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Insulin and Oral Hypoglycemic Drugs Drug Regular Insulin short-acting soluble Zn crystalline insulin only form that injectable IV or infusion pumps NPH Insulin neutral protamine Hagedon intermediate-acting contains protamine and insulin so neither is uncomplexed insulin complexed to protamine to prolong its action Ultralente long-acting poorly soluble crystals from Zn and bovine insulin Lente intermediate-acting 30% semi/70% ultra Semilente fast-acting amorphous ppt. of Zn and insulin Pharmacokinetics normally secreted by beta cells of the pancreas at the rate of 30-50 units per day glucose is the primary secretogogue rapidly metablized by reduction of the disulfide binds to A and B chains followed by proteolysis of the peptide chains in the liver and kidney; peripheral tissues (e.g. fat) may also degrade insulin t ½ 5-15 min MOA Effects on liver: reversal of catabolic features of insulin delivery inhibits glycogenolysis inhibits FA and aa keto acid formation inhibits aa glucose Anabolic Action: promotes glucose storage as glygogen inc. TG synth. and VLDL synth. Inc. Glycogen synth.: inc. glucose transport induces glycogen synthase and inhibits phosphorylase Effect on adipose tissue: inc. TG storage LPL induced and activated to hydrolyze TG from lipoprotein intracellular lipase is inhibited by insulin SE hypoglycemic rxns allergic rxns/anaphylaxis lipodystrophy (at site of injection) hypokalemia (due to insulin stim. of K+ uptake by activation of Na+/K+ ATPase drug interactions Use DM Sulfonureas Tolbutamide Chlorpropamide Tolazamide Acetohexamide Glyburide Glipizide Tolbutamide: t ½ 4-6 hrs. given 2-3 times/day Chlorpropamide: t ½ 60 hrs. given once/day Others: t ½ 12-24 hrs. given 1-2 times/day All: hepatic metabolism highly bound to albumin renal excretion Pancreatic Effects:* stim. rapid secretion of preformed insulin by beta cells potentiate the stim. effect of glucose on insulin secretion (maybe synthesis, too) drug effect related to glucose concentration may stim. regeneration of beta cell Extra-pancreatic Effects: potentiate ability of insulin to stim. glucose transport into muscle, fat reduce hepatic glucose output (inhibit glycogenolysis and gluconeogenesis) stim. hepatic glycolysis *pancreatic betas cells have specific K+ channels which extrude K+ from the cell to maintain resting potential various stimuli (esp. glucose) inhibits the channels, to decrease K+ extrusion causes Mb depolarization opens specific Ca2+ channel allow Ca2+ influx increased Ca2+ stim. the movement of insulin granules to surface of the beta cell and extrusion of insulin sulfonureas bind to a receptor on the beta cell Mb, to inhibit K+ channels, and stim. insulin secretion may decrease secretion of glucagon in response to secretory stim. hypoglycemia (esp. elderly) GI complaints, skin rashes, bone marrow depression, hepatotoxic effects, goiter hyponatremia (inapprop. ADH secretion & action on tubules) possible inotropic and chronotropic effects in the heart pharm-kinetic SE: due to inc. binding to plasma proteins; drugs that induce hep. metabolism (like phenobarb.) may antagonize effects; drugs that inhibit hepatic met. or compete for renal secretion may enhance hypoglycemic effects pharm-dynamic SE: may occur with drugs that alter insulin secretion and exert met. effects (e.g. glucocorticoids) NIDDM those who fail control by diet and weight reduction; or who are unwilling to take insulin Biguanides Metformin Thiazolidinediones Troglitazone Pioglitazone a-Glucosidase Inhibitors Acarbose absorbed from SI does not bind plasma proteins excreted unchanged in urine plasma t ½ is 1.3-4.5 hrs. rapid absorption from GI tract peak blood levels in 2-3 hrs food increases absorption by 30-85% hepatic metabolism elim. in feces steady-state within 3-5 days poorly absorbed dec. liver gluconeogenesis and increases glucose uptake by increasing insulin action in peripheral tissues NO effect on pancreatic insulin secretion REQUIRES presence of insulin to be effective dec. blood glucose by improving insulin sensitivity in muscle and adipose and by directly inhibiting hepatic gluconeogenesis do not stim. insulin secretion by pancreas lowers TG levels by 20% and may inc. HDL reduce intestinal absorption of starch, dextrin, and disacchs. by inhibiting action of intestinal brush border a-glucosidase slowing the absorption dec. post-prandial rise in plasma glucose lactic acidosis – by inhibiting lactate metabolism (esp. associated with renal impairment, high EtOH intake, hypoxia, shock, hepatic failure) SE: metallic taste, diarrhea, N, V, anorexia also inhibits absorption of vit. B12 and folic acid may induce drug metabolism by CYP3A4 (to dec. plasma concentrations of terfenadine, cyclosporine, tacrolimus, OCs, and some HMG-CoA reductase inhibitors) may increase plasma volume by 6-8 % malabsorption, flatulence, and abdominal bloating NIDDM insulin resistance impaired glucose tolerance