is necessary.

Special Precuations

 In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring. Factors favouring hypoglycaemia include .

Drug Interactions                                                    Back to Top

 Patients who take or discontinue taking certain other medicine while undergoing treatment with Glimepiride may experience changes in blood sugar control. Based on experience with Glimepiride and on what is known of other sulfonylureas, the following interactions must be considered. Potentiation of the blood-sugar-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following medicines is taken, for example insulin and other oral antldiabetlcs, ACE inhibitors, allopurinol, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanethidine, MAO inhibitors, miconazole, para- aminosalicyclic acid, pentoxifylline (high dose parenteral), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, sulfonamides, tetracyclines, tritoqualine, trofosfamide.

Weakening of the blood-sugar-lowering effect and, thus, raised blood sugar levels may occur when one of the following medicines is taken, for example: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) and other sympathomimetic agents, glucagon, laxatives (after protracted use), nicotinic acid (in high doses), oestrogens and progestogens, - phenothiazines, phenytoin, rifampicin, thyroid - hormones. H2 receptor antagonists, clonidine and reserpine may lead to either potentiation or weakening of the blood-sugar-lowering effect. Beta-blockers decrease glucose tolerance. In patients with diabetes mellitus, this may lead to deterioration of metabolic control. In addition, beta-blockers may increase the tendency to hypoglycaemia (due to impaired counter-regulation). Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter regulation to hypoglycaemia may be reduced or absent. Both acute and chronic alcohol intake may potentiate or weaken the blood sugar lowering action of Glimepiride unpredictably. The effect of coumarin derivatives may be potentiated or weakened.

Adverse Effects                                                                Back to Top

 Based on experience with Glimepiride and on what is known of other sulfonylureas, the following adverse effects must be considered:

Hypoglycaemia : As a result of the blood sugar lowering action of Glimepiride, hypoglycaemia may occur, and may also be prolonged. It may initiate cardiac arrhythmias.

Digestive side effects: Occasionally, gastrointestinal symptoms such as the following may occur- nausea, vomiting, sensations of pressure, fullness in the epigastrium, abdominal pain and diarrhoea. In isolated cases, liver enzyme levels may increase, and impairment of liver function (e.g. with cholestasis and jaundice) or hepatitis may develop, possibly resulting the liver failure.

Blood: Severe changes in the blood picture may occur Rarely thrombopenia and haemolytic anaemia or e.g. erythrocytopenia, granulocytopenia, agranulocytosis, or pancytopenia {e.g. due to myelosuppression may develop.

Other adverse reactions: Occasionally allergic or pseudoallergic reactions may occur, e.g., in the form of itching, urticaria or rashes. Such reactions are mild, but may become more serious and be accompanied, by dyspnoea and a fall in blood pressure sometimes progressing to shock. In isolated cases, the following may occur- allergic vasculitis, hypersensitivity of the skin to light, and a decrease in serum sodium.

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