Pancreatic Hormones and Anti-Diabetic Drugs PDF

PANCREATIC HORMONES AND C ANTI-DIABETIC DRUGS The endocrine pancreas Hormones produced: insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; gl...

PANCREATIC HORMONES AND C ANTI-DIABETIC DRUGS The endocrine pancreas Hormones produced: insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; gastrin, which stimulates gastric acid secretion; pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified. Diabetes mellitus defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. Classification: Type 1- insulin dependent DM Type 2- non-insulin dependent DM Type 3- others Type 4- gestational DM Type 1 DM selective beta cell (B cell) destruction and severe or absolute insulin deficiency further subdivided into immune (most common) and idiopathic causes most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age insulin replacement therapy is necessary to sustain life. Type 1 DM Diabetic ketoacidosis- caused by insufficient or absent insulin and results from excess release of fatty acids and subsequent formation of toxic levels of ketoacids. Type 2 DM characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. 10–20% of individuals in whom type 2 diabetes was initially diagnosed actually have both type 1 and type 2 or a slowly progressing type 1 called latent autoimmune diabetes of adults (LADA), and they ultimately require full insulin replacement. Dehydration in individuals with untreated or poorly controlled type 2 diabetes can lead to a life-threatening condition called non-ketotic hyperosmolar coma Type 3 refers to multiple other specific causes of an elevated blood glucose: pancreatectomy, pancreatitis, non-pancreatic diseases, drug therapy, etc. Type 4 DM Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. Insulin (chemistry) small protein with a molecular weight in humans of 5808. contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges Proinsulin- long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Insulin secretion released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants: other sugars (eg, mannose), amino acids (especially gluconeogenic amino acids, eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity Stimulatory drugs: sulfonylureas, meglitinide and nateglinide, isoproterenol, and acetylcholine. Inhibitory signals: insulin itself and leptin, α-adrenergic sympathetic activity, chronically elevated glucose, and low concentrations of fatty acids. Inhibitory drugs: diazoxide, phenytoin, vinblastine, and colchicine. Insulin degradation Liver (60%) and kidney (35-40%): main organ to remove insulin from the circulation. insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30–40%. Circulating insulin Basal insulin values of 5–15 μU/mL (30–90 pmol/L) are found in normal humans, with a peak rise to 60–90 μU/mL (360–540 pmol/L) during meals. The insulin receptor Effects of insulin on its targets promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues Insulin preparations Types: rapid acting, with very fast onset and short duration; short-acting, with rapid onset of action; intermediate-acting; and long-acting, with slow onset of action Insulin preparations Injected rapid acting and short-acting insulin- dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. Injected intermediate-acting NPH insulin- modified to provide prolonged action and are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin). Insulin glargine and insulin detemir- clear, soluble long-acting insulin Rapid-acting insulin — insulin lispro, insulin aspart , and insulin glulisine— permit more physiologic prandial insulin replacement because their rapid onset and early peak action more closely mimic normal endogenous prandial insulin secretion than does regular insulin, and they have the additional benefit of allowing insulin to be taken immediately before the meal without sacrificing glucose control. Duration of action: more than 4-5 hours have the lowest variability of absorption (approximately 5%) of all available commercial insulin (compared with 25% for regular insulin and 25% to over 50% for long- acting analog for mutations and intermediate insulin, respectively). preferred insulin for use in continuous subcutaneous insulin infusion devices. Insulin lispro first monomeric insulin analog to be marketed, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28 Advantage: very low propensity—in contrast to human insulin—to self associate in antiparallel fashion and form dimers. Onset of action: 5–15 minutes Peak of activity: early as 1 hour. Insulin aspart created by the substitution of the B28 proline with a negatively charged aspartic acid. Its absorption and activity profile are similar to those of insulin lispro, and it is more reproducible than regular insulin Insulin glulisine formulated by substituting a lysine for asparagine at B3 and glutamic acid for lysine at B29. Short-acting insulin Regular insulin is a short-acting soluble crystalline zinc insulin that is now made by recombinant DNA techniques to produce a molecule identical to that of human insulin. effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection, and generally lasts 5–8 hours. hexameric nature of regular insulin causes a delayed onset and prolongs the time to peak action should be injected 30–45 or more minutes before the meal. particularly useful for intravenous therapy in the management of diabetic ketoacidosis and when the insulin requirement is changing rapidly, such as after surgery or during acute infections.  