Drugs for Diabetes Mellitus

Blood glucose concentrations are strictly maintained within homeostatic limits by the balance among absorption, storage, production, and use. Glucagon and insulin are the two most important hormones that maintain glucose homeostasis when blood concentrations are perturbed. Diabetes mellitus result from a deficiency of insulin or resistance to insulin action Type I diabetes or insulin-dependent diabetes mellitus (juvenile-onset) is caused by an absolute deficiency of insulin. Type II diabetes or insulin-independent diabetes mellitus (adult-onset) is caused by a down-regulation of insulin receptors. Symptoms of DM excessive urine production (polyuria) excessive thirst (polydipsia) excessive eating (polyphagia)

Treatment Insulin-dependent diabetes mellitus (IDDM) Insulin is the only therapy. Non-insulin-dependent diabetes mellitus (NIDDM) Controlled by diet, exercise, and weight reduction Otherwise, oral hypoglycemic agents should be given Insulin may be required Therapeutic objectives are: 1. prevention of life-threatening hyperglycemic (diabetic) coma; 2. prevention of diabetic sequelae (angiopathy with blindness, myocardial infarction, renal failure; 3. prevention of insulin overdosage leading to life-threatening hypoglycemic shock (CNS disturbance due to lack of glucose).

 Insulin It is synthesized in the B- (or -) cells of the pancreatic islets of Langerhans. It is a protein (MW 5800) consisting of two peptide chains linked by two disulfide bridges (the A chain has 21 and the B chain 30 amino acids). It stimulates cellular transport of glucose, amino acids and nucleotides It promotes synthesis of complex organic molecules (glycogen, protein, triglycerides) Sources of therapeutic insulin preparations Insulin can be obtained from pancreatic tissue of animals: Porcine insulin differs from human insulin merely by one B chain amino acid, bovine insulin by two amino acids in the A chain and one in the B chain. Human insulin produced by gene technology involving insertion of the appropriate human DNA into E. coli bacteria. Insulin Preparations As a peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutaneously. The duration of action depends on the rate of absorption from the injection site. 1. 2. 3. 4. Rapid acting insulin (05 hours), Short acting insulin (08 hours), Intermediate acting insulin (2 to 16 hours), Long acting insulin (4 to 36 hours).

1. Rapid Acting Insulin They are insulin analogues (have been engineered to contain amino acid modifications that promote rapid entry into the circulation from subcutaneous tissue They begin to exert their effects as early as 5 to 10 minutes after administration. Lispro insulin (Humalog) the first insulin analogue, produced by switching the positions of lysine-proline amino acid residues 28 and 29 of the carboxy terminus of the -chain. displays very similar actions to insulin and has a similar affinity for the insulin receptor, but it cannot form stable hexamers or dimers in subcutaneous tissue, which promotes its rapid uptake and absorption. Aspart insulin (Novolog) Insulin aspart is absorbed nearly twice as fast as regular insulin

2. Short Acting, or Regular Insulin Humulin-R & Novolin-R Need ~30 minutes to begin to exert their effect but have a longer duration of action than does either lispro or aspart. It is dispensed as a clear neutral solution known as regular insulin. In emergencies, (e.g., diabetes ketoacidosis or hyperglycemic coma, it can be given IV (by infusion because IV injections have too brief an action; plasma t1/2 ~ 9 min). With the usual subcutaneous application, the effect is evident within 15 to 20 min, reaches a peak after ~ 3 h, and lasts for ~ 6 h. Typically, regular insulin is administered several minutes before a meal; it has a more gradual onset of action and is designed to control postprandial hyperglycemia. It is also the preparation of choice for glucose management during surgery, trauma, shock, or diabetic ketoacidosis. Rapid-acting and short-acting insulins are often administered two to three times a day or more.

