1 Drugs used to treat diabetes mellitus Ján Mojžiš Department of Pharmacology Ján Mojžiš...

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Transcript of 1 Drugs used to treat diabetes mellitus Ján Mojžiš Department of Pharmacology Ján Mojžiš...

  • Jn MojiDepartment of PharmacologyDrugs used to treat diabetes mellitus


    Pancreas - endocrine gland (peptide hormones insulin, glucagon, and somatostatin) and exocrine gland (digestive enzymes). Peptide hormones - from cells Langerhans islets or B-cells -insulin2 or A-cells glucagon1 or D-cells - somatostatin

    Hormones play an important role in regulating the metabolic activities of the body, particularly the homeostasis of blood glucose.

  • Metabolic roles of insulin and glucagon:

    High serum glucose insulin release from beta cells of the pancreas.

    Increased serum insulin lower blood glucose levels by driving carbohydrate into cells.

    Low serum glucose in insulin and glucagon.

    Elevated serum glucagon mobilization of energy storage forms. Used to fuel gluconeogenesis in the liver, producing glucose.

    Somatostatin - regulates the secretion of insulin and glucagon within the islets).

  • DIABETES MELLITUS Rapidly growing incidence - 135 million people worldwide are afflicted with Type 2 Diabetes is not a single disease - it is a heterogeneous group of syndromes characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin. Insulin-dependent diabetes mellitus (Type 1), and non-insulin-dependent diabetes mellitus (Type 2).

  • Comparison of Type 1 and Type 2 diabetesAge of onset

    Nutritional status at time of onset


    Genetic predisposition

    Defect or deficiencyType 1(Insulin-dependentdiabetes)Type 2(Non-insulin-dependent diabetes)Usually during childhood or puberty

    Frequently undernourished

    10 to 20 percent of diagnosed diabetics


    b Cells are destroyed, eliminating the production of insulinFrequently over age 35

    Obesity usually present

    80 to 90 percent of diagnosed diabetics

    Very strong

    Inability of b cells to produce appropriate quantities of insulin; insulin resistance; other defects(according to Lippincotts Pharmacology, 2006

  • Summary of hypoglycemic agentsHYPOGLYCEMIC DRUGSINSULINORAL HYPOGLYCEMIC DRUGSa-GLUCOSIDASE INHIBITORSGASTROINTESTINALHORMONESAspart insulinExtended zinc insulinGlargine insulinGlulisine insulinInsulin zinc suspensionLispro insulinNPH insulin suspensionProtamine zinc insulinSemilente insulinUltralente insulinGlipizideGlimepirideGlyburideMetforminNateglinidePioglitazoneRepaglinideRosiglitazoneTolbutamideTroglitazoneAcarboseMiglitolExenatide

  • Type 1 diabetes Treatment: Exogenous (injected) insulin to control hyperglycemia, avoid ketoacidosis, and maintain acceptable levels of glycosylated hemoglobin (HbA1c). to maintain blood glucose as close to normal as possible, and to avoid wide swings in their levels (that contribute to long-term complications).Pancreas transplantation; transplantation of islet cells - also under investigation.

  • Type 2 diabetes Treatment: To maintain blood glucose within normal limits and to prevent the development of complications. Weight reduction, exercise, dietary modification - decrease insulin resistance and correct the hyperglycemia in some patients. Mostly dependent on oral hypoglycemic agents. As the disease progresses, b-cell function declines, and insulin therapy is often required to achieve satisfactory serum glucose levels.

  • Major factors contributing to hyperglycemia observed in Type 2 diabetes1 Insulin resistance in peripheral tissues2 Inadequate insulin secreation from b cellsPANCREASInsulinADIPOSETISSUEMUSCLEGlucoseLIVERIncreased productionof glucoseDecreasedglucose uptake

  • INSULIN AND ITS ANALOGSpolypeptide hormone; two peptide chains connected by disulfide bonds. Synthesized as a precursor (pro-insulin) proteolytic cleavage insulin and peptide C - both are secreted by b-cells.

    Sources: Human insulin - replaced I. from beef or pork pancreas. By recombinant DNA technology - special strains of E. coli or yeast

    Modifications of amino acid sequence different pharmacokin. properties:lispro, aspart - faster onset and shorter duration of action than regular insulin (they do not aggregate or form complexes). glargine, detimir - long-acting, prolonged, flat levels of the hormone following a single injection.