Intermediate-acting and long-acting insulin a. NPH (neutral protamine Hagedorn, or isophane) insulin— intermediate-acting insulin whose absorption and onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncomplexed form (“isophane”) After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. Onset: 2-5 hours Duration of action: 4-12 hours usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement. Intermediate-acting and long-acting insulin b. Insulin glargine soluble, “peakless” (ie, having a broad plasma concentration plateau), long-acting insulin analog. designed to provide reproducible, convenient, background insulin replacement. Slow onset of action (1-1.5 hour) and maximum effect after 4-6 hours Intermediate-acting and long-acting insulin c. Insulin detemir most recently developed long-acting insulin analog. The terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29 lysine. Onset of action: 1-2 hours Duration: more than 12 hours Given 2x daily Mixture of insulin mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption. 50%/50% and 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart premixed formulations. Insulin glargine and detemir must be given as separate injections 70%/30% NPH/regular Insulin production carried out by inserting the human or a modified human proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the insulin or insulin analog molecules. Concentration available in a concentration of 100 U/mL (U100). Insulin delivery system Standard delivery: subcutaneous injection Portable Pen Injectors: facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. regular insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, and several mixtures of NPH with regular, lispro, or aspart insulin Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps): external open- loop pumps for insulin delivery. have a user programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results.  Insulin treatment of special circumstances A. Diabetic ketoacidosis Management: aggressive intravenous hydration and insulin therapy and maintenance of potassium and other electrolyte levels. B. Hyperosmolar Hyperglycemic Syndrome diagnosed in persons with type 2 diabetes and is characterized by profound hyperglycemia and dehydration. Management: aggressive rehydration and restoration of glucose and electrolyte homeostasis and low dose of insulin may be required Complications of insulin therapy A. Hypoglycemia S/S: (tachycardia, palpitations, sweating, tremulous ness) and parasympathetic (nausea, hunger)—and may progress to convulsions and coma if untreated. Management: simple sugar or glucose should be given, preferably in liquid form. 20–50 mL of 50% glucose solution by intravenous infusion over a period of 2–3 minutes- unconscious 1 mg of glucagon injected either SC/IM may restore consciousness within 15 mins Complications of insulin therapy B. Immunotherapy of insulin therapy Insulin allergy immediate type hyper sensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. Immune insulin resistance A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Complications of insulin therapy C. Lipodystrophy at Injection Sites atrophy of subcutaneous fatty tissue at the site of injection. D. increased cancer risk attributed to insulin resistance and hyperinsulinemia Oral anti-diabetic agents Insulin secretagogues: Sulfonylureas and Meglitinide Insulin secretagogues: Sulfonylureas MOA: increase insulin release from the pancreas and a reduction of serum glucagon levels and closure of potassium channels in extrapancreatic tissue Insulin Release from Pancreatic Beta Cells: Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel. Reduction of Serum Glucagon Concentrations: Long-term administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to the hypo glycemic effect of the drugs Efficacy & Safety of the Sulfonylureas Hypoglycemia Cardiovascular events (Esp. Tulbutamide) First generation Tolbutamide Chlorpropamide Tolazamide Acetohexamide Second generation Glyburide C/I in the presence of hepatic impairment and in patients with renal insufficiency. Glipizide shortest half-life (2–4 hours) of the more potent agents Ingested 30 minutes before breakfast Glimiperide approved for once-daily use as monotherapy or in combination with insulin. long duration of effect with a half-life of 5 hours Gliclazide Insulin secretagogue: Meglitinide Repaglinide--first member MOA: modulate beta cell insulin release by regulating potassium efflux through the potassium channels previously discussed. Fast onset of action To be taken just before each meal used in type 2 diabetics with sulfur or sulfonylurea allergy.  