3. Intermediate Acting Insulin They have a more delayed onset of action, but they act longer. When the hormone is injected as a suspension of insulin-containing particles, its dissolution and release in subcutaneous tissue are retarded. Conjugation of the insulin molecule with either zinc or the polycationic protein protamine or both will convert the normally rapidly absorbed parenterally administered insulin to a preparation with a longer duration of action. Semilente insulin: an amorphous precipitate of insulin with zinc ions in acetate buffer that has a relatively rapid onset of action Isophane insulin suspension (also called neutral protamine Hagedorn, NPH) has a rate of absorption that has been slowed by complexing insulin with protamine. Lente insulin is a mixture of 30% semilente with 70% ultralente insulin

4. Long Acting Insulin Slow insulin preparations called Ultralente insulin or extended zinc insulin. It is a poorly soluble crystal of zinc insulin It does not contain protamine It has a delayed onset and prolonged duration of action for up to 36 h Duration of Action of Various Types of Insulin

 Complication of Insulin Therapy Hypoglycemia results from absolute or relative overdosage. Mild: Headache, confusion, drowsiness, and fatigue Moderate: Tachycardia, palpitation, sweating, nervousness Severe: Convulsions, coma, and death Allergic reactions are rare locally: redness at injection site, atrophy of adipose tissue (lipodystrophy) systemically: urticaria, skin rash, anaphylaxis A possible local lipohypertrophy can be avoided by alternating injection sites. Drug interaction: Hypoglycemic agents: sulfonylurea, -blockers, and alcohol Hyperglycemic agents: thiazide diuretic, glucocorticoids, sympathomimetics

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 Oral Hypoglycemic Agents Sulfonylurea Type They are derivatives of the antibacterial sulfonamides, includes tolbutamide (5002000 mg/d) and glyburide (glibenclamide) (1.7510.5 mg/d). Mechanism of Action direct stimulation of insulin release from the pancreatic B-cells by increasing the sensitivity of B-cells towards glucose. Suppress hepatic gluconeogenesis Increase binding of insulin to its receptor

First-Generation Sulfonylureas: They are not frequently used in the modern management of DM because of their relatively low specificity of action, delay in time of onset, occasional long duration of action, and a variety of side effects. Acetohexamide is the only sulfonylurea with uricosuric activity used in diabetic patients who also have gout. Chlorpropamide has a relatively slow onset of action (1 or 2 weeks), causes hyponatremia. Tolbutamide is a relatively short-acting compound.

Second-Generation Sulfonylureas They display a higher specificity and affinity for the sulfonylurea receptor and have fewer side effects (may exert mild diuretic effect and are highly protein bound). Glyburide, also known as glibenclamide, ~ 150 times as potent as tolbutamide. Its average duration of action is 24 hours. Glipizide, Glimepiride

Hypoglycemia is the most important unwanted effect. NIDDM pregnant women should be treated with insulin

 Biguanide derivative, Phenformin, was briefly used in the United States more than 30 years ago but was withdrawn from the market because it produced severe lactic acidosis in some patients. Metformin (Glucophage) was used in Europe for many years before it was approved for use in the United States in 1995. Metformin is the only approved biguanide for the treatment of patients with NIDDM Metformin does not affect insulin secretion but requires the presence of insulin to be effective. Mechanism of Action Decrease glucose release from the liver (inhibit gluconeogenesis), and enhance its Inhibit glucose absorption from intestine Stimulate peripheral glucose uptake, in the presence of insulin Adverse effects The danger of hypoglycemia apparently is not increased. Frequent adverse effects include: anorexia, nausea, and diarrhea. Overproduction of lactic acid (lactate acidosis) is a rare, but lethal. It is contraindicated in renal insufficiency and should therefore be avoided in elderly patients.

 Thiazolidinediones (glitazones: rosiglitazone, pioglitazone) They are a novel class of drugs that were initially identified for their insulinsensitizing properties. Mechanism of Action Augment tissue responsiveness by promoting the synthesis or the availability of plasmalemmal glucose transporters via activation of a transcription factor. Decrease insulin resistance and enhance insulin action in target tissues.

-Glucosidase Inhibitors They primarily act to decrease postprandial hyperglycemia by slowing the rate at which carbohydrates are absorbed from the gastrointestinal tract, by competitively inhibiting -glucosidases. They must be taken before or with meals. Acarbose is an oligosaccharide derivative that has a higher affinity for the - glucosidase enzymes than do other dietary oligosaccharides. Systemic absorption of acarbose is very low. Miglitol, in contrast to acarbose, is systemically absorbed prior to its activity in the small intestine.