  • Secretion of insulin

  • Administration Polypeptide degraded in GIT if taken orally mostly by subcutaneous injection (in a hyperglycemic emergency, regular insulin intravenously Continuous s.c. infusion also - it does not require multiple injections. Aerosol preparation (inhaled and absorbed in the deep lung) or oral spray (absorbed through the buccal mucosa) - in trials

  • Adverse reactions to insulin

    Hypoglycemia - the most serious and common adverse reactions to an overdose

    Lipodystrophy (less common with human insulin)

    - Allergic reactions (less common with human insulin)

  • A. Rapid-onset and short-acting preparations

    Regular insulin - short-acting, soluble, crystalline zinc insulin. Usually s.c. (i.v. in emergencies); rapidly blood sugar. Safely used in pregnancy

    Effect - within 30 min; peaks between 2 - 3 hours after s.c. injection; lasts 5-8 hours. When administered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia should be injected 30-45 or more min before the meal to minimize the mismatching.

  • Rapid-acting insulin

    Three injected rapid-acting insulin analogs: lispro, aspart, and glulisine, are commercially available.

    their rapid onset and early peak action more closely mimic normal endogenous prandial insulin secretion than regular insulin additional benefit: allowing insulin to be taken immediately before the meal without sacrificing glucose control.

    Duration of action is rarely more than 3-5 hours

  • B. Intermediate-acting insulin preparations 1. Lente insulin: Amorphous precipitate of insulin with zinc ion Onset and peak effect - slower than in regular insulin, but are sustained for a longer period. Not suitable for i.v. 2. Neutral protamine Hagedorn (NPH)- suspension of crystalline zinc insulin combined with polypeptide, protamine. Intermediate duration of action Onset cca 2-5 hours; duration of 4-12 hoursOnly s.c. (never i.v.).

  • C. Prolonged-acting insulin preparations 1. Ultralente insulin (extended zinc insulin): Suspension of zinc insulin crystals in acetate buffer large particles that are slow to dissolve slow onset of action and long-Iasting effect 2. Insulin glargine (GLAR geen): Precipitation at the injection site longer action. Slower onset than NPH insulin; flat, prolonged hypoglycemic effect (i.e., it has no peak ). Slow onset of action (1-1.5 hours); maximum effect after 4-6 hours. This maximum activity is maintained for 11-24 hours or longer. Must be given s.c.

  • Onset and duration of action of human insulin and insulin analogs.0 6 12 18 24Hours Relative plasma insulin level Glulisine insulinAspart insulin, lispro insulinRegular insulinNPH insulinExtended zinc insulinGlargine insulin(according to Lippincotts Pharmacology, 2006)

  • Patients with type 1 DM Soluble insulin is used (i.v.) in emergency treatment of hyperglycaemic diabetic emergencies (e.g. diabetic ketoacidosis). Many patients with type 2 DM ultimately require insulin treatment. Short-term treatment of patients with type 2 DM or impaired glucose tolerance during intercurrent events (e.g. operations, infections, myocardial infarction). During pregnancy, for gestational diabetes not controlled by diet alone. Clinical uses of insulin

  • ORAL HYPOGLYCEMIC AGENTS: INSULIN SECRETAGOGUES Useful in the treatment of Type 2 diabetes The patient most likely to respond well to oral hypoglycemic agents is one who develops diabetes after age 40 and has had diabetes less than 5 years. Patients with long-standing disease may require a combination of hypoglycemic drugs with or without insulin to control their hyperglycemia.

  • A. Sulfonylureas they promote insulin release from the b-cells1. Mechanisms of action of the sulfonylureas: 1) stimulation of insulin release from the -cells blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx; 2) reduction of serum glucagon levels; and 3) increasing binding of insulin to target tissues and receptors. 2. Pharmacokinetics and fate: Given orally; bind to serum proteins; metabolized by the liver; excreted by the liver or kidney. Tolbutamide has the shortest duration of action (6-12 hours),whereas the second-generation agents last about 24 hours.

    1st generation: TOLBUTAMIDE (tole BYOO ta mide), CHLORPROPAMIDE (klor PROE pa mide), TOLAZAMIDE (tole AZ a mide), ACETOHEXAMIDE (a seat oh HEX a mide),

    2nd generation: GLIBENCLAMIDE, GLYBURIDE (GLYE byoor ide) ; GLIPIZIDE (GLIP i zide), GLIMEPIRIDE

  • Mechanism of actionSU derivatives

  • Administration, fate: given orally, metabolized by the liver, and excreted by the liver or kidney. Contraindicated in patients with hepatic or renal insuficiency (delayed excretion of the drug may cause hypoglycemia).All bind strongly to plasma albumins interactions with other drugs (e.g. salicylates, sulfonamides) which compete for binding sites hypoglycaemia Adverse effects:- hypoglycemia- disulfiram-like reactions (flushing, nausea, headache after alcohol)- allergic reactions GIT disturbances weight gain, hyperin