Endocrinology Drug Introduction Endocrine medications can be broken down into the following categories Diabetic Agents Hormone Agonists Hormone Antagonists Overview Goals of diabetes treament lower serum glucose to physiologic range keep insulin levels in physiologic range eliminate insulin resistance Modalities of diabetes treatment type I DM insulin low-sugar diet type II DM exercise diet insulin 6 classes of drugs shown below Class Example ↑ Insulin secretion ↑ Insulin utilization ↓ Glucose production ↓ Glucose absorption Weight Hypoglycemia Insulin Insulin ↑ ++ Sulfonylureas Glyburide ++ + + ↑ ++ Biguanides Metformin + ++ None Glitazones(thiazolidinediones) Pioglitazone ++ +/- ↑↓ + α-glucosidase inhibitors Acarbose ++ None GLP-1 mimetics (incretin mimetics) Exenatide ++ + ↓ + Amylin analog Pramlintide + + + Insulin Insulin is only given parenterally (subcutaneous or IV) Various preparations have different durations of action Preparation Onset (hrs) Peak (hrs) Duration (hrs) Lispro (short-acting) 15 min 0.5-1.5 3-4 Regular (short-acting) 0.5-1 2-4 5-7 NPH (intermediate) 1-2 6-12 18-24 Glargine (long-acting) 1 None >24 Other preparations include aspart (short), detemir (long) Mechanism bind transmembrane insulin receptor activate tyrosine kinase phosphorylate specific substrates in each tissue type liver ↑ glycogenesis store glucose as glycogen muscle ↑ glycogen and protein synthesis ↑ K+ uptake fat increase triglyceride storage Clinical use type I DM type II DM life-threatening hyperkalemia increases intracellular K+ stress-induced hyperglycemia Toxicity hypoglycemia hypersensitivity reaction (very rare) Sulfonylureas Drugs first generation tolbutamide chlorpropamide second generation glyburide glimepiride glipizide Mechanism glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP → closes K+ channels → depolarization → ↑ Ca2+ influx → insulin release sulfonylureas mimic action of glucose by closing K+ channels in pancreatic β cells → depolarization → ↑ Ca2+ influx → insulin release continued use results in ↓ glucagon release ↑ insulin sensitivity in muscle and liver Clinical use type II DM stimulate release of endogenous insulin cannot be used in type I DM due to complete lack of islet function Toxicity first generation disulfiram-like effects especially chlorpropamide second generation hypoglycemia weight gain Biguanides Drugs metformin Mechanism ↓ gluconeogenesis exact mechanism unknown appears to inhibit complex 1 of respiratory chain may also ↑ insulin sensitivity ↑ glycolysis ↓ serum glucose levels ↓ postprandial glucose levels Clinical use type I and II DM Toxicity no hypoglycemia no weight gain lactic acidosis is most serious side effect contraindicated in renal failure Glitazones (thiazolidinediones) Thiazolidinediones, also known as the "-glitazones" Drugs pioglitazone rosiglitazone Mechanism bind to nuclear receptors involved in transcription of genes mediating insulin sensitivity peroxisome proliferator-activating receptors (PPARs) ↑ insulin sensitivity in peripheral tissue ↓ gluconeogenesis ↑ insulin receptor numbers ↓ triglycerides Clinical use type II DM as monotherapy or in combination with other agents Toxicity weight gain edema hepatotoxicity CV toxicity less risk of hypoglycemia vs. sulfonylureas α-glucosidase inhibitors Drugs acarbose miglitol Mechanism inhibit α-glucosidases in intestinal brush border delayed sugar hydrolysis delayed glucose absorption ↓ postprandial hyperglycemia ↓ insulin demand Clinical use type II DM as monotherapy or in combination with other agents Toxicity no hypoglycemia GI upset Amylin mimetics Drugs pramlintide Mechanism synthetic analogue of human amylin that acts in conjunction with insulin basis for drug mechanism is the observation that more insulin secreted with oral glucose load compared to IV ↓ release of glucagon delay gastric emptying Clinical use type I and II DM Toxicity hypoglycemia if given with insulin nausea diarrhea GLP-1 analogs Drugs exenatide Mechanism GLP-1 is an incretin released from the small intestine that aids glucose-dependent insulin secretion exenatide is a GLP-1 agonist ↑ insulin ↓ glucagon release the class of dipeptidyl peptidase inhibitors ↓ degradation of endogenous GLP-1 e.g.) -gliptins Clinical use type II DM patients requiring two drugs and looking to lose weight administer metformin and exenatide Toxicity nausea, vomiting pancreatitis hypoglycemia if given with sulfonylureas