Insulin secretagogue: D-Phenylalanine derivative Nateglinide MOA: stimulates very rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K + channel. It also partially restores initial insulin release in response to an intravenous glucose tolerance test. Biguanides Metformin MOA: reduce hepatic glucose production through activation of the enzyme AMP- activated protein kinase (AMPK). recommended as first-line therapy for type 2 diabetes. Toxicity: gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), which occur in up to 20% of patients, reduction in the absorption of vitamin B12 C/I: renal disease, alcoholism, hepatic disease, conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction) because of the increased risk of lactic acidosis induced by these drugs Thiazolidineones act to decrease insulin resistance. ligands of peroxisome proliferator-activated receptor gamma (PPAR-f), part of the steroid and thyroid superfamily of nuclear receptors. considered euglycemics and are efficacious in about 70% of new users. A/E: fluid retention, Loss of bone mineral density and increased atypical extremity bone fractures in women, Long-term therapy is associated with a drop in triglyceride levels and a slight rise in HDL and LDL cholesterol values. C/I: pregnancy and liver disease Pioglitazone Rosiglitazone Alpha glucosidase inhibitors Acarbose and Miglitol MOA: competitive inhibitors of the intestinal α-glucosidases and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides A/E: flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas. C/I: inflammatory bowel disease and with renal impairment Bile acid sequestrants Colesevelam hydrochloride MOA: exact is unknown but pre sumed to involve an interruption of the enterohepatic circulation and a decrease in farnesoid X receptor (FXR) activation. S/E: gastrointestinal complaints (constipation, indigestion, flatu lence). D/I: fat-soluble vitamins, glyburide, levothyroxine, and oral contraceptives C/I: individuals with hypertriglyceridemia, a history of pancreatitis secondary to hypertriglyceridemia, or esophageal, gastric, or intestinal disorders. Amylin analogs Pramlintide , modulates postprandial glucose levels MOA: suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system mediated anorectic effects. should be injected immediately before eating A/E: hypoglycemia and gastrointestinal symptoms, including nausea, vomiting, and anorexia.  Glucagon-like polypeptide-1 (GLP-1) receptor agonists Exenatide and Liraglutide MOA: potentiation of glucose mediated insulin secretion, suppression of postprandial glucagon release through as-yet unknown mechanisms, slowed gastric emptying, and a central loss of appetite Exenatide- a derivative of the exendin-4 peptide in Gila monster venom, was the first incretin therapy to become available for the treatment of diabetes. injected subcutaneously within 60 minutes before a meal. A/E: necrotizing and hemorrhagic pancreatitis. Liraglutide- long-acting synthetic GLP-1 analog with 97% homology to native GLP-1 but has a prolonged half-life that permits once-daily dosing. S/E: headache, nausea, and diarrhea; antibody formation, urticaria, and other immune reactions also are observed and Pancreatitis “black box” warning that liraglutide is contraindicated in individuals with a personal or family history of medullary cancer or multiple endocrine neoplasia type 2.  Dipeptidyl peptidase-4 (DDP-4) inhibitors MOA: increase circulating levels of native GLP-1 and glucose-dependent insulin-tropic polypeptide (GIP), which ultimately decreases postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels. Sitagliptin A/E: nasopharyngitis, upper respiratory infections, headaches, and hypoglycemia when the drug is combined with insulin secretagogues or insulin. Saxagliptin Dosage adjustment is recommended for individuals with renal impairment and concurrent use of strong CYP3A4/5 inhibitors such as antiviral, antifungal, and certain antibacterial agents. A/E: increased rate of infections (upper respiratory tract and urinary tract), headaches, peripheral edema (when combined with a Tzd), hypoglycemia (when combined with a sulfonylurea), and hypersensitivity reactions (urticaria, facial edema) Linagliptin  Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors MOA: prevents the reabsorption of glucose in the kidneys, which leads to lower blood glucose levels: Bexagliflozin (Brenzavvy) Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Ertugliflozin (Steglatro) Be taken once daily before the first meal Semaglutide Ozempic Drug class: GLP-1 agonist; incretin mimetic MOA: stimulate your pancreas to release more insulin after you eat, prevents your liver from releasing stored sugars, and slows down the movement of food through your body.  Combination Therapy in Type 1 Diabetes Mellitus Combination Therapy with Pramlintide Glucagon synthesized in the alpha cells of the pancreatic islets of Langerhans “Glut glucagon”- also known as enteroglucagon, is a glucagon-like peptide that is released from enteroendocrine cells in the small and large intestine. Glucagon-like Peptide 1 (GLP-1) potent stimulant of insulin synthesis and release and beta-cell mass. inhibits glucagon secretion, slows gastric emptying, and has an anorectic effect. Pharmacologic effects of glucagon Severe hypoglycemia Endocrine diagnosis Beta-Adrenoceptor Blocker Overdose Radiology of the bowel A/E: Transient nausea and occasional vomiting can result from gluca gon administration. C/I: patient with pheochromocytoma. Islet amyloid polypeptide Amylin is a 37-amino-acid peptide originally derived from islet amyloid deposits in pancreas material from patients with long standing type 2 diabetes or insulinomas. reduces glucagon secretion, slows gastric emptying by a vagally medicated mechanism, and centrally decreases appetite