Insulin And Oral Hypoglycemic Agents

Chapter 34 Insulin and oral hypoglycemic agents

OVERVIEW OF DIABETES MELLITUS *Approximately 150 million people have diabetes mellitus worldwide, and this number may well double by the year 2025 (WHO report). * Adult blindness, amputation, renal failure, heart attacks and strokes. * Diabetes is heterogeneous group of syndromes characterized by an elevation of fasting blood glucose due to relative or absolute lack of insulin. * Metabolic alterations due to insulin deficiency are exacerbated by the excess of glucagon. Two types of Diabetes Mellitus : Insulin-dependent diabetes mellitus (IDDM) or Type I Non-insulin-dependent diabetes mellitus (NIDDM) or Type II

Diabetes Mellitus Virtually all forms of diabetes mellitus are caused by a decrease in the circulating concentration of insulin (insulin deficiency) and a decrease in the response of peripheral tissues to insulin (insulin resistance). These abnormalities lead to alterations in the metabolism of carbohydrates, lipids, ketones, and amino acids; the central feature of the syndrome is hyperglycemia.

Treatment of diabetes mellitus 1. Attention to diet 2. Physical exercise 3. Medication

Drug classification 1. Insulin 2. Oral hypoglycemic Agents: Sulfonylureas Biguanides α-Glucosidase Inhibitor

Discovery of insulin In 1921, Frederick G. Banting, a young Canadian surgeon, convinced a professor of physiology in Toronto, J. J. R. Macleod, to allow him access to a laboratory to search for the antidiabetic principle of the pancreas. Banting assumed that the islet tissues secreted insulin but that the hormone was destroyed by proteolytic digestion prior to or during extraction. Then he attempted to overcome the problem by tying the pancreatic ducts. The acinar tissue Frederick G. Banting degenerated, leaving the islets undisturbed; the remaining tissue was then extracted with ethanol and acid. Banting and Macleod thus obtained a pancreatic extract that was effective in decreasing the concentration of blood glucose in diabetic dogs. In 1923, the Nobel Prize in Medicine and Physiology was awarded to Banting and Macleod with remarkable rapidity. J. J. R. Machleod

Insulin

β(B) cells produce insulin A cells produce glucagons D cells produce somatostatin These hormones play an important role in regulating the metabolic activities of the body, and in doing so, help maintain the homeostasis of blood glucose.

Insulin is secreted from B cells located in the islets of Langerhans, and it is an acidic protein. Insulin is a small protein consisting of two polypeptide chains that are connected by disulfide bonds. Insulin is isolated from beef and pork pancreas. However, human insulin is replacing the animal hormone for therapy. Pork insulin is closest in structure to human insulin, differing by only one amino acid.

【 Pharmacokinetics 】 Because insulin is a protein, it is degraded in the gastrointestinal tract if taken orally. Therefore, it is generally administered by subcutaneous injection. The half-life of insulin in plasma is about 9~10 minutes. Insulin is inactivated by the reducing enzyme, insulinase, found mainly in the liver and kidney. Insulin preparations vary primarily in their times of onset of activity and duration of the insulin crystals in the preparations. Dose, site of injection, blood supply, temperatures and physical activity can affect the duration of action of the various preparations.

【 Pharmacologic effects 】 1. Insulin reduces blood glucose by promoting glucogen synthesis and storage, converting glucose into fat, and inhibiting glycogenolysis and gluconeogenesis. 2. Insulin promotes fatty acid and glucose transport, and increases adipose synthesis and inhibits it breakdown, and reduces circulating free fatty acids. 3. Insulin promotes protein synthesis by increasing amino acid transport and depresses protein breakdown. 4. Insulin increases heart rate, and enhances myocardial contraction, and reduces renal blood flow. 5. Insulin enables glucose to pass across cell membranes, and the transit of potassium into the cell is enhanced.

【 Insulin receptor 】 Once insulin has entered the circulation, it is bound by specialized receptors that are found on the membranes of most tissues. The insulin receptor consists of two heterodimers, each containing an alpha subunit, which is entirely extracellular and constitutes the recognition site, and a beta subunit that spans the membrane. The beta subunit contains a tyrosine kinase. When insulin binds to the alpha subunit at the outside surface of the cell, tyrosine kinase activity is stimulated in the beta portion. Then the network of phosphorylations within the cell is stimulated, which results in some actions such as hypoglycemia, and so on.

Insulin receptor

【 Preparations 】 1. Short-acting insulins: Regular Insulin: soluble; peak 2-4 hours, duration 5-7 hours, used in subcutaneous or intravenously, is a good agent for controlling ketoacidosis.

2. Intermediate-acting insulins Neutral Protamine Hagedorn ( NPH ): peak 8-12 hours, duration 18-24 hours.

3. Long-acting insulins Protamine Zinc Insulin: less soluble; injected as a tissue depot-slow absorption; peak 16-18 hours, lasting up to 36 hours; Fine control of hyperglycemia is difficult with such a long-acting preparation.

4. Human insulins Useful for individual with an allergy to insulin from animal sources.

【 Therapeutic uses 】 1. Treatment of Type 1 diabetes: all patients with type 1 DM 2. Treatment of Type 2 diabetes: not adequately controlled by diet and/or oral hypoglycemic agents, and for patients with postpancreatectomy diabetes or gestational diabetes. 3. Insulin is critical for the management of diabetic ketoacidosis, and it has an important role in the treatment of hyperglycemic, nonketotic coma and in the preoperative management of both type 1 DM and type 2 DM patients. In all case, the goal is the normalization not only of blood glucose but also of all aspects of metabolism; the latter is difficult to achieve. Optimal treatment requires a coordinated approach to diet, exercise, and the administration of insulin.

