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Thread: [Mechanism] Secondary-Line Antidiabetic Agents

  1. #1
    PharmD Year 1 TomHsiung's Avatar
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    Default [Mechanism] Secondary-Line Antidiabetic Agents

    There are four second-line antidaibetic agents:

    sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors, and SGLT2 inhibitors.
    Last edited by admin; Tue 19th January '16 at 1:39pm.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease.

  2. #2
    PharmD Year 1 TomHsiung's Avatar
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    Default Sulphonylureas

    Glimepiride

    Mechanism of Action

    Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta- cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

    So the depolarization of beta-cell’s membrane, caused by the ATP-sensitive K+ channel (target of sulfonylurea anti-diabetic drugs) enhances the influx of calcium and the resultant increased secretion of insulin.

    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease.

  3. #3

    Default Meglitinides

    Repaglinide

    Mechanism of Action

    Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.

    Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.

    Clinical Pharmacy Specialist - Infectious Diseases

  4. #4

    Default Thiazolidinediones

    Pioglitazone

    Mechanism of Action

    Pioglitazone hydrochloride is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone hydrochloride decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.


    In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.


    Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
    Clinical Pharmacy Specialist - Infectious Diseases

  5. #5

    Default Alpha-Glucosidase Inhibitors

    Acarbose

    Mechanism of Action

    In contrast to sulfonylureas, acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.


    Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.
    Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.
    Clinical Pharmacy Specialist - Infectious Diseases

  6. #6

    Default Dipeptyl Peptidase-4 Inhibitors

    Saxagliptin

    Mechanism of Action

    Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.
    Clinical Pharmacy Specialist - Infectious Diseases

  7. #7

    Default SGLT-2 Inhibitors

    Canagliflozin

    Mechanism of Action

    Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE).
    Clinical Pharmacy Specialist - Infectious Diseases

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