【 Adverse effects 】

1. Hypoglycemia: the most common adverse reaction This may result from an inappropriately large dose, from a mismatch

between the time of peak delivery of insulin and food intake. Hypoglycemia may lead to hunger, palpitations, sweating, tremulousness, coma and even death(<2.77mmol/L). All insulin-treated diabetic patients and family members should be instructed in the recognition of hypoglycemia, and the sue of sugar water for normal patients and injection 50% glucose solution for severe patients.

2. Insulin allergy Allergic reactions are very rare, but may occur to any insulin and to any constituent of the formulation.

【 Adverse effects 3. Insulin】 resistance Most insulin-treated patients develop a low titer of circulating IgG antiinsulin antibodies that neutralize the action of insulin to a small extent. In some diabetic patients, principally those with some degree of tissue insensitivity to insulin (such as occurs in obese diabetics) and a history of interrupted insulin therapy with preparations of less-than-pure beef insulin, a high titer of circulating IgG anti-insulin antibodies develops. This results in extremely high insulin requirements.

4. Lipoatrophy and lipohypertrophy Atrophy of subcutaneous fat at the site of insulin injection (lipoatrophy) is probably a variant of an immune response to insulin, whereas lipohypertrophy (enlargement of subcutaneous fat depots) has been ascribed to the lipogenic action of high local concentrations of insulin.

Oral hypoglycemic Agents These agents are useful in the treatment of patients who have non-insulin-dependent diabetes (NIDDM) but cannot be managed by diet alone. The patient most likely to respond well to oral hypoglycemic agents is one who develops diabetes after ages 40 and has had diabetes less than 5 years. Patients with long-standing disease may require a combination of a hypoglycemic drug and insulin to control their hyperglycemia. And oral hyperglycemic agents should not be given to patients with Type 1 diabetes.

Oral hypoglycemic Agents: Sulfonylureas Biguanides α-Glucosidase Inhibitor

Sulfonylureas The first generation agents: tolbutamide, acetohexamide, tolazamide, chlorpropamide The second generation agents: glibenclamide, glipizide, gliclazide, glimepiride

【 Pharmacokinetics 】 The different sulfonylureas all are effectively absorbed from the gastro-intestinal tract. Sulfonylureas in plasma are largely (90% to 99%) bound to serum proteins, and are metabolized by the liver, and the metabolites are excreted in the urine. The half-life of acetohexamide is short, but the drug is reduced to an active compound with a half-life that is similar to those of tolbutamide and tolazamide (4 to 7 hours). Chlorpropamide has a long half-life (24 to 48 hours). The second generation agents are approximately 100 times more potent than those first generation agents. Although their half-lives are short (3 to 5 hours), their hypoglycemic effects are evident from 12 to 24 hours, and it is often possible to administer them once daily. These drugs are contraindicated in patients with hepatic or renal insufficiency because they may cause hypoglycemia.

【 Pharmacologic effects 】 The mechanisms of the action of the sulfonylureas include: (1) to stimulate insulin release from the β-cells of the pancreas; (2) to reduce serum glucagons levels; (3) to potentiate insulin action on target tissues.

【 Therapeutic uses 】 Treatment of diabetes mellitus Sulfonylureas are used to control hyperglycemia in type 2 DM patients who cannot achieve appropriate control with changes in diet alone. In all patients, however, continued dietary restrictions are essential to maximize the efficacy of the sulfonylureas. Patients with type 2 DM whose disease is controlled with relatively low doses of insulin are more likely to respond to sulfonylureas, as those who are obese and/or older than 40 years of age.

【 Adverse effects 】 Adverse effects of the second-generation sulfonylureas are slightly less than those of the first-generation agents in patients. 1. Hypoglycemic reactions, including coma. 2. Other side effects: nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions and dermatological reactions. Contraindications: type 1 DM, pregnancy, lactation, and significant hepatic or renal insufficiency.

Biguanides The biguanides includes metformin, phenformin and buformin. Metformin is well absorbed mainly from the small intestine. The drug does not bind to plasma proteins, and is excreted unchanged in the urine. Its half-life is about 1.5 hours. Metformin acts primarily by decreasing hepatic glucose output and by increasing insulin action in muscle and fat, largely by inhibiting gluconeogenesis. Metformin given alone or in combination with a sulfonylurea improves glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone.

Adverse effects are largely gastrointestinal, include diarrhea, abdominal discomfort, nausea, metallic taste, and anorexia. Rarely, potentially fatal lactic acidosis has occurred.

α-Glucosidase Inhibitor α-Glucosidase inhibitors (for example, acarbose) reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border α-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates; The postprandial rise in plasma glucose is blunted in both normal and diabetic subjects treated with these agents. These agents may be considered as monotherapy in elderly patients or in patients with predominantly postprandial hyperglycemia. α-Glucosidase inhibitors typically are used in combination with other oral antidiabetic agents and/or insulin.

Adverse effects: These agents cause dose-related malabsorption, flatulence, diarrhea, and abdominal bloating. Titrating the dose of drug slowly will reduce gastrointestinal